Process For Preparation of Imeglimin and Salts Thereof

Abstract

The present invention discloses an improved process for the preparation of Imeglimin & salts thereof. More particularly, the present invention discloses chiral resolution of Racemic Imeglimin and its salts which is industrially advantageous and economically significant.

Claims

1. A process for the preparation of an imeglimin HCl compound of formula (I), which process comprises: a) reacting a compound of formula (II) ##STR00022## with a compound of formula (III) in a solvent ##STR00023## in the presence of p-toluene sulphonic acid monohydrate under a suitable condition to obtain a racemic compound of formula (IV), ##STR00024## b) reacting the racemic compound of formula (IV) with a suitable chiral amino acid or its derivative in the presence of a base and a solvent to obtain R-imeglimin L-amino acid salt compound of formula (V) ##STR00025## c) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain imeglimin hydrochloride of formula (I) ##STR00026## and d) optionally purifying the imeglimin hydrochloride of formula (I) obtained in step (c) using an alcoholic solvent.

2. A process for the preparation of an imeglimin HCl compound of formula (I) via resolution of a racemic imeglimin base or an imeglimin HCl, which process comprises the steps of: a) reacting a racemic compound of formula (IV) or a compound of formula (VI) with a suitable chiral amino acid or its derivative in the presence or absence of a base and in the presence of a solvent to obtain R-imeglimin L-amino acid salt compound of formula (V), ##STR00027## b) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain imeglimin hydrochloride of formula (I), and c) optionally purifying the imeglimin hydrochloride of formula (I) obtained in step (b) using an alcoholic solvent.

3. The process as claimed in claim 1, wherein the solvent used in step a) is selected from the group consisting of C.sub.1-C.sub.4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol, water and a mixture thereof.

4. The process as claimed in claim 1, wherein, the chiral amino acid is selected from the group consisting of L-glutamic acid, N-tosyl-L-glutamic acid, L-alanine, L-aspartic acid, L-leucine, L-phenyl alanine, L-tyrosine and, and L-valine.

5. The process as claimed in claim 1, wherein the solvent used in the chiral resolution step is selected from the group consisting of acetonitrile, a C.sub.1-C.sub.4 alcohol, and a mixture thereof.

6. The process as claimed in claim 1, wherein the solvent used in the reaction of the compound of formula (V) with hydrochloric acid is selected from the group consisting of a C.sub.1-C.sub.4 alcohol, and a C.sub.1-C.sub.5 ketone, preferably acetone or methyl ethyl ketone.

7. The process as claimed in claim 1, wherein the solvent used in the purification of the imeglimin hydrochloride of formula (I) is selected from the group consisting of a C.sub.1-C.sub.4 alcohol, water, and a mixture thereof.

8. The process as claimed in claim 1, wherein the chiral amino acid is L-glutamic acid or its derivative.

9. The process as claimed in claim 8, wherein the derivative of L-glutamic acid is selected from the group consisting of N-tosyl-L-glutamic acid and N-sulfonyl-L-glutamic acid.

10. The process for the preparation of the imeglimin HCl compound of formula (I), wherein the process comprising the steps of: ##STR00028## a) reacting a compound of formula (II) ##STR00029## with a compound of formula (III) in a solvent ##STR00030## in the presence of p-toluene sulphonic acid monohydrate under a suitable condition to obtain a racemic compound of formula (IV), ##STR00031## b) reacting the racemic compound of formula (IV) with L-glutamic acid or its derivative in the presence of a base and a solvent to obtain a compound of formula (V); and ##STR00032## c) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain imeglimin hydrochloride of formula (I), and d) optionally purifying the imeglimin hydrochloride of formula (I) obtained in step (c) using an alcoholic solvent.

11. The process as claimed in claim 10, wherein; the derivative of L-glutamic acid is selected from the group consisting of N-tosyl-L-glutamic acid and N-sulfonyl-L-glutamic acid.

12. The process as claimed in claim 2, wherein the chiral amino acid is selected from L-glutamic acid, N-tosyl-L-glutamic acid, L-alanine, L-aspartic acid, L-leucine, L-phenyl alanine, L-tyrosine and, and L-valine.

13. The process as claimed in claim 2, wherein the solvent used in the chiral resolution step is selected from the group consisting of acetonitrile, a C.sub.1-C.sub.4 alcohol, and a mixture thereof.

14. The process as claimed in claim 2, wherein the solvent used in the reaction of the compound of formula (V) with hydrochloric acid is selected from the group consisting of a C.sub.1-C.sub.4 alcohol and a C.sub.1-C.sub.5 ketone.

