Claims:I / We Claim:
1. A process for preparation of Imeglimin HCl compound of formula (I)

comprising steps of:
a) reacting compound of formula (II)

with compound of formula (II) in solvent

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

b) reacting compound of formula (IV) in solvent with base to obtain in-situ racemic compound of (V),

c) reacting compound of formula (V) with L (+)-Tartaric acid under suitable condition to obtain compound of formula (VI),

d) reacting compound of formula (VI) in solvent with base to obtain to compound of formula (VII), and

e) converting compound of formula (VII) to Imeglimin HCl compound of formula (I).

2. The process as claimed in claim 01, wherein solvent of step a) selected from C1-C4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably solvent is solvent is isobutanol.

3. The process as claimed in claim 01, wherein step a) reaction is suitably carried out at temperature range 90-1100 C, more preferably reaction is carried out at temperature range 90-1050 C and step a) suitably carried out at reaction time 20-30 hours, more preferably 24-26 hours.

4. The process as claimed in claim 01, wherein solvent of step b) is selected from group consisting of C1-C4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof; more preferably solvent is mixture of ethanol & water.

5. The process as claimed in claim 01, wherein base step b) selected from inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, calcium hydroxide, and calcium carbonate, more preferably base is sodium hydroxide.

6. The process as claimed in claim 01, wherein step c) resolution reaction suitably carried out at temperature range 70-800 C, more preferably resolution reaction is carried out at temperature 75-800 C.

7. The process as claimed in claim 01, wherein s solvent is selected from group consisting of C1-C4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably solvent is solvent is isobutanol and base selected from inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, calcium hydroxide, and calcium carbonate, more preferably base is sodium hydroxide.

8. A process for preparation of Imeglimin HCl compound of formula (I)

comprising steps of:
a) reacting compound of formula (VI) in solvent

with base under suitable condition to obtain to compound of formula (VII), and

b) converting compound of formula (VII) to Imeglimin HCl compound of formula (I)

9. The process as claimed in claim 08, wherein step a) reaction is suitably carried out at temperature in the range of 20-400 C, more preferably reaction is carried out 25-350 C and reaction time in the range of 0-2 hours, more preferably 1-2 hours.

10. The process as claimed in claim 08, wherein step a) solvent is isobutanol & base is sodium hydroxide.

Dated this 04th day of February 2022
, Description:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:

“IMPROVED PROCESS FOR PREPARATION OF IMEGLIMIN AND SALTS THEREOF”

2. APPLICANT(S):

a) NAME: Ami Lifesciences Private Limited

b) NATIONALITY: Indian

c) ADDRESS: 7th Floor, Lilleria 1038, Gotri Sevasi Road, New Alkapuri, Vadodara – 390 021, Gujarat, India

3. PREAMBLE TO THE INVENTION:

COMPLETE:

The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE: “IMPROVED PROCESS FOR PREPARATION OF IMEGLIMIN AND SALTS THEREOF”

FILED OF THE INVENTION:
The present invention relates to an improved process for preparation of Imeglimin & its salts. More particularly, the present invention relates to the improved process parameter such as reaction condition & reaction solvent to prepare Imeglimin base & its salts which is industrially advantageous and economically significant.
BACKGROUND OF THE INVENTION:
Imeglimin is chemically known as (6R)-(+)-4-dimethylamino-2-imino-6-methyl-1,2,5,6-tetrahydro-1,3,5-triazine hydrochloride, having the structure compound of formula (I)

Imeglimin was discovered by Poxel and developed in the partnership with Sumitomo Dainippon Pharma Co. Ltd launched in the brand name of Twymeeg® in Japan for the treatment of type-2 diabetes mellitus. Imeglimin is approved in Japan on June 23rd, 2021. Imeglimin is under phase-3 clinical trial in USA & Europe.

USA patent publication US 7034021B2 (herein after US ‘021) first discloses the Imeglimin. Further US ‘021 does not disclose process for preparation of Imeglimin in any specific examples.

USA patent publication US 7501511B2 (herein after US ‘511) discloses resolution process for preparation of Imeglimin HCl comprising reacting racemic Imeglimin free base with derivative of L-tartaric acid in alcohol solvent followed by stirring & filtration. Further recrystallized from a DMF / ethanol mixture to obtain tartrate salt of compound of formula (VII) having 33 % yield & chiral purity is 70% ee followed by addition of hydrochloric acid & recrystallized from ethanol to obtain Imeglimin HCl compound of formula (I) as white powder having overall yield 10%.

