WO2015011609A1 - Procédé de préparation de linagliptine et d'un intermédiaire de celle-ci - Google Patents

Procédé de préparation de linagliptine et d'un intermédiaire de celle-ci Download PDF

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Publication number
WO2015011609A1
WO2015011609A1 PCT/IB2014/063132 IB2014063132W WO2015011609A1 WO 2015011609 A1 WO2015011609 A1 WO 2015011609A1 IB 2014063132 W IB2014063132 W IB 2014063132W WO 2015011609 A1 WO2015011609 A1 WO 2015011609A1
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WO
WIPO (PCT)
Prior art keywords
formula
preparation
iii
linagliptin
quinazoline
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PCT/IB2014/063132
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English (en)
Inventor
Suresh Babu Jayachandra
Udaibhan Singh GAHLOT
Raghuram Morampudi
Pratibha Singh
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Ranbaxy Laboratories Limited
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Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2015011609A1 publication Critical patent/WO2015011609A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Definitions

  • the present invention provides an improved process for the preparation of linagliptin and an intermediate thereof.
  • Linagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. It is chemically designated as lH-purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl] -7-(2-butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 -[(4-methyl-2-quinazolinyl)methyl] - . Its chemical structure is depicted below in Formula I.
  • Linagliptin is marketed in the United States under the trade name Tradjenta ® , for the treatment of type 2 diabetes mellitus. It is also marketed in the United States in combination with metformin hydrochloride, under the trade name Jentadueto ® , for the treatment of type 2 diabetes mellitus.
  • PCT Publication No. WO 2004/018468 and U.S. Patent No. 7,407,955 disclose a process for the preparation of linagliptin using a fert-butyloxycarbonyl protected intermediate of Formula II.
  • U.S. Patent No. 7,820,815 discloses that the preparation of linagliptin using the fert-butyloxycarbonyl protected intermediate of Formula II is not suitable for an industrial scale preparation of linagliptin due to the formation of impurities attributable to the protecting group used. It further mentions that these impurities are difficult to remove on an industrial scale, and that the preparation of an enantiomerically pure precursor of Formula II is complicated and expensive.
  • U.S. Publication No. 2012/0165525 discloses a process for the preparation of a fert-butyloxycarbonyl protected derivative of Formula II using azide intermediates.
  • the present invention provides an improved, economical, and industrially advantageous process for the preparation of the intermediate of Formula II having a controlled amount of the quinazoline dimethyl aminoxanthine impurity of Formula V.
  • the process of the present invention involves the preparation of the intermediate of Formula II by the reaction of the intermediate of Formula III with the intermediate of Formula IV in the presence of sodium carbonate in N-methyl-2-pyrrolidone solvent.
  • the process of the present invention avoids the need for purification of the intermediate of Formula II using column chromatography.
  • a first aspect of the present invention provides a process for the preparation of the fert-butyloxycarbonyl protected intermediate of Formula II
  • a second aspect of the present invention provides a process for the preparation of a fert-butyloxycarbonyl protected intermediate of Formula II
  • a third aspect of the present invention provides a process for the preparation of linagliptin of Formula I
  • a fourth aspect of the present invention provides a process for the preparation of linagliptin of Fonnula I
  • a fifth aspect of the present invention provides the intermediate of Formula II having an HPLC purity greater than 99%.
  • a sixth aspect of the present invention provides the intermediate of Formula II substantially free of the quinazoline dimethyl aminoxanthine impurity of Formula V.