15. The process as claimed in claim 2, wherein the solvent used in the purification of the imeglimin hydrochloride of formula (I) is selected from the group consisting of a C.sub.1-C.sub.4 alcohol, water, and a mixture thereof.

16. The process as claimed in claim 2, wherein the solvent used in the chiral resolution step is methanol, ethanol, isopropanol, isobutanol or a mixture thereof; the solvent used in the reaction of the compound of formula (V) with hydrochloric acid is selected from the group consisting of methanol, ethanol, isopropanol, isobutanol, acetone, methyl ethyl ketone, and a mixture thereof; and the solvent used in the purification of the imeglimin hydrochloride of formula (I) is selected from the group consisting of methanol, ethanol, isopropanol, isobutanol, water, and a mixture thereof.

17. The process as claimed in claim 2, wherein the chiral amino acid is L-glutamic acid or its derivative.

18. The process as claimed in claim 17, wherein the derivative of L-glutamic acid is selected from the group consisting of N-tosyl-L-glutamic acid and N-sulfonyl-L-glutamic acid.

19. The process as claimed in claim 1, wherein the solvent used in the chiral resolution step is methanol, ethanol, isopropanol, isobutanol or a mixture thereof; the solvent used in the reaction of the compound of formula (V) with hydrochloric acid is selected from the group consisting of methanol, ethanol, isopropanol, isobutanol, acetone, methyl ethyl ketone, and a mixture thereof; and the solvent used in the purification of the imeglimin hydrochloride of formula (I) is selected from the group consisting of methanol, ethanol, isopropanol, isobutanol, water, and a mixture thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0025] In an attempt to develop an improved process for the preparation of Imeglimin HCl and to overcome the disadvantages of prior arts, the present inventors have developed a process which results in high chiral, HPLC purity and good yield of Imeglimin HCl.

[0026] The present invention provides a process for preparation of Imeglimin HCl compound of formula (I), which process comprises; [0027] a) reacting compound of formula (II)

##STR00009## [0028] with compound of formula (III) in a solvent

##STR00010## [0029] in presence of p-toluene sulphonic acid monohydrate under suitable condition to obtain racemic compound of formula (IV),

##STR00011## [0030] b) reacting the racemic compound of formula (IV) with a suitable chiral amino acid or its derivative in the presence of a base and a solvent to obtain R-Imeglimin L-amino acid salt compound of formula (V),

##STR00012## [0031] c) reacting the compound of formula (V) with hydrochloric acid in the presence of solvent to obtain Imeglimin Hydrochloride formula (I), and [0032] d) optionally purifying the Imeglimin Hydrochloride of formula (I) obtained in step (c) using an alcoholic solvent.

[0033] In the embodiment of step, a), the solvent is selected from group consisting of C.sub.1-C.sub.4 alcohol, preferably, methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably, the solvent is isobutanol.

[0034] In the embodiment of step b), the chiral amino acid is selected from the group consisting of L-glutamic acid, N-Tosyl-L-glutamic acid, L-Alanine, L-aspartic acid, L-Leucine, L-phenyl alanine, L-tyrosine and, L-Valine.

[0035] In the embodiment of step b), the solvent is selected from group consisting of C.sub.1-C.sub.4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof and the base is organic base such as triethylamine or inorganic base such as sodium hydroxide.

[0036] In the embodiment step c), the solvent is selected from group consisting of C.sub.1-C.sub.4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof or C.sub.1-C.sub.5 ketone, preferably acetone, methyl ethyl ketone.

[0037] In the embodiment step d), the solvent is selected from group consisting of C.sub.1-C.sub.4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably, the solvent is mixture of methanol and isopropyl alcohol.

[0038] In one of the preferred embodiments, the chiral amino acid is selected from the group consisting of L-glutamic acid or its derivative such as N-tosyl-L-glutamic acid or N-sulfonyl-L-glutamic acid etc.

[0039] Accordingly, the process for preparation of Imeglimin HCl compound of formula (1) is demonstrated herein below in scheme III, using L-amino acid or its derivative as a chiral resolving agent.

