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WO 2016024224, New Patent, Trelagliptin, SUN PHARMA

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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.

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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.

/////////////WO 2016024224, New Patent, Trelagliptin, SUN PHARMA


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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