WO2015087240A1 - 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
WO2015087240A1
WO2015087240A1 PCT/IB2014/066734 IB2014066734W WO2015087240A1 WO 2015087240 A1 WO2015087240 A1 WO 2015087240A1 IB 2014066734 W IB2014066734 W IB 2014066734W WO 2015087240 A1 WO2015087240 A1 WO 2015087240A1
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Prior art keywords
intermediate
formula
methyl
formula ii
preparation
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PCT/IB2014/066734
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French (fr)
Inventor
Suresh Babu Jayachandra
Udaibhan Singh GAHLOT
Raghuram Morampudi
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Ranbaxy Laboratories Limited
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Priority to IN3607/DEL/2013 priority
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Publication of WO2015087240A1 publication Critical patent/WO2015087240A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/02Heterocyclic compounds containing purine ring systems with oxygen, sulfur or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04Heterocyclic compounds containing purine ring systems with oxygen, sulfur or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06Heterocyclic compounds containing purine ring systems with oxygen, sulfur 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

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-[(3i?)-3-amino-l- piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-memyl-2-quinazolinyl)methyl]. Its chemical structure is depicted below as Formula I.

Figure imgf000002_0001

Formula I

l-[(4-Memyl-2-quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine of Formula II is one of the key intermediates used for the preparation of linagliptin.

Figure imgf000002_0002

Formula II

U.S. Patent No. 7,550,455 discloses a process for the preparation of the intermediate of Formula II by the reaction of a 2-chloromethyl-4-methylquinazoline intermediate of Formula III with a 3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine intermediate of Formula IV in the presence of potassium carbonate in N- methylpyrrolidone .

Figure imgf000003_0001

Formula III Formula IV

U.S. Patent No. 7,820,815 discloses a process for 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 anhydrous sodium carbonate in N-methyl-2- pyrrolidone.

PCT Publication No. WO 2013/074817 discloses a process for 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 a base and a phase transfer catalyst in a mixture of N-methylpyrrolidone and toluene.

PCT Publication No. WO 2013/098775 and Indian Patent Application No.

2090/CHE/2011 disclose processes for 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 potassium carbonate in Ν,Ν-dimethylacetamide or N,N- dimethylformamide.

The present inventors have observed that the preparation of the intermediate of Formula II by the reported processes is accompanied by the formation of impurities appearing at relative retention times (RRT) of 1.03, 1.18, and 1.47. The removal of these impurities is difficult, and the presence of these impurities in the intermediate of Formula II impacts the description and purity of linagliptin of Formula I.

Thus, there exists a need for an industrially advantageous process for the preparation of the intermediate of Formula II that controls the formation of the impurities appearing at relative retention times of 1.03, 1.18, and 1.47 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 substantially free of the impurities appearing at relative retention times (RRT) of 1.03, 1.18, and 1.47. 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 a base and a phase transfer catalyst in N,N- dimethylformamide.

A first aspect of the present invention provides a process for the preparation of 1- [(4-methyl-2-quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine of Formula II

Figure imgf000004_0001

Formula II

comprising reacting an intermediate of Formula III

Figure imgf000004_0002

Formula III

with an intermediate of Formula IV

Figure imgf000004_0003

Formula IV

in the presence of a base and a phase transfer catalyst in N,N-dimethylformamide. A second aspect of the present invention provides a process for the preparation of l-[(4-methyl-2-quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine 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

in the presence of potassium carbonate and a phase transfer catalyst in N,N- dimethylformamide .

A third aspect of the present invention provides a process for the preparation of 1-

[(4-methyl-2-quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine of Formula II

Figure imgf000006_0001

Formula II

comprising reacting an intermediate of Fonnula III

Figure imgf000006_0002

with an intermediate of Formula IV

Figure imgf000006_0003

Formula IV

in the presence of potassium carbonate and tetrabutvlammonium bromide in N.N- dimethylformamide .