The schematic representation of Imeglimin HCl process as disclosed in US ‘511 is given below in scheme-01

The process as disclosed in US ‘511 has several disadvantages such as low yield & low chiral purity, further during process many impurities are generated which is carried forward in the final Imeglimin HCl API. The present invention provides high yield & high chiral purity of Imeglimin HCl. Therefore, the present invention overcomes all the disadvantages of US ‘511 process.
USA patent publication US 8742103B2 (herein after US ‘103) discloses the process for preparation of Imeglimin HCl comprising reacting compound of formula (II) with compound of formula (III) in solvent in presence of PTSA to obtain racemic compound of formula (IV). Further racemic compound of formula (IV) reacts with L(+)-Tartaric acid to obtain mixture of compound of formula (VI) & compound of formula (VIa). Further mixture of compound of formula (VI) & compound of formula (VIa) converted to compound of formula (VI) having 40-45 % yield. Further tartrate salt of compound of formula (VI) in solvent reacted with hydrochloric acid to obtain Imeglimin HCl compound of formula (I) having 50-55 % yield followed by additional steps the mother liquors can be used for the recovery of Imeglimin HCl compound of formula (I).

The schematic representation of Imeglimin HCl process as disclosed in US ‘103 is given below in scheme-02.

The major disadvantage of Imeglimin HCl process as disclosed in US ‘103 very low yield i.e. 40-45 % & silent about chiral purity of tartrate salt of compound of formula (VI), whereas present invention of provides high yield & high chiral purity of compound of formula (VI). One more disadvantage of Imeglimin HCl process as disclosed in US ‘103 yield of final Imeglimin HCl is 50-55 % followed by additional steps the mother liquors can be used for the recovery of Imeglimin HCl compound of formula (I) which is not suitable for large scale Industrial production of Imeglimin HCl compound of formula (I). Therefore, the present invention overcomes all the disadvantages of US ‘511 process.
All the prior arts discussed above suffer from many disadvantages like tedious and cumbersome work up procedures, high temperature condition, longer reaction times, use of excess reagent and solvents which affect the overall yield as well as the quality of the final product.
Therefore, there is a need for improved process for the preparation of Imeglimin HCl having high chiral purity and high yield which overcome the drawbacks of the prior arts process. The present inventors surprisingly found an efficient process for the preparation of Imeglimin HCl which offer advantage over the prior art processes in term high yield, high chiral purity and less effluents and simple scalable procedure suitable for large scale industrial production of Imeglimin HCl.

OBJECT OF THE INVENTION:

? The principal object of the present invention is to provide process for preparation of Imeglimin HCl compound of formula (I) having high yield & high chiral purity by isolating in single lot and avoiding any requirement of isolating second lot from mother liquor, whereas as prior art reference US ‘103 isolating compound of formula (I) from mother liquors in two lots.

? Another one object of the present invention is to provide process for preparation of Imeglimin HCl compound of formula (I) via improved route i.e. converting compound of formula (II) to compound of formula (IV) by using PTSA. Further converting compound of formula (IV) to compound of formula (VI). Furthermore, converting compound of formula (VI) to free base compound of formula (VII) & finally converting compound of formula (VII) to Imeglimin HCl having high yield, more than 99.85% Chiral purity & 100% HPLC purity.

SUMMARY OF INVENTION:
The first aspect of the present invention is to provide process for preparation of Imeglimin HCl compound of formula (I)

comprising steps of:
a) reacting compound of formula (II)

with compound of formula (II) in solvent

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

b) reacting compound of formula (IV) in solvent with base to obtain in-situ racemic compound of (V),

c) reacting compound of formula (V) with L (+)-Tartaric acid under suitable condition to obtain compound of formula (VI),

d) reacting compound of formula (VI) in solvent with base to obtain to compound of formula (VII), and

e) converting compound of formula (VII) to Imeglimin HCl compound of formula (I).

Second aspect of the present invention is to provide process for preparation of Imeglimin HCl compound of formula (I)

comprising steps of:
a) reacting compound of formula (VI) in solvent

with base under suitable condition to obtain to compound of formula (VII), and

b) converting compound of formula (VII) to Imeglimin HCl compound of formula (I)

BRIEF DESCRIPTION OF DRAWINGS:

Figure 01: Discloses x-ray powder diffractogram (XRPD) of crystalline Imeglimin HCl obtain in Example 05
Figure 02: Discloses differential scanning calorimetry (DSC) of crystalline Imeglimin HCl obtain in Example 05
Figure 03: Discloses 1H-NMR of Imeglimin HCl obtain in Example 05.
Figure 04: Discloses 13C-NMR of Imeglimin HCl obtain in Example 05.