##STR00013##

[0040] The starting material i.e. metformin hydrochloride, the compound of formula (II) & compound of formula (III) of the present invention are commercially available. Accordingly, in one of the embodiments, the present invention provides a process for preparation of Imeglimin HCl compound of formula (I)

##STR00014## [0041] comprising steps of: [0042] a) reacting compound of formula (II)

##STR00015## [0043] with compound of formula (III) in a solvent

##STR00016## [0044] in presence of p-toluene sulphonic acid monohydrate under suitable condition to obtain racemic compound of formula (IV),

##STR00017## [0045] b) reacting the racemic compound of formula (IV) with L-Glutamic acid or its derivative in the presence of a base and a solvent to obtain compound of formula (V),

##STR00018## [0046] c) reacting the compound of formula (V) with hydrochloric acid in the presence of solvent to obtain Imeglimin Hydrochloride formula (I), and [0047] d) optionally purifying the Imeglimin Hydrochloride of formula (I) obtained in step (c) using an alcoholic solvent.

[0048] In one of the preferred embodiments, the chiral amino acid is selected from the group consisting of L-glutamic acid or its derivative such as N-tosyl-L-glutamic acid or N-sulfonyl-L-glutamic acid etc.

[0049] Accordingly, the process for preparation of Imeglimin HCl compound of formula (I) is demonstrated herein below in scheme IV, using L-glutamic acid or its derivative as a chiral resolving agent.

##STR00019##

[0050] In yet another embodiment, the invention provides a process for preparation of Imeglimin HCl compound of formula (I) via resolution of racemic Imeglimin base compound of formula (IV) or racemic Imeglimin hydrochloride (VI), which process comprises the steps of; [0051] a) reacting racemic compound of formula (IV) or compound of formula (VI) with a suitable chiral amino acid or its derivative in the presence or absence of a base and a solvent to obtain R-Imeglimin L-amino acid salt compound of formula (V),

##STR00020## [0052] b) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain Imeglimin Hydrochloride formula (I), and [0053] c) optionally purifying the Imeglimin Hydrochloride formula (I) obtained in step (b) using an alcoholic solvent.

[0054] In the embodiment of step a), the chiral amino acid is selected from the group consisting of L-glutamic acid, N-Tosyl-L-glutamic acid, L-Alanine, L-aspartic acid, L-Leucine, L-phenyl alanine, L-tyrosine and, L-Valine.

[0055] In the embodiment of step, a), the solvent is selected from group consisting of acetonitrile, C.sub.1-C.sub.4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof.

[0056] In the embodiment step b), the solvent is selected from group consisting of C1-C4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof or C1-C5 ketone, preferably acetone, methyl ethyl ketone.

[0057] In the embodiment step c), the solvent is selected from group consisting of C1-C4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably, the solvent is mixture of methanol and isopropyl alcohol.

[0058] Accordingly, the process for preparation of Imeglimin HCl compound of formula (I) via resolution of racemic Imeglimin base compound of formula (IV) or Imeglimin HCl compound of formula (VI), is demonstrated herein below in Scheme V, using L-glutamic acid or its derivative as a chiral resolving agent.

##STR00021##

EXAMPLES

[0059] The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

Example 1: Synthesis of Racemic Imeglimin Hydrochloride

[0060] Metformin hydrochloride (100 g) was suspended into isobutanol (400 ml), acetaldehyde diethyl acetal (85.94 g) and para toluene sulfonic acid (11.52 g) were added to the suspension. The suspension was heated to reflux until a clear solution is obtained. After completion of the reaction solvent was partially distilled. The suspension was cooled to 10-20 C. & stirred for 2 hrs. The solid was isolated by filtration & washed with isobutanol (50 ml). The solid was dried to obtain racemic Imeglimin Hydrochloride (100 g).

Example 2: Chiral Resolution of Racemic Imeglimin Hydrochloride to Obtain (R)-Imeglimin-L-Glutamate Salt

[0061] Racemic Imeglimin hydrochloride (20 g) & L-glutamic acid (15.4 g) were added in methanol (250 ml) at 20-35 C. Triethylamine (10.6 g) was added and the suspension was heated to 55-60 C. & stirred for 2 hrs. The suspension was cooled to room temperature is seeded with little quantity of R-Imeglimin L-glutamate salt and stirred for overnight to obtain solid. The reaction mass was cooled to 5-10 C. and stirred for 2 hrs. The white crystals obtained were isolated by filtration and washed with methanol (10 ml). Dried the solid to obtain R-(+)-Imeglimin-L-glutamate salt (15.3 gm).