  • a seventh aspect of the present invention provides linagliptin of Formula I substantially free of the quinazoline dimethyl aminoxanthine impurity of Formula V.
  • An eighth aspect of the present invention provides a process for the preparation of the quinazoline dimethyl aminoxanthine impurity of Formula V
  • the quinazoline dimethyl aminoxanthine impurity of Formula V is chemically 7- (but-2-yn-l-yl)-8-(dimethylamino)-3-methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7- dihydro-lH-purine-2,6-dione.
  • ambient temperature refers to a temperature in the range of about 20°C to about 35°C.
  • substantially free refers to the intermediate of Formula II, or linagliptin of Formula I, having less than 1%, preferably less than 0.5%, and most preferably having no detectable amount of the quinazoline dimethyl aminoxanthine impurity of Formula V.
  • the preparation of the quinazoline bromoxanthine intermediate of Formula III may be carried out by the processes known in the literature, such as by the process disclosed in PCT Publication No. WO 2004/018468, which is incorporated herein by reference.
  • the R-Boc-aminopiperidine intermediate of Formula IV is available commercially.
  • the present inventors have carried out an extensive study for controlling the formation of the quinazoline dimethyl aminoxanthine impurity of Formula V in the intermediate of Formula II.
  • the present inventors have found that the use of sodium carbonate in N-methyl-2-pyrrolidone is advantageous over the use of potassium carbonate in ⁇ , ⁇ -dimethylformamide, as it controls the formation of the quinazoline dimethyl aminoxanthine impurity of Formula V to pharmaceutically acceptable levels.
  • the present inventors further observed that changing the base from potassium carbonate to sodium carbonate while using the same solvent, / ' . e. , ⁇ , ⁇ -dimethylformamide, controlled the formation of the quinazoline dimethyl aminoxanthine impurity of Formula V.
  • reaction of the intermediate of Formula III with the intermediate of Formula IV is carried out at a temperature of about 80°C to 90°C.
  • the intermediate of Formula II may be purified by crystallization in a solvent selected from the group comprising of nitriles, ketones, or mixtures thereof.
  • nitriles include acetonitrile, propionitrile, or mixtures thereof.
  • ketones include acetone, ethyl methyl ketone, methyl z ' so-butyl ketone, or mixtures thereof.
  • the intermediate of Formula II is purified by crystallization in acetonitrile.
  • Formula II is purified by crystallization in acetone.
  • the conversion of the intermediate of Formula II into linagliptin of Formula I may be carried out by processes known in the literature, such as the process disclosed in PCT Publication No. WO 2004/018468.
  • Formula I is carried out by deprotection of the fert-butyloxycarbonyl group of the intermediate of Formula II by treatment with trifluoroacetic acid in iso-propanol at about 0°C to 80°C.
  • the preparation of the quinazoline dimethyl aminoxanthine impurity of Formula V is carried out by the reaction of the quinazoline bromoxanthine of Formula III with dimethyl amine in the presence of sodium carbonate in N,N-dimethylformamide.
  • the reaction may be carried out at ambient temperature to the reflux temperature of the solvent. In a preferred embodiment of the present invention, the reaction is carried out at ambient temperature to about 80°C.
  • Isolation may be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by drying. Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying. Drying may be carried out at ambient temperature to about 100°C for about 30 minutes to about 20 hours.
  • the isolation is carried out by concentrating the reaction mixture under reduced pressure followed by drying at a temperature of about 40°C to about 80°C.
  • the process of the present invention provides the intermediate of Formula II having an HPLC purity greater than 99%.
  • the process of the present invention provides the intermediate of Formula II substantially free of the quinazoline dimethyl aminoxanthine impurity of Formula V.
