Japan

Firategrast, 402567-16-2;

Firategrast, MS, Alpha4beta1 integrin

PHASE 2 GSK

Mitsubishi Tanabe Pharma INNOVATOR

Tanabe Seiyaku Co

Glaxo Group Limited, Mitsubishi Tanabe Pharma Corporation

MECHANISMS/EFFECTS

 

Firategrast

SYNTHESIS

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PATENT

http://www.google.tl/patents/WO2011048091A1?cl=en

Scheme 1

Scheme 2

In a further aspect the present invention provides for a process for the preparation of compound of formula (II) which comprises coupling the compound of formula (V)

Suitable coupling conditions for the compound of formula (V) and the compound of formula (VI) include those shown in Scheme 2. In a further aspect of the invention there is provided the compound of formula (V):

¹H NMR characterisation data for the compound of formula (V) were generated on an isolated and purified batch. ¹H-NMR spectra were recorded on a Bruker Avance 400 at 400MHz, using TMS as an internal reference.¹H NMR (400 MHz, DMSO-D6) δ ppm 1.17 (t, J=7.09 Hz, 3 H) 2.96 (dd, J=13.82, 9.90 Hz, 1 H) 3.1 1 (dd, J=13.82, 5.26 Hz, 1 H) 4.12 (q, J=7.09 Hz, 2 H) 4.63 (ddd, J=9.78, 7.82, 5.38 Hz, 1 H) 7.15 (t, J=7.95 Hz, 2 H) 7.25 (d, J=8.31 Hz, 2 H) 7.47 – 7.55 (m, 3 H) 9.23 (d, J=7.83 Hz, 1 H).

The present invention provides a process for the preparation of the compound of formula

which process comprises the steps: a) hydrolysis of an ester of formula (I la):

Recrvstallisation of (2S)-2-{r(2,6-difluorophenyl)carbonyllamino)-3-r4′-r(ethyloxy)methyll- 2′,6′-bis(methyloxy)-4-biphenylyllpropanoic acid

(2S)-2-{[(2,6-difluorophenyl)carbonyl]amino}-3-[4′-[(ethyloxy)methyl]-2′,6′-bis(methyloxy)- 4-biphenylyl]propanoic acid (9.38Kg) was charged into a clean reactor, followed by ethyl acetate (46.9L). The solution was heated to 50°C and filtered into the pre-warmed (35°C) crystallizing vessel. A line-wash with ethyl acetate (9.4L) was carried out. The combined ethyl acetate solutions were heated to 50°C, stirred to ensure complete dissolution. Filtered heptane (9.4L) was added maintaining the temperature at 50°C then the solution cooled to 30°C and seeded with (2S)-2-{[(2,6-difluorophenyl)carbonyl]amino}-3-[4 – [(ethyloxy)methyl]-2′,6′-bis(methyloxy)-4-biphenylyl]propanoic acid (47g) slurried in 1 :9 ethyl acetate:heptane (0.47L). The slurry was aged for 2 hours at 30°C. Filtered heptane (75L) was added over 3 hours. The slurry was then cooled to 0°C over 1 hour. The mixture was aged at 0°C for 1 hour then the solid was filtered off, washed with isopropyl ether (29.6L and dried under vacuum at 50±3°C to give the product (8.55Kg, 91 %). Characterised by having an infrared absorption spectrum with significant absorption bands at about 754, 768, 800, 820, 849, 866, 1006, 1 100, 1 122, 1 157, 1 188, 1225, 1242, 1268, 1292, 1317, 1352, 1417, 1466, 1530, 1580, 1624, 1650, 1662, 171 1 , 1728, 2938, 3302cm^“

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PATENT

http://www.google.co.in/patents/WO2002018320A2

Example 10: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine ethyl ester.

(1) The product obtained in Example l-(4) (2.1 g) was acylated with 2 , 6-difluorobenzoyl chloride in a similar manner as described in Example 1 -(5) to give N- (2, 6-difluorobenzoyl) – 4- (2 , 6-dimethoxy-4-hydroxymethylphenyl) -L-phenylalanine ethyl ester (2.75 g) . mp . 70-72 °C; IR (Nujol) 3400, 3263, 1735, 1654, 1624 cm^“1; MS (APCI) m/z 500 (M+H) . (2) To a solution of the product obtained above (1.72 g) in DMSO (20 ml) were added Et₃N (4.8 ml) and S0₃«pyridine (5.6 g) successively at room temperature. The whole mixture was stirred at room temperature for 25 minutes. The reaction mixture was poured into ice-water, and then the mixture was extracted with EtOAc. The organic layer was sequentially washed with 5% aqueous HCl, H₂0 and brine, dried (Na₂S0₄) and then evaporated. The residue was purified by column chromatography (silica gel; eluent: n-hexane/EtOAc 5:1 to 1:1) to yield N-(2,6- difluorobenzoyl) -4- (2 , 6-dimethoxy-4-formylphenyl) -L- phenylalanine ethyl ester (1.54 g) . mp. 114-116°C; IR (Nujol)

3332, 1735, 1695, 1657, 1644, 1623 cm^“1; MS (APCI) m/z 498 (M+H) .

(3) The product obtained above (716 mg) was converted into the title compound (428 mg) in a similar manner as described in Example 1- (7) . mp . 87-89°C; IR (Neat+CHC1₃) 3300, 1739, 1668 cm^{“ 1}; MS (APCI) m/z 528 (M+H) .

Example 11: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl ) -L-phenylalanine methyl ester.

(1) The product obtained in Example 2- (4) (1.00 g) was acylated with 2 , 6-difluorobenzoyl chloride to give N-(2,6- difluorobenzoyl) -4- (2 , 6-dimethoxy-4-hydroxymethylphenyl) -L- phenylalanine methyl ester (873 mg) in a similar manner as described in Example l-(5). IR (Nujol) 3257, 1743, 1655, 1624 cm^{“ 1}; MS (APCI +Q1MS) m/z 503 (M+NH₄) , 486 (M+H) . (2) The product obtained above (860 mg) was converted into the title compound (220 mg) in a similar manner as described in Example 2- (6) and (7).

Example 12: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine .

The product obtained in Example 10 (200 mg) was hydrolyzed in a similar manner as described in Example 3 to give the title compound (160 mg) . The product obtained in Example 11 (220 mg) was also hydrolyzed in a similar manner as described in Example 3 to give the title compound (167 mg) . mp. 156-158°C; IR (Nujol) 1735, 1655 cm^“1; MS (ESI) m/z 498 (M-H) .

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PATENT

 https://www.google.com/patents/WO2003072536A1?cl=en

OUT LINE

phenylalanine derivative of the formula (I) :

wherein X¹ is a halogen atom, X² is a halogen atom, Q is a group of the formula -CH₂– or -(CH₂)₂– and Y is a lower alkyl group, or a pharmaceutically acceptable salt thereof, which has excellent inhibitory activity against α₄ integrin-mediated cell adhesion.

Thus, the present invention relates to a process for preparing a compound of the formula (I) :

wherein the symbols are the same as defined above, or a pharmaceutically acceptable salt thereof, comprising : (1) coupling a compound of the formula (VI) :

wherein Z is a leaving group, R¹NH is a protected amino group and C0₂R is a protected carboxyl group with a compound of the formula (V) :

wherein the symbols are the same as defined above, removing the protecting group from the protected amino group, and if necessary, converting the resulting compound into a salt, to yield a compound of the formula (IV) :

wherein the symbols are the same as defined above, or a salt thereof,

(2) condensing the compound (IV) or a salt thereof with a compound of the formula (III) :

wherein the symbols are the same as defined above, a salt or a reactive derivative thereof to yield a compound of the formula (II) :

Ethyl (ocS) – – [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4- hydroxybenzene propionate and ethyl (otS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy) benzene propionate are described in J. Med. Chem. , 33: 1620 (1990) and JP-A-7- 157472, respectively. 4-Bromo-3, 5-dimethoxybenzyl alcohol is described in, for example, J. Med. Chem. , 20: 299 (1977), and can also be prepared according to the following process.

Firstly, 4-bromo-3, 5-dihydroxybenzoic acid is methylated to give methyl 4-bromo-3, 5-dimethoxybenzoate, which is then reduced to yield 4-bromo-3, 5-dimethoxy benzyl alcohol. The methylation can be carried out by reacting with dimethyl sulfate in the presence of a base in a suitable solvent (e.g., ethyl acetate). The reduction can be carried out by reacting with an reducing agent (e.g., lithium alminium hydride, sodium borohydride and calcium borohydride) in a suitable solvent (e.g., tetrahydrofuran) .

EXAMPLES

The following Examples are provided to further illustrate the process of preparation according to the present invention. In the following examples, some compounds may be referred to by different compound name depending on the nomenclature, as illustrated below.

Ethyl (αS) -α-amino-4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionate

Another name: ethyl (2S) -2-amino-3- [4- (4-ethoxymethyl- 2, 6-dimethoxyphenyl) phenyl]propanoate

Ethyl (αS) – [ [1, 1-dimethylethoxy] carbonyl] amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionate

Another name 1: ethyl (2S) -2- [ (t-butoxycarbonyl) – amino] -3- [4- (4-ethoxymethyl-2, 6-dimethoxyphenyl) – phenyl]propanoate

Another name 2: Ethyl N- (t-butoxycarbonyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

Ethyl (αS) – – [ (2, 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4-propionate Another name 1: Ethyl (2S) -2- [ (2, 6- difluorobenzoyl) amino] -3- [4- (4-ethoxymethyl-2, 6- di ethoxyphenyl) phenyl] propanoate

Another name 2: Ethyl N- [2 , 6-difluorobenzoyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

(ocS) – – [ (2, 6-Difluorobenzoyl) amino] -4′ -ethoxymethyl- 2′ , 6′ -dimethox (1,1′ -biphenyl) -4-propionic acid

Another name 1: (2S) -2- [ (2, 6-difluorobenzoyl) amino] -3- [4- (4-ethoxymethyl-2, 6-dimethoxyphenyl) phenyl]propanoic acid

Another name 2: N- [ 2 , 6-difluorobenzoyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

EXAMPLE 1 (1) Under nitrogen atmosphere, pyridine (130.3 g) and trifluoromethanesulfonic anhydride (170.4 g) were added dropwise to a solution of ethyl (αS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-hydroxybenzenepropionate

(170.0 g) in dichloromethane (1.7 L) at 10 ° C or below. After stirring for 1 hour at the same temperature, water

(850 ml) was added dropwise to the mixture and the mixture was stirred for 2 hours at the same temperature. The organic layer was washed with 10 % aqueous citric acid solution and aqueous saturated sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy)benzenepropionate (242.5 g) as oil . MS (m/z) : 441 (M⁺) (2) Under nitrogen atmosphere, to a mixture of ethyl (αS)- – [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy) benzenepropionate (66.2g), 4- ethoxymethyl-2, 6-dimethoxyphenylboric acid (54.0 g) , triphenylphosphine (9.83 g) and N-methylpyrrolidone (330 ml) were added palladium acetate (1.68 g) and diisopropylamine (24.9 g ), and the mixture was heated at 90 °C. After stirring for 1 hour at the same temperature, the mixture was cooled and toluene and water were added. The organic layers were washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS) -α- [[ (1, 1-dimethylethoxy) carbonyl] amino] – 4′ -ethoxymethyl-2′ , 6′ -dimethox (1,1′ -biphenyl) -4-propionate (90.1 g) as oil.

The product was dissolved in ethanol (330 ml) , and after addition of p-toluenesulfonic acid monohydrate (28.5 g) , the mixture was stirred for 2 hours at 75 °C. After cooling to room temperature, the mixture was filtrated over charcoal and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate with heating. After cooling, the crystalline precipitates were collected by filtration and dried to yield ethyl (αS)-α- amino-4′ -ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4- propionate p-toluenesulfonate (63.4 g) .

MS (m/z) : 387 (M⁺-p-toluenesulfonic acid), M.p. 127-129°C

(3) To a mixture of ethyl (αS) -α-amino-4′ -ethoxymethyl- 2′ , 6′ -dimethox (1, 1′ -biphenyl) -4-propionate p- toluenesulfonate (29.0 g) , sodium hydrogen carbonate (15. 2 g) , water (290 ml) and ethyl acetate (290 ml) was added dropwise 2, 6-difluorobenzoyl chloride (9. 6 g) at 15 °C or below and the mixture was stirred for 30 minutes at the same temperature. The ethyl acetate layer was washed with saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was recrystallized from isopropanol-water to yield ethyl (αS) -oi- [ (2, 6-difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethox (1, 1′ -biphenyl) -4-propionate (26.4 g) . MS (m/z) : 527 (M⁺) , M.p. 87-89°C (4) To a solution of sodium hydroxide (2.9 g) in water- tetrahydrofuran (317 ml-159 ml) was added ethyl (oιS)-α- [ (2, 6-difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionate (31.7 g) at 15°C and the mixture was stirred for 4 hours at the same temperature. After neutralizing with IN HC1, the organic solvent was removed in vacuo. The aqueous layer was cooled, the crystalline precipitates were collected by filtration and recrystallized from ethanol-water to yield (αS) -a- [ (2, 6- difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionic acid (28.8 g) . MS (m/z): 499 (M⁺) , M.p. 154-155°C

EXAMPLE 2 (1) Under nitrogen atmosphere, a mixture of ethyl (oιS)-o:- [[ (1, 1-dimethylethoxy) carbonyl] amino] -4-bromobenzene propanoate (11.17 g) , 4-ethoxymethyl-2, 6- dimethoxyphenylboronic acid (10.80 g ), palladium acetate (0.34 g), triphenylphosphine (1.57 g) , anhydrous potassium carbonate (12.44 g) , iV-methylpyrrolidone (56 ml) and water (11 ml) was stirred for 50 minutes at 80 °C. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution, dried over magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure to yield ethyl (αS)-α- [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4′ -ethoxymethyl- 2′ , 6′ -dimethox (1, 1′ -biphenyl) -4-propionate (20.4 g) as oil. The product was dissolved in ethanol (100 ml) , and after addition of p-toluenesulfonic acid monohydrate (5.7 g) , the mixture was stirred for 1.5 hours at 75 °C. After cooling, the mixture was filtrated over charcoal and the filtrate was concentrated under reduced pressure. The residue was suspended in toluene with heating. After cooling, the crystalline precipitates were collected by filtration and dried to yield ethyl (αS) – -amino-4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionate p- toluenesulfonate (13.80 g) . (2) The compound obtained in the above step (1) was treated in the same manner as described in Example 1 (2) to (4) to yield (αS) -a- [ [2 , 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4-propionic acid. The physicochemical data were the same as that obtained in Example 1.

EXAMPLE 3

To a solution of ethyl (αS) -α- [ (2, 6- difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethox (1, 1′ -biphenyl) -4-propionate (500 g ) in water (12.6 ml) and dioxane (50 ml) was added hydrochloric acid (12.4 g) and the mixture was stirred for 60 hours at 60 “C. The organic solvent was removed in vacuo and the aqueous layer was cooled. The crystalline precipitates were collected by filtration and recrystallized from ethanol- water to yield (αS) – – [ (2, 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionic acid (426 mg) . The physicochemical data were the same as that obtained in Example 1.

REFERENCE EXAMPLE 1

(1) To a mixture of 4-bromo-3, 5-dimethoxybenzylalcohol (44.5 g) , triethylammonium benzyl chloride (2.05 g) and 20% aqueous sodium hydroxide solution (288 g) was added diethyl sulfate (41.7 g) under ice-cooling, and the mixture was stirred overnight at 25-30 °C. After stirring for 1 hour at 70 °C, the mixture was cooled and extracted with toluene. The toluene layer was washed with water and saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo to yield 4-bromo-3, 5- dimethoxybenzyl ethyl ether (49.5 g) as colorless oil. MS (m/z): 276 (M⁺+2) , 274 (M⁺)

(2) Under nitrogen atmosphere, to a solution of 4-bromo- 3, 5-dimethoxybenzyl ethyl ether (440.0 g) in tetrahydrofuran (4.0 L) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 1.1 L) at -60°C. After stirring for 15 minutes at the same temperature, trimethyl borate (249.3 g) was added. The temperature of the mixture was gradually elevated, followed by stirring for 1 hour under ice-cooling. To the mixture was added dropwise 10% aqueous sulfuric acid solution (835 g ) . The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated aqueous NaCl solution. After drying over magnesium sulfate, the solvent was removed in vacuo. The residue was dissolved in isopropyl ether with heating and cooled. The crystalline precipitates were collected by filtration and dried to yield 4-ethyoxymethyl-2, 6- dimetoxyphenylboronic acid (312.9 g) . M.p. 59-61°C

REFERENCE EXAMPLE 2

(1) To a suspension of 4-bromo-3, 5-dihydroxybenzoic acid (95.0 kg) in ethyl acetate (950 L) were added anhydrous potassium carbonate (270.8 kg) and dimethyl sulfate (174.7 kg) . The mixture was heated at 50-80 ‘C for about 4 hours and partitioned by adding water. The organic layer was washed with water and saturated aqueous NaCl solution and concentrated under reduced pressure. The residue was suspended into methanol, stirred under heating and cooled. The crystalline precipitates were collected by filtration and dried to yield methyl 4-bromo-3, 5-dimethoxybenzoate (98.8 kg) as pale yellow crystals. MS (m/z): 277 (M⁺+2) , 275 (M⁺) , M.p. 120-122°C

(2) To a solution of calcium chloride (46.5 kg) in ethanol (336 L) were added tetrahydrofuran (672 L) and methyl 4- bromo-3, 5-dimethoxybenzoate (96.0 kg) to obtain a suspension. To the suspension was added sodium borohydride

(31.7 kg) by portions at room temperature, and the mixture was stirred for about 9 hours at temperature of room temperature to 45 °C. The reaction mixture was added dropwise to aqueous HC1 solution and stirred for about 16 hours at room temperature. Organic solvent was removed in vacuo, and water (1440 L) was added to the residue and stirred for 1 hour at 50 °C. After cooling, the crystalline precipitates were collected by filtration and dried to yield 4-bromo-3, 5-dimethoxybenzyl alcohol (83.3 kg) as colorless crystals. MS (m/z): 249 (M⁺+2), 247 (M⁺) , M.p. 100-102°C.

INDUSTRIAL APPLICABILITY The process for preparation of the present invention makes it possible to afford a compound of the formula (I) or a pharmaceutically acceptable salt thereof with high- purity, in a high yield and inexpensively, and, therefore, the process of the present invention is industrially very useful.

References

1. ChemIDplus Advanced

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Note: Compound name must be entered under “Substance Identification” and then “Names and Synonyms” selected to view synonyms.

2. GlaxoSmithKline Protocol Summaries: Firategrast

GlaxoSmithKline

Accessed on 13 Feb 2012 from http://www.gsk-clinicalstudyregister.com/protocol_comp_list.jsp?compound=firategrast.

3. Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial.

Miller DH, Weber T, Grove R, Wardell C, Horrigan J, Graff O, Atkinson G, Dua P, Yousry T, Macmanus D, et al.

Lancet Neurol. 2012 Feb; 11(2):131-9. Epub 2012 Jan 05. PMID: 22226929. Abstract

4. Firategrast: natalizumab in a pill?

Prat A, Stüve O

Lancet Neurol. 2012 Feb; 11(2):120-1. Epub 2012 Jan 05. PMID: 22226930. Abstract

5. Firategrast

American Medical Association

Accessed on 13 Feb 2012 from http://www.ama-assn.org/resources/doc/usan/firategrast.pdf.

6. GlaxoSmithKline Product Development Pipeline

GlaxoSmithKline website

Accessed on 4 Aug 2012 from http://www.gsk.com/investors/product_pipeline/docs/gsk-pipeline-2010.pdf.

US8822527

16 Out 2012

2 Set 2014

Biotheryx, Inc.

Substituted biaryl alkyl amides

WO2002018320A2	27 Ago 2001	7 Mar 2002	Tanabe Seiyaku Co	INHIBITORS OF α4 MEDIATED CELL ADHESION
WO2003072536A1	27 Fev 2003	4 Set 2003	Tanabe Seiyaku Co	A process for preparing a phenylalanine derivative and intermediates thereof
WO2003072537A2	6 Fev 2003	4 Set 2003	Abbott Lab	Selective protein tyrosine phosphatatase inhibitors

Mitsubishi Tanabe Pharma Corporation

Mitsubishi Tanabe Pharma Corporation
Pharmacological research building

■Mitsubishi Tanabe Pharma Corporation Pharmacological research building

 

 

 

 

 

 

 

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

 

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

MARIZEV® (Omarigliptin), Merck’s Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes, Approved in Japan

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved MARIZEV^® (omarigliptin) 25 mg and 12.5 mg tablets, an oral, once-weekly DPP-4 inhibitor indicated for the treatment of adults with type 2 diabetes. Japan is the first country to have approved omarigliptin……….http://www.mercknewsroom.com/news-release/prescription-medicine-news/marizev-omarigliptin-mercks-once-weekly-dpp-4-inhibitor-type

syn…….http://newdrugapprovals.org/2014/04/18/omarigliptin-mk-3102-in-phase-3-for-type-2-diabetes/

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

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/////////////MARIZEV,  (Omarigliptin), Merck’s,  Once-Weekly,  DPP-4 Inhibitor,   Type 2 Diabetes, Approved, Japan

Fosfluconazole

Fosfluconazole; 194798-83-9; UNII-3JIJ299EWH; 3JIJ299EWH; NCGC00182029-01;

2-(2,4-difluorophenyl)-1,3-di(1h-1,2,4-triazol-1-yl)propan-2-yl dihydrogen phosphate;

2,4-difluoro-α,α-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol, dihydrogen phosphate

Agouron Pharmaceuticals, Inc.

