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WO2015011609A1 - Process for the preparation of linagliptin and an intermediate thereof - Google Patents

Process for the preparation of linagliptin and an intermediate thereof 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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Prior art keywords
formula
preparation
iii
linagliptin
quinazoline
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PCT/IB2014/063132
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French (fr)
Inventor
Suresh Babu Jayachandra
Udaibhan Singh GAHLOT
Raghuram Morampudi
Pratibha Singh
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides an improved process for the preparation of linagliptin and an intermediate thereof.

Description

PROCESS FOR THE PREPARATION OF LINAGLIPTIN AND AN
INTERMEDIATE THEREOF
Field of the Invention
The present invention provides an improved process for the preparation of linagliptin and an intermediate thereof.
Background of the Invention
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.
Figure imgf000002_0001
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.
Figure imgf000002_0002
Formula II
The process disclosed in PCT Publication No. WO 2004/018468 involves the preparation of the intermediate of Formula II by the reaction of a quinazoline bromoxanthine intermediate of Formula III with an R-Boc-amino piperidine intermediate of Formula IV in the presence of potassium carbonate in an N,N-dimethylformamide solvent, followed by purification using column chromatography.
Figure imgf000003_0001
Formula III Formula IV
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 inventors have found that the preparation of the fert-butyloxycarbonyl protected intermediate of Formula II, as per the process disclosed in PCT Publication No. WO 2004/018468, results in the formation of 1.19% of a quinazoline dimethyl aminoxanthine impurity of Formula V appearing at a relative retention time (RRT) of 0.65.
Figure imgf000003_0002
Formula V
Thus, there exists a need for an industrially advantageous process for the preparation of linagliptin that controls the formation of the quinazoline dimethyl aminoxanthine impurity of Formula V to pharmaceutically acceptable levels. Summary of the Invention
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
Figure imgf000004_0001
Formula II
comprising reacting the intermediate of Formula III
Figure imgf000004_0002
Formula III
with the intermediate of Formula IV
Figure imgf000004_0003
Formula IV
using sodium carbonate. A second aspect of the present invention provides a process for the preparation of a fert-butyloxycarbonyl protected intermediate of Formula II
Figure imgf000005_0001
Formula II
comprising reacting an intermediate of Formula III
Figure imgf000005_0002
Formula III
with an intermediate of Formula IV
Figure imgf000005_0003
Formula IV
using sodium carbonate in N-methyl-2-pyrrolidone.
A third aspect of the present invention provides a process for the preparation of linagliptin of Formula I
Figure imgf000005_0004
Formula I
comprising the steps of: reacting an intermediate of Fonnula III
Figure imgf000006_0001
Formula III
with an intermediate of Fonnula IV
Figure imgf000006_0002
Formula IV
using sodium carbonate to obtain an intennediate of Fonnula II; and
Figure imgf000006_0003
Formula II
b) converting the intennediate of Fonnula II into linagliptin of Fonnula I.
A fourth aspect of the present invention provides a process for the preparation of linagliptin of Fonnula I
Figure imgf000006_0004
Formula I
comprising the steps of: a) reacting an intermediate of Formula III
Figure imgf000007_0001
Formula III
with an intermediate of Formula IV
Figure imgf000007_0002
Formula IV
using sodium carbonate in N-methyl-2-pyrrolidone to obtain an intermediate of Formula II; and
Figure imgf000007_0003
Formula II
b) converting the intermediate of Formula II into linagliptin of Formula 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
Figure imgf000008_0001
Formula V
comprising reacting a quinazoline bromoxanthine of Formula III
Figure imgf000008_0002
Formula III
with dimethyl amine in the presence of sodium carbonate in N,N-dimethylformamide.
Detailed Description of the Invention
Various aspects and embodiments of the present invention are described hereafter.
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.
The term "about", as used herein, refers to any value which lies within the range defined by a variation of up to ± 10% of the value.
The term "ambient temperature", as used herein, refers to a temperature in the range of about 20°C to about 35°C.
The term "substantially free", as used herein, 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. On the basis of various experiments carried out for controlling the formation of the impurity of Formula V, 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 Ν,Ν-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. , Ν,Ν-dimethylformamide, controlled the formation of the quinazoline dimethyl aminoxanthine impurity of Formula V.
However, when both the base and the solvent were changed, in addition to controlling the formation of the quinazoline dimethyl aminoxanthine impurity of Formula V, the reaction also occurred at a lower temperature. Table 1 summarizes the results of the various experiments carried out by the present inventors.
Table 1: Experiments carried out for controlling the impurity of Formula V
Figure imgf000009_0001
As is evident from Experiment 1, Experiment 2, and Experiment 3 provided in