  • the process of the present invention provides linagliptin of Formula I substantially free of the quinazoline dimethyl aminoxanthine impurity of Formula V.
  • the NMR spectrum was recorded using a Bruker ® Avance III 400 MHz.
  • the Mass spectrum was recorded using an AB SCIEX ® QTRAP ® 2000.
  • HPLC purity was determined using a Kromasil ® C18 (250 x 4.6 mm), 5 ⁇ column with a flow rate of 1.0 mL/minute; Column oven temperature 30°C; Sample tray temperature: 10°C; Detector UV: 225 nm; Injection volume: 10 ⁇ ; Run time: 50 minutes.
  • N,N-dimethylformamide (10 mL), quinazoline bromoxanthine (Formula III; 1 g), potassium carbonate (0.47 g), and R-Boc-aminopiperidine (Formula IV; 0.47 g) were added into a reaction vessel at ambient temperature.
  • the reaction mixture was heated to 100°C to 110°C and stirred for 18 hours.
  • the reaction mixture was cooled to ambient temperature and deionized water (40 mL) was added.
  • the reaction mixture was stirred for 2 hours, filtered, washed with deionized water (10 mL), and dried under reduced pressure at 45°C to 48°C for 2 hours and 30 minutes to obtain the intermediate of Formula II.
  • N, N-dimethylformamide (562.5 mL), quinazoline bromoxanthine (Formula III; 75 g), sodium carbonate (35 g), and R-Boc-aminopiperidine (Formula IV; 36.4 g) were added into a reaction vessel at ambient temperature.
  • the reaction mixture was heated to 130°C to 140°C and stirred for 4 hours.
  • the reaction mixture was cooled to ambient temperature and water (1700 mL) was added at 10°C to 20°C.
  • the reaction mixture was stirred at ambient temperature for 30 minutes, filtered, washed with water (1500 mL), and dried under reduced pressure at 45°C to 50°C to obtain a solid.
  • the wet solid (388g) was added into a reaction vessel containing water (87 mL) and acetonitrile (400 mL). The reaction mixture was heated to 70°C to 75°C for 30 minutes, and then cooled to 40°C to 50°C. The reaction mixture was stirred for 1 hour, further cooled to 25°C to 30°C, and stirred for 1 hour. The solid obtained was filtered, washed with a mixture of acetonitrile (50 mL) and water (50 mL), and then dried at 50°C to 55°C under reduced pressure to obtain the pure intermediate of Formula II.
  • the wet solid (46 g) was added into another reaction vessel containing water (36.6 mL) and acetone (140 mL). The reaction mixture was heated to 60°C to 65 °C for 30 minutes, and then cooled to 25°C to 30°C. The reaction mixture was stirred for 2 hours. The solid obtained was filtered, washed with a mixture of acetone (20 mL) and deionized water (20 mL), and then dried at 50°C to 60°C under reduced pressure for 12 hours to obtain the pure intermediate of Formula II.
  • fert-Butyloxycarbonyl protected intermediate (Formula II; 35 g; prepared according to the process of Working Example 2 and dichloromethane (525 mL) were added into a reaction vessel at ambient temperature. The moisture content was adjusted to less than 0.1% by azeotropically distilling dichloromethane from the reaction mixture. The reaction mixture was cooled to 1°C, and trifluroacetic acid (139.6 g) was added slowly into the reaction mixture at 1°C to 4°C. The reaction mixture was stirred at 10°C to 15 °C for 20 hours. Progress of the reaction was monitored by HPLC.
  • the reaction mixture was cooled to 2°C, and aqueous sodium hydroxide solution (56 g in 560 mL water) was slowly added at 2°C to 13°C.
  • the reaction mixture was stirred at 26°C to 28°C for 4 hours followed by layer separation.
  • the organic layer was washed with water (2 x 175 mL).
  • Activated carbon (3.5g) was added to the organic layer, and the contents were stirred for 30 minutes at 27°C to 28°C.
  • the contents were filtered through a Hyflo ® bed and washed with dichloromethane (2 x 35 mL).
  • the organic layer was concentrated at 30°C under reduced pressure.
  • Iso-propanol 105 mL was added, and the contents were stirred at about 28°C for 2 hours and 30 minutes. The contents were filtered, washed with iso-propanol (35 mL), and dried under reduced pressure at 60°C to 65°C for 14 hours to obtain linagliptin.