Research Code：UK-292663, UK 292663, F-FLCZ, F FLCZ

Trade Name：Prodif^{® PFIZER}

MOA：Azole antifungal

Indication：Cryptococcus neoformans; Candidiasis

Status：Approved, Japan PMDA OCT 16 2003

Company：Pfizer (Originator)

Candidiasis,Cryptococcus neoformans, Injection, Solution, Eq. 100 mg/200 mg/400 mg fluconazole per vial

Fosfluconazole (INN) is a water-soluble phosphate prodrug of fluconazole – a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. The phosphate ester bond is hydrolysed by the action of a phosphatase – an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group (see dephosphorylation).

Fosfluconazole was approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on Oct 16, 2003. It was developed and marketed as Prodif^® by Pfizer in Japan.

Fosfluconazole is a water-soluble phosphate prodrug of fluconazole – a triazole antifungal drug. It is indicated for the treatment of candida and cryptococcus infections.

Prodif^® is available as solution for intravenous use, containing 100, 200 or 400 mg of free Fosfluconazole per vial. The recommended dose is 50 to 100 mg administered intravenously once daily for candidiasis. Another dose is 50 to 200 mg fluconazole once daily for cryptococcosis.

Route 1

Reference：1. WO9728169A1 / US6977302B2.

2. Org. Process Res. Dev.2002, 6, 109-112.

http://pubs.acs.org/doi/pdf/10.1021/op010064%2B

2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazole-1-yl)- 2-propyl dihydrogen phosphate (2). A slurry of dibenzyl 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazole-1-yl)-2-propyl phosphate (30.1 kg, 53.13 mol), 5% palladium-on-carbon catalyst (50% wet, type 5R39, 1.5 kg), and sodium hydroxide (4.36 kg, 108.9 mol) in low-endotoxin water (75.7 L) was hydrogenated at ambient temperature and 414 kPa (60 psi) for 12 h. The slurry was filtered, and the catalyst was washed with low-endotoxin water (9.8 L). After separating the toluene by-product, the aqueous phase was slurried with carbon (3.1 kg) for 30 min. After the carbon was removed by filtration, the aqueous phase was acidified to pH 1.45 by that addition of sulfuric acid (6.69 kg) in low-endotoxin water (25 L) over 2 h. The resulting slurry was granulated at ambient temperature for 1 h and then filtered. The product was sequentially washed with filtered low-endotoxin water (103 L) and filtered acetone (103 L). The product was dried under vacuum at 50 °C for 12 h to give the title compound (18.1 kg, 88%) a white powder: mp 223-224 °C.

1H NMR (DMSO) δ 5.07 (2H, d), 5.24 (2H, d), 6.77-6.83 (1H, m), 7.00-7.18 (2H, m), 7.75 (2H, s), 8.53 (2H, s).

Found: C, 40.28; H, 3.39; N, 21.63;

[MH]+ 387.0786. C13H13F2N6O4P requires: C, 40.43; H, 3.39; N, 21.78; [MH]+ 387.0782.

US6977302

https://www.google.com/patents/US6977302

EXAMPLE 1 1-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl dihydrogen phosphate

(a) Dibenzyl 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl phosphate

Method A

A solution of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (also known as fluconazole, 10.0 g, 32.6 mmol), 1H-tetrazole (6.85 g, 97.8 mmol), dibenzyl diisopropyl phosphoramidite (22.55 g, 65.2 mmol) in methylene chloride (100 ml) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was then cooled to 0° C., and a solution of 3-chloroperoxybenzoic acid (13.5 g, 50-55% w/w, 39.1 mmol) in methylene chloride (50 ml) was added maintaining the temperature at 0° C. The resulting mixture was allowed to warm to room temperature for 1 hour before washing with aqueous sodium metabisulphite and sodium bicarbonate. After drying (MgSO₄) the solvent was removed and replaced with methyl isobutyl ketone (37 ml) and tert-butyl methyl ether (74 ml). After granulating at −10° C. for 1 hour the product was filtered and washed with ice cold methyl isobutyl ketone and tert-butyl methyl ether (1:3, 15 ml) and dried at 50° C. under vacuum for 18 hours to give the subtitle compound (16.05 g, 87%), m.p. 93° C.

Found: C, 57.12; H, 4.46; N, 14.85. C₂₇H₂₅F₂N₆O₄P requires C, 57.24; H, 4.46; N, 14.84%. m/z 567 (MH⁺) ¹H NMR (300 MHz, CDCl₃) δ=4.90 (d, 2H), 4.95 (d, 2H), 5.05 (d, 2H), 5.19 (d, 2H), 6.58-6.73 (m, 2H), 6.88-6.95 (m, 1H), 7.20-7.30 (m, 4H) 7.32-7.38 (m; 6H), 7.80 (s, 2H), 8.36 (s, 2H).

Method B

To stirred ethyl acetate (1530 ml) was added 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (also known as fluconazole, 306 g, 1.00 mol) and pyridine (237.3 g, 3.00 mol) before cooling to 0° C. Phosphorus trichloride (137.4 g, 1.00 mol) was added dropwise to the reaction mixture maintaining the temperature between 0-5° C. before allowing the reaction mixture to warm to 15° C. over 30 minutes. Benzyl alcohol (216 g, 2.00 mol) was then added over 30 minutes at 15-20° C. After a further 30 minutes hydrogen peroxide (27.5% w/w in water, 373 g) was added maintaining the temperature at 15-20° C. After 30 minutes the aqueous phase was removed and the organic phase washed with aqueous sodium metabisulphite, dilute hydrochloric acid and water. The solvent was removed at reduced pressure and replaced with methyl isobutyl ketone (850 ml) and tert-butyl methyl ether (1132 ml). After granulating at 20° C. for 1 hour and at 0° C. for 1 hour, the product was filtered and washed with ice cold tert-butyl methyl ether (2×220 ml) and dried at 50° C. under vacuum for 18 hours to give the subtitle compound (358 g, 63%). The melting point and spectroscopic data was identical to that stated in method A.
(b) 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl dihydrogen phosphate

A slurry of the compound of step (a) (9.80 g, 17.3 mmol), 5% palladium on carbon catalyst (50% wet, 1.0 g) and sodium hydroxide (1.38 g, 34.6 mmol) in water (26 ml) was hydrogenated at room temperature and 414 kPa (60 p.s.i.) for 20 hours. The solution was filtered through a pad of celite (trade mark) and washed with water (5 ml). The toluene was separated and the aqueous phase cooled to 0° C. whereupon sulphuric acid (1.70 g, 17.3 mmol) was added. The resulting slurry was granulated at 0° C. for 1 hour and then filtered, washed with water (2×5 ml) and dried under vacuum at 50° C. to give the title compound (5.80 g, 87%). m.p. 223-224° C.

Found: C, 40.28; H, 3.39; N, 21.63. C₁₃H₁₃F₂N₆O₄P requires C, 40.43; H, 3.39; N, 21.76%. ¹H NMR (300 MHz, DMSO) δ=5.07 (d, 2H) 5.24 (d, 2H), 6.77-6.83 (m, 1H), 7.00-7.18 (m, 2H), 7.75 (s, 2H), 8.53 (s, 2H).

EXAMPLE 2 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl disodium phosphate

A solution of the compound of Example 1(a) (10.0 g, 17.7 mmol) and sodium acetate (2.90 g, 35.3 mmol) in ethanol (160 ml) and water (20 ml) was hydrogenated over Pearlman’s catalyst (1.00 g) at room temperature and at 345 kPa (50 p.s.i.) for 16 hours. The solution was filtered through a pad of celite (trade mark) and the solvents removed at reduced pressure to leave a thick syrup. This was dissolved in ethanol (100 ml) with the aid of sonication and warmed to reflux. The resulting solution was allowed to cool slowly and granulate for 1 hour at room temperature. The product was filtered, washed with ethanol (10 ml) and dried under vacuum at 50° C. to give the title compound (4.48 g, 59%). m.p. 160-162° C.

¹H NMR (300 MHz, D₂O) δ=5.01 (d, 2H), 5.40 (d, 2H), 6.60 (m, 1H), 6.79 (m, 1H), 7.11 (m, 1H), 7.63 (s, 2H), 8.68 (s, 2H).

Route 2

Reference：1. CN103864844A.

http://www.google.com/patents/CN103864844A?cl=en

TRANSLATED BY MACHINE…….TEXT MAY VARY

forskolin fluconazole (fosf Iuconazole, Formula I) is fluconazole (Formula IV) of monophosphate prodrugs, fluconazole in the tertiary alcohol into a phosphate ester, not only did not introduce a chiral center, also increased water solubility, because a long time to overcome the low water solubility of fluconazole resulting larger infusion volume defects. After intravenous administration in the role of phosphatases in vivo hydrolysis into fluconazole, pharmacological effect. Blessing from the Central Institute of the United States Secretary of fluconazole Fai end developed, launched in Japan in 2004 I May 15, for the treatment of candidiasis and cryptococcal infections caused deep as true bacteremia, respiratory fungal disease, fungal peritoneum

Inflammation, gastrointestinal fungal disease, fungal urinary tract infections, fungal meningitis.

 

Synthesis gas itraconazole on forskolin in W09728169, Organic Process Research & Development (200 2), 6 (2), 109-112, CN1789270, Art of Drug Synthesis (2007), 71-82, etc. have been reported in the literature . Which Organic Process Research & Development (2002) described in detail in the first blessing Secretary fluconazole and improved synthetic route for the route problems to adapt to industrial mass production of synthetic routes.

  Document Organic Process Research & Development (2002), 6,109-112 discloses the following two synthetic routes.

Route One:

 

Route two:

 

  The final step is a route to the removal of benzyl group in a methanol solvent by palladium on carbon catalyzed hydrogenation reaction yield was 65%. Since forskolin fluconazole final product insoluble in methanol, and therefore there is a route following shortcomings: a catalyst poisoning, the final product is easy to form methanol solvate, removing the catalyst in the loss of product, the final product are difficult to separate, low yield not suitable for industrial production.

Two routes still using palladium on carbon hydrogenation debenzylation, except that the solvent was changed to sodium hydroxide solution, the product of soluble and stable in aqueous sodium hydroxide solution, after filtering off the catalyst, forskolin fluoro itraconazole by acidification of sodium sulfate can be easily obtained blessing Secretary of fluconazole, the reaction yield of 85-90%.

  In the prior art, the removal of benzyl preparation blessing Secretary of fluconazole, the use of a pressure hydrogenation, relatively harsh reaction conditions; and blessing Secretary of fluconazole in water and slightly soluble in methanol, for blessing Secretary fluconazole further refined and purified more difficult. The present invention aims to provide a new and suitable for industrial production methods blessing Secretary fluconazole.

Example 1

  2- (2,4-gas-phenyl) -1,3-bis (1H-1, 2,4- two P sat 1-yl) -2-propyl-di-benzyl-pity Cool ( Preparation blessing Secretary fluconazole dibenzyl ester)

Step  The method according to CN1210540A in Example 1 A or Method B of (a), was prepared to give the title compound, having 1H-NMR shown in Figure 1 (SOi) MHz, DMS0-D6) spectrum.

  Example 2

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas

Itraconazole ammonium salt) Preparation

  Formula III blessing Secretary fluconazole two benzyl ester (566g, lmol), 120g of dry Pd / C (containing 5% palladium) and ammonium formate (315g, 5mol) in methanol (6L), and stirred under reflux for 5h , TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (566ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 415g, yield 98.8%.

] lH-Mffi (500MHz, DMS0-D6) δ: 4.87-4.90, 5.58-5.61,6.56-6.60, 6.94-7.03,7.52-7.61,8.96, having 1H-NMR shown in Figure 2 (500MHz, DMS0 -D6) spectrum.

  Example 3

2- (2,4-gas-phenyl) -1,3-bis (1H-1, 2,4- two 1-yl) -2-propyl-pity acid dioxide Cool (forskolin

Fluconazole) Preparation of

[0052] Formula II forskolin fluconazole salt (420g, Imol), in water (IL) while stirring, filtered, 2mol / L sulfuric acid aqueous solution (500ml), 5 ° C under stirring for lh, filtered, cold water ( 200ml) wash, 50 ° C under dry blessed Division fluconazole 379g, yield 98%.

  1H-Mffi (SOOMHz) DMSO-De) δ:. 5.09-5.12,5.25-5.28,6.80-6.84,7.05-7.16,7.77,8.55,10.32 [0054] Example 4

  2_ (2,4_ two gas-phenyl) -1, double 3_ (1Η-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

  Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 84g of dry Pd / C (5% containing button) and ammonium formate (189g, 3mol) in anhydrous methanol (5L) in the mixture was stirred at reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 410g, yield 97.5%.

Example 5

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 30g of dry Pd / C (containing 10% palladium) and ammonium formate (315g, 5mol) in anhydrous methanol (5L) in the mixture was stirred at reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 405g, yield 96.4%.

  Example 6

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

  Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 30g of dry Pd / C (containing 10% palladium) and ammonium formate (315g, 5mol) in ethanol (12L) and stirred was refluxed for 5h, TLC monitoring completion of the reaction, was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 395g, 94% yield.

  Example 7

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

  forskolin fluconazole dibenzyl ester (566g, lmol), 170g of dry Pd / C (containing 5% of palladium) and ammonium formate (315g, 5mol) in ethanol (16L) was stirred under reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 398g, yield 94.7%.

  Example 8

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 120g of dry Pd / C (containing 5% palladium) and ammonium formate (315g, 5mol) in isopropanol (12L) in the mixture was stirred at reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 402g, a yield of 95.7%.

Example 9

  2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

[0071] under nitrogen blessing Secretary fluconazole dibenzyl ester (566g, lmol), 60g of dry Pd / C (containing 5% palladium) and ammonium formate (504g, 8mol) in methanol (8L) in, 50 ° C under stirring reaction 40h, TLC monitoring completion of the reaction, was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added ^ OOml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 398g, yield 94.8%.

Example 10

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

  Under nitrogen, forskolin fluconazole dibenzyl ester (5668,111101), 8 (^ dry? (1 / (:( containing palladium 5%) and ammonium formate (315g, 5mol) for n-propyl alcohol (12L) in, 60 ° C the reaction was stirred 20h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 398g 95% yield.

Example 11

2- (2,4-gas-phenyl) -1,3-bis (1H-1, 2,4- sit two P-1-yl) -2-propyl-pity acid dioxide Cool (forskolin fluconazole) Preparation of [0077] under nitrogen blessing Secretary fluconazole dibenzyl ester 566 g (Imol) adding 56g of dry Pd / C (containing 5% palladium), methanol 6L, 315 g of ammonium formate, stirring boil under reflux for 5h, TLC after completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, addition of IL of water and dissolved with stirring, filtered, 2mol / L sulfuric acid 500mL, 5 ° C with stirring to precipitate lh, filtered, 200mL cold water, 50 ° C drying 365 g, 95% yield.

  Example 12 forskolin fluconazole salt and HPLC detection methods blessing Secretary fluconazole:

  High performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two Appendix VD): octadecylsilane bonded silica as a filler, Column: Thermo BDS C18 (4.6 X 150mm, 3.5 μ m); methanol as mobile phase A, phosphate buffer (take potassium dihydrogen phosphate 0.68g, set 1000ml water, triethylamine 6ml, adjusted to pH 5.0 with phosphoric acid) as the mobile phase B, a flow rate of 1.0ml / min; column temperature 35 ° C; detection wavelength was 210nm, linear gradient.

  After the examination, according to the peak area calculation, purity prepared in Example 2-11 was the implementation of the target product of 99.5%.

IMPURITIES

1

Impurity Name:Molecular Formula:Molecular Weight:CAS No.:

Fosfluconazole Impurity A C13H12F2N6O306.2786386-73-4

2

Impurity Name:Molecular Formula:Molecular Weight:CAS No.:

Fosfluconazole Impurity B C13H13F2N6O4P386.25

3

Impurity Name:Molecular Formula:Molecular Weight:CAS No.:

Fosfluconazole Impurity C C13H14FN6O4P368.26

4

Impurity Name:Molecular Formula:Molecular Weight:CAS No.:

Fosfluconazole Impurity D C13H14FN6O4P368.26

5

Impurity Name:Molecular Formula:Molecular Weight:CAS No.:

Fosfluconazole Impurity E C27H25F2N6O4P566.5

6

Impurity Name:Molecular Formula:Molecular Weight:CAS No.:

Fosfluconazole Impurity F C20H19F2N6O4P476.37

7

Impurity Name:Molecular Formula:Molecular Weight:CAS No.:

Fosfluconazole Impurity G C13H13F2N6O5P402.25

8

Impurity Name:Molecular Formula:Molecular Weight:CAS No.:

Fosfluconazole Impurity H C13H15N6O4P350.27

9

Impurity Name:Molecular Formula:Molecular Weight:CAS No.:

Fosfluconazole Impurity I C13H14FN6O4P368.26

Fosfluconazole

Systematic (IUPAC) name
{[2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-yl]oxy}phosphonic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	℞ (Prescription only)
Routes of administration	IV
Identifiers
CAS Number	194798-83-9
ATC code	None
PubChem	CID 214356
ChemSpider	185843
UNII	3JIJ299EWH
ChEMBL	CHEMBL1908301
Chemical data
Formula	C13H13F2N6O4P
Molar mass	386.25 g/mol

//////UK-292663, UK 292663, F-FLCZ, F FLCZ, Fosfluconazole,  194798-83-9, UNII-3JIJ299EWH, 3JIJ299EWH, NCGC00182029-01

Fc1ccc(c(F)c1)C(OP(=O)(O)O)(Cn2ncnc2)Cn3ncnc3

Trelagliptin

865759-25-7; UNII-Q836OWG55H

2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxopyrimidin-1-yl]methyl]-4-fluorobenzonitrile

(R) -2 – ((6 (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) synthesis of 4-fluoro-benzonitrile

(R)-2-((6-(3-amino-3-methylpiperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile

A dipeptidyl peptidase-4 (DPP-4) inhibitor used to treat type 2 diabetes.

Dipeptidyl Peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) is a type π membrane protein that has been referred to in the literature by a wide a variety of names including DPP4, DP4, DAP-IV, FAPβ, adenosine deaminase complexing protein 2, adenosine deaminase binding protein (AD Abp), dipeptidyl aminopeptidase IV; Xaa-Pro-dipeptidyl-aminopeptidase; Gly-Pro naphthylamidase; postproline dipeptidyl aminopeptidase IV; lymphocyte antigen CD26; glycoprotein GPI lO; dipeptidyl peptidase IV; glycylproline aminopeptidase; glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pep X; leukocyte antigen CD26; glycylprolyl dipeptidylaminopeptidase; dipeptidyl-peptide hydrolase; glycylprolyl aminopeptidase; dipeptidyl-aminopeptidase IV; DPP ΓV/CD26; amino acyl-prolyl dipeptidyl aminopeptidase; T cell triggering molecule TρlO3; X-PDAP. Dipeptidyl Peptidase IV is referred to herein as “DPP-IV.” [0003] DPP-W is a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV dependent slow release of dipeptides of the type X-GIy or X-Ser has also been reported for some naturally occurring peptides.
DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26. DPP-IV has been implicated in a number of disease states, some of which are discussed below.
[0005] DPP-IV is responsible for the metabolic cleavage of certain endogenous peptides (GLP-I (7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (GHRH, NPY, GLP-2, VIP) in vitro.

GLP-I (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine. GLP-I (7-36) has multiple actions in vivo including the stimulation of insulin secretion, inhibition of glucagon secretion, the promotion of satiety, and the slowing of gastric emptying. Based on its physiological profile, the actions of GLP-I (7-36) are believed to be beneficial in the prevention and treatment of type II diabetes and potentially obesity. For example, exogenous administration of GLP-I (7-36) (continuous infusion) in diabetic patients has been found to be efficacious in this patient population. Unfortunately, GLP-I (7-36) is degraded rapidly in vivo and has been shown to have a short half -life in vivo (t_1/2=1.5 minutes).
Based on a study of genetically bred DPP-IV knock out mice and on in vivo I in vitro studies with selective DPP-IV inhibitors, DPP-IV has been shown to be the primary degrading enzyme of GLP-I (7-36) in vivo. GLP-I (7-36) is degraded by DPP-IV efficiently to GLP-I (9-36), which has been speculated to act as a physiological antagonist to GLP-I (7-36). Inhibiting DPP-TV in vivo is therefore believed to be useful for potentiating endogenous levels of GLP-I (7-36) and attenuating the formation of its antagonist GLP-I (9-36). Thus, DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (WG), metabolic acidosis, ketosis, appetite regulation and obesity.