Table 1, preparation of the intermediate of Formula II in the presence of sodium carbonate controlled the formation of the quinazoline dimethyl aminoxanthine impurity of Formula V. Preparation of the intermediate of Formula II in the presence of sodium carbonate in N-methyl-2-pyrrolidone is industrially advantageous as the reaction occurred at a lower temperature. Thus, in the processes of the present invention, the reaction of the intermediate of Formula III with the intermediate of Formula IV to obtain the fert-butyloxycarbonyl protected intermediate of Formula II is carried out in the presence of sodium carbonate in N-methyl-2-pyrrolidone .
The reaction of the intermediate of Formula III with the intermediate of Formula
IV is carried out at a temperature of about 60°C to about 95°C. In a preferred embodiment of the present invention, the 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. Examples of nitriles include acetonitrile, propionitrile, or mixtures thereof. Examples of ketones include acetone, ethyl methyl ketone, methyl z'so-butyl ketone, or mixtures thereof.
In a preferred embodiment of the present invention, the intermediate of Formula II is purified by crystallization in acetonitrile.
In another preferred embodiment of the present invention, the intermediate of
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.
In general, the conversion of the intermediate of Formula II into linagliptin of
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.
In the preferred embodiments of the present invention, 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.
Methods
The NMR spectrum was recorded using a Bruker®Avance III 400 MHz.
The Mass spectrum was recorded using an AB SCIEX® QTRAP® 2000.
The HPLC purity was determined using a Kromasil®C18 (250 x 4.6 mm), 5 μιη 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 μί; Run time: 50 minutes.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents may be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
EXAMPLES
Comparative Examples
Comparative Example 1 : Preparation of ferZ-butyloxycarbonyl protected intermediate (Formula ID in the presence of potassium carbonate in N.N-dimethylformamide
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. On completion, 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.
Yield: 91.2%
HPLC Purity: 95.75%
Impurity of Formula V : 1.19%
Comparative Example 2: Preparation of ferf-butyloxycarbonyl protected intermediate (Formula ID in the presence of sodium carbonate in N.N-dimethylformamide
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. On completion, 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 solid was dissolved in dichloromethane (1 125 mL), and the organic and aqueous layers were separated. Activated carbon (7.5 g) was added to the organic layer. The contents were stirred at ambient temperature for 30 minutes, and then filtered through a Hyflo® bed. The solvent was removed by distillation under reduced pressure to obtain the intermediate of Formula II.
Yield: 89%
HPLC Purity: 97.79%
Impurity of Formula V: 0.63%
Working Examples
Working Example 1 : Preparation of ferf-butyloxycarbonyl protected intermediate (Formula II) in the presence of sodium carbonate in N-methyl-2-pyrrolidone
Quinazoline bromoxanthine (Formula III; 140 g), R-Boc-aminopiperidine (Formula IV; 68 g), and sodium carbonate (66 g) were added into a reaction vessel containing N-methyl-2-pyrrolidone (560 mL) at ambient temperature. The reaction mixture was heated to 85°C to 90°C and stirred for 8 hours. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to 26°C and water (1 120 mL) was added at 26°C to 40°C. The reaction mixture was stirred at 30°C to 35°C for 30 minutes. The solid obtained was filtered and washed with water (700 mL) to obtain a wet solid (910 g).
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.
Yield: 86%
HPLC Purity: 99.95%
Impurity of Formula V: Not detected
Working Example 2: Preparation of ferf-butyloxycarbonyl protected intermediate
(Formula II) in the presence of sodium carbonate in N-methyl-2-pyrrolidone
Quinazoline bromoxanthine (Formula III; 10 g), R-Boc-aminopiperidine (Formula IV; 4.86 g), and sodium carbonate (4.68 g) were added into a reaction vessel containing N- methyl-2-pyrrolidone (40 mL) at ambient temperature. The reaction mixture was heated to 85°C to 90°C and stirred for 12 hours. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to 40°C and deionized water ( 120 mL) was added at 40°C to 45°C. The reaction mixture was stirred for 1 hour. The solid obtained was filtered and washed with water (150 mL) to obtain a wet solid (Impurity of Formula V: 0.04%).
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.
Yield: 83% HPLC Purity: 99.94%
Impurity of Formula V: Not detected
Working Example 3 : Preparation of Linagliptin (Formula I)
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.
Yield: 79%
HPLC Purity: 99.83%
Working Example 4: Preparation of quinazoline dimethyl aminoxanthine impurity (Formula V)
Quinozoline bromoxanthine (Formula III; lg), N,N-dimethylformamide (7.6 mL), and sodium carbonate (0.5 g) were added into a reaction vessel at 25°C to 30°C under a nitrogen atmosphere. Dimethyl amine (7.5 mL) was added into the reaction vessel at 25°C to 30°C under a nitrogen atmosphere. The temperature of the reaction mixture was raised to 50°C to 55°C, and the reaction mixture was stirred for 24 hours. The progress of the reaction was monitored by HPLC. Water (80 mL) was added to the reaction mixture at ambient temperature, and the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered to obtain a solid. The solid was washed with water (20 mL), and then dried in a hot air oven at 35°C to 40°C for 3 hours to obtain quinazoline dimethyl aminoxanthine.
Yield: 71.66%
1H NMR (400 MHz, DMSO), δ (in ppm): 1.78 (t, 3H), 2.89 (s, 3H), 3.11 (t, 6H), 3.40 (s, 3H), 4.99 (s, 2H), 5.31 (s, 2H), 7.66-8.26 (m, 4H).
Mass: 418.2 [M + H]+; MS/MS: 418.2, 365.2, 350.1, 336.1, 208.1, 167.0, 158.0, 139.1.
IR in KBr, (in cm"1): 2222 (HCHCH stretching), 1695 (-C=N stretching), 1662 (-C=0 stretchings), 735, 760 (aryl C-H bendings).

