CLIAMS:1. A process for the preparation of intermediate of Anagliptin, amino pyrrolidine of Formula II:

Formula II

or pharmaceutically acceptable salt thereof, which comprises:

a) protection of 1-amino-2-methyl propanamine with Boc-anhydride in presence of dichloromethane to provide 1-tert-butoxycarbonylamino-2-methyl-2-propanamine of formula V;

Formula V

b) condensation of the compound of formula V with (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile of formula IV

Formula IV
in presence of organic base to provide Boc-aminopyrrolidine of formula III; and

Formula III

c) deprotection of compound of formula III using acid in presence of alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof.

2. The process of claim 1, wherein the protection of step a) is performed at 5-10 °C.

3. The process of claim 1, wherein the compound of formula V having less than 1% of dimer of diamine impurity.

4. The process of claim 1, wherein the condensation of step b) is performed in presence of dichloromethane.

5. The process of claim 1, wherein the organic base is diisopropylamine.

6. The process of claim 1, wherein the acid is hydrochloric acid and alcohol is isopropyl alcohol.

7. The process of claim 1, wherein the compound of formula II is having greater than or equal to 98% purity and dimer impurity less than or equal to 1%.

8. The process of claim 1, wherein the compound of formula II is further converted to Anagliptin or a pharmaceutically acceptable salt thereof.

9. A process for the aminopyrrolidine of Formula II

Formula II

or pharmaceutically acceptable salt thereof, which comprises:

a) condensation of 1-tert-butoxycarbonylamino-2-methyl-2-propanamine with (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile of formula IV:

Formula IV

in presence of organic base to provide Boc-aminopyrrolidine of formula III; and

Formula III

b) deprotection of compound of formula III using acid in presence of alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof.

10. The process of claim 9, wherein the organic base is diisopropylamine. ,TagSPECI:Field of Invention

Aspects of the present invention relates to a process for the preparation of Anagliptin, intermediates thereof, or a pharmaceutically acceptable salt thereof.

Background of the invention

The drug compound having the adopted name “Anagliptin” has chemical name: N-[2 - ({2 - [(2S)-2-Cyanopyrrolidin-1-yl]-2-oxoethyl} amino)-2-methylpropyl]-2-methylpyrazolo [1,5-a] pyrimidine-6-carboxamide; and has the structural formula I:

Formula I

The pharmaceutical product Suini® tablets contains Anagliptin as active ingredient. Anagliptin is DPP-4 (dipeptidyl peptidase-4) inhibitor useful for the treatment of diabetes.

U.S.Pat.No. 7,345,180 describes Anagliptin and process for the preparation thereof. The process of US ‘180 involves reaction of (S)-1-[(2-amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloride with 2-methylpyrazole [1,5-a]pyrimidin-6-yl acid in presence of triethylamine and tetrahydrofuran.

Kato Noriyasu et al., in Bioorganic & Medicinal Chemistry, 19(23), 7221-7227; 2011 discloses a process for the preparation of amino pyrrolidine, which involves reaction of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile with 1-tert-Butoxycarbonylamino-2-methyl-2-propanamine using potassium carbonate in presence of sodium iodide and acetone to provide [2-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-2-methylpropyl]- carbamic acid tert-butyl ester, which is deprotected using hydrochloric acid in presence of dioxane and dichloromethane to provide aminopyrrolidine. However, the reported process suffer from disadvantages including use of number of reagents, solvents, and yields low purity for the key intermediate due the formation of impurities, which may be present as impurity in active ingredient, Anagliptin. Hence, removal of impurities may require tedious purification process at final API or its intermediate stages.

The reported processes for intermediates as well as Anagliptin make the process expensive and industrially unviable.

Therefore, there is a need to develop an improved and industrially feasible process for preparing Anagliptin, intermediates thereof, or a pharmaceutically acceptable salt thereof to eliminate or to reduce the formation of impurities.