Abstract

La présente invention concerne un procédé amélioré pour la préparation de linagliptine et d'un intermédiaire de celle-ci.
PCT/IB2014/063132 2013-07-23 2014-07-15 Procédé de préparation de linagliptine et d'un intermédiaire de celle-ci WO2015011609A1 (fr)

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IN2193/DEL/2013 2013-07-23
IN2193DE2013 2013-07-23

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105936634A (zh) * 2016-03-28 2016-09-14 赤峰赛林泰药业有限公司 一种利格列汀的合成方法
WO2019064214A1 (fr) * 2017-09-27 2019-04-04 Biocon Limited Intermédiaire de linagliptine cristallin et procédé de préparation de linagliptine
CN110684026A (zh) * 2019-10-24 2020-01-14 扬子江药业集团上海海尼药业有限公司 一种利格列汀的工业化制备方法
JP2020070296A (ja) * 2018-10-31 2020-05-07 ヤマサ醤油株式会社 リナグリプチンの製造法
EP4349837A1 (fr) * 2022-10-05 2024-04-10 Zaklady Farmaceutyczne "Polpharma" S.A. Produit intermédiaire pharmaceutique

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WO2004018468A2 (fr) 2002-08-21 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, leur production et leur utilisation comme medicament
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
US20120165525A1 (en) 2010-12-23 2012-06-28 Dipharma Francis S.R.L. Process for the preparation of linagliptin
WO2013098775A1 (fr) * 2011-12-28 2013-07-04 Dr. Reddy's Laboratories Limited Procédé amélioré pour la préparation de linagliptine pure
WO2014059938A1 (fr) * 2012-10-19 2014-04-24 药源药物化学（上海）有限公司 Procédé de préparation d'intermédiaire important de linagliptine
WO2014097314A1 (fr) * 2012-12-17 2014-06-26 Mylan Laboratories Ltd Procédé amélioré pour la préparation de linagliptine

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WO2004018468A2 (fr) 2002-08-21 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, leur production et leur utilisation comme medicament
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
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WO2013098775A1 (fr) * 2011-12-28 2013-07-04 Dr. Reddy's Laboratories Limited Procédé amélioré pour la préparation de linagliptine pure
WO2014059938A1 (fr) * 2012-10-19 2014-04-24 药源药物化学（上海）有限公司 Procédé de préparation d'intermédiaire important de linagliptine
WO2014097314A1 (fr) * 2012-12-17 2014-06-26 Mylan Laboratories Ltd Procédé amélioré pour la préparation de linagliptine

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105936634A (zh) * 2016-03-28 2016-09-14 赤峰赛林泰药业有限公司 一种利格列汀的合成方法
CN105936634B (zh) * 2016-03-28 2018-05-25 赤峰赛林泰药业有限公司 一种利格列汀的合成方法
WO2019064214A1 (fr) * 2017-09-27 2019-04-04 Biocon Limited Intermédiaire de linagliptine cristallin et procédé de préparation de linagliptine
CN111511743A (zh) * 2017-09-27 2020-08-07 拜康有限公司 结晶的利拉利汀中间体及利拉利汀的制备方法
JP2020535193A (ja) * 2017-09-27 2020-12-03 バイオコン・リミテッド 結晶のリナグリプチン中間体およびリナグリプチンの調製のためのプロセス
US11040974B2 (en) 2017-09-27 2021-06-22 Biocon Limited Crystalline linagliptin intermediate and process for preparation of linagliptin
JP2020070296A (ja) * 2018-10-31 2020-05-07 ヤマサ醤油株式会社 リナグリプチンの製造法
CN110684026A (zh) * 2019-10-24 2020-01-14 扬子江药业集团上海海尼药业有限公司 一种利格列汀的工业化制备方法
EP4349837A1 (fr) * 2022-10-05 2024-04-10 Zaklady Farmaceutyczne "Polpharma" S.A. Produit intermédiaire pharmaceutique
WO2024074612A1 (fr) * 2022-10-05 2024-04-11 Zaklady Farmaceutyczne Polpharma S.A. Intermédiaire pharmaceutique

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