Claims

We claim :
1. A process for the preparation of the fert-butyloxycarbonyl protected intermediate of Formula II
Figure imgf000016_0001
Formula II
comprising reacting the intermediate of Formula III
Figure imgf000016_0002
Formula III
with the intermediate of Formula IV
Figure imgf000016_0003
Formula IV
using sodium carbonate.
2. A process for the preparation of a fert-butyloxycarbonyl protected intermediate of Formula II
Figure imgf000016_0004
Formula II
comprising reacting an intermediate of Formula III
Figure imgf000017_0001
Formula III
with an intermediate of Formula IV
Figure imgf000017_0002
Formula IV
sodium carbonate in N-methyl-2-pyrrolidone.
3. A process for the preparation of linagliptin of Formula I
Figure imgf000017_0003
Formula I
comprising the steps of:
a) reacting an intermediate of Fonnula III
Figure imgf000017_0004
Formula III
with an intermediate of Formula IV
σ ΝΗ
BOC
Formula IV
using sodium carbonate to obtain an intermediate of Formula II; and
Figure imgf000018_0001
Formula II
b) converting the intennediate of Formula II into linagliptin of Formula I. A process for the preparation of linagliptin of Fonnula I
Figure imgf000018_0002
Formula I
comprising the steps of:
a) reacting an intennediate of Fonnula III
Figure imgf000018_0003
Formula III
with an intennediate of Fonnula IV
Figure imgf000018_0004
Formula IV
using sodium carbonate in N-methyl-2-pyrrolidone to obtain an intennediate of Fonnula II; and
Figure imgf000019_0001
Formula II
b) converting the intermediate of Formula II into linagliptin of Formula I. 5. The process according to any of claims 1-4, wherein the reaction of the intermediate of Formula III with the intermediate of Formula IV is carried out at a temperature of about 60°C to about 95°C.
6. The fert-butyloxycarbonyl protected intermediate of Formula II having an HPLC purity greater than 99%.
7. The fert-butyloxycarbonyl protected intermediate of Formula II substantially free of the quinazoline dimethyl aminoxanthine impurity of Formula V
Figure imgf000019_0002
Formula V.
8. Linagliptin of Formula I substantially free of the quinazoline dimethyl aminoxanthine impurity of Formula V.
9. A process for the preparation of the quinazoline dimethyl aminoxanthine impurity of Formula V
Figure imgf000019_0003
Formula V
comprising reacting a quinazoline bromoxanthine of Formula III
Figure imgf000020_0001
Formula III
with dimethyl amine in the presence of sodium carbonate in N,N-dimethylformamide.
10. The process according to claim 10, wherein the reaction is carried out at ambient temperature to about 80°C.
PCT/IB2014/063132 2013-07-23 2014-07-15 Process for the preparation of linagliptin and an intermediate thereof Ceased WO2015011609A1 (en)

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