DEFINATION:
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25º C and normal pressure unless otherwise designated.

All temperatures used herein are in degrees Celsius unless specified otherwise.

All ranges recited herein include the endpoints, including those that recite a range "between" two values.

As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.

The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise

DETAIL DESCRIPTION OF IVENTION:
While the following specification concludes with claims particularly pointing out and distinctly claiming the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description and by studying the included examples

The best methods and materials of performing the present invention are described here.
In an attempt to develop an improved process for the preparation of Imeglimin HCl and to overcome the disadvantages of prior art, the present inventors have developed a process which results in high chiral, HPLC purity and good yield of Imeglimin HCl.

The process for preparation of Imeglimin as per the present invention can be summarized in the following schematic representation.

The starting material compound of formula (II) & compound of formula (III) of the present invention is commercially available or can be prepared by known prior art process.

In the first embodiment of the present invention is to provide process for preparation of Imeglimin HCl compound of formula (I)

comprising steps of:
a) reacting compound of formula (II)

with compound of formula (II) in solvent

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

b) reacting compound of formula (IV) in solvent with base to obtain in-situ racemic compound of (V),

c) reacting compound of formula (V) with L (+)-Tartaric acid under suitable condition to obtain compound of formula (VI),

d) reacting compound of formula (VI) in solvent with base to obtain to compound of formula (VII), and

e) converting compound of formula (VII) to Imeglimin HCl compound of formula (I).

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

In the embodiment of step, a) reaction is suitably carried out at temperature range 90-1100 C, more preferably reaction is carried out at temperature range 90-1050 C and step a) suitably carried out at reaction time 20-30 hours, more preferably 24-26 hours.

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

In the embodiment of step, b) base selected from inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, calcium hydroxide, and calcium carbonate, more preferably base is sodium hydroxide.

In the embodiment of step, b) obtained compound of formula (V) is not isolated from the reaction mixture, which is used for next step without any purification.

In the embodiment of step, c) resolution reaction suitably carried out at temperature range 70-800 C, more preferably resolution reaction is carried out at temperature 75-800C.

In the embodiment of step, d) solvent is selected from group consisting of C1-C4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably solvent is solvent is isobutanol.
In the embodiment of step, d) base selected from inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, calcium hydroxide, and calcium carbonate, more preferably base is sodium hydroxide.

In the embodiment of step, e) compound of formula (VII) reacted with hydrochloric acid to obtain Imeglimin HCl compound of formula (I).

Second embodiment of the present invention is to provide process for preparation of Imeglimin HCl compound of formula (I)

comprising steps of:
a) reacting compound of formula (VI) in solvent

with base under suitable condition to obtain to compound of formula (VII), and

b) converting compound of formula (VII) to Imeglimin HCl compound of formula (I)

In the embodiment of step, a) reaction is suitably carried out at temperature in the range of 20-400 C, more preferably reaction is carried out 25-350 C and reaction time in the range of 0-2 hours,s more preferably 1-2 hours.

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

In the embodiment of step, a) base selected from inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, calcium hydroxide, and calcium carbonate, more preferably base is sodium hydroxide.

In the embodiment of step, b) compound of formula (VII) reacted with hydrochloric acid to obtain Imeglimin HCl compound of formula (I).
EXAMPLE:
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 01: Preparation of compound of formula (IV)

Metformin hydrochloride compound of formula (II) (100.0 g, 0.60 Mole) was condensed with acetaldehyde diethyl acetal compound of formula (III) (86.00 g, 0.7245 mole) in 4.0 volumes of isobutanol (400.0 mL) using p-toluene sulphonic acid monohydrate (5.74 g, 0.030 mole) as catalyst. Resulted suspension was heated to reflux until a clear solution was obtained. After completion of reaction checked by HPLC, 2.5 volumes (250. 0 mL) of the solvent are removed by distillation to get suspension. The resulted suspension is cooled to 10 °C. After maintaining for 2 hours, resulted solid suspension was isolated by filtration and washed with acetone (50.0 mL, 0.50 Volumes) to obtain racemic compound of formula (IV) 105.0 g
Yield: 90.57 %.
1H NMR (DMSO d6) d ppm: 1.327-1.342 (3H, -CH3), 3.039 (6H, -N(CH3)2), 4.802-4.825 (1H, Cyclic -CH), 7.396 (2H Broad signal, Aromatic -NH & HCl), 8.507-8.650 (2H, Primary amine -NH2).
13C NMR (DMSO d6) d ppm: 22.08 (1C, -CH3 group), 36.86 (2C, -N(CH3)2), 57.70 (1C, Chiral carbon), 156.33 (1C, -C=N carbon attached with -NH2), 157.86 (1C, -C=N carbon attached with -N(CH3)2),
Mass (M/Z): 156.1 (M + 1 - HCl).
HPLC Purity: Not less than 97.0%.