Summary of the Invention

The present invention provides a process for the preparation of Anagliptin, intermediates thereof, or pharmaceutically acceptable salt thereof.

In an aspect, the present invention is to provide a process for the preparation of intermediate of Anagliptin, amino pyrrolidine of Formula II:

Formula II

or pharmaceutically acceptable salt thereof, which comprises:

a) protection of 1-amino-2-methyl propanamine with Boc-anhydride in presence of dichloromethane to provide 1-tert-butoxycarbonylamino-2-methyl-2-propanamine of formula V;

Formula V

b) condensation of the compound of formula V with (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile of formula IV

Formula IV

in presence of organic base to provide Boc-aminopyrrolidine of formula III; and

Formula III

c) deprotection of compound of formula III using acid in presence of alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a process for the aminopyrrolidine of Formula II

Formula II

or pharmaceutically acceptable salt thereof, which comprises:

a) condensation of 1-tert-butoxycarbonylamino-2-methyl-2-propanamine with (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile of formula IV:

Formula IV

in presence of organic base to provide Boc-aminopyrrolidine of formula III; and

Formula III

b) deprotection of compound of formula III using acid in presence of alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a process for the preparation of Anagliptin or a pharmaceutically acceptable salt thereof, which comprises:
a) condensation of 1-tert-butoxycarbonylamino-2-methyl-2-propanamine with (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile in presence of organic base to provide Boc-aminopyrrolidine;
b) deprotection of compound of formula III using acid in presence of alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof; and
c) conversion of aminopyrrolidine of formula II to pure Anagliptin or a pharmaceutically acceptable salt.

Description of the Invention

The term “substantially free” as used herein, unless otherwise defined, refers to Anagliptin, an intermediate thereof, or salt thereof that contains dimer pyrrolidine impurity less than 5%.

The intermediates and starting materials of the present invention may be used as free bases or its salts.

The term “pure” as used herein, unless otherwise defined, the compound that has purity of greater than about 95 % or greater than about 98 %.

The salt or pharmaceutically acceptable salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.

In an aspect, the present invention is to provide a process for the preparation of intermediate of Anagliptin, amino pyrrolidine of Formula II:

Formula II

or pharmaceutically acceptable salt thereof, which comprises:

a) protection of 1-amino-2-methyl propanamine with Boc-anhydride in presence of dichloromethane to provide 1-tert-butoxycarbonylamino-2-methyl-2-propanamine of formula V;

Formula V

b) condensation of the compound of formula V with (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile of formula IV

Formula IV

in presence of organic base to provide Boc-aminopyrrolidine of formula III; and

Formula III

c) deprotection of compound of formula III using acid in presence of alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof.

The step a) involves a process for the preparation of 1-tert-butoxycarbonylamino-2-methyl-2-propanamine of formula V.

Reported prior arts, US 7,345,180, WO 2011/075699, WO 2006/060122, WO 2009/047240 WO 2011/026241, and WO 2011/006074, JP 2010/064982, Freire Felix et. al., in Journal of the American Chemical Society, 131(23), 7970-7972; 2009, Isfort, Christian Schulze et al., in Chemistry - A European Journal, 13(8), 2344-2357; 2007, disclose processes for the compound of formula V. However, the reported processes suffers one or the other problems like formation of impurities, longer duration of reaction, use of number of solvents, use of bases, etc.. and made the process expensive.

The present inventors developed a simple and inexpensive process for intermediate of formula V, which comprises reaction of 1-amino-2-methyl propanamine with Boc-anhydride in presence of dichloromethane at below 15 °C, particularly at 5-10 °C. Further, the process of the present invention for formula V reduces/removes the formation of impurities, for example, dimer of diamine of formula B. The process of the present invention directly provides pure compound of formula V free from dimer of diamine impurity without purification step.