DPP-IV expression is increased in T-cells upon mitogenic or antigenic stimulation (Mattem, T., et al., Scand. J. Immunol, 1991, 33, 737). It has been reported that inhibitors of DPP-IV and antibodies to DPP-IV suppress the proliferation of mitogen-stimulated and antigen-stimulated T-cells in a dose-dependant manner (Schon, E., et al., Biol. Chem., 1991, 372, 305). Various other functions of T-lymphocytes such as cytokine production, IL-2 mediated cell proliferation and B-cell helper activity have been shown to be dependent on DPP-IV activity (Schon, E., et al., Scand. J. Immunol, 1989, 29, 127). DPP-IV inhibitors, based on boroProline, (Flentke, G. R., et al., Proc. Nat. Acad. Set USA, 1991, 88, 1556) although unstable, were effective at inhibiting antigen-induced lymphocyte proliferation and IL-2 production in murine CD4+ T-helper cells. Such boronic acid inhibitors have been shown to have an effect in vivo in mice causing suppression of antibody production induced by immune challenge (Kubota, T. et al, Clin. Exp. Immun., 1992, 89, 192). The role of DPP-IV in regulating T lymphocyte activation may also be attributed, in part, to its cell-surface association with the transmembrane phosphatase, CD45. DPP-IV inhibitors or non-active site ligands may possibly disrupt the CD45-DPP-TV association. CD45 is known to be an integral component of the T-cell signaling apparatus. It has been reported that DPP-IV is essential for the penetration and infectivity of HTV-I and HTV-2 viruses in CD4+ T-cells (Wakselman, M., Nguyen, C, Mazaleyrat, J.-P., Callebaut, C, Krust, B., Hovanessian, A. G., Inhibition of HIV-I infection of CD 26+ but not CD 26-cells by a potent cyclopeptidic inhibitor of the DPP-IV activity of CD 26. Abstract P.44 of the 24.sup.th European Peptide Symposium 1996). Additionally, DPP-IV has been shown to associate with the enzyme adenosine deaminase (ADA) on the surface of T-cells (Kameoka, J., et al., Science, 193, 26 466). ADA deficiency causes severe combined immunodeficiency disease (SCID) in humans. This ADA-CD26 interaction may provide clues to the pathophysiology of SCID. It follows that inhibitors of DPP-TV may be useful immunosuppressants (or cytokine release suppressant drugs) for the treatment of among other things: organ transplant rejection; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; and the treatment of AIDS.
It has been shown that lung endothelial cell DPP-IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells (Johnson, R. C, et al., J. Cell. Biol, 1993, 121, 1423). DPP-IV is known to bind to fibronectin and some metastatic tumor cells are known to carry large amounts of fibronectin on their surface. Potent DPP-IV inhibitors may be useful as drugs to prevent metastases of, for example, breast and prostrate tumors to the lungs.
High levels of DPP-PV expression have also been found in human skin fibroblast cells from patients with psoriasis, rheumatoid arthritis (RA) and lichen planus (Raynaud, F., et al., J. Cell. Physiol, 1992, 151, 378). Therefore, DPP-TV inhibitors may be useful as agents to treat dermatological diseases such as psoriasis and lichen planus. [0011] High DPP-TV activity has been found in tissue homogenates from patients with benign prostate hypertrophy and in prostatosomes. These are prostate derived organelles important for the enhancement of sperm forward motility (Vanhoof, G., et al., EMr. /.

Clin. Chem. Clin. Biochem., 1992, 30, 333). DPP-IV inhibitors may also act to suppress sperm motility and therefore act as a male contraceptive agent. Conversely, DPP-IV inhibitors have been implicated as novel for treatment of infertility, and particularly human female infertility due to Polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome) which is a condition characterized by thickening of the ovarian capsule and . formation of multiple follicular cysts. It results in infertility and amenorrhea.
DPP-IV is thought to play a role in the cleavage of various cytokines
(stimulating hematopoietic cells), growth factors and neuropeptides.
[0013] Stimulated hematopoietic cells are useful for the treatment of disorders that are characterized by a reduced number of hematopoietic cells or their precursors in vivo. Such conditions occur frequently in patients who are immunosuppressed, for example, as a consequence of chemotherapy and/or radiation therapy for cancer. It was discovered that inhibitors of dipeptidyl peptidase type PV are useful for stimulating the growth and differentiation of hematopoietic cells in the absence of exogenously added cytokines or other growth factors or stromal cells. This discovery contradicts the dogma in the field of hematopoietic cell stimulation, which provides that the addition of cytokines or cells that produce cytokines (stromal cells) is an essential element for maintaining and stimulating the growth and differentiation of hematopoietic cells in culture. (See, e.g., PCT Intl. Application No. PCT/US93/017173 published as WO 94/03055).
[0014] DPP-IV in human plasma has been shown to cleave N-terminal Tyr-Ala from growth hormone-releasing factor and cause inactivation of this hormone. Therefore, inhibitors of DPP-IV may be useful in the treatment of short stature due to growth hormone deficiency (Dwarfism) and for promoting GH-dependent tissue growth or re-growth.
DPP-IV can also cleave neuropeptides and has been shown to modulate the activity of neuroactive peptides substance P, neuropeptide Y and CLIP (Mentlein, R., Dahms, P., Grandt, D., Kruger, R., Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV, Regul. Pept., 49, 133, 1993; Wetzel, W., Wagner, T., Vogel, D., Demuth, H.-U., Balschun, D., Effects of the CLIP fragment ACTH 20-24 on the duration of REM sleep episodes, Neuropeptides, 31, 41, 1997). Thus DPP-IV inhibitors may also be useful agents for the regulation or normalization of neurological disorders.
Several compounds have been shown to inhibit DPP-IV. Nonetheless, a need still exists for new DPP-IV inhibitors that have advantageous potency, stability, selectivity, toxicity and/or pharmacodynamics properties. In this regard, synthetic methods are provided that can be used to make a novel class of DPP-IV inhibitors.

Trelagliptin (Zafatek) is a pharmaceutical drug used for the treatment of type 2 diabetes (diabetes mellitus).^[1]

Indications for Medical Use

It is a highly selective dipeptidyl peptidase (DPP-4) inhibitor that is typically used as an add on treatment when the first line treatment of metformin is not achieving the expected glycemic goals; though it has been approved for use as a first line treatment when metformin cannot be used.^[1]

Biochemistry

DPP-4 inhibitors activate T-cells and are more commonly known as T-cell activation antigens (specifically CD26).^[1][2] Chemically, it is a fluorinated derivative of alogliptin.

Development

Formulated as the salt trelagliptin succinate, it was approved for use in Japan in March 2015.^[3] Takeda, the company that developed trelagliptin, chose to not get approval for the drug in the USA and EU.^[1] The licensing rights that Takeda purchased from Furiex Pharmaceuticals for DPP-4 inhibitors included a clause specific to development of this drug in the USA and EU.^[1] The clause required that all services done for phase II and phase III clinical studies in the USA and EU be purchased through Furiex.^[1] Takeda chose to cease development of this drug in the USA and EU because of the high costs quoted by Furiex for these services.^[1] Gliptins have been on the market since 2006 and there are 8 gliptins currently registered as drugs (worldwide).^[4] Gliptins are an emerging market and are thus being developed at an increasing rate; there are currently two gliptins in advanced stages of development that are expected to be on the market in the coming year.^[4]

Gliptins are thought to have cardiovascular protective abilities though the extent of these effects is still being studied.^[4] They are also being studied for the ability that this class of drugs has at promoting B-cell survival.^[4]

Administration and Dosing

Similar drugs in the same class as trelagliptin are administered once daily while trelagliptin is administered once weekly.^[1][5] Alogliptin (Nesina) is the other major DPP-4 inhibitor on the market. It is also owned by Takeda and is administered once daily. A dosing of once per week is advantageous as a reduction in the frequency of required dosing is known to increase patient compliance.^[1][2]

Zafatek is administered in the form trelagliptin succinate in a 1:1 mixture of trelagliptin and succinic acid.^[6] The drug is marketed with the IUPAC name Succinic acid – 2-({6-[(3R)-3-amino-1-piperidinyl]-3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl}methyl)-4-fluorobenzonitrile (1:1), has a molecular mass of 475.470143 grams/mol, and has the molecular formula | C=22 | H=26 | F=1 | N=5 | O=6 .^[6][7]

SYNTHESIS …………….

PAPER

DOI: 10.1021/jm101016w

http://pubs.acs.org/doi/abs/10.1021/jm101016w

The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.

2-[6-(3-Aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile, TFA salt (27j)

A mixture of 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol), and K₂CO₃ (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄, and the solvent was removed. The residue was purified by column chromatography to give 0.66 g of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluorobenzonitrile (60%). ¹H NMR (400 MHz, CDCl₃): δ 7.73 (dd, J = 7.2, 8.4 Hz, 1H), 7.26 (d, J = 4.0 Hz, 1H), 7.11−7.17 (m, 1H), 6.94 (dd, J = 2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [M + H] calcd for C₁₃H₉ClFN₃O₂, 293; found 293.

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluorobenzonitrile (300 mg, 1.0 mmol), 3-(R)-aminopiperidine dihydrochloride (266 mg, 1.5 mmol), and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100 °C for 2 h. The final compound (367 mg, 81% yield) was obtained as a TFA salt after HPLC purification. ¹H NMR (400 MHz, CD₃OD): δ 7.77−7.84 (m, 1H), 7.16−7.27 (m, 2H), 5.46 (s, 1H), 5.17−5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33−3.47 (m, 2H), 3.22 (s, 3H), 2.98−3.08 (m, 1H), 2.67−2.92 (m, 2H), 2.07−2.17 (m, 1H), 1.82−1.92 (m, 1H), 1.51−1.79 (m, 2H). MS (ES) [M + H] calcd for C₁₈H₂₀FN₅O₂, 357; found, 357.

PATENT

WO 2007035629

http://www.google.com/patents/WO2007035629A3?cl=en

(R)-2-((6-(3-amino-3-methylpiperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile (30). 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro-benzonitrile (300 mg, 1.0 mmol), (R)-3-amino-3-methyl-piperidine dihydrochloride (266 mg, 1.4 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100⁰C for 2 hrs. The final compound was obtained as TFA salt after HPLC purification. ¹H-NMR (400 MHz, CD3OD): δ. 7.78-7.83 (m, IH), 7.14-7.26 (m, 2H), 5.47 (s, IH), 5.12-5.36 (ABq, 2H, J = 105.2, 15.6 Hz), 3.21 (s, IH), 2.72-3.15 (m, 4H), 1.75-1.95 (m, 4H), 1.39 (s, 3H). MS (ES) [m+H] calc’d for C19H22FN5O2, 372.41; found, 372.41.
Compound 34

4-Fluoro-2-methylbenzonitrile (31). A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄ and the solvent removed to give product 31 (yield 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, IH), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
2-Bromomethyl-4-fluorobenzonitrile (32). A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl₄ was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J= 5.2, 8.4 Hz, IH), 7.28 (dd, J= 2.4, 8.8 Hz, IH), 7.12 (m, IH), 4.6 (s, 2H).
Alternatively, 32 was made as follows. 4-Fluoro-2-methylbenzonitrile (1 kg) in DCE (2 L) was treated with AJJBN (122 g) and heated to 75⁰C. A suspension of DBH (353 g) in DCE (500 mL) was added at 75⁰C portionwise over 20 minutes. This operation was repeated 5 more times over 2.5 hours. The mixture was then stirred for one additional hour and optionally monitored for completion by, for example, measuring the amount of residual benzonitrile using HPLC. Additional AJ-BN (e.g., 12.5 g) was optionally added to move the reaction toward completion. Heating was stopped and the mixture was allowed to cool overnight. N,N-diisopropylethylamine (1.3 L) was added (at <10°C over 1.5 hours) and then diethyl phosphite (1.9 L) was added (at <20°C over 30 min). The mixture was then stirred for 30 minutes or until completion. The mixture was then washed with 1% sodium metabisulfite solution (5 L) and purified with water (5 L). The organic phase was concentrated under vacuum to afford 32 as a dark brown oil (3328 g), which was used without further purification (purity was 97% (AUC)).
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro-benzonitrile (33). A mixture of crude 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃ (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 6O⁰C for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄ and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, 1=1.2, 8.4Hz, IH), 7.26 (d, J-4.0Hz, IH), 7.11-7.17 (m, IH), 6.94 (dd, J=2.0, 9.0 Hz, IH), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C₁₃H₉ClFN₃O₂, 293.68; found 293.68.
Alternatively, 33 was made as follows. To a solution of 6-chloro-3-methyluracil (750 g) and W,iV-diisopropylethylarnine (998 mL) in NMP (3 L) was added (at <30°C over 25 min) a solution of 32 (2963 g crude material containing 1300 g of 32 in 3 L of toluene). The mixture was then heated at 6O⁰C for 2 hours or until completion (as determined, for example, by HPLC). Heating was then stopped and the mixture was allowed to cool overnight. Purified water (3.8 L) was added, and the resultant slurry was stirred at ambient temperature for 1 hour and at <5°C for one hour. The mixture was then filtered under vacuum and the wet cake was washed with IPA (2 X 2.25 L). The material was then dried in a vacuum oven at 40±5°C for 16 or more hours to afford 33 as a tan solid (>85% yield; purity was >99% (AUC)).
2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl]-4-fluoro-benzonitrile (34). 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro-benzonitrile (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100⁰C for 2 hrs. The final compound was obtained as TFA salt after HPLC purification. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, IH), 7.16-7.27 (m, 2H), 5.46 (s, IH), 5.17-5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, IH), 2.67-2.92 (m, 2H), 2.07-2.17 (m, IH), 1.82-1.92 (m, IH), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.
Alternatively, the free base of 34 was prepared as follows. A mixture of 33 (1212 g), IPA (10.8 L), (R)-3-amino-piperidine dihydrochloride (785 g), purified water (78 mL) and potassium carbonate (2.5 kg, powder, 325 mesh) was heated at 6O⁰C until completion (e.g., for >20 hours) as determined, for example, by HPLC. Acetonitrile (3.6 L) was then added at 6O⁰C and the mixture was allowed to cool to <25°C. The resultant slurry was filtered under vacuum and the filter cake was washed with acetonitrile (2 X 3.6 L). The filtrate was concentrated at 45⁰C under vacuum (for >3 hours) to afford 2.6 kg of the free base of 34.
The HCl salt of 34 was prepared from the TFA salt as follows. The TFA salt (34) was suspended in DCM, and then washed with saturated Na₂CO₃. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0⁰C. The HCl salt was obtained after removing the solvent. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, IH), 7.12-7.26 (m, 2H), 5.47 (s, IH), 5.21-5.32 (ABq, 2H, J = 32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, IH), 2.69-2.93 (m, 2H), 2.07-2.17 (m, IH), 1.83-1.93 (m, IH), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.
Alternatively, the HCl salt was prepared from the free base as follows. To a solution of free base in CH₂Cl₂ (12 L) was added (at <35°C over 18 minutes) 2 M hydrochloric acid (3.1 L). The slurry was stirred for 1 hour and then filtered. The wet cake was washed with CH₂Cl₂ (3.6 L) and then THF (4.8 L). The wet cake was then slurried in THF (4.8 L) for one hour and then filtered. The filter cake was again washed with THF (4.8 L). The material was then dried in a vacuum oven at 5O⁰C (with a nitrogen bleed) until a constant weight (e.g., >26 hours) to afford 34 as the HCl salt as a white solid (1423 g, >85% yield).
The succinate salt of 34 was prepared from the HCl salt as follows. To a mixture of the HCl salt of 34 (1414 g), CH₂Cl₂ (7 L) and purifed water (14 L) was added 50% NaOH solution (212 mL) until the pH of the mixture was >12. The biphasic mixture was stirred for 30 min and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (5.7 L) and the combined organic layers were washed with purified water (6 L). The organic layer was then passed through an in-line filter and concentrated under vacuum at 3O⁰C over three hours to afford the free base as an off-white solid. The free base was slurried in prefiltered THF (15 L) and prefiltered IPA (5.5 L). The mixture was then heated at 6O⁰C until complete dissolution of the free base was observed. A prefiltered solution of succinic acid (446 g) in THF (7 L) was added (over 23 min) while maintaining the mixture temperature at >57°C. After stirring at 6O⁰C for 15 min, the heat was turned off, the material was allowed to cool, and the slurry was stirred for 12 hours at 25±5°C. The material was filtered under vacuum and the wet cake was washed with prefiltered IPA (2 X 4.2 L). The material was then dried in a vacuum oven at 70±5°C (with a nitrogen bleed) for >80 hours to afford the succinate salt of 34 as a white solid (1546 g, >90% yield).
The product was also converted to a variety of corresponding acid addition salts. Specifically, the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated. In this way, salts of 34 were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(-)-Mandelic and benzenesulfonic. The succinate was found to be crystalline as determined by x-ray powder diffraction analysis.
In addition, the methanesulfonate salt was prepared as follows. A 10.5 g aliquot of the benzonitrile product was mixed with 400 mL of isopropylacetate. The slurry was heated to 75°C and filtered through #3 Whatman filter paper. The solution was heated back to 75⁰C and a IM solution of methanesulfonic acid (30.84 mL) was added slowly over 10 minutes while stirring. The suspension was cooled to room temperature at a rate of about 20°C/hr. After 1 hr at room temperature, the solid was filtered and dried in an oven overnight to obtain the methanesulfonate salt.

PATENT

US 2008227798

http://www.google.com/patents/US20080227798

EXAMPLES

Example 1Preparation of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile succinate (Compound I)
• Compound I may be prepared by the follow synthetic route (Scheme 1)

A. Preparation of 4-fluoro-2-methylbenzonitrile (Compound B)

• Compound B was prepared by refluxing a mixture of 2-bromo-5-fluoro-toluene (Compound A) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄ and the solvent removed to give product B (yield 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

B. Preparation of 2-bromomethyl-4-fluorobenzonitrile (Compound C)

• Compound C was prepared by refluxing a mixture of 4-fluoro-2-methylbenzonitrile (Compound B) (2 g, 14.8 mmol), N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile (AIBN) (100 mg) in CCl₄ under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give the crude product the form of an oil, which was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

C. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound D)

• Compound E was prepared by stirring a mixture of crude 3-methyl-6-chlorouracil D (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃ (0.5 g, 4 mmol) in DMSO (10 mL) at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄ and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C₁₃H₉ClFN₃O₂, 293.68; found 293.68.

D. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound F)

• Compound F was prepared by mixing and stirring 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound E) (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as trifluoroacetate (TFA) salt after HPLC purification. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J=35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.

E. Preparation of Compound I: the succinic acid salt of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile

• The TFA salt prepared in the above step (Example 1, Step D) was suspended in DCM, and then washed with saturated Na₂CO₃. The organic layer was dried and removed in vacuo. The benzonitrile product (approximately 10 mg) was dissolved in MeOH (1 mL) and to which succinic acid in THF (1.05 equivalents) was added. The solutions were allowed to stand for three days open to the air. If a precipitate formed, the solid was collected by filtration. If no solid formed, the mixture was concentrated in vacuo, and the succinate salt was obtained after removing the solvent. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.
• Compound I such prepared was found to be crystalline as determined by x-ray powder diffraction analysis (FIG. 1). The crystal material was designated Form A.

 PATENT

WO2012118180

Reference Example 2
in the following formula 2, 2 – ((6 – ((3R) -3- amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H ) – yl) shown in the following example of a production process of a methyl) -4-fluoro-benzonitrile succinate (4b).

[Formula 2]

[In the formula 2, 2 – ((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) -4-fluorobenzonitrile (2b) manufacturing process]
ethyl acetate (3.5 vol), 2- (bromomethyl) -4-fluorobenzonitrile (1b) (1 equiv, 1wt.), 6- chloro-3-methyl uracil (1.05 eq, 0.79wt), N- methylpyrrolidone (NMP;.. 3.5 times the amount), diisopropylethylamine (Hunig’s base, 2.1 eq, 1.27wt) was heated to an internal temperature of 60 ~ 70 ℃ a.
The mixture was stirred until 2-4 hours or the completion of the reaction at 60 ~ 70 ℃.
Then cooling the solution to 40 ~ 50 ℃, after stirring at least 30 minutes, 40 ~ 50 ℃ isopropanol (1.5 times) while maintaining, water (3.5 times the amount) was added, then at least one hour stirring did. The solution was cooled to 20 ~ 30 ℃, was then stirred for at least 1 hour. The solution was cooled to 0 ~ 10 ℃, was then stirred for at least 1 hour. The resulting slurry was filtered, washed with 0 ~ 10 ℃ in cold isopropanol (4.0 vol), and vacuum dried at 45 ~ 55 ℃, to give the above compound (2b).

[In the formula 2, 2 – ((6 – ((3R) -3- amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) -4-manufacturing process of the fluorobenzonitrile (3b)]
the above compound (2b) (1 eq, 1wt.), (R) -3- aminopiperidine dihydrochloride (1.1 eq, 0.65wt .), potassium carbonate (2.5 equivalents, 1.18wt.), isopropanol (5.0 vol), water (1.5 times) until the completion of the reaction with 65 ~ 75 ℃ (eg, 3 to 7 hours ) was allowed to react. Potassium carbonate in 65 ~ 75 ℃ (7.05 eq, 3.32wt.), Water (5.5 vol) was added, and after stirring for about 30 minutes, the phases were separated at 50 ℃ ~ 70 ℃. The organic solvent was concentrated under reduced pressure to approximately 5 times. And water (5 vol) was added to the solution and concentrated under reduced pressure to approximately 5 times. The solution was stirred for about 40 minutes at 55 ℃ ~ 75 ℃. The solution was cooled to 20 ℃ ~ 30 ℃, was then stirred for at least 1 hour. The solution was cooled to 0 ~ 10 ℃, subsequently stirred for at least 1 hour, the resulting slurry was filtered, washed with 0 ~ 10 ℃ in cold water (2.0 times the amount), 45 ~ 55 ℃ was vacuum dried to give the above compound (3b).