A fourth aspect of the present invention provides a process for the preparation of linagliptin of Formula I

Figure imgf000006_0004

Formula I comprising the steps of:

a) reacting an intermediate of Formula III

Figure imgf000007_0001

Formula III

intermediate of Formula IV

Figure imgf000007_0002

Formula IV

in the presence of a base and a phase transfer catalyst in N,N- dimethylformamide to obtain an intermediate of Formula II;

Figure imgf000007_0003

Formula II

and

b) converting the intermediate of Formula II into linagliptin of Formula I.

A fifth aspect of the present invention provides l-[(4-methyl-2- quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxantliine of Formula II substantially free of an impurity appearing at an RRT of 1.03.

A sixth aspect of the present invention provides l-[(4-methyl-2- quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine of Formula II substantially free of an impurity appearing at an RRT of 1.18. A seventh aspect of the present invention provides l-[(4-methyl-2- quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine of Formula II substantially free of an impurity appearing at an RRT of 1.47.

Detailed Description of the Invention

The following abbreviations are used in the present invention:

NMP N-Methylpyrrolidone

DMF N,N-Dimethylformamide

TBAB Tetrabutylammonium bromide

Various aspects and embodiments of the present invention are described hereafter.

The term "about," as used herein, refers to any value which lies within the range defined by a number 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 l-[(4-methyl-2- quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine of Formula II having less than 0.05% of impurities appearing at an RRTs of 1.03, 1.18, and/or 1.47.

In one embodiment of the present invention, the l-[(4-methyl-2- quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine of Formula II contains 0.02% of the impurity appearing at an RRT of 1.03.

In another embodiment of the present invention, the l-[(4-methyl-2- quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine of Formula II does not contain any detectable amount of the impurity appearing at an RRT of 1.18.

In yet another embodiment of the present invention, the l-[(4-methyl-2- quinazolinyl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine of Formula II does not contain any detectable amount of the impurity appearing at an RRT of 1.47.

The 2-chloromethyl-4-methylquinazoline intermediate of Formula III and the 3- methyl-7-(2-butyn-l-yl)-8-bromoxanthine intermediate of Formula IV may be prepared by processes known in the literature, such as that disclosed in U.S. Patent No. 7,407,955. The present inventors have studied the effect of the use of various bases and solvents on the purity of the intermediate of Formula II. On the basis of the several experiments carried out for controlling the formation of the impurities appearing at RRTs of 1.03, 1.18, and 1.47 in the intermediate of Formula II, the present inventors have surprisingly found that the formation of these impurities in the intermediate of Formula II is controlled to pharmaceutically acceptable levels by reacting the intermediate of Formula III with the intermediate of Formula IV in the presence of potassium carbonate and a phase transfer catalyst in N,N-dimethylformamide. The present inventors have further found that the use of a phase transfer catalyst in the preparation of the intermediate of Formula II is advantageous as it controls the formation of these impurities, and in addition to this, it also lowers the reaction temperature and increases the yield of the reaction. Table 1 summarizes the results of the various experiments carried out by the present inventors for controlling the formation of these impurities in the intermediate of Formula II.

Table 1: Experiments carried out for controlling the impurities appearing at relative retention times (RRT) of 1.03, 1.18, and 1.47

Figure imgf000009_0001

As is evident from Experiment 1, Experiment 2, and Experiment 3 provided in Table 1, 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 potassium carbonate and a phase transfer catalyst in Ν,Ν-dimethylformamide controlled the formation of the impurities appearing at RRTs of 1.03, 1.18, and 1.47. However, when the preparation is carried out in the presence of sodium carbonate in N-methylpyrrolidone (Experiment 1), or potassium carbonate in N,N-dimethylformamide in the absence of a phase transfer catalyst (Experiment 2), larger quantities of the impurities appeared at RRTs of 1.03, 1.18, and 1.47. In the process of the present invention, the reaction of the intermediate of Formula

III with the intermediate of Formula IV to obtain the intermediate of Formula II is carried out in the presence of potassium carbonate and a phase transfer catalyst in N,N- dimethylformamide .