[0062] Purity: HPLC 99.70%

Example 3: Resolution of Racemic Imeglimin Hydrochloride

[0063] Racemic Imeglimin hydrochloride (20 g) & N-tosyl-L-glutamic acid (31.54 g) were dissolved in methanol (50 ml) at 20-35 C., triethyl amine (10.59 g) was added at below 30 C. The suspension was heated to 55-60 C. & stirred for 2.0 hrs. The suspension was cooled to RT. The suspension was seeded with R-Imeglimin N-tosyl-L-glutamate salt. The solution was stirred for 6 hrs, cooled the reaction mass to 5-10 C. for 2.0 hrs, to obtain solid. The white crystals thus obtained were isolated by filtration and washed with methanol (5 ml). The solid was dried to obtain R-Imeglimin N-tosyl-L-glutamate salt (20 g).

[0064] Purity: HPLC 99.95%

Example 4: Resolution of Racemic Imeglimin Hydrochloride

[0065] Racemic Imeglimin hydrochloride (70 g) & N-Tosyl-L-glutamic acid (110.42 g) were added in Acetonitrile (700 ml) at 20-35 C. Triethyl amine (37.08 g) was added at below 30 C. The suspension was heated to 60-65 C. and water (35 ml) was added. The reaction mass was stirred for 2.0 hrs, cooled to RT. The white crystals were isolated by filtration and washed with Acetonitrile (35 ml), the wet cake was further purified in acetonitrile & water mixture. The solid thus obtained was dried to yield (82.6 g) R-Imeglimin N-tosyl-L-glutamate salt.

[0066] Purity: HPLC 99.95%

Example 5: Preparation of R-Imeglimin Hydrochloride from (R)-Imeglimin N-Tosyl-L-Glutamate

[0067] Imeglimin N-tosyl-L-glutamate salt (80 g) was suspended in Acetone (400 ml) and IPA.Math.HCl (84 g) was added. The suspension was heated to reflux and continued for 2.0 hrs, cooled the suspension to RT, stirred for 2 hrs. Filtered the solid & washed with Acetone (80 ml). The solid was dried to obtain crude (R) Imeglimin Hydrochloride (32.0 g).

[0068] Purity: HPLC 99.5%

Example 6: Preparation of R-Imeglimin Hydrochloride from (R)-Imeglimin N-Tosyl-L-Glutamate

[0069] Imeglimin N-tosyl-L-glutamate salt (20 g) was suspended in Acetone (100 ml) added conc. HCl (4.8 g). The suspension was heated to reflux and continued for 2.0 hrs, cooled RT. Stirred for 2 hrs. Filtered the solid & washed with Acetone (80 ml). Dried the solid to obtain crude (R)-Imeglimin Hydrochloride (7.4 g).

[0070] Purity: HPLC 99.5%

Example 7: Purification of (R) Imeglimin Hydrochloride

[0071] Crude (R)-Imeglimin hydrochloride (10.0 g) was dissolved in methanol (20 ml) at 55-60 C. Filtered the clear solution & distilled out solvent to obtain suspension. Added IPA (50 ml) and heated to 55-60 C. Stirred for 1.0 hr & cooled to RT. Filtered the solid & washed with IPA (10 ml). Dried the solid to obtain pure (R) Imeglimin hydrochloride (8.5 g).

[0072] Purity: HPLC 99.99%, Specific Optical Rotation=+5.3

Example-8: Preparation of Racemic Imeglimin Base from Imeglimin Hydrochloride

[0073] Racemic Imeglimin Hydrochloride (25 g) was reacted with sodium methoxide (7.04) g in methanol (100 ml) at room temperature. Salt was removed by filtration. Methanol was collected as filtrate and was distilled out to obtain Imeglimin base (19 g).

Example-9: Resolution of Racemic Imeglimin Base

[0074] Racemic Imeglimin (18 g) & N-Tosyl-L-glutamic acid (34.87 g) were added in Acetonitrile (90 ml) at 50-55 C. Stirred for 2 hours, the white crystals were isolated by filtration and washed with Acetonitrile (18 ml). The solid thus obtained was dried to yield R-Imeglimin N-tosyl-L-glutamate salt (22.0 g).

Example 10: Preparation of R-Imeglimin Hydrochloride from (R)-Imeglimin N-Tosyl-L-Glutamate

[0075] Imeglimin N-tosyl-L-glutamate salt (20 g) obtained from Example-9 was suspended in Acetone (100 ml) and IPA.Math.HCl (21.0 g) was added. The suspension was heated to reflux and continued for 2.0 hrs, cooled the suspension to RT, stirred for 2 hrs. Filtered the solid & washed with Acetone (20 ml). The solid was dried to obtain crude (R) Imeglimin Hydrochloride (8.0 g).

[0076] Purity: HPLC 99.5%