[In the above formula 2, the compound production step of succinate (4b) of (3b)]
Compound (3b), tetrahydrofuran (6.0 vol), isopropanol (3.0 vol), water (0. a 6-fold amount) was heated to 55 ~ 65 ℃. Tetrahydrofuran solution of succinic acid (20 ℃ ~ 30 ℃) was added and the solution was stirred for about 15 minutes and maintained at 55 ~ 65 ℃.
The solution was cooled to 20 ~ 30 ℃, the mixture was stirred for at least 1 hour. The solution was cooled to 0 ~ 10 ℃, was then stirred for at least 1 hour. After the resulting slurry filtered and washed with isopropanol (6.0 vol). The resulting wet crystals were dried at 65 ~ 75 ℃, was obtained succinate of the compound (3b) and (4b) as a white crystalline solid.

PATENT

http://www.google.com/patents/CN103030631A?cl=en

2 – ({6 -! [(3R) -3- amino-piperidin-1-yl] -3-methyl-dihydro-pyrimidin _3,4_ _2,4_ dioxo-1 (2 1) – yl} methyl) benzonitrile is an effective DPP-1V inhibitors class of drugs in recent years in Japan, the structural formula

As shown below.

  Chinese Patent Application CN1926128 discloses a process for preparing 2_ ({6_ [(3R) -3- amino-piperidin-1-yl] -3-methyl-2,4-dioxo-3,4- dihydropyrimidine-1 (2 1!) – yl} methyl) benzonitrile method, as shown in Scheme I:

Scheme I

In the above reaction scheme, 6-chloro-uracil and 2-bromomethyl-benzene cyanide in a mixed solvent of DMF-DMSO, in the presence of NaH and LiBr alkylation reaction to give compound 2 in a yield of 54%. Compound 2 is further alkylation reaction of compound yield 3 is 72%. The total yield of the compound 4 prepared in 20% yield is low, and the preparation of compound 4 obtained purity is not high, but also the need for further purification, such as recrystallization, column chromatography and other means in order to obtain high-purity suitable Pharmaceutically acceptable 2 – ({6 – [(3R) -3- amino-piperidin-1-yl] -3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin _1 (2! 1) – yl} methyl) benzonitrile compound. Preparation still find more suitable for industrial production, a higher yield of the 2- ({6- [(3R) -3- amino-piperidin-1-yl] -3-methyl-2,4-dioxo -3, (2Η) 4- dihydropyrimidine-1 – yl} methyl) benzonitrile or a salt or the like.

 PATENT

WO 2015137496

Example 15
(R) -2 – ((6 (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) synthesis of 4-fluoro-benzonitrile

100mL four-necked flask of water and isopropanol 1/1 (v / v) mixture 60mL was added, pyridine 21.4μL [d = 0.98, mw.79.10, 0.26mmol], (R) -1- (3- (2 – cyano-5-fluoro-benzyl) -1-methyl-2,6-dioxo-1,2,3,6-tetra-hydro-4-yl) piperidin-3-carboxamide 2.00g [mw.385.39, 5.19mmol] of It was added to the order. Then, iodobenzene diacetate 1.84g [mw.322.10, 5.71mmol] was added, and the mixture was stirred for 3 h at 20 ℃. After volatile components were distilled off under reduced pressure by an evaporator, and the aqueous solution was washed twice with ethyl acetate 20mL. After cooling to near 0 ℃, potassium carbonate 16g added stepwise at 15 ℃ or less, was extracted by the addition of toluene 6mL and isopropanol 6mL. After separation, the organic layer was washed with saturated brine 10mL, adding toluene 6mL after concentration under reduced pressure by an evaporator, and further subjected to vacuum concentration. It was suspended by the addition of toluene 6mL to concentrate, by the addition of n-heptane 6mL, after 1 hour and aged at 0 ℃, reduced pressure filtration, to obtain the desired compound after drying under reduced pressure at 50 ℃. White crystalline powder, 1.6g, 86% yield.

1 H-NMR (500 MHz, CDCl 3 ) delta (ppm) 1.23 (D, J = 11.03 Hz, 1H) 1.30 (BRS, 2H) 1.56-1.67 (M, 1H) 1.72-1.83 (M, 1H) 1.95 (dd , J = 12.77 Hz, 3.94 Hz, 1H) 2.41 (m, 1H) 2.61 (m, 1H) 2.87-2.98 (m, 2H) 2.99-3.05 (m, 1H) 3.32 (s, 3H) 5.23-5.32 (m , 2H) 5.39 (s, 1H) 6.86 (dd, J = 8.99 Hz, 2.36 Hz, 1H) 7.09 (td, J = 8.04 Hz, 2.52 Hz, 1H) 7.69 (dd, J = 8.51 Hz, 5.36 Hz, 1H ).

13 C NMR (126 MHz, CDCl 3 ) ppm 28.0, 33.4, 46.1, 51.9, 59.7, 90.8, 114.6,114.7, 115.6, 115.8, 116.4, 135.4, 135.5, 144.6, 152.7, 159.5, 162.9.
Reference Example 4
(R) -2 – ((6 (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) – yl) methyl) synthesis of 4-fluoro-benzonitrile succinate

50mL eggplant-shaped flask (R) -2 – ((6- (3- amino-1-yl) -3-methyl-2,4-dioxo-3,4-dihydro-pyrimidine -1 (2H) – yl) methyl) -4-fluorobenzonitrile 1.0g [mw.357.38, 2.8mmol], it was added tetrahydrofuran 4.5mL and water 2 drops. After heated and dissolved at 65 ℃, was dropped to the solution was dissolved at the same temperature 0.331g succinic acid [mw.118.09, 2.8mmol] with tetrahydrofuran 4mL and isopropanol 2.5mL. Aged for 16 hours at room temperature after stirring for 30 min at 65 ℃, and stirred for a further 2 hours at 0 ℃. The crystallization product was collected by terrorism to vacuum filtration. To obtain the desired compound after drying under reduced pressure at 45 ℃. White crystalline powder, 1.2g, 93% yield.

1 H-NMR (500 MHz, DMSO) delta (ppm) 1.35 (D, J = 8.83 Hz, 1H) 1.42-1.57 (M, 1H) 1.66-1.97 (M, 2H) 2.54-2.77 (M, 2H) 2.91 ( d, J = 11.35 Hz, 1H) 3.00-3.07 (m, 1H) 3.08 (m, 1H) 3.09 (s, 3H) 3.14 (m, 1H) 5.12 (d, J = 16.08 Hz, 1H) 5.20 (d, J = 16.39 Hz, 1H) 5.38 (s, 1H) 7.17 (dd, J = 9.62 Hz, 2.36 Hz, 1H) 7.35 (td, J = 8.51 Hz, 2.52 Hz, 1H) 7.95 (dd, J = 8.67 Hz, 5.52 Hz, 1H).

13 C NMR (126 MHz, DMSO) delta ppm 27.9, 31.6, 46.3, 47.0, 51.7, 55.8, 90.3, 106.9, 115.7, 117.1, 136.45, 136.53, 145.8, 152.3, 159.7, 162.7, 164.1 , 166.1, 175.2.

PATENT

http://www.google.com/patents/CN102964196A?cl=en

PATENT

WO 2016024224,

New Patent, Trelagliptin, SUN PHARMA

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

BARMAN, Dhiren, Chandra; (IN).
NATH, Asok; (IN).
PRASAD, Mohan; (IN)

The present invention provides a process for the preparation of 4-fluoro-2- methylbenzonitrile of Formula (II), and its use for the preparation of trelagliptin or its salts. The present invention provides an efficient, simple, and commercially friendly process for the preparation of 4-fluoro-2-methylbenzonitrile, which is used as an intermediate for the preparation of trelagliptin or its salts. The present invention avoids the use of toxic and hazardous reagents, high boiling solvents, and bromo intermediates such as 2-bromo-5-fluorotoluene, which is lachrymatory in nature and thus difficult to handle at a commercial scale.

Trelagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor, chemically designated as 2- [[6-[(3i?)-3 -aminopiperidin- 1 -yl] -3 -methyl -2,4-dioxopyrimidin- 1 -yljmethyl] -4-fluorobenzonitrile, represented by Formula I.

Formula I

Trelagliptin is administered as a succinate salt of Formula la, chemically designated as 2-[[6-[(3i?)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxopyrimidin-l-yl]methyl]-4-fluorobenzonitrile butanedioic acid (1 : 1).

Formula la

U.S. Patent Nos. 7,795,428, 8,288,539, and 8,222,411 provide a process for the preparation of 4-fluoro-2-methylbenzonitrile by reacting 2-bromo-5-fluorotoluene with copper (I) cyanide in N,N-dimethylformamide.

Chinese Patent No. CN 102964196 provides a process for the preparation of 4-fluoro-2-methylbenzonitrile by reacting 4-fluoro-2-methylbenzyl alcohol with cuprous iodide in the presence of 2,2′-bipyridine and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) in an anhydrous ethanol.

Copper (I) cyanide is toxic to humans, and therefore its use in the manufacture of a drug substance is not advisable. In addition, 2-bromo-5-fluorotoluene is converted to 4-fluoro-2-methylbenzonitrile by refluxing in N,N-dimethylformamide at 152°C to 155°C for 24 hours. This leads to some charring, resulting in a tedious work-up process and low yield. Furthermore, the use of reagents like cuprous iodide, 2,2′-bipyridine, and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) is hazardous and/or environmentally-unfriendly, and therefore their use in the manufacture of a drug substance is not desirable.

The present invention provides an efficient, simple, and commercially friendly process for the preparation of 4-fluoro-2-methylbenzonitrile, which is used as an intermediate for the preparation of trelagliptin or its salts. The present invention avoids the use of toxic and hazardous reagents, high boiling solvents, and bromo intermediates such as 2-bromo-5-fluorotoluene, which is lachrymatory in nature and thus difficult to handle at a commercial scale.

EXAMPLES

Example 1 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (1.38 g) was added to ethanol (10 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (2.76 g) and pyridine (1 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 3 hours. The solvent was recovered up to maximum extent from the reaction mixture under reduced pressure to afford the title compound. Yield: 3.1 g

Example 2: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (5 g) was added to ethanol (37 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (10 g) and N,N-diisopropylethylamine (3.6 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 2 hours. The solvent was recovered up to maximum extent from the reaction mixture under reduced pressure to afford the title compound. Yield: 3.1 g

Example 3 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (10 g) was added to ethanol (40 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (20 g) and N,N-diisopropylethylamine (7.5 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to afford the title compound. Yield: 11.0 g

Example 4: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (50 g) was added to ethanol (500 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (70 g) and N,N-diisopropylethylamine (36 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 6 hours. The solvent was recovered from the reaction mixture under reduced pressure to afford the title compound. Yield: 51.0 g

Example 5 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (20 g) was added to ethanol (200 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (20 g) and N,N-diisopropylethylamine (18 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to obtain a residue. Deionized water (60 mL) was charged into the residue, and then the slurry was stirred at 0°C to 5°C for 1 hour. The solid obtained was filtered, then washed with deionized water (2 x 20 mL). The wet solid was dried in an air oven at 40°C to 45 °C for 4 hours to 5 hours. The crude product obtained was recrystallized in ethanol (50 mL) to afford the pure title compound. Yield: 21.0 g

Example 6: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methyl benzaldehyde (50 g) was added to ethanol (500 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (50 g) and N,N-diisopropylethylamine (46.4 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to obtain a residue. Deionized water (150 mL) was charged to the residue, and then the slurry was stirred at 0°C to 5°C for 1 hour. The solid obtained was filtered, then washed with deionized water (2 x 50 mL). The wet solid was dried in an air oven at 40°C to 45 °C for 4 hours to 5 hours. The crude product obtained was recrystallized in ethanol (200 mL) to afford the pure title compound. Yield: 53.5 g

Example 7: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (3.1 g) and phosphorous pentoxide (1 g) were added to toluene (30 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (30 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 1.1 g

Example 8: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (3 g) and phosphorous pentoxide (2 g) were added to toluene (30 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (30 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 1.0 g

Example 9: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (5 g) and concentrated sulphuric acid (2 mL) were added to toluene (100 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (50 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 3.24 g

Example 10: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (25 g) and concentrated sulphuric acid (35 g) were added to toluene (500 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (250 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 20.5 g

Example 11 : Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methyl benzaldoxime (5 g) and sodium bisulphate monohydrate (3.1 g) were added to toluene (50 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C, then filtered, and then washed with toluene (10 mL). The filtrate was concentrated under reduced pressure to afford the title compound. Yield: 3.0 g

Example 12: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methyl benzaldoxime (50 g) and sodium bisulphate monohydrate (31.6 g) were added to toluene (500 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C using a Dean-Stark apparatus for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25 °C to 30°C, then filtered, and then washed with toluene (100 mL). The filtrate was concentrated under reduced pressure to afford a crude product. The crude product obtained was recrystallized in a mixture of toluene (200 mL) and hexane (500 mL) to afford the title compound.

Yield: 38.0 g

Sun Pharma managing director Dilip Shanghvi.

References

• 1 McKeage, Kate (2015-06-27). “Trelagliptin: First Global Approval”. Drugs 75 (10): 1161–1164. doi:10.1007/s40265-015-0431-9. ISSN 0012-6667.
• 2 Inagaki, Nobuya; Onouchi, Hitoshi; Sano, Hiroki; Funao, Nobuo; Kuroda, Shingo; Kaku, Kohei. “SYR-472, a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial”. The Lancet Diabetes & Endocrinology 2 (2): 125–132. doi:10.1016/s2213-8587(13)70149-9.
• 3″New Drug Application Approval of Zafatek® Tablets for the treatment of Type 2 Diabetes in Japan | Takeda Pharmaceutical Company Limited”. http://www.takeda.com. Retrieved 2015-11-13.
• 4 Cahn, Avivit; Raz, Itamar (2013-06-01). “Emerging gliptins for type 2 diabetes”. Expert Opinion on Emerging Drugs 18 (2): 245–258. doi:10.1517/14728214.2013.807796. ISSN 1472-8214. PMID 23725569.
• 5Inagaki, Nobuya; Onouchi, Hitoshi; Maezawa, Hideaki; Kuroda, Shingo; Kaku, Kohei. “Once-weekly trelagliptin versus daily alogliptin in Japanese patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study”. The Lancet Diabetes & Endocrinology 3 (3): 191–197. doi:10.1016/s2213-8587(14)70251-7.
• 6″TRELAGLIPTIN SUCCINATE | C22H26FN5O6 – PubChem”. pubchem.ncbi.nlm.nih.gov. Retrieved 2015-11-13.
• 7″Trelagliptin succinate | C22H26FN5O6 | ChemSpider”. http://www.chemspider.com. Retrieved 2015-11-13.

http://www.cbijournal.com/paper-archive/may-june-2014-vol-3/Review-Paper-1.pdf

Trelagliptin

Systematic (IUPAC) name
Succinic acid – 2-({6-[(3R)-3-amino-1-piperidinyl]-3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl}methyl)-4-fluorobenzonitrile (1:1)
Clinical data
Trade names	Zafatek
Chemical data
Formula	C22H26FN5O6
Molar mass	475.470143 g/mol

/////////Trelagliptin, PMDA, JAPAN 2015

Cn1c(=O)cc(n(c1=O)Cc2cc(ccc2C#N)F)N3CCC[C@H](C3)N

1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine fumarate

Vonoprazan (Takecab(®)) is an orally bioavailable potassium-competitive acid blocker (P-CAB) being developed by Takeda for the treatment and prevention of acid-related diseases. The drug is approved in Japan for the treatment of acid-related diseases, including erosive oesophagitis, gastric ulcer, duodenal ulcer, peptic ulcer, gastro-oesophageal reflux, reflux oesophagitis and Helicobacter pylori eradication. Phase III development is underway for the prevention of recurrence of duodenal and gastric ulcer in patients receiving aspirin or NSAID therapy. Phase I development was conducted in the UK for gastro-oesophageal reflux; however, no further development has been reported. This article summarizes the milestones in the development of vonoprazan leading to this first approval for acid-related diseases.

Vonoprazan Fumarate was approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on December 26, 2014. It was co-developed and marketed as Takecab^® by Takeda & Otsuka.
Vonoprazan has a novel mechanism of action called potassium-competitive acid blockers (P-CABs) which competitively inhibits the binding the potassium ions to H⁺, K⁺-ATPase (also known as the proton pump) in the final step of gastric acid secretion in gastric parietal cells. Vonoprazan provides a strong and sustained acid section inhibitory effect. It is indicated for the treatment of gastric ulcer, duodenal ulcer and reflux esophagitis.
Cometriq^® is available as tablet for oral use, containing 10 or 20 mg of free Vonoprazan, and the recommended dose is 20 mg orally once daily for adluts.

Vonoprazan fumarate (Takecab(®)) is a first-in-class potassium-competitive acid blocker that has been available in the market in Japan since February 2015. Vonoprazan is administered orally at 20 mg once daily for the treatment of gastroduodenal ulcer, at 20 and 10 mg once daily for the treatment and secondary prevention of reflux esophagitis, respectively, at 10 mg once daily for the secondary prevention of low-dose aspirin- or non-steroidal anti-inflammatory drug-induced peptic ulcer, and at 20 mg twice daily in combination with clarithromycin and amoxicillin for the eradication of Helicobacter pylori. It inhibits H(+),K(+)-ATPase activities in a reversible and potassium-competitive manner with a potency of inhibition approximately 350 times higher than the proton pump inhibitor, lansoprazole. Vonoprazan is absorbed rapidly and reaches maximum plasma concentration at 1.5-2.0 h after oral administration. Food has minimal effect on its intestinal absorption. Oral bioavailability in humans remains unknown. The plasma protein binding of vonoprazan is 80 % in healthy subjects. It distributes extensively into tissues with a mean apparent volume of distribution of 1050 L. Being a base with pKa of 9.6 and with acid-resistant properties, vonoprazan is highly concentrated in the acidic canaliculi of the gastric parietal cells and elicited an acid suppression effect for longer than 24 h after the administration of 20 mg. The mean apparent terminal half-life of the drug is approximately 7.7 h in healthy adults. Vonoprazan is metabolized to inactive metabolites mainly by cytochrome P450 (CYP)3A4 and to some extent by CYP2B6, CYP2C19, CYP2D6, and SULT2A1. A mass balance study showed that 59 and 8 % of the orally administered radioactivity was recovered in urine as metabolites and in an unchanged form, respectively, indicating extensive metabolism. Genetic polymorphism of CYP2C19 may influence drug exposure but only to a clinically insignificant extent (15-29 %), according to the population pharmacokinetic study performed in Japanese patients. When vonoprazan was co-administered with clarithromycin, the mean AUC from time 0 to time of the next dose (dosing interval) of vonoprazan and clarithromycin were increased by 1.8 and 1.5 times, respectively, compared with the corresponding control values, indicating mutual metabolic inhibition. The mean area under the curve from time zero to infinity obtained from patients with severe liver and renal dysfunction were elevated by 2.6 and 2.4 times, respectively, compared with healthy subjects, with no significant changes in plasma protein binding. Vonoprazan increases intragastric pH above 4.0 as early as 4 h after an oral dose of 20 mg, and the extensive anti-secretory effect is maintained up to 24 h post-dose. During repeated dosing of 20 mg once daily, the 24-h intragastric pH >4 holding time ratios were 63 and 83 % on days 1 and 7, respectively. Because vonoprazan elicited a more extensive gastric acid suppression than the proton pump inhibitor, lansoprazole, it also gave rise to two to three times greater serum gastrin concentrations as compared with lansoprazole. In pre-approval clinical studies for the treatment of acid-related disorders, mild to moderate adverse drug reactions (mostly constipation or diarrhea) occurred at frequencies of 8-17 %. Neither severe liver toxicity nor neuroendocrine tumor has been reported in patients receiving vonoprazan.

Vonoprazan fumarate is a first-in-class potassium-competitive acid blocker. It was approved in the Japanese market in February, 2015.^[1]

Vonoprazan can be used for the treatment of gastroduodenal ulcer, reflux esophagitis, and for some drug-induced peptic ulcers. It can be combined with other antibiotics for the eradication of Helicobacter pylori.^[2]

PATENT

CN102421753B

Route 1

Reference：1. WO2006036024A1 / US8048909B2.

2. WO2007026916A1 / US7498337B2.

3. CN104327051A.

1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine fumarate Takeda single An R & D for the gastric acid secretion inhibitors (codename: TAK-438, generic name: vonoprazan fumarate), the drug belongs to the potassium ion (K +) competitive acid blocker (P-CAB) for a new inhibitors, with a strong, long-lasting inhibition of gastric acid secretion, while the gastric parietal cells in the final stage of gastric acid secretion by inhibiting K + for H +, K + -ATP enzyme (proton pump) binding effect on gastric acid secretion also advance termination action.

Its molecular formula is: C17H16FN3O2S · C4H4O4, MW: 461.46, the chemical structure of formula I as shown.

 

CN101300229A discloses 1- [5- (2_-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1Η- pyrrol -3-yl] -N- methylmethanamine fumarate alone, but not related to its crystalline form.

The present invention discloses a I- [5- (2- fluorophenyl) -I- (pyridin-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine single rich fumarate A method for preparing a crystalline form. 1- [5- (2_-fluorophenyl) -1- (Batch-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine fumarate single crystalline form A, according to prepared by the following routes:

Example 1

  A method of preparing polymorph having pyrrole derivatives maleate described in detail below.