Dimer of diamine of formula B:

Formula B

Furthermore, the present invention provides simple process and the reaction completes in shorter period of time, for example, less than 5 hours.
The reaction of step a) involves addition of Boc-anhydride at 5 to 10 °C to the reaction mixture containing diamine and dichloromethane for a period of 10 minutes to 30 minutes or more to avoid exothermic reaction. The reaction may be maintained for 30 minutes to 1 hour or more at below 15 °C and then maintained for 1 to 3 hours at room temperature to avoid the formation of impurities.

After completion of the reaction, the reaction mixture may be combined with water, separated organic layer and then concentrated completely or subjected for isolation of solid.

The compound of formula V of the present invention may be formed in-situ and then used directly for further reaction.

In an embodiment, the present invention provides the compound of Formula V having less than 1% or less than 0.5% or less than 0.1% of dimer of diamine impurity.

The step b) involves condensation of the compound of formula V with (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile of formula IV in presence of organic base to provide Boc-aminopyrrolidine of formula III.

Reported processes for preparing the compound of formula III in the prior art, for example, Kato Noriyasu et al., in Bioorganic & Medicinal Chemistry, 19(23), 7221-7227; 2011 and US 7,345,180, involves condensation using potassium carbonate in presence of acetone. However, the prior art process has disadvantages including formation of dimer of pyrrolidine of Formula A more than 10%.

The process of the present invention provides a simple and inexpensive process for preparing the compound of formula III and reduces formation of dimer impurity to less than 5%.

The dimer of pyrrolidine of Formula A:

Formula A

The condensation reaction is performed in presence of organic base such as triethyl amine, diisopropyl amine, pyridine, N-methyl pyrrolidine (NMP) and the like. The reaction may be carried out in presence of solvent such as chlorinated solvents like dichloromethane, dichloroethane, chloroform and chlorobenzene.
In an embodiment, the condensation reaction is performed in presence of organic base and dichloromethane.

The reaction of condensation may be conducted in presence of metal catalyst, for example, sodium iodide, potassium iodide, lithium iodide and the like. Preferred catalyst for condensation reaction of the present invention is sodium iodide.

The reaction is conducted at a temperature of about 25 to about 50 °C, or at 35 to 40 °C. The reaction may be maintained for a period of about 1 to 5 hours to complete the reaction without affecting the formation of impurities.

After completion of the reaction, the reaction mixture may be combined with water and then separated layers. The resultant organic layer may be concentrated or subjected for solid isolation.

The step c) involves deprotection of compound of formula III using acid in presence of alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof.

The acid used for deprotection includes but are not limited to inorganic acid such as hydrochloric acid, hydrobromic acid, and the like; organic acid such as acetic acid, formic acid and the like.

The alcohol used is selected from the group of methanol, ethanol, isopropyl alcohol, n-butanol and phenol. In an embodiment, the present invention involves use of the acid is hydrochloric acid and the alcohol is isopropyl alcohol.

The reaction may be carried out at elevated temperature of about 35 to 70 °C or more. The reaction may be maintained at elevated temperature for a period of about 1 to 5 hours or more. The resultant reaction mixture may be cooled to below 15 °C or below 10 °C and maintained for a period of about 30 minutes or more to increase the precipitation of solid.

The resultant compound of formula II of the present invention may have the purity greater than 98 % and dimer impurity less than 3% or less than 1%.

In another aspect, the present invention relates to a process for the aminopyrrolidine of Formula II

Formula II

or pharmaceutically acceptable salt thereof, which comprises:

a) condensation of 1-tert-butoxycarbonylamino-2-methyl-2-propanamine with (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile of formula IV:

Formula IV

in presence of organic base to provide Boc-aminopyrrolidine of formula III; and

Formula III

b) deprotection of compound of formula III using acid in presence of alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof.

The condensation reaction is performed in presence of organic base such as diisopropyl amine and in presence of solvent such as dichloromethane at a temperature of about 35 to 40 °C. The reaction of condensation is conducted in presence of metal catalyst, for example, sodium iodide.