The reaction of the intermediate of Formula III with the intermediate of Formula

IV is carried out at a temperature of about 40°C to about 65 °C for about 10 hours to about 30 hours. 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 50°C to about 55°C for about 20 hours.

Isolation of the intermediate of Formula II is carried out by concentration, then filtration, followed by drying under reduced pressure at ambient temperature to about 100°C for about 30 minutes to about 20 hours.

The process of the present invention provides the intermediate of Formula II substantially free of the impurities appearing at RRTs of 1.03, 1.18, and/or 1.47.

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 by the processes disclosed in U.S. Patent Nos. 7,407,955 and 7,820,815; PCT Publication Nos. WO 2013/074817 and WO 2013/098775; and Indian Patent Application No. 2090/CHE/2011.

Methods

The High Performance Liquid Chromatographic (HPLC) purity was determined using a Kromasil® C18 (250 x 4.6 mm) 5μπι 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 aspects and 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 Example 1 : Preparation of l-r(4-methyl-2-quinazolinyl)methyll-3-methyl-7- (2-butyn-l-yl)-8-bromoxanthine (Formula ID in the presence of sodium carbonate in N- methylpyrrolidone

N-methylpyrrolidone (200 mL), 2-chloromethyl-4-methylquinazoline (Formula III;

35.5 g), sodium carbonate (19.6 g), and 3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine (Formula IV; 50 g) were added into a reaction vessel at ambient temperature. The reaction mixture was heated to 125°C to 135°C, then stirred for 4 hours. The progress of the reaction was monitored by HPLC. The reaction mixture was cooled to ambient temperature, then deionized water (400 mL) was added. The reaction mixture was stirred for 30 minutes, filtered, then washed with deionized water (1000 mL).

The wet material was charged in denatured spirit (500 mL), heated to 75 °C, and stirred at 75°C to 77°C for 1 hour. The reaction mixture was cooled to ambient temperature, stirred for 120 minutes, filtered, washed with denatured spirit (100 mL), and dried under reduced pressure at 45°C to 50°C for 12 hours to obtain the intermediate of Formula II.

Yield: 77%

Impurity appearing at 1.03 RRT: 0.52%

Impurity appearing at 1.18 RRT: 0.18%

Impurity appearing at 1.47 RRT: 0.62%

Comparative Example 2: Preparation of l-r(4-methyl-2-quinazolinyl)methyll-3-methyl-7- (2-butvn-l-yl)-8-bromoxanthine (Formula II) in the presence of potassium carbonate in N.N-dimethylformamide

N,N-dimethylformamide (15 mL), 2-chloromethyl-4-methylquinazoline (Formula III; 1.4 g), potassium carbonate (1.5 g), and 3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine (Formula IV; 2 g) were added into a reaction vessel at ambient temperature. The reaction mixture was heated to 110°C to 120°C, and then stirred for 3.5 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was cooled to ambient temperature, and then deionized water (10 mL) was added. The reaction mixture was stirred for 1 hour and 30 minutes, filtered, washed with deionized water (10 mL), and dried under reduced pressure at 45°C to 50°C for 10 hours to obtain the intermediate of Formula II.

Yield: 83%

Impurity appearing at 1.03 RRT: 0.31%

Impurity appearing at 1.18 RRT: 0.56%

Impurity appearing at 1.47 RRT: 0.11%

Working Example: Preparation of 1 (4-methyl-2-quinazolinyl)methyll-3-methyl-7-(2- butvn-l-yl)-8-bromoxanthine (Formula II) in the presence of potassium carbonate and a phase transfer catalyst in N.N-dimethylformamide