Step I: 5- (2- fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrole-3-carbaldehyde Synthesis of

Compound II (260mg) was dissolved in tetrahydrofuran (50ml) was added 60% NaH, the reaction was stirred for 30 minutes at room temperature. Was added 15-crown–5 (I. 5g), the reaction mixture was stirred at room temperature for 1 hour and then pyridine-3-sulfonyl chloride was added, stirred at room temperature for 2 hours until complete reaction was followed by thin layer chromatography, and then was added to the reaction system 20mL saturated brine with ethyl acetate (IOOmLX2) and the combined organic phase was washed with saturated brine 50ml organic phase, an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude compound IV (200mg) administered directly in the next reaction.

Synthesis 1_ [5- (2-fluorophenyl) -1- (piperidin-3-sulfonyl batch) -IH- pyrrol-3-yl] -N- methylmethanamine of: Step 2

The brown residue obtained in the previous step IV compound (200mg) was dissolved in 30mL methanol was added 27% -33% methyl amine solution, the reaction was stirred for 1.5 hours. Sodium borohydride (68mg), the reaction was stirred for 20 minutes, was added lmol / LHCl to an acidic aqueous solution, and stirred until complete reaction was followed by thin layer chromatography. To the reaction mixture was added saturated sodium bicarbonate solution until weakly basic system was extracted with ethyl acetate (IOOmLX2), the combined organic phases with saturated brine (50mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product ( 208mg, yellow oil). Yield: 100%.

  Step 3: 1_ [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine fumarate single synthesis

Compound V obtained in the previous step was dissolved in 20mL of ethyl acetate, taking the mass fraction of equivalents of fumaric acid was dissolved in 2ml of methanol. Added dropwise with stirring to a solution of compound V in ethyl acetate, stirred for 30 minutes at room temperature. Then warmed to 55-65 degrees reflux one hour, cooled to room temperature and filtered to give an off-white solid was washed with cold ethyl acetate IOml and dried in vacuo to give 170mg of crystalline Compound I, about 20% overall yield. X- ray diffraction spectrum of the crystalline sample is shown in Figure 1. DSC spectrum shown in Figure 2, this polymorph is defined as A crystalline form.

Route 2

Reference：1. CN105085484A.

http://www.google.com/patents/CN105085484A?cl=en

Fumaric Wonuo La Like (TAK-438, Vonoprazan fumarate) is Takeda Pharmaceuticals and Otsuka Pharmaceutical to launch a new type of oral anti-acid drugs. As a potassium ion (K +) competitive acid blocker (P-CAB), Wonuo La Like gastric acid secretion in the gastric parietal cells play a role in the final step, by inhibiting K + for H +, K + -ATP enzyme (proton chestnut) combine to inhibit gastric acid secretion and early termination. Compared to the current power of the proton chestnut inhibitors (PPIs), due to the absence of praise Wonuo La CYP2C19 metabolism, so the performance in clinical trials showing good effect: the treatment of gastric ulcer / duodenal ulcer, reflux esophagitis eradication of H. pylori and other effects are better than lansoprazole, while having a similar security.

  fumarate Wonuo La Like chemical name: I- [5_ (2_ gas) -1- (pyridin _3_ cross-acyl group) -IH- P ratio slightly 3-yl] – N- methylmethanamine fumarate, structured as follows:

  Preparation of fumaric Wonuo La Like synthetic route mainly follows:

  Takeda patent CN200680040789 original study discloses a 5- (2-fluorophenyl) -lH- pyrrole-3-carbaldehyde as a starting material, the solvent is tetrahydrofuran, sodium hydride doing acid binding agent, crown ethers do a phase transfer catalyst, with 3-pyridine sulfonyl chloride to give the intermediate 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrole-3-carbaldehyde, then to form a Schiff base with methylamine boron sodium hydride reduction to give Wonuo La Like the free base and then fumaric acid salt formation, generate fumaric Wonuo La Chan, the reaction equation is as follows:

  Takeda company disclosed in 2010 it 0 01,080,018,114 in improved synthetic route: Intermediate 5- (2-fluorophenyl) -I- (pyridine-3-ylsulfonyl) -IH–3 formaldehyde synthesis, instead of acetonitrile as solvent, DIEA do acid-binding agent, DMAP as catalyst, but side reactions, tedious post-processing operation, the lower the yield, the overall yield of less than 40%.

CN201080018114 improved synthetic route to 5- (2-fluorophenyl) -IH- pyrrole-3-carbonitrile as a starting material of the synthesis route, but this route is converted to the cyano aldehyde used Raney catalytic hydrogenation, industrial scale there is a big security risk, its reaction equation is as follows:

  Y. Arikawa et J. Med Chem 2012, 55, 4446-4456 reported the following synthetic route.:

In phenyl pyrrole-3-carbaldehyde and methylamine alcohol imine by metal borohydride reduction, to give further protection to give Boc ((5-phenyl -IH- pyrrol-3-yl) -N -) methyl carbamate; the above product with an arylsulfonyl chloride, and then de-Boc protection to give 1- (5-phenyl-1 aromatic sulfonyl -IH- pyrrol-3-yl) – N- methyl methylamine;

Y. Arikawa et al reported that the above process step is prolonged, the probability g [J reacting a corresponding increase in the above reaction scheme conditional optimization, control side reactions is one of the present invention is to solve the problem. On the other hand the above literature after the synthesis process used in chromatography, is not conducive to fumaric Wonuo La Like industrial production. Therefore, the development of fumaric acid Wonuo La Like New synthesis process, simplify the synthesis operations, reduce costs, improve productivity, it has important implications for fumaric Wonuo La Like this one which attract anti-acid drugs.

PAPER

J. Med Chem 2012, 55, 4446-4456

http://pubs.acs.org/doi/abs/10.1021/jm300318t

Discovery of a Novel Pyrrole Derivative 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Fumarate (TAK-438) as a Potassium-Competitive Acid Blocker (P-CAB)

In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log D and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound 13e exhibited potent H⁺,K⁺-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound 13e (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases.

SYNTHESIS

References

References

1: Arikawa Y, Nishida H, Kurasawa O, Hasuoka A, Hirase K, Inatomi N, Hori Y, Matsukawa J, Imanishi A, Kondo M, Tarui N, Hamada T, Takagi T, Takeuchi T, Kajino M. Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB). J Med Chem. 2012 May 10;55(9):4446-56. doi: 10.1021/jm300318t. Epub 2012 Apr 30. PubMed PMID: 22512618.

2: Kondo M, Kawamoto M, Hasuoka A, Kajino M, Inatomi N, Tarui N. High-throughput screening of potassium-competitive acid blockers. J Biomol Screen. 2012 Feb;17(2):177-82. doi: 10.1177/1087057111421004. Epub 2011 Sep 22. PubMed PMID: 21940711.

3: Shin JM, Inatomi N, Munson K, Strugatsky D, Tokhtaeva E, Vagin O, Sachs G. Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e monofumarate (TAK-438). J Pharmacol Exp Ther. 2011 Nov;339(2):412-20. doi: 10.1124/jpet.111.185314. Epub 2011 Aug 9. PubMed PMID: 21828261; PubMed Central PMCID: PMC3199995.

4: Hori Y, Matsukawa J, Takeuchi T, Nishida H, Kajino M, Inatomi N. A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals. J Pharmacol Exp Ther. 2011 Jun;337(3):797-804. doi: 10.1124/jpet.111.179556. Epub 2011 Mar 16. PubMed PMID: 21411494.

5: Matsukawa J, Hori Y, Nishida H, Kajino M, Inatomi N. A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands. Biochem Pharmacol. 2011 May 1;81(9):1145-51. doi: 10.1016/j.bcp.2011.02.009. Epub 2011 Mar 1. PubMed PMID: 21371447.

6: Hori Y, Imanishi A, Matsukawa J, Tsukimi Y, Nishida H, Arikawa Y, Hirase K, Kajino M, Inatomi N. 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases. J Pharmacol Exp Ther. 2010 Oct;335(1):231-8. doi: 10.1124/jpet.110.170274. Epub 2010 Jul 12. PubMed PMID: 20624992.

• 1 “Vonoprazan: first global approval. – PubMed – NCBI”. Ncbi.nlm.nih.gov. 2015-09-28. Retrieved 2016-03-30.
• 2

“The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate: Pharmacokinetic and Pharmacodynamic Considerations. – PubMed – NCBI”. Ncbi.nlm.nih.gov. 2015-09-28. Retrieved 2016-03-30.

/////

• Originator Kowa Pharmaceutical
• Class Antihyperlipidaemics
• Mechanism of Action Peroxisome proliferator-activated receptor alpha agonists

• Preregistration Dyslipidaemias

Most Recent Events

• 01 Feb 2016 Kowa Research Institute completes a phase I drug-interaction trial in Healthy volunteers in USA (PO) (NCT02719431)
• 12 Jan 2016 Kowa Research Institute plans the phase III PROMINENT trial for Dyslipidaemia (In patients with diabetes mellitus) in countries worldwide
• 01 Jan 2016 Kowa Research Institute initiates a phase I drug-interaction trial in Healthy volunteers in USA (PO) (NCT02719431)

Pemafibrate, also known as K-877 and (R)-K 13675, is a PPAR alpha agonist. (R)-K-13675 decreases the secretion of inflammatory markers without affecting cell proliferation or tube formation. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a key regulator of lipid and glucose metabolism and has been implicated in inflammation. (R)-K-13675 was associated with the inhibition of inflammatory responses without affecting cell proliferation or angiogenesis, and subsequently may induce an anti-atherosclerotic effect.

Pemafibrate had been filed NDA by Kowa for the treatment of dyslipidemia in the Japan in 2015.

Pemafibrate is in phase II clinical trials for the treatment of dyslipidemia in the US and EU.

Route 1

Reference：1. US2009023944A1.

Route 2

Reference：1. US2009076280A1.

http://www.google.com/patents/US20090076280

Example 5 Synthesis of (R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butyric acid (Compound (6))

• Ethyl (R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butylate (26.0 g) was dissolved in ethanol (200 mL), and 1.5N NaOH (50 mL) was added to the solution, followed by stirring for 1 hour at room temperature. The reaction mixture was washed with diethyl ether, and the formed aqueous layer was acidified with 4N HCl under ice cooling. The thus-treated aqueous layer was extracted with ethyl acetate, and the extract was washed sequentially with water and saturated brine. The washed extract was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol=10/1), to thereby yield the target product (21.3 g, 87%, 98% ee).

Optical Purity:

• Measurement conditions: HPLC
• Column: CHIRALPAK AD
• Solvent: n-hexane/IPA/TFA=100/30/0.1
• Flow rate: 2 mL/min
• Retention time: 4.19 min (S-form; 3.68 min)
• ¹H-NMR (400 MHz, CD₃OD) δ ppm: 0.94 (t, J=7 Hz, 3H), 1.81 (m, 2H), 1.99 (quintet, J=6 Hz, 2H), 3.60 (t, J=7 Hz, 2H), 3.61 (s, 3H), 3.85 (t, J=6 Hz, 2H), 4.40 (t, J=6 Hz, 1H), 4.65 (s, 2H), 6.69-6.80 (m, 7H), 6.91 (dt, J=7, 1 Hz, 1H), 7.05 (dt, J=7, 1 Hz, 1H), 7.12-7.18 (m, 4H).

Route 3

Reference：1. Bioorg. Med. Chem. Lett. 2007, 17, 4689-4693.

 

Landmark Trial Entitled “PROMINENT” To Explore The Prevention Of Heart Disease In Diabetic Patients With High Triglycerides And Low HDL-C

Trial will evaluate if lowering triglycerides and increasing functional HDL with Kowa’s potent selective peroxisome proliferator activator receptor-alpha (PPAR-alpha) modulator, K-877 (pemafibrate) can reduce the elevated risk of cardiovascular disease in high-risk diabetic patients who are already taking statins

Jan 12, 2016, 09:00 ET from Kowa Research Institute, Inc.

///////Pemafibrate, NDA,  Kowa, dyslipidemia,  Japan, 2015, phase II clinical trials,  US and EU, K-877, K-13675, (R)-

CC[C@H](C(=O)O)Oc1cccc(c1)CN(CCCOc2ccc(cc2)OC)c3nc4ccccc4o3

CC[C@@H](OC1=CC=CC(CN(C2=NC3=CC=CC=C3O2)CCCOC4=CC=C(OC)C=C4)=C1)C(O)=O

Imidafenacin

イミダフェナシン

Cas 170105-16-5

C₂₀H₂₁N₃O, 319.408

APPROVED JAPAN 2015-07-29

イミダフェナシン
Imidafenacin

C₂₀H₂₁N₃O : 319.4
[170105-16-5]

Imidafenacin (INN) is a urinary antispasmodic of the anticholinergic class. It’s molecular weight is 319.40 g/mol

Kyorin and Ono have developed and launched imidafenacin, an oral M1 and M3 muscarinic receptor antagonist. Family members of the product case, WO9515951, expire in the US in 2019

Imidafenacin was approved by Pharmaceuticals Medical Devices Agency of Japan (PMDA) on Apr 18, 2007. It was marketed as Uritos^® by Kyorin, and marketed as Staybla^® by Ono.

Imidafenacin is a potent M1 and M3-subtype antagonist indicated for the treatment of urinary urgency, frequent urination and urgency urinary incontinence due to overactive bladder.

Uritos^® is available as tablet for oral use, containing 0.1 mg of free Imidafenacin. The recommended dose is 0.1 mg twice daily, and it can be increased to 0.2 mg twice daily, if the efficacy was not enough.

Uritos^® / Staybla^®

MOA：Muscarinic acetylcholine receptor antagonist

Indication：Urinary incontinence; Urinary urgency and frequency

PAPER

WO-2016142173

Imidafenacin, the compound of formula (I), is an antimuscarinic agent marketed in Japan under the brand name Uritos® used to treat overactive bladder, a disease defined by the presence of urinary urgency, usually accompanied by frequency and nocturia, with or without urge incontinence. Overactive bladder dysfunction has a considerable impact on patient quality of life, although it does not affect survival.

(I)

Synthesis of 4-(2-methyl-1 -imidazolyl)-2,2-diphenylbutanamide is first disclosed in Japanese patent JP3294961 B2 as shown in Scheme 1 . 4-bromo-2,2-diphenylbutanenitrile (II) is reacted with three equivalents of 2-methylimidazol, in dimethylformamide and in the presence of triethylamine as a base, to afford 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile, compound of formula (III), which is purified by column chromatography and, further, converted into its hydrochloride salt and recrystallized. Then, compound (III) is hydrolyzed with an excess of 70% sulfuric acid at 140-150 °C, followed by basification and recrystallization to provide imidafenacin (I), in an overall yield of only 25% (as calculated by data provided in docume

(III) (I)

Scheme 1

This route of document JP3294961 B2 implies several drawbacks. Firstly, purification of intermediate (III) is carried out by means of chromatographic methods, which are generally expensive, environmentally unfriendly and time consuming. Secondly, the hydrolysis of the nitrile group is carried out under strong acidic conditions and high temperature not convenient for industrial application.

Japanese document JP2003-201281 discloses a process for preparing imidafenacin as shown in Scheme 2. 4-bromo-2,2-diphenylbutanenitrile (II) is reacted, with five equivalents of 2-methylimidazol, which acts also as a base, in dimethylsufoxide to provide intermediate (III), which after an isolation step is further reacted with phosphoric acid in ethanol to provide the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile. Hydrolysis with potassium hydroxide, followed by purification with a synthetic adsorbent provides imidafenacin (I) in a moderate overall yield

(II) (I)

Scheme 2

The use of a synthetic adsorbent is associated with problems with operativities and purification efficiencies from the viewpoint of industrial production, therefore, the process disclosed in document JP2003-201281 is not suitable for industrial application.

EP1845091 A1 discloses a process for preparing imidafenacin, according to previous document JP2003-201281 , however the purification step is carried out by either preparing the hydrochloride or the phosphate salt of imidafenacin followed by neutralization as shown in Scheme 3. Purified imidafenacin is provided in low yield, overall yield of about 31 % (as calculated by data provided in document EP1845091 A1 ). This process has several disadvantages. Firstly, EP1845091 A1 states that the penultimate intermediate, the 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate is hygroscopic, which implies handling problems. Secondly, the additional steps carried out for purification increases the cost of the final imidafenacin process and the pharmaceutical compositions containing it, which already resulted in expensive medications.

(II) (I)

HCI or

H3PO4

purified (I) HCI or Ή3ΡΟ4

Scheme 3

The intermediate phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile obtained and used in prior art processes is a solid form having needle-shaped crystals, which are difficult to filtrate. Moreover, said needle-shaped crystals are very hygroscopic and unstable and transform over time to other solid forms. In addition, the water absorbed by this solid form described in the prior art may react with the intermediate to generate further impurities.

Therefore, there is still a need to develop an improved industrially feasible process for the manufacture of imidafenacin in good purity and good yield, involving the use of stable intermediates having also improved handling characteristics.

Example 1 :

Preparation of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate in solid Form I

4-bromo-2,2-diphenylbutanenitrile (II, 1.000 Kg, 3.33 mol) and 2-methylimidazol (1 .368 Kg, 16.66 mol) were heated in DMSO (0.8 L) at 100-105 °C for 7 hours. The solution was then cooled to 20-25 °C and toluene (2 L) and water (4 L) were added and stirred for 30 minutes. After phase separation, the aqueous layer was extracted with toluene (1 L). Organic layers were combined and washed twice with water (2 x 1 L). Distillation of toluene provided 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile as a brown oil (0.915 Kg), which was, then, dissolved in dry acetone (3 L) and water (0.1 L), heated to 40-45°C and seeded with 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate. A solution of orthophosphoric acid (0.391 Kg, 3.39 mol) in acetone (2 L) was then added dropwise, maintaining temperature at 40-45 °C. Once the addition was finished, the reaction mixture was maintained 1 hour at 40-45 °C, cooled to 20-25 °C and stirred for 1 hour. The solid was filtered, washed with acetone (1 L), suspended in 2-propanol (10 L), heated at 80 °C and 2 L of solvent were distilled. The obtained suspension was then seeded with 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate solid Form I and maintained at 80 °C for 5 hours. The suspension was cooled down to 20-25°C, filtered off, washed with 2-propanol (1 L) and, finally, dried (45 °C, 0.5 torr, 12 hours).

Yield: 0.967 Kg (73%)

HPLC: 99.5 %

KF: 0.2 %

Optical microscopy: plate-shaped crystal habit as substantially in accordance to Figure 2.

PSD: D90 of 105 m

PXRD: Crystalline solid form as substantially in accordance to Figure 3.

DSC (10 °C/min): Endothermic peak with onset at 177 °C (-1 18 J/g), as substantially in accordance to Figure 4.

TGA (10 °C/min): Decomposition starting at 180 °C.

DVS: No significant weight gain up to 90% of relative humidity. At this humidity, a total increase of only 0.45% in weight was observed.

SCXRD: Crystal structure substantially in accordance to Figure 5. There are not water or solvent molecules in the crystal structure.

PATENT

https://www.google.com/patents/CN103351344A?cl=en

Overactive Bladder (symptomatic overactive bladder, 0AB) is a common chronic lower urinary tract dysfunction. Its incidence, United States and Europe over 75 year-old male incidence up to 42%, slightly lower incidence of women 31%; the incidence of domestic in Beijing 50 years of age for men was 16.4% for women over the age of 18 mixed The overall incidence of urinary incontinence and urge incontinence was 40.4 percent, seriously affecting the physical and mental health of the patient, reduced quality of life. Common antimuscarinic drugs in vivo and in vivo M receptor in some or all of binding with different affinities to improve the symptoms of OAB, but will also cause many side effects, such as dry mouth, constipation, cognitive impairment , tachycardia, blurred vision and so on. Imidafenacin have diphenylbutanoic amide structure, is a new high anticholinergic drugs, which selectively acts on the M3 and Ml receptors, blocking the contraction of the detrusor choline, so detrusor relaxation, reduce side effects of drugs. Meanwhile imidafenacin inhibit smooth muscle of the bladder and inhibiting acetylcholine free dual role, and selectivity for the bladder stronger than the salivary glands.

imidafenacin is a new diphenylbutanoic amides from Japan Ono Pharmaceutical Co., Ltd. jointly developed with Kyorin Pharmaceutical anticholinergics, structure (I) as follows:

The goods listed in June 2007 in Japan under the trade name: STAYBLA, chemical name: 4- (2-methyl-1-imidazolyl) _2,2- diphenylbutyric amide.

At present the preparation imidafenacin few reports, can be summed up as the following ways:

China Patent CN10699098 reported to bromoethyl diphenyl acetonitrile and 2-methylimidazole as a raw material, at 150 ° C condition, after the reaction DMF / triethylamine system, sulfuric acid hydrolysis reuse imidafenacin. The reaction equation is as follows:

BACKGROUND OF THE INVENTION This two-step method was 24% overall yield is too low, and the second step of the reaction is difficult to control. And the reaction product was purified by column chromatography required to obtain a purified product, is not conducive to industrial production.

Chinese patent CN101362721A referred to as the hydrolysis conditions for the preparation of sulfuric acid and organic acid mixed use imidafenacin yield have mentioned the smell.

 Although this method increases the yield, but still more by-product of the reaction, the product is not easy purification.