After completion of the condensation reaction, the reaction mixture may be combined with water and then separated layers. The resultant organic layer may be concentrated or subjected for solid isolation.

The deprotection of compound of formula III using acid, for example, hydrochloric acid, in presence of isopropyl alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof.

The deprotection reaction may be carried out at elevated temperature of about 35 to 70 °C or more. The reaction may be maintained at elevated temperature for a period of about 1 to 5 hours or more. The resultant reaction mixture may be cooled to below 15 °C or below 10 °C and maintained for a period of about 30 minutes or more to increase the precipitation of solid.

The resultant compound of formula II of the present invention may have the purity greater than 98 % and dimer impurity less than 3% or less than 1%.

In another aspect, the present invention relates to a process for the preparation of Anagliptin or a pharmaceutically acceptable salt thereof, which comprises:
a) condensation of 1-tert-butoxycarbonylamino-2-methyl-2-propanamine with (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile in presence of organic base to provide Boc-aminopyrrolidine;
b) deprotection of compound of formula III using acid in presence of alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof; and
c) conversion of aminopyrrolidine of formula II to pure Anagliptin or a pharmaceutically acceptable salt.

The process of the present invention reduces formation of dimer impurity to less than 5%. The condensation reaction is performed in presence of organic base such as such as diisopropyl amine, and in the presence of solvent such as dichloromethane.

The deprotection of compound of formula III using acid such as hydrochloric acid in presence of alcohol such as isopropyl alcohol to provide aminopyrrolidine of Formula II or pharmaceutically acceptable salt thereof at an elevated temperatures.

The resultant compound of formula II is useful for the preparation of Anagliptin or a pharmaceutically acceptable salt thereof. The process of Anagliptin is schematically presented in the following scheme 1:

SCHEME-1

The resultant Anagliptin or a pharmaceutically acceptable salt thereof obtained from the present invention is useful for pharmaceutical composition.

In another aspect, the present invention relates to pharmaceutical composition comprising Anagliptin or a pharmaceutically acceptable salt, which is substantially free from its dimer pyrrolidine impurity, and pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, subcutaneously, intramuscularly or topically for the treatment of type 2 diabetes in a mammal in need thereof.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES
Example 1: A process for preparing Boc-aminopyrrolidine

To the mixture of 1-amino-2-methyl propanamine (500 gm) in dichloromethane (2.5 L) at 5-10 °C was added Boc-anhydride solution slowly (310 gm in 0.5 L dichloromethane). The reaction mixture was maintained at the same temperature for 1 hour. After 1 hour, reaction mixture was brought to 25-30 °C and maintained for 3 hours. To the reaction mixture, water (1.5 L) was added and continued stirring. After 30 minutes, separated organic layer and distilled the solvent to get 1-tert-butoxycarbonylamino-2-methyl-2-propanamine residue in dichloromethane.

To the above residue, dichloromethane (3.5 L), (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (chloro pyrrolidine) (400 gm), sodium iodide (334 gm), and diisopropyl amine (226 gm) were added. The reaction mixture was heated to 35-40 °C and maintained for 5 hours. The reaction mixture was cooled to 25-30 °C and water (2.5 L) was added and stirred the solution for 30 minutes. The organic layer was separated and distill-off the solvent to get the title compound (850 gm).

HPLC purity: >90 % and dimer impurity 2.5%.

Example-2: A process for preparing amino pyrrolidine

To the mixture of Boc-aminopyrrolidine (100 gm) in isopropyl alcohol (1000 ml), aqueous hydrochloric acid (80.4 gm) were added. The reaction mixture was heated to 60-65 °C and maintained for 5 hours. The mixture was cooled to 40-45 °C and then added isopropyl alcohol (200 ml). The mixture was further cooled to 5-10 °C and maintained for 2 hours. The solid was filtered and washed with chilled isopropyl alcohol to get pure amino pyrrolidine dihydrochloride (72.1 gm).
HPLC purity: 98% and dimer impurity 1%.