N,N-dimethylformamide (750 mL), 2-chloromethyl-4-methylquinazoline (Formula

III; 93 g), potassium carbonate (63.9 g), 3-methyl-7-(2-butyn-l-yl)-8-bromoxanthine (Formula IV; 125 g), and tetrabutylammonium bromide (13.56 g) were added into a reaction vessel at ambient temperature. The reaction mixture was heated to 50°C to 55°C, then stirred for 20 hours. The progress of the reaction was monitored by HPLC. The reaction mixture was cooled to ambient temperature, and then deionized water (1500 mL) was added. The reaction mixture was stirred for about 2 hours, filtered, and then washed with deionized water (625 mL). The wet material was charged in denatured spirits (1250 mL), heated to 75°C, and then stirred at 75°C to 77°C for 1 hour. The reaction mixture was cooled to ambient temperature, stirred for 120 minutes, filtered, and dried under reduced pressure at 55°C to 60°C for 12 hours to obtain the intermediate of Formula II.

Yield: 86%

Impurity appearing at 1.03 RRT: 0.02%

Impurity appearing at 1.18 RRT: Not detected

Impurity appearing at 1.47 RRT: Not detected

Claims

We claim:
1. A process for the preparation of l-[(4-methyl-2-quinazolinyl)methyl]-3-methyl-7- (2-butyn- 1 -yl)-8-bromoxanthine of Formula II
Figure imgf000013_0001
Formula II
comprising reacting an intermediate of Formula III
Figure imgf000013_0002
with an intermediate of Formula IV
Figure imgf000013_0003
Formula IV
in the presence of a base and a phase transfer catalyst in N,N-dimethylformamide.
2. A process for the preparation of linagliptin of Formula I
Figure imgf000013_0004
comprising the steps of:
a) reacting an intermediate of Formula III
Figure imgf000014_0001
Formula III
with an intermediate of Formula IV
Figure imgf000014_0002
Formula IV
in the presence of a base and a phase transfer catalyst in N,N- dimethylformamide to obtain an intermediate of Formula II;
Figure imgf000014_0003
Formula II
and
b) converting the intermediate of Formula II into linagliptin of Formula I.
3. The process according to claim 1 or claim 2, wherein the reaction of the intermediate of Formula III with the intermediate of Formula IV is carried out at a temperature of about 40°C to about 65°C.
4. The process according to claim 1 or claim 2, wherein the base is potassium carbonate.
5. The process according to claim 1 or claim 2, wherein the phase transfer catalyst is tetrabutylammonium bromide.
6. The intermediate of Formula II, substantially free of an impurity appearing at a relative retention time of 1.03.
7. The intermediate of Formula II, substantially free of an impurity appearing at a relative retention time of 1.18.
8. The intermediate of Formula II, substantially free of an impurity appearing at a relative retention time of 1.47.
PCT/IB2014/066734 2013-12-11 2014-12-09 Process for the preparation of linagliptin and an intermediate thereof WO2015087240A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US7550455B2 (en) 2003-11-27 2009-06-23 Boehringer Ingelheim International Gmbh 8-(piperazin-1yl)- and 8-([1,4]diazepan-1yl)-xanthines, the preparation thereof and their use as pharmaceutical composition
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
WO2013074817A1 (en) 2011-11-16 2013-05-23 Assia Chemical Industries Ltd. Solid state forms of linagliptin
WO2013098775A1 (en) 2011-12-28 2013-07-04 Dr. Reddy's Laboratories Limited Improved process for preparation of pure linagliptin

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US7550455B2 (en) 2003-11-27 2009-06-23 Boehringer Ingelheim International Gmbh 8-(piperazin-1yl)- and 8-([1,4]diazepan-1yl)-xanthines, the preparation thereof and their use as pharmaceutical composition
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
WO2013074817A1 (en) 2011-11-16 2013-05-23 Assia Chemical Industries Ltd. Solid state forms of linagliptin
WO2013098775A1 (en) 2011-12-28 2013-07-04 Dr. Reddy's Laboratories Limited Improved process for preparation of pure linagliptin

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