 Japanese Patent No. JP2005 / 023216 proposes hydrolysis under alkaline environment, and the use of products and solutions of salts hydrochloride salt and then purified product.

This method improves the yield of the second step of the hydrolysis reaction and simplified purification methods. But the need to use this method to purify salt activated carbon, and filtration devices require more stringent; and a need to be re-crystallized salt solution salt after the operation, a total of four steps of unit operations. Process more cumbersome and more stringent requirements for equipment, it is not conducive to industrial scale production. In addition, the product is dried for a long time, still remaining after solvent treatment product obtained, the purity of the product is still low.

DETAILED DESCRIPTION

 The following typical examples are intended to illustrate the present invention, simple replacement of skill in the art of the present invention or improvement made in all part of the present invention within the protection of technical solutions.

Example 1

4- (2-methyl-1-imidazolyl) -2,2-diphenyl butanamide hydrobromide. The 16.5 g (52 mmol) 4- (2- methyl-1-imidazolyl) -2,2-diphenyl butyramide crude into 100 mL of isopropanol, stirring was added 8.0 mL hydrobromic acid and isopropyl alcohol mixed solution (volume ratio of 1: 1), the solid gradually dissolved, was nearly colorless and transparent liquid. After maintaining the reaction mixture was stirred for half an hour, the reaction mixture was added to 100 mL of ethyl acetate, stirred for I hour at room temperature, solid precipitated. Filtration, and the cake was rinsed with an appropriate amount of ethyl acetate. The solid was collected, 40 ° C drying oven and dried to constant weight to give 19.5 g white 4- (2-methyl-1-imidazolyl) -2,2-diphenyl butyramide hydrobromide, yield 98.9%. ?] \ 1 .228.4-229.00C0MS (m / z): 320 [M + 1] +. 1H-NMR (DMS0-1 / 6, 400 MHz) δ: 2.25 (3H, s), 2.73-2.74 (2H, m), 3.68-3.91 (2H, m), 6.81 (1H, s), 7.28-7.35 (I OH, m), 7.39 (1H, s), 7.49 (1H, d, /=2.4 Hz), 7.55 (1H, d, J = 2.2 Hz), 14.39 (1¾ br s).

Example 2

4- (2-methyl-1-imidazolyl) -2,2-diphenyl butyramide. -2,2-Diphenyl butyric acid amide acetate was dissolved in 900 mL of water to 19.5 g (0.051mmol) obtained in Example 1 4- (2-methyl-1-imidazolyl) embodiment. Extracted with 900mL diethyl ether solution, collecting the inorganic layer. Was added to an aqueous solution of 200 mL of ethanol, was added to the system with stirring in an aqueous solution of KOH 2mol / L, there is a solid precipitated. The reaction was stirred I h after filtration. Cake was washed with 40% ethanol solution rinse, rinsed with water several times. Collect the cake, put 40 ° C drying oven dried to constant weight to give 14.8 g white 4- (2-methyl-1-imidazolyl) -2,2-diphenyl methylbutanamide, yield 91.0% (total yield 90% two steps). Μ.p.192.3-193.00C (CN101076521A 191-193O). MS (m / z): 320 [M + l] +. 1H-NMR (DMSO-J6, 400MHz) δ: 2.11 (3Η, s), 2.69-2.73 (2H, m), 3.61-3.65 (2H, m), 6.75 (1H, d, J = L OMHz), 7.01 (1H, br s), 7.04 (1H, d, J = L 0 MHz), 7.34-7.49 (11H, m).

Example 3

4- (2-methyl-1-imidazolyl) -2,2-diphenyl butyramide. The 14.5 g (0.045mmol) obtained in Example 4- (2-methyl-1-imidazolyl) -2,2-diphenyl butanamide 2 was added 116 mL of ethyl acetate was slowly heated to reflux reflux for 30 min, cooled to room temperature for crystallization 5 h. Suction filtered, the filter cake was rinsed with a small amount of ethanol, collected cake was put 40 ° C drying oven and dried to constant weight to give 13.4 g white 4- (2-methyl-1-imidazolyl) -2,2- diphenyl methylbutanamide refined products, yield 92.4% (three-step total yield 83.1%). Mp192.5-193 (TC (CN101076521A 191_193 ° C) .MS (m / z):.. 320 [M + 1] + 1H-NMR (DMSO-J6, 400 MHz) δ

2.11 (3H, 7.01 (1H,

s), 2.69-2.73 (2H, br s), 7.04 (1H, d,

m), 3.61-3.65 (2H, m), 6.75 (1H, J = L 0 MHz), 7.34-7.49 (11H, m).

PATENT

CN103772286A.

imidafenacin (Imidafenacin) is a new diphenylbutanoic amides from Japan Ono Pharmaceutical Co., Ltd. jointly developed with Kyorin Pharmaceutical anticholinergic drugs, bladder is highly selective for the treatment of overactive bladder, in 2007 in June in Japan. Its chemical name is 4- (2-methyl -1H- imidazol-1-yl) -2,2-diphenyl butyramide chemical structure shown by the following formula I:

Reported in U.S. Patent No. US5932607 imidafenacin preparation method, the method is based on 4-bromo-2 ‘2 ~ phenyl butyronitrile, 2-methylimidazole, triethylamine as raw materials, with DMF as a solvent at 150 ° C reaction 30h, to give the intermediate 4- (2-methyl-imidazol-1-yl) -2,2-diphenyl-butyronitrile, 77% yield, then body 140 ~ 150 ° C with 70% sulfuric acid The resulting intermediate hydrolyzed to the amide, after completion of the reaction required excess soda and sulfuric acid, the reaction is as follows:

Which preclude the use of the dilute sulfuric acid hydrolysis, although succeeded in getting the product, but the yield is very low, only 32%, greatly increasing the production cost, mainly due to 70% sulfuric acid, the reaction is difficult to control amide phase, the product will continue to acid hydrolysis byproducts, resulting in decreased yield.

 European Patent No. EP1845091 reports imidafenacin Another preparation method, the method using potassium hydroxide and isopropyl alcohol 4- (2-methyl-imidazol-1-yl) diphenyl _2,2- Hydrolysis of nitrile to amide phosphates, and the crude product was converted to the hydrochloride or phosphate, and recrystallized to remove impurities and then basified imidafenacin obtained, which reaction is as follows:

This method uses a lot of bases, product purification is too much trouble, and the total yield of 45%.

 Chinese Patent Publication No. CN102746235 also disclosed imidafenacin preparation method of 4- (2-methyl-1-yl) -2,2-diphenyl phosphate or nitrile salt in methanol / ethanol, dimethyl sulfoxide, and the presence of a base, with hydrogen peroxide in 40 ~ 60 ° C under through improved Radziszewski the target compound, the reaction is as follows:

The method used in the hydrogen peroxide solution, but a solution of hydrogen peroxide has strong oxidizing, and has a certain corrosive, inhalation of the vapor or mist respiratory irritation strong, direct eye contact with the liquid may cause irreversible damage and even blindness, security It is not high on the human body and environmentally unfriendly. Alkaline environment, easily decomposed hydrogen peroxide, as the temperature increases, the decomposition reaction increased, and therefore reaction requires a large excess of hydrogen peroxide solution.

The method comprises the steps of: (1) 4-Bromo-2,2-diphenyl-butyronitrile is hydrolyzed to the amide under basic conditions; (2) The obtained 4-bromo-2,2-diphenylbutyric amide is reacted with 2-methylimidazole to give the desired product.

Example 1

2L reaction flask was added 400mL of dry tetrahydrofuran, under a nitrogen atmosphere was added 60% sodium hydride (82.8g, 2.06mol), stirred to obtain a gray turbid solution A. With 400mL dry tetrahydrofuran was sufficiently dissolved diphenyl acetonitrile (200g, 1.04mol), I, 2- dibromoethane (204.2g, 1.08mol), to give a colorless clear liquid B; 5 ~ 15 ° C, a solution of turbid solution B dropwise to solution A, 10 ~ 15 ° C the reaction was incubated 6h, TLC until the reaction was complete, to the reaction system a small amount of water was added dropwise until no bubbles. After addition of 800mL water, 400mL ethyl acetate and stirred, liquid separation, the organic layer was washed with water, saturated sodium chloride solution, respectively, and the organic layer was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure to give a yellow liquid 310g.

[0018] The resulting yellow liquid with 800mL 90% ethanol and stirred to dissolve at 40 ° C, then cooling and crystallization, filtration, 45 ° C and concentrated under reduced pressure to give a white solid 232.8g, 75% yield.

Preparation of bromo-2,2-diphenyl 4_ butanamide: [0019] Example 2

3L reaction flask was added 4-bromo-2,2-diphenyl-butyronitrile (15 (^, 0.511101), 7501 ^ 6mol / L KOH solution, 750mL dimethylsulfoxide and heated to 100 ~ 120 ° C under stirring The reaction, the reaction lh, until the reaction was complete by TLC after cooling to 40 V, add 2000mL water, 2000mL of methylene chloride was stirred, liquid separation, the organic layer was washed with water, washed with saturated sodium bicarbonate and sodium chloride solution, separated, dried over anhydrous The organic layer was dried over sodium sulphate, filtration, concentrated under reduced pressure to give brown oily liquid 161.92g, 96% yield.

Preparation of bromo-2,2-diphenyl 4_ butanamide: [0020] Example 3

3L reaction flask was added 4-bromo-2,2-diphenyl-butyronitrile (150g, 0.5mol), 666mL 6mol / L NaOH solution, 750mL dimethylsulfoxide, the reaction mixture was stirred and heated to 100 ~ 120 ° C under The reaction lh, until the reaction was complete by TLC after cooling to 40 ° C, add water 2000mL, 2000mL of methylene chloride was stirred, liquid separation, the organic layer was washed with water, washed with saturated sodium bicarbonate and sodium chloride solution, separated, dried over anhydrous sulfate sodium organic layer was dried, filtration, concentrated under reduced pressure to give brown oily liquid 146.73g, 87% yield.

Preparation of bromo-2,2-diphenyl 4_ butanamide: [0021] Example 4

The reaction was stirred 3L reaction flask was added 4-bromo-2,2-diphenyl-butyronitrile (15 (^, 0.511101), 8331 ^ 36% Na2CO3 solution, 750mL dimethylsulfoxide and heated to 100 ~ 120 ° C under The reaction lh, until the reaction was complete by TLC after cooling to 40 ° C, add water 2000mL, 2000mL of methylene chloride was stirred, liquid separation, the organic layer was washed with water, washed with saturated sodium bicarbonate and sodium chloride solution, separated, dried over anhydrous The organic layer was dried over sodium sulphate, filtration, concentrated under reduced pressure to give brown oily liquid 153.48g, yield 91%.

`[0022] Example 5: 4- (2-methyl-imidazol _1_ -1H- yl) butyramide _2,2_ diphenyl (imidafenacin) Preparation 5L reaction flask was added 4-bromo-2 2-diphenyl butyric amide (160g, L 5mol), 2- methyl imidazole (123g,

1.5mol), triethylamine (50.6g, 0.5mol), potassium iodide (5g, 0.03mol), fully dissolved with 1000mL DMF solution was heated to 120 ° C at a reaction 5h, until completion of the reaction by TLC, heating was stopped, to be After cooling, water was added 3000mL system stirred 0.5h, filtration, washed with water until the filtrate is neutral, concentrated under reduced pressure and dried to give a brown solid 146.14g, a yield of 91%.

[0023] Example 6: 4- (2-methyl-imidazol _1_ -1H- yl) butyramide _2,2_ diphenyl (imidafenacin) Preparation 5L reaction flask was added 4-bromo-2, 2- diphenyl butyramide (160g, 0.5mol), 2- methyl imidazole (82.1g,

1.011101), triethylamine (50.68,0.5mol), potassium iodide (5g, 0.03mol), fully dissolved with 1000mL DMF solution was heated to 120 ° C at a reaction 5h, until completion of the reaction by TLC, heating was stopped, the system was cooled until After adding 3000mL water, stirring 0.5h, filtration, washed with water until the filtrate is neutral, concentrated under reduced pressure and dried to give a brown solid 120.45g, 80% yield.

[0024] Example 7: 4- (2-methyl-imidazol _1_ -1H- yl) butyramide _2,2_ diphenyl (imidafenacin) Preparation 5L reaction flask was added 4-bromo-2, 2- diphenyl butyramide (160g, 0.5mol), 2_ methylimidazole (164.2g,

2.011101), triethylamine (50.68,0.5mol), potassium iodide (5g, 0.03mol), fully dissolved with 1000mL DMF solution was heated to 120 ° C at a reaction 5h, until completion of the reaction by TLC, heating was stopped, the system was cooled until After adding water, stirring 3000mL

0.5h, suction filtered, washed with water until the filtrate was neutral, and concentrated under reduced pressure, and dried to give a brown solid 141.33g, yield 88%.

[0025] Example 8: 4- (2-methyl imidazole -1H- _1_ group) _2,2_ diphenylbutanoic amide (imidafenacin) refining up to 80g microphone said that new crude added 300mL of absolute ethanol, the system was warmed to reflux, refluxed

0.5h, after cooling the ethanol was distilled off to IOOmL about 500mL of ethyl acetate was added to precipitate a white solid, a small amount of ethyl acetate and wash the filter cake, 45 ° C and dried in vacuo to give 74.6g of white crystals, yield 93%.

CLIP

Alkylation of diphenylacetonitrile (I) with dibromoethane provided bromide (II). This was condensed with 2-methylimidazole (III) in the presence of Et3N in DMF to afford the substituted imidazole (IV). Finally, hydrolysis of the cyano group of (IV) with 70% sulfuric acid produced the target amide.

Treatment of acetonitrile derivative (I) with dibromoethane (II) in toluene in the presence of NaNH2 affords bromo compound (III), which is then condensed with imidazole derivative (IV) by means of Et3N in DMF to provide compound (V). Hydrolysis of the cyano group of (V) with aqueous H2SO4 yields amide derivative (VI), which is finally subjected to alkyl quaternization by reaction with bromobenzyl bromide (VI) in acetone to furnish the desired product.

Paper

Bioorganic & Medicinal Chemistry Letters 9 (1999) 3003-3008

PAPER

Bioorganic & Medicinal Chemistry 7 (1999) 1151±1161

 4-(2-methyl-1-imidazolyl)- 2,2-diphenylbutyramide (2.02 g, 24%) as a colorless needle:

mp 189.0±190.0 C (from ethyl acetate:ethanol);

High MS (EI+) m/z calcd for C20H21N3O 319.1685, found 319.1671;

1 H NMR (400 MHz, CDCl3) d 2.23 (3H, s), 2.69±2.74 (2H, m), 3.77±3.82 (2H, m), 5.33 (1H, s), 5.49 (1H, s), 6.73 (1H, s), 6.85 (1H, s), 7.31±7.42 (10H, m).

PATENT

CN103880751A.

imidafenacin chemical name 4- (2-methyl–1H–1-yl) -2,2-diphenyl methylbutanamide (I).

In Patent JP93-341467, JP94-319355 and literature Bioorganic & Medicinal ChemistryLetters, 1999, vol.9,3003 – 3008 reported in the chemical synthesis routes to diphenyl acetonitrile (4) as the starting material,

Condensation and hydrolysis reaction step to give imidafenacin (1).

The new method is simple, mild reaction conditions, easy to control, good high yield and purity of the product, do not pollute the environment, suitable for industrial production.

[0012] The first method from 2-methylimidazole and I, 2- dibromoethane under phase transfer catalyst is tetrabutylammonium bromide (TBAB) and inorganic base catalyzed generate 1- (2-bromoethyl) – methyl -1H- imidazole (5), and diphenyl acetonitrile (4) a phase transfer catalyst and an inorganic base catalyzed condensation of 4- (2-methyl–1H- imidazol-1-yl) -2,2 – diphenylbutyronitrile hydrochloride (2), and then hydrolyzed to imidafenacin (I)

PATENT

CN 105399678

https://www.google.com/patents/CN105399678A?cl=en

CLIP

http://dmd.aspetjournals.org/content/35/9/1624/T3.expansion.html

FIG. 1.

Chemical structures of [¹⁴C]imidafenacin and postulated metabolites, and their fragment ions. ^*, ¹⁴C labeled position; broken line, precursor and product ions obtained by collision-induced dissociation in LC/MS/MS.

1. Kobayashi F, Yageta Y, Segawa M, Matsuzawa S: Effects of imidafenacin (KRP-197/ONO-8025), a new anti-cholinergic agent, on muscarinic acetylcholine receptors. High affinities for M3 and M1 receptor subtypes and selectivity for urinary bladder over salivary gland. Arzneimittelforschung. 2007;57(2):92-100. [PubMed:17396619 ]
2. Miyachi H, Kiyota H, Uchiki H, Segawa M: Synthesis and antimuscarinic activity of a series of 4-(1-Imidazolyl)-2,2-diphenylbutyramides: discovery of potent and subtype-selective antimuscarinic agents. Bioorg Med Chem. 1999 Jun;7(6):1151-61. [PubMed:10428387 ]

Reference

• Kobayashi F, Yageta Y, Segawa M, Matsuzawa S (2007). “Effects of imidafenacin (KRP-197/ONO-8025), a new anti-cholinergic agent, on muscarinic acetylcholine receptors. High affinities for M3 and M1 receptor subtypes and selectivity for urinary bladder over salivary gland”. Arzneimittelforschung. 57 (2): 92–100. doi:10.1055/s-0031-1296589. PMID 17396619.
• Miyachi H, Kiyota H, Uchiki H, Segawa M (June 1999). “Synthesis and antimuscarinic activity of a series of 4-(1-Imidazolyl)-2,2-diphenylbutyramides: discovery of potent and subtype-selective antimuscarinic agents”. Bioorg. Med. Chem. 7 (6): 1151–61.doi:10.1016/S0968-0896(99)00003-6. PMID 10428387.

Imidafenacin

Systematic (IUPAC) name
4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide
Clinical data
Routes of administration	Oral
Legal status
Legal status	℞ (Prescription only)
Identifiers
CAS Number	170105-16-5
ATC code	none
PubChem	CID 6433090
ChemSpider	4938278
UNII	XJR8Y07LJO
ChEMBL	CHEMBL53366
Chemical data
Formula	C20H21N3O
Molar mass	319.40 g/mol
SMILES CC1=NC=CN1CCC(C2=CC=CC=C2)(C3=CC=CC=C3)C(=O)N

//////////イミダフェナシン , D06273, KRP-197, KRP 197, ONO-8025, ONO 8025, UNII:XJR8Y07LJO, Kyorin, Ono ,Imidafenacin, 170105-16-5, JAPAN 2015,  Uritos^® , Staybla^®

Camostat

• Molecular FormulaC₂₀H₂₂N₄O₅
• Average mass398.413 Da

Camostat (INN; development code FOY-305) is a serine protease inhibitor. Serine protease enzymes have a variety of functions in the body, and so camostat has a diverse range of uses. It is used in the treatment of some forms of cancer and is also effective against some viral infections, as well as inhibiting fibrosis in liver or kidney disease or pancreatitis.^{[1][2][3][4][5]} It is approved in Japan for the treatment of pancreatitis.^[6][7]

An in vitro study shows that Camostat reduces significantly the infection of Calu-3 lung cells by SARS-CoV-2, the virus responsible for COVID-19.^[8]

SYN

DE 2548886; FR 2289181; GB 1472700; JP 76054530; US 4021472

The reaction of p-hydrophenylacetic acid (I) with N,N-dimethylbromoacetamide (II) by means of triethylamine in reftuxing acetonitrile gives N,N-dimethylcarbamoylmethyl-p-hydroxyphenylacetate (III), which is then condensed with p-guanidinobenzoyl chloride (IV) [obtained from the corresponding acid p-guanidinobenzoic acid (V) and thionyl chloride] in pyridine.

By reaction of N,N-dimethylcarbamoylmethyl-p-(p-aminobenzoyloxy)phenylacetate (VI) with cyanamide (VII).

PATENT

DE 2548886

JP 52089640

JP 54052052

PATENT

CN 104402770

https://patents.google.com/patent/CN104402770A/en

Camostat mesilate, chemical name is 4-(4-guanidine radicals benzoyloxy group) toluylic acid-N, N-dimethyl carbamoyl methyl esters mesylate, be the non-peptide proteinoid enzyme inhibitors of Japanese little Ye medicine Co., Ltd. exploitation, first in January, 1985 go on the market with trade(brand)name Foipan in Japan.Pharmacological evaluation shows: camostat mesilate has very strong restraining effect to trypsinase, kallikrein, Tryptase, zymoplasm, C1 esterase, oral rear kassinin kinin generation system, fibrinolytic system, blood coagulation system and the complement system acting on rapidly body, suppress the exception of the enzymic activity of these systems hyperfunction, thus control the symptom of chronic pancreatitis, alleviating pain, reduce amylase value, the clinical alleviation for chronic pancreatitis acute symptom.In addition, this product is also used for the treatment of diffusivity blood vessel blood coagulation disease.Pharmacological evaluation also finds, camostat mesilate also has the effects such as anticancer, antiviral, and effectively can reduce proteinuria, and play the effect of preliminary conditioning, further research is still underway.Current this product not yet in Discussion on Chinese Listed, also without the report succeeded in developing.

A preparation method for camostat mesilate, comprises the steps:

(1), by 160g methylene dichloride DCM join stirring in reaction vessel, cooling, be cooled to start when 0–10 DEG C to drip 51g 50% dimethylamine agueous solution, drip 30g chloroacetyl chloride simultaneously; Drip process control temp 5–10 DEG C, system pH controls 4-7, at 5–10 DEG C, react 1h after dripping off, reaction process pH controls 5-7, and reaction terminates rear standing 20min, separatory, water layer is with 54g dichloromethane extraction, and organic layer is concentrating under reduced pressure below 80 DEG C, obtains 3-pyrrolidone hydrochloride, crude, 3-pyrrolidone hydrochloride, crude carries out underpressure distillation within 130 DEG C, obtains 3-pyrrolidone hydrochloride distillation product; Output is 31g;

(2), the 3-pyrrolidone hydrochloride of 30.6g, 9g triethylamine TEA, 0.4g sodium bisulfite and 40g p-hydroxyphenylaceticacid p-hydroxyphenylaceticacid drop in order in reaction vessel and carry out stirring at low speed, and then drip the triethylamine of 17.6g, dropping temperature 40-95 DEG C, drip off rear maintenance 80-95 DEG C reaction 3h, after reaction terminates, add aqueous solution of sodium bisulfite (0.05gNaHSO3+90gH2O), add and start more than temperature 70 C, add finishing temperature more than 48 DEG C, after adding, cool, crystal seed is added when 40 DEG C, keep cooling temperature 0-5 DEG C, crystallization 2h, filter after crystallization, filter cake 100g purified water is washed, camostat mesilate crude product is obtained after draining, camostat mesilate crude product, 50mL ethyl acetate are joined heating for dissolving in aqueous solution of sodium bisulfite (0.2g NaHSO3+20g H2O), after having dissolved, cooling crystallization, keep recrystallization temperature 0-5 DEG C, crystallization time 1h, suction filtration after crystallization, filter cake, with 10mL water washing, washs with 20mL ethyl acetate after draining again, again at 60 ± 3 DEG C of drying under reduced pressure 2h after draining, obtain camostat mesilate refined silk, output is about 47g,

(3), the camostat mesilate refined silk of 47g is joined heating for dissolving in 30mL acetonitrile, after dissolving terminates, cooling temperature is to 0-5 DEG C, crystallization 1h, after crystallization terminates, suction filtration, filter cake with 17mL acetonitrile wash, drain, drying under reduced pressure 2h at 60 ± 3 DEG C, obtain camostat mesilate product, output is about 45g.

PATENT

https://patents.google.com/patent/CN104402770B/en

Clip

https://www.pharmaceutical-technology.com/news/german-researchers-covid-19-drug/

German researchers identify potential drug for Covid-19

Scientists at the German Primate Center – Leibniz Institute for Primate Research have found that an existing drug may help treat Covid-19.

As well as Charité – Universitätsmedizin Berlin, the scientists worked with researchers at the University of Veterinary Medicine Hannover Foundation, the BG-Unfallklinik Murnau, the LMU Munich, the Robert Koch Institute and the German Center for Infection Research.

The research aimed to understand the entry of the novel coronavirus, SARS-CoV-2, into host cells, as well as determine approaches to block the process.

Research findings showed that SARS-CoV-2 requires cellular protein TMPRSS2 to enter hosts’ lung cells.

German Primate Center Infection Biology Unit head Stefan Pöhlmann said: “Our results show that SARS-CoV-2 requires the protease TMPRSS2, which is present in the human body, to enter cells. This protease is a potential target for therapeutic intervention.”

CLIP

https://neurosciencenews.com/tmprss2-coronavirus-treatment-15873/

Potential drug to block coronavirus identified

NEUROSCIENCE NEWSMARCH 6, 2020

FEATUREDNEUROSCIENCENEUROSCIENCE VIDEOSOPEN NEUROSCIENCE ARTICLES0 COMMENTS 24 MIN READ

References

External links

• Kunze H, Bohn E (May 1983). “Effects of the serine protease inhibitors FOY and FOY 305 on phospholipase A1 (EC 3.1.1.32) activity in rat – liver lysosomes”. Pharmacol Res Commun. 15 (5): 451–9. doi:10.1016/S0031-6989(83)80065-4. PMID 6412250.
• Göke B, Stöckmann F, Müller R, Lankisch PG, Creutzfeldt W (1984). “Effect of a specific serine protease inhibitor on the rat pancreas: systemic administration of camostate and exocrine pancreatic secretion”. Digestion. 30 (3): 171–8. doi:10.1159/000199102. PMID 6209186.

Camostat

Clinical data
Trade names	Foipan
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	B02AB04 (WHO)
Legal status
Legal status	US: Not FDA approved In general: ℞ (Prescription only)
Identifiers
IUPAC name[show]
CAS Number	59721-28-7
PubChem CID	2536
IUPHAR/BPS	6432
ChemSpider	2440
UNII	0FD207WKDU
ChEMBL	ChEMBL590799
CompTox Dashboard (EPA)	DTXSID6044010
Chemical and physical data
Formula	C20H22N4O5
Molar mass	398.419 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] CN(C)C(=O)COC(=O)CC1=CC=C(C=C1)OC(=O)C2=CC=C(C=C2)N=C(N)N

/////////////Camostat, SARS-CoV-2, COVID-19,  coronavirus, SARS-CoV-2, COVID-19, FOY305,  FOY-S980, カモスタットメシル酸塩　日局収載 , Japan,  Ono, oral treatment of postoperative reflux esophagitis, chronic pancreatitis.

CN(C)C(=O)COC(=O)CC1=CC=C(C=C1)OC(=O)C2=CC=C(C=C2)N=C(N)N.CS(=O)(=O)O

Tepotinib hydrochloride

CS-977;Tepotinib;Veledimex;MSC2156119;EMD-1214063

3-[1-[[3-[5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl]phenyl]methyl]-6-oxopyridazin-3-yl]benzonitrile;hydrate;hydrochloride

Benzonitrile, 3-(1,6-dihydro-1-((3-(5-((1-methyl-4-piperidinyl)methoxy)-2-pyrimidinyl)phenyl)methyl)-6-oxo-3-pyridazinyl)-, hydrochloride, hydrate

3- (1- {3- [5- (1-methylpiperidin-4-ylmethoxy) pyrimidine) -2-yl] -benzyl} -6-oxo-1,6-dihydro-pyridazin-3-yl) -benzonitrileтепотиниб [Russian] [INN]تيبوتينيب [Arabic] [INN]特泊替尼 [Chinese] [INN]

• 3-[1,6-Dihydro-1-[[3-[5-[(1-methyl-4-piperidinyl)methoxy]-2-pyrimidinyl]phenyl]methyl]-6-oxo-3-pyridazinyl]benzonitrile
• 3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile
• EMD 1214063
• MSC 2156119

JAPAN 25/3 2020 APPROVED, Tepmetko

SYN

Bioorganic & Medicinal Chemistry Letters, 25(7), 1597-1602; 2015

PATENT

WO 2009006959

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009006959

Example 40

The preparation of the compound 3- (1- {3- [5- (1-Methyl-piperidin-4-ylmethoxy) -pyrimidin-2-yl] -benzyl} -6-oxo-1,6-dihydro-pyridazin-3 -yl) -benzonitrile (“A257”) takes place analogously to the following scheme

40.1 17.7 g (67.8 mmol) triphenyl are added to a suspension of 13.0 g (56.5 mmol) 3- (5-hydroxypyrimidin-2-yl) -benzoic acid methyl ester and 13.4 g (62.1 mmol) N-Boc-piperidinemethanol in 115 ml THF -phosphine and cooled to 5 ° C. To the suspension kept at this temperature, 13.3 ml (67.8 mmol) of diisopropylazodicarboxylate are added dropwise with stirring within 45 minutes. The reaction mixture is stirred for 1 hour at room temperature. Then a further 22.2 g (84.7 mmol) triphenylphosphine and 16.6 ml (84.7 mmol)

Diisopropyl azodicarboxylate added. The reaction mixture turns 18

Stirred for hours at room temperature and concentrated in vacuo. The resulting solid is filtered off with suction, washed with diethyl ether and chromatographed on a silica gel column with dichloromethane / methanol as the mobile phase: 4- [2- (3-methoxycarbonyl-phenyl) -pyrimidin-5-yloxymethyl] -piperidine-1-carboxylic acid tert .-butyl ester as lemon yellow crystals;
166 ° C .; ESI 428.

40.2 To a suspension of 1.71 g (3.99 mmol) of 4- [2- (3-methoxycarbonyl-phenyl) -pyrimidin-5-yloxymethyl] -piperidine-1-carboxylic acid tert-butyl ester in 20 ml of THF are added under nitrogen 25 ml (25 mmol) of a 1 M solution of diisobutylaluminum hydride in THF were added dropwise. The reaction mixture is stirred at room temperature for 1 hour, and 1 ml of a saturated sodium sulfate solution is added. The resulting precipitate is filtered off with suction and washed with THF and hot 2-propanol. The filtrate is evaporated and recrystallized from tert-butyl methyl ether: {3- [5- (1-Methyl-piperidin-4-ylmethoxy) -pyrimidin-2-yl] -phenyl} -methanol as beige crystals; Mp 175 ° C; ESI 314.

40.3 To a solution of 313 mg (1.00 mmol) {3- [5- (1-methyl-piperidin-4-ylmethoxy) -pyrimidin-2-yl] -phenyl} -methanol in 2 ml THF are successively added 264 mg (1.30 mmol) 3- (6-oxo-1, 6-dihydro-pyridazin-3-yl) benzonitrile and 397 mg (1.5 mmol) triphenylphosphine are added. The reaction mixture is cooled in an ice bath and
294 μl (1.5 mmol) of diisopropylazodicarboxylate are added dropwise with stirring. The

The reaction mixture is stirred for 18 hours at room temperature and evaporated. The residue is chromatographed on a silica gel column using dichloromethane / methanol. The product-containing fractions are combined, evaporated, the residue digested with tert-butyl methyl ether, filtered off with suction and dried in vacuo: 3- (1- {3- [5- (1-methylpiperidin-4-ylmethoxy) pyrimidine) -2-yl] -benzyl} -6-oxo-1,6-dihydro-pyridazin-3-yl) -benzonitrile as colorless crystals; M.p. 177 ^° C; ESI 493;
¹ H-NMR (de-DMSO): δ [ppm] = 1.33 (m, 2H), 1.75 (m, 3H), 1.89 (m, 2H), 2.17 (S, 3H), 2.80 (m, 2H), 4.05 (d, J = 6.1 Hz ₁ 2H), 5.45 (s, 2H) ₁ 7.16 (d, J = 10 Hz, 1 H), 7.49 (m, 2H), 7.73 (t, J = 7.8 Hz, 1H ), 7.93 (d, J = 7.8 Hz, 1H) ₁ 8.17 (d, J = 10 Hz, 1H), 8.24 (m, 2H), 8.38 (m, 2H), 8.64 (s, 2H).

The hemisulfate, citrate, tartrate, sulfate, succinate and hydrochloride are obtained from “A257” by salt formation.

PATENT

WO 2009007074

PAPER

Bioorganic & Medicinal Chemistry Letters (2015), 25(7), 1597-1602.

https://www.sciencedirect.com/science/article/abs/pii/S0960894X15000955

PAPER

 Molecules (2019), 24(6), 1173/1-1173/16.

https://www.mdpi.com/1420-3049/24/6/1173

Scheme 1. Reagents and conditions: a) PdCl₂(PPh₃)₂, Na₂CO₃, ethanol/toluene/water, 90 °C, 8 h; b) SOCl₂, CHCl₃, reflux; c) SeO₂, dioxane:H₂O = 10:1, reflux, 12 h; d) NaOH, −30 °C; e) NaH, DMF/THF, 0 °C—room temperature, 12 h; f) dry ethanol, reflux; g) NaOH, DMF/H₂O, 60 °C, 8 h, N₂.

Scheme 2. Reagents and conditions: a) N,N-diisopropylethylamine, dry CH₂Cl₂, 0 °C—room temperature, 6 h; b) PdCl₂(PPh₃)₂, Na₂CO₃, ethanol/toluene/water, 90 °C, 8 h; c) 10% aq. HCl, MeOH, reflux; d) K₂CO₃, dry DMF, 80 °C, 12 h; e) NaOH, DMF/H₂O, 60 °C, 8 h, N₂; f) PPh₃, DIAD, THF, 0 °C—room temperature; g) SOCl₂, CHCl₃, reflux; h) 35% formaldehyde, NaBH₄, MeOH.

Scheme 3. Reagents and conditions: a) PdCl₂(PPh₃)₂, Na₂CO₃, ethanol/toluene/water, 90 °C, 8 h; b) NaBH₄, MeOH, 0 °C—room temperature, 1 h; c) SOCl₂, CHCl₃, reflux; d) K₂CO₃, dry DMF, 80 °C, 12 h; e) 31a–31b: NaOH, DMF/H₂O, 60 °C, 8 h, N₂; f) 31c–31g: NaH, dry DMF, 0 °C—room temperature, 5 h.

Scheme 4. Reagents and conditions: a) K₂CO₃, dry DMF, 80 °C, 12 h; b) PdCl₂(PPh₃)₂, Na₂CO₃, DME/DMF/water, 89 °C, 12 h; c) NaOH, DMF/H₂O, 60 °C, 8 h, N_2.

Scheme 5. Reagents and conditions: a) K₂CO₃, dry DMF, 80 °C, 12 h; b) PdCl₂(PPh₃)₂, Na₂CO₃, DME/DMF/water, 89 °C, 12 h; c) NaOH, DMF/H₂O, 60 °C, 8 h, N_2.

///////////Tepotinib,  Tepotinib hydrochloride, Tepmetko, JAPAN 2020, 2020 APPROVALS, тепотиниб , تيبوتينيب , 特泊替尼 , EMD 1214063, MSC 2156119

CN1CCC(CC1)COC2=CN=C(N=C2)C3=CC=CC(=C3)CN4C(=O)C=CC(=N4)C5=CC=CC(=C5)C#N.O.Cl

Borofalan (10B), ボロファラン (10B), 硼[10B]法仑

APPROVED JAPAN, 2020/3/25, Steboronine

Antineoplastic, Diagnostic aid, Radioactive agent

(2S)-2-amino-3-(4-(¹⁰B)dihydroxy(¹⁰B)phenyl)propanoic acid

• 4-(Borono-¹⁰B)-L-phenylalanine
• (¹⁰B)-4-Borono-L-phenylalanine
• Borofalan (10b)
• L-(p-[¹⁰B]Boronophenyl)alanine
• L-4-[¹⁰B]Boronophenylalanine
  • p-[¹⁰B]Borono-L-phenylalanine

• L-Phenylalanine, 4-borono-¹⁰B-
  Marketed Head and neck cancer
• Originator Stella Pharma
• Developer Osaka University; Stella Pharma; Sumitomo Heavy Industries
• Class Antineoplastics; Borates; Propionic acids; Radiopharmaceuticals
• Mechanism of Action Ionising radiation emitters

• Phase IIGlioma
• Phase I Haemangiosarcoma; Malignant melanoma

• 20 May 2020 Launched for Head and neck cancer (Inoperable/Unresectable, Late-stage disease, Locally recurrent) in Japan (IV)
• 25 Mar 2020 Registered for Head and neck cancer (Inoperable/Unresectable, Late-stage disease, Locally recurrent) in Japan (IV) – First global approval
• 03 Mar 2020 Chemical structure information added
• Melting Point (Experimental)Value: 285-298 °C (decomp) Hattori, Yoshihide; Tetrahedron Letters 2008, VOL49(33), PG 4977-4980 
• SP ROT -5.2 ° Conc: 0.50 g/100mL; Solv: hydrochloric acid 589.3 nm; Temp: 25 °C, Hattori, Yoshihide; Tetrahedron Letters 2008, VOL49(33), PG 4977-4980 

Borofalan (¹⁰B)

4-[(¹⁰B)Borono]-L-phenylalanine

C₉H₁₂¹⁰BNO₄ : 208.21
[80994-59-8]

With the development of atomic science, radiation therapy such as cobalt hexahydrate, linear accelerator, and electron beam has become one of the main methods of cancer treatment. However, traditional photon or electron therapy is limited by the physical conditions of the radiation itself. While killing the tumor cells, it also causes damage to a large number of normal tissues on the beam path. In addition, due to the sensitivity of tumor cells to radiation, traditional radiation therapy For the more radiation-resistant malignant tumors (such as: glioblastoma multiforme, melanoma), the treatment effect is often poor.

In order to reduce the radiation damage of normal tissues around the tumor, the concept of target treatment in chemotherapy has been applied to radiation therapy; and for tumor cells with high radiation resistance, it is currently actively developing with high relative biological effects (relative Biological effectiveness, RBE) radiation sources, such as proton therapy, heavy particle therapy, neutron capture therapy. Among them, neutron capture therapy combines the above two concepts, such as boron neutron capture therapy, by the specific agglomeration of boron-containing drugs in tumor cells, combined with precise neutron beam regulation, providing better radiation than traditional radiation. Cancer treatment options.

Boron Neutron Capture Therapy (BNCT) is a high-capture cross-section of thermal neutrons using boron-containing ( ¹⁰ B) drugs, with ¹⁰ B(n,α) ⁷ Li neutron capture and nuclear splitting reactions. Two heavy charged particles of ⁴ He and ⁷ Li are produced. The average energy of the two charged particles is about 2.33 MeV, which has high linear energy transfer (LET) and short range characteristics. The linear energy transfer and range of α particles are 150 keV/μm and 8 μm, respectively, while the ⁷ Li heavy particles are For 175 keV/μm, 5 μm, the total range of the two particles is equivalent to a cell size, so the radiation damage caused to the organism can be limited to the cell level, when the boron-containing drug is selectively aggregated in the tumor cells, with appropriate The sub-radiation source can achieve the purpose of locally killing tumor cells without causing too much damage to normal tissues.

Since the effectiveness of boron neutron capture therapy depends on the concentration of boron-containing drugs in the tumor cell position and the number of thermal neutrons, it is also called binary cancer therapy; thus, in addition to the development of neutron sources, The development of boron-containing drugs plays an important role in the study of boron neutron capture therapy.

4-( ¹⁰ B)dihydroxyboryl-L-phenylalanine (4-( ¹⁰ B)borono-L-phenylalanine, L- ¹⁰ BPA) is currently known to be able to utilize boron neutron capture therapy (boron neutron capture therapy) , BNCT) An important boron-containing drug for the treatment of cancer.

Therefore, various synthetic methods of L-BPA have been developed. As shown in the following formula (A), the prior art L-BPA synthesis method includes two methods of forming a bond (a) and a bond (b):

Among them, the method for synthesizing L-BPA by forming the bond (a) is to try to introduce a substituent containing a dihydroxylboryl group or a borono group into the skeleton of the phenylalanine, thereby the pair of the amide substituent. The position forms a carbon-boron bond to produce L-BPA.

J. Org. Chem. 1998, 63, 8019 discloses a method for the cross-coupling reaction of (S)-4-iodophenylalanine with a diboron compound by palladium-catalyzed amine end treatment. Amine-protected (S)-4-iodophenylalanine (eg (S)-N-tert-butoxycarbonyl-4-iodophenylalanine ((S)-N-Boc-4-) Iodophenylalanine)) is prepared by cross-coupling with a diboron compound such as bis(pinacolato diboron) to give (S)-N-tert-butoxycarbonyl-4-pentanoylboryl phenylalanine The amine-terminated (S)-4-boranyl ester phenylalanine of the acid ((S)-N-Boc-4-pinacolatoborono phenylalanine); afterwards, the protecting group on the amine end and the boronic end are removed. The above substituents complete the preparation of L-BPA.

However, since the selected ¹⁰ B-doped divaleryl diboron is not a commercially available compound, this method requires additional pretreatment of the preparation of the borating agent, resulting in a high process complexity and a long time consuming process. It is impossible to prepare a high yield of L-BPA. In addition, the carboxylic acid group of the protected (S)-4-iodophenylalanine at the amine end needs to be protected by a substituent to form a benzyl ester group to increase the process yield to 88%; however, The preparation of L-BPA in this manner also requires an additional step of deprotecting the carboxylic acid group, which in turn increases the process complexity of L-BPA.

Accordingly, the method provided in this document not only involves pre-treatment of the preparation of the borating agent, but also requires a large amount of process time and synthesis steps to complete the steps of protecting and deprotecting the carboxylic acid group, and is not advantageous as an industry. The main method of synthesizing L-BPA.

On the other hand, a method for synthesizing L-BPA by forming a bond (b) is a coupling reaction of an amino acid with a boron-containing benzyl fragment or a boron-containing benzaldehyde fragment. To synthesize L-BPA. Biosci. Biotech. Biochem. 1996, 60, 683 discloses an enantioselective synthesis of L-BPA which gives the hands of a cyclic ethers of boronic acid and L-proline The chiral derivatives from L-valine are subjected to a coupling reaction to produce L-BPA. However, this method requires the formation of a cyclic ether compound of boric acid from 4-boronobenzylbromide, followed by a coupling reaction with a chiral derivative of L-proline, and in the latter stage. The amino acid undergoes an undesired racemization in the synthesis step, so that the method requires an enzymatic resolution step to reduce the yield to obtain L-BPA having a certain optical purity.

Accordingly, the method provided in the literature still includes the steps of pretreatment of the preparation of the borating agent and post-treatment of the enzymatic resolution, so that the process involved in the method is complicated and takes a long time, and cannot be obtained. High yield of L-BPA.

In addition, L- ¹⁰ BPA (4-( ¹⁰ B)borono-L-phenylalanine, 4-( ¹⁰ B)dihydroxyboryl-L-phenylalanine) containing ¹⁰ boron is currently known to accumulate in tumor cells. The key factor is to use the thermal neutron beam to irradiate the boron element accumulated in the tumor cells to kill the tumor cells by capturing the high-energy particles generated by the reaction, thereby achieving the purpose of treating cancer. Therefore, ¹⁰ boron can promote the treatment of L- ¹⁰ BPA by boron neutron capture treatment.

However, the boron element present in nature contains about 19.9% of ¹⁰ boron and about 80.1% of ¹¹ boron. Therefore, many researchers are still actively developing methods that can be applied to the synthesis of L-BPA, especially for the synthesis of ^10- boron-rich L-BPA.

J.Org.Chem.1998,63,8019 additionally provides a method of synthesizing ¹⁰ boronated agents, since the method involves multiple steps, it is easy to greatly reduce the boron content of ^10 10 boron enriched material in the manufacturing process. Therefore, the method provided in this document is not suitable for the synthesis of ^10- boron-rich L-BPA.

Another example is the Biosci.Biotech.Biochem.1996,60,683, before the enzymatic resolution step is not performed, the method provided by the articles could not be obtained with a certain L-BPA optical purity; ¹⁰ and the method for preparing boronated agents when also relates to multi-step, resulting in conversion of boron-rich material ¹⁰ occurs during the manufacturing process. Therefore, the method provided in this document is also not suitable for the synthesis of ^10- boron-rich L-BPA.

Furthermore, Bull. Chem. Soc. Jpn. 2000, 73, 231 discloses the use of palladium to catalyze 4-iodo-L-phenylalanine with 4,4,5,5-tetramethyl-1,3,2 A method in which a dioxonium pentoxide (common name: pinacolborane) is subjected to a coupling reaction. However, this document does not mention how to prepare articles ¹⁰ boron enriched L-BPA using this method, and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane not a commercial ¹⁰ The compounds available in the literature are not suitable for the synthesis of ^10- boron-rich L-BPA.

In addition, Synlett. 1996, 167 discloses a method for coupling a iodophenylborate with a zinc derivative of L-serine zinc derivatives, which involves first preparing phenyl iodoborate. The ester and the preparation of a zinc derivative of L-type serine acid, etc., result in a lower yield of the produced L-BPA. In addition, since the ^10- boron-rich triiodide ¹⁰ boron and 1,3-diphenylpropane-1,3-diol selected for this method are not commercially available compounds, the methods provided in this document are also provided. Still not suitable for the synthesis of ^10- boron-rich L-BPA.

SYN

Repub. Korean Kongkae Taeho Kongbo, 2018060319,

PAPER

Research and Development in Neutron Capture Therapy, Proceedings of the International Congress on Neutron Capture Therapy, 10th, Essen, Germany, Sept. 8-13, 2002 (2002), 1-8.

PAPER

European Journal of Pharmaceutical Sciences (2003), 18(2), 155-163

https://www.sciencedirect.com/science/article/abs/pii/S0928098702002567

PAPER

Tetrahedron Letters (2008), 49(33), 4977-4980

PATENT

WO 2004009135

PATENT

US 20130331599

PATENT

WO 2017028751

https://patents.google.com/patent/WO2017028751A1/en

Example 1

Before preparing (S)-N-tert-butoxycarbonyl-4-dihydroxyborylphenylalanine from (S)-N-tert-butoxycarbonyl-4-iodophenylalanine, it is necessary to reveal Process for preparing (S)-N-tert-butoxycarbonyl-4-iodophenylalanine by using (S)-4-iodophenylalanine as a starting material and a process for preparing ¹⁰ tributyl borate with ¹⁰ boric acid.

1. Preparation of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine from (S)-4-iodophenylalanine

Please refer to the following reaction formula I, which is (S)-4-iodophenylalanine in a solvent of 1,4-dioxane (1,4-dioxane) and water (H ₂ O) with hydrogen peroxide. Sodium (NaOH) and di-tert-butyl dicarbonate (Boc ₂ O) are reacted to obtain a chemical reaction formula of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine.

In the preparation process, two reaction vessels were selected for the reaction.

The specific operation process is as follows:

1. Set up a reaction using a 3L three-neck bottle.

2. (S)-4-iodo-L-phenylalanine (200.00 g, 687.10 mmol, 1.00 eq) was added to the reaction system.

3. Add 1,4-dioxane (1.00 L) and water (1.00 L) to the reaction system, respectively.

4. Sodium hydroxide (68.71 g, 1.72 mol, 2.50 eq) was added to the reaction system, the solution gradually became clear, and the temperature rose slightly to 19 °C.

5. When the system is cooled to 0-10 ° C, di-tert-butyl dicarbonate (254.93 g, 1.17 mol, 268.35 mL, 1.70 eq) is added to the reaction system, and the temperature of the reaction system is naturally raised to 10 to 30 ° C and Stir at room temperature (about 30 ° C) for 8 hours.

6. The reaction was detected using high performance liquid chromatography (HPLC) until the starting of the reaction.

7. The temperature of the control system is less than 40 ° C, and the 1,4-dioxane in the reaction solution is concentrated.

8. The reaction system was lowered to room temperature (about 25 ° C), 100 mL of water was added, and the pH was adjusted to 1.8-2 with hydrochloric acid (2M (ie, molarity, M)).

9. Extract three times with ethyl acetate (2 L).

10. Combine the organic phases and wash twice with saturated brine (1 L).

11. The organic phase was dried over sodium sulfate (200 g).

12. Continue drying in an oven (40-45 ° C) to give (S)-N-tert-butoxycarbonyl-4-iodo-L-phenylalanine (250.00 g, 626.28 mmol, HPLC analysis, yield 93.00 %, purity 98%).

The prepared (S) -N- tert-butoxycarbonyl-4-iodo-phenylalanine was -L- Hydrogen ¹ nuclear magnetic resonance spectrum analysis ⁽¹ HNMR) as follows:

¹ H NMR: (400 MHz DMSO-d ₆ )

δ 7.49 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 7.8 Hz, 2H), 5.80 (d, J = 5.9 Hz, 1H), 3.68 (d, J = 5.5 Hz, 1H), 3.00-2.90 (m, 1H), 2.87-2.75 (m, 1H), 1.35-1.15 (m, 9H).

Second, tributyl borate ¹⁰ was prepared from boronic acid ¹⁰

See the following reaction formulas II, ¹⁰ as boric acid (H ₂ SO ₄₎ is reacted with sulfuric acid in a solvent (butan-1-ol), and toluene (Toluene) in n-butanol, to obtain ¹⁰ tributyl borate ⁽¹⁰ The chemical reaction formula of B(OBu) ₃ ).

The specific operation process is as follows:

1. Set up a reaction device R1 using a 3L three-necked bottle, and configure a water separator on the device.

2. ¹⁰ boric acid (150.00 g, 2.46 mol, 1.00 eq) was added to the reaction R1 at room temperature (about 25 ° C).

3. Add n-butanol (1.00 L) to the reaction R1 at room temperature (about 25 ° C) and stir, and most of the boric acid cannot be dissolved.

4. Toluene (1.00 L) was added to the reaction R1 at room temperature (about 25 ° C) and stirred.

5. Concentrated sulfuric acid (4.82 g, 49.16 mmol, 2.62 mL, 0.02 eq) was added dropwise to the reaction at room temperature (about 25 ° C), at which time a large amount of solid remained undissolved.

6. The reaction system was heated to 130 ° C, and the water was continuously removed, stirred for 3.5 hours, and water (about 140 g) was formed in the water separator. The solids were all dissolved, and the solution changed from colorless to brown. .

7. TLC (DCM: MeOH = 5:1, Rf = 0.43, bromocresol green).

8. Distill off most of the toluene at atmospheric pressure.

9. After most of the toluene is distilled off, the temperature of the system is lowered to 20 to 30 ° C, and the reaction liquids of the two reactions are combined, and the apparatus is changed for distillation.

10. Oil bath external temperature 108-110 ° C pump distillation under reduced pressure, Kelvin thermometer 45 ° C, distilled n-butanol.

11. Oil bath external temperature 108-110 ° C oil pump distillation under reduced pressure, the residual butanol was distilled off.

12. Oil bath external temperature 118-120 ° C oil pump vacuum distillation, Kelvin thermometer 55 ° C, began to produce products.

13. The temperature is raised to 135-140 ° C oil pump vacuum distillation, the product is completely distilled.

14. The product is obtained as a colorless liquid ¹⁰ tributyl borate (830.00g, 3.62mol, yield 73.58%).

The results of the ¹ H NMR analysis of the obtained tributyl ¹⁰ borate were as follows:

¹ H NMR: (400 MHz CDCl ₃ )

δ 3.82-3.68 (m, 6H), 1.57-1.42 (m, 6H), 1.34 (qd, J = 7.4, 14.9 Hz, 6H), 0.95-0.80 (m, 9H).

Three, -N- tert-butoxycarbonyl-4-iodo-phenylalanine was prepared (S) of (S) -N- ^{tert-butoxycarbonyl-4-hydroxy-10-yl} -L- phenylalanine boron

Please refer to the following reaction formula III, which is (S)-N-tert-butoxycarbonyl-4-iodophenylalanine with tributyl ¹⁰ borate, t-butyl magnesium chloride (t-BuMgCl) and bis (2-A) yl aminoethyl) ether (BDMAEE) reaction, to produce (S) -N- tert-butoxycarbonyl group -4- ⁽¹⁰ B) dihydroxyboryl -L- phenylalanine chemical reaction.

In the preparation process, two reaction vessels were selected for the reaction.

The specific operation process is as follows:

1. Set up a reaction using a 3L three-neck bottle.

2. Tributyl ¹⁰ borate (187.60 g, 87.98 mmol, 3.20 eq) was placed in the reaction system at room temperature (about 22 ° C).

3. Sodium hydride (20.45 g, 511.24 mmol, purity 60%, 2.00 eq) was added to the reaction system at room temperature (about 22 ° C). The reaction solution was a suspension and stirred at room temperature (about 22 ° C). 5 minutes.

4. Bis(2-methylaminoethyl)ether (327.73 g, 2.04 mol, 8.00 eq) was added to the reaction at room temperature (about 22 ° C).

5. N-tert-Butoxycarbonyl-4-iodo-L-phenylalanine (100.00 g, 255.62 mmol, 1.00 eq) was added to the reaction system at room temperature (about 22 ° C), and a large amount of solid was not dissolved.

6. Lower the temperature of the reaction system to 0-5 ° C, add t-butyl magnesium chloride (1.7 M, 1.20 L, 2.04 mol, 8.00 eq) to the reaction, control the temperature between 0-10 ° C, the dropping time is about It is 1.5 hours.

7. After the completion of the charging, the temperature of the reaction system was naturally raised to room temperature (20 to 30 ° C) and stirred at this temperature for 12 hours.

8. Using high performance liquid chromatography (HPLC) to detect about 9.00% of the remaining material.

9. When the temperature of the reaction system was lowered to -5 to 0 ° C, it was quenched by dropwise addition of 500 mL of water.

10. Lower the temperature of the system to 0-5 ° C, add methyl tert-butyl ether (500 mL) to the reaction system and adjust the pH to 2.9-3.1 (using a pH meter) with 37% HCl (about 500 mL). Exothermic, the temperature of the control system is between 0-15 °C.

11. The aqueous phase obtained by liquid separation was extracted once with methyl tert-butyl ether (500 mL), and the obtained organic phases were combined to give an organic phase of about 1.1 L.

12. Slowly add a sodium hydroxide aqueous solution (1 M, 400 mL) to the obtained organic phase, exotherm during the dropwise addition, and control the system temperature between 0-15 °C.

13. After the completion of the dropwise addition, the pH of the system was about 10, and the pH was adjusted to between 12.10 and 12.6 with an aqueous sodium hydroxide solution (4M). (measured with a pH meter)

14. Dispensing.

15. The aqueous phase 1 obtained after liquid separation was extracted once with n-butanol (500 ml) to obtain aqueous phase 2.

16. Combine the aqueous phase 2 of the two reaction vessels.

17. Adjust the pH of the aqueous phase to 2.9-3.1 with 37% HCl, stir for about 40 minutes, and precipitate a large amount of solid.

18. Filtration gave a white solid which was washed once with dichloromethane (50 mL).

19. At 25 ° C, the precipitated solid was slurried with dichloromethane (150 mL) and stirred for 10 min.

20. A white solid was filtered to give (S) -N- tert-butoxycarbonyl group -4- ⁽¹⁰ B) dihydroxyboryl -L- phenylalanine (75.00g, 240.82mmol, by HPLC analysis, a yield of 47.11% , purity 99%).

The prepared (S) -N- tert-butoxycarbonyl group -4- ⁽¹⁰ B) results dihydroxyboryl -L- phenylalanine ¹ HNMR was as follows:

¹ H NMR: (400 MHz DMSO-d ₆ )

Δ12.55 (br.s., 1H), 7.91 (s, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 7.5 Hz, 2H), 4.08-4.01 (m, 1H) ), 3.61-3.53 (m, 1H), 2.98 (dd, J = 4.2, 13.9 Hz, 1H), 2.79 (dd, J = 10.4, 13.5 Hz, 1H), 1.79-1.67 (m, 1H), 1.35- 1.17 (m, 9H).

Preparation of L- ¹⁰ BPA from (S)-N-tert-Butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine

See the following reaction scheme IV, which is (S) -N- tert-butoxycarbonyl group -4- ⁽¹⁰ B) of amine end dihydroxyboryl -L- phenylalanine deprotection of the chemical reaction, to obtain L- ¹⁰ BPA.

The specific operation process is as follows:

1. Set up a reaction using a 1L three-neck bottle.

2. room temperature (20-30 deg.] C) to (S) -N- tert-butoxycarbonyl group -4- ⁽¹⁰ B) dihydroxyboryl -L- phenylalanine (67.00g, 217.31mmol, 1.00eq) was added the reaction In the system.

3. room temperature (20-30 deg.] C) water (23.75mL) and acetone (Acetone, 420.00mL) were added dropwise to the reaction flask, stirred (S) -N- tert-butoxycarbonyl group -4- ⁽¹⁰ B) dihydroxy Boronyl-L-phenylalanine.

4. Concentrated hydrochloric acid (23.93 g, 656.28 mmol, 23.46 mL, 3.02 eq) was added dropwise to the reaction system at room temperature (20-30 ° C). After the addition was completed, the reaction system was heated to 55-60 ° C and stirred for 4.5 hours.

5. HPLC detection until the reaction of the starting material is completed.

6. The temperature is controlled below 40 ° C, and the acetone in the reaction system is concentrated.

7. Lower the concentrated system to below 15 °C, adjust the pH of the system to about 1.5 with sodium hydroxide solution (4M) (pH meter detection), stir for 40 minutes and continue to adjust the pH of the system to 6.15 using sodium hydroxide solution (4M). ～6.25, a large amount of white solid precipitated, which was filtered to give a white solid, and rinsed with acetone (200mL).

8. Obtained as a white solid L- ¹⁰ BPA (36.00 g, 171.17 mmol, HPLC, yield 78.77%, purity 99%).

The analytical results obtained by the L- ¹⁰ BPA ¹ HNMR are as follows:

¹ H NMR: (400 MHz D ₂ O, CF ₃ COOH)

δ 7.44 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 4.06 (dd, J = 5.7, 7.5 Hz, 1H), 3.11-3.01 (m, 1H), 2.98 -2.87 (m, 1H).

xample 6

Preparation of (S)-N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine from (S)-N-tert-butoxycarbonyl-4-iodophenylalanine

Please refer to the following reaction formula VII, which is a reaction of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine with tributyl borate and t-butylmagnesium chloride (t-BuMgCl) to obtain (S The chemical reaction formula of -N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine.

The specific operation process is as follows:

1. Construct a reaction unit with a 250 mL three-neck bottle.

2. Tributyl borate (17.65 g, 76.68 mmol, 3.00 eq) was placed in a 250 mL reaction flask at 20-30 °C.

3. Sodium hydride (1.02 g, 25.56 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.

4. (S)-N-tert-Butoxycarbonyl-4-iodo-L-phenylalanine (10.00 g, 25.56 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.

5. Reduce the temperature of the reaction system to 0 ° C under nitrogen atmosphere, slowly add t-butyl magnesium chloride (1.7 M in THF, 120 mL, 8.00 eq) to the reaction, the dropping time is about 30 minutes, and the control temperature is 0. Between °C and 10 °C.

Stir at 20.20 ~ 30 ° C for 20 hours.

7. HPLC detection of the basic reaction of the raw materials, leaving only about 0.7% of the raw materials.

8. At a temperature of 0 ° C, 5 mL of water was added dropwise to the reaction to quench it. After complete quenching, stirring was continued for 10 minutes.

9. Cool down to 0 ° C, add methyl tert-butyl ether (50 mL) to the reaction and adjust the pH to 3 with 37% HCl (about 50 mL) (detected with a pH meter), adjust the pH during the process to exotherm, control the temperature at 0 Between °C and 15 °C.

12. The aqueous phase obtained by liquid separation was extracted once with methyl t-butyl ether (50 mL) and the organic phases were combined.

12. Add NaOH solution (1M, 55mL) to the obtained organic phase to adjust the pH to between 12.10-12.6. The process is exothermic and the temperature is controlled between 0 °C and 15 °C.

13. Liquid separation, the obtained aqueous phase was extracted once with n-butanol (50 mL), and most of the impurities were extracted and removed.

14. The aqueous phase obtained by liquid separation was adjusted to pH 3 with 37% HCl and stirred for about 30 minutes to precipitate a white solid.

15. Filtration gave a white solid which was washed once with dichloromethane (50 mL).

16. The precipitated solid was slurried with 25 mL of dichloromethane at 25 ° C and stirred for 10 minutes.

17. Filtration of (S)-N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine (6.8 g, HPLC, yield: 83.15%, purity 98%).

Example 7

Please continue to refer to Reaction Scheme VII. The specific operation process is as follows:

1. Construct a reaction unit with a 250 mL three-neck bottle.

2. Tributyl borate (8.82 g, 38.34 mmol, 3.00 eq) was added to a 250 mL reaction vial at 20-30 °C.

3. Sodium hydride (511.25 mg, 12.78 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.

4. (S)-N-tert-Butoxycarbonyl-4-iodo-L-phenylalanine (5.00 g, 12.78 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.

5. The temperature of the reaction system was lowered to 0 ° C under nitrogen atmosphere, and t-butyl magnesium chloride (1.7 M in THF, 60 mL, 8.00 eq) was added dropwise to the reaction, the dropwise addition time was about 30 minutes, and the control temperature was 0 ° C. -10 ° C between.

Stir at 6.20 ~ 30 ° C for 22 hours.

7. HPLC detection of the raw material reaction is completed.

8. At a temperature of 0 ° C, 2.5 mL of water was added dropwise to the reaction to quench it. After complete quenching, stirring was continued for 10 minutes.

9. Cool down to 0 ° C, add methyl tert-butyl ether (25 mL) to the reaction and adjust the pH to 3 with 37% HCl (about 25 mL) (detected with a pH meter), adjust the pH during the process to exotherm, control the temperature at 0 Between °C and 15 °C.

12. The aqueous phase obtained by liquid separation was extracted once with methyl t-butyl ether (25 mL) and the organic phases were combined.

12. Add NaOH solution (1M, 30mL) to the obtained organic phase to adjust the pH to between 12.10-12.6. The process is exothermic and the temperature is controlled between 0 °C and 15 °C.

13. Liquid separation, the obtained aqueous phase was extracted once with n-butanol (25 ml), and most of the impurities were extracted and removed.

14. The aqueous phase obtained by liquid separation was adjusted to pH 3 with 37% HCl and stirred for about 30 minutes to precipitate a white solid.

15. Filtration gave a white solid which was washed once with dichloromethane (25 mL).

16. The precipitated solid was slurried with 15 mL of dichloromethane at 25 ° C and stirred for 10 minutes.

17. Filtration gave (S)-N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine (3.4 g, obtained by HPLC, yield: 85.26%, purity 98%).

Bis(2-methylaminoethyl)ether is a complexing agent for Mg, which can reduce the occurrence of side reactions in the reaction. The reactions of Examples 6 and 7 were carried out without adding bis(2-methylaminoethyl)ether. The analysis showed that the iodine impurity in the reaction of Example 6 was about 17%, and the iodine impurity in the reaction of Example 7 was observed. About 28%. Therefore, it has been proved from the side that the addition of bis(2-methylaminoethyl)ether can protect the reaction from reducing iodine.

The BPA or ¹⁰ BPA obtained in the above examples were analyzed by chiral HPLC, and the ratio of the L-enantiomer to the D-enantiomer was 100:0.

The boron-containing drug L-BPA for neutron capture therapy disclosed in the present invention is not limited to the contents described in the above examples. The above-mentioned embodiments are only examples for convenience of description, and the scope of the claims should be determined by the claims.

PATENT

KR 2018060319

PATENT

WO 2019163790

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019163790

///////////Borofalan (10B), Borofalan, Steboronine, JAPAN 2020, 2020 APPROVALS, ボロファラン (10B), ボロファラン , 硼[10B]法仑 , 

B(C1=CC=C(C=C1)CC(C(=O)O)N)(O)O