EXAMPLE 02: Preparation of compound of formula (VI)

Racemic compound of formula (IV) (100.0 g, 0.52 mole) obtained in Example 01 reacts with sodium hydroxide (48% solution) (43.5 g, 0.52 mole) in ethanol (600.0 mL, 6.0 volumes) and water (22.0 mL, 0.22 volumes) followed by filtration of salt to obtain clear solution of racemic in-situ compound of formula (V).
racemic in-situ compound of formula (V) was further reacted with L (+)-Tartaric acid (86.0 g, 0.572 mole). The resulted solution was heated to reflux for 4.0 hours and cooled to 20 °C for 4.0 hours solid white crystals was observed. Solid material isolated by filtration and washed with ethanol (25.0 mL, 0.25 volumes). The wet cake was further purified using 10% aq. Ethanol (500.0 mL, 5.0 Volumes) to obtain compound of formula (VI) 64.0 g.
Yield: 80.00 %.
1H-NMR (DMSO d6) d ppm: 1.320-1.334 (3H, -CH3), 3.011 (6H, -N(CH3)2), 4.068 (2H, two -CH proton attached with -OH group), 4.772-4.813 (1H, Cyclic -CH), 7.246 (4H, -COOH & -OH Protons), 8.128-8.428 (2H, Cyclic -NH Protons), 10.024 (1H, -NH Proton).
13C-NMR (DMSO d6) d ppm: 21.75 (1C, -CH3 group), 36.65 (2C, -N(CH3)2), 57.76 (1C, Chiral carbon), 72.28 (2C, two carbon attached with -OH group 156.61 (1C, -C=N carbon attached with -NH-), 158.26 (1C, -C=N carbon attached with -N(CH3)2), 175.03 (2C, -COOH carbon
Mass (M/Z): 306.9 (M + 1).
Chiral purity: Not less than 97.5%.
HPLC Purity: Not less than 99.00 %.

EXAMPLE 03: Preparation of compound of formula (VII)

The compound of formula (VI) (100.0 g, 0.3275 mole) obtained in Example 02 was further reacted with sodium hydroxide (40.0 g, 1.00 mole) solution in water (200.0 mL, 2.0 volumes) and compound of formula (VII) was extracted using Isobutanol (400.0 mL, 4.0 volumes) to obtain compound of formula (VII)
1H NMR (DMSO d6) d ppm: 1.114-1.129 (3H, -CH3), 2.792 (6H, -N(CH3)2), 4.615-4.658 (1H, Cyclic -CH), 5.572 (2H Broad signal, Aromatic -NH-Proton).
13C NMR (DMSO d6) d ppm: 25.39 (1C, -CH3 group), 36.41 (2C, -N(CH3)2), 62.95 (1C, Chiral carbon), 158.42 (1C, -C=N carbon attached with -NH2), 158.67 (1C, -C=N carbon attached with -N(CH3)2).
Mass (M/Z): 156.1 (M + 1).
Chiral purity: Not less than 99.0%.
HPLC Purity: Not less than 99.0 %.
Tartaric acid content: Not detected.

EXAMPLE 04: Preparation of Imeglimin HCl compound of formula (I)

The compound of formula (VII) obtained in Example 03 was reacted with ~20% Isopropyl alcohol hydrochloride (60.0 g). Reaction mass stirred for 0.5 to 1 hr. Further, 3.0 times Isobutanol (300.0 mL) is distilled out to obtain white suspension. The resulted suspension is cooled to 10 °C and maintained for 2 hours at 10 °C. White crystalline material was isolated by filtration to obtain Imeglimin HCl compound of formula (I) 62.0 g.

EXAMPLE 05: Purification of Imeglimin HCl compound of formula (I)
The Imeglimin hydrochloride (62.0 g) obtained in Example 04 was heated in Ethanol (350.0 mL) to get clear reaction mass and followed by filter the reaction mass and wash with ethanol (50.0 mL). Further, 3.0 times ethanol (300.0 mL) was distilled out to obtain white suspension. The resulted suspension was cooled to 20 °C and maintain for 2 hours at 20 °C. The solid mass was filtered to obtain pure crystalline white Imeglimin hydrochloride 44.0 g.
Yield: 71.0 %.
1H NMR (DMSO d6) d ppm: 1.330-1.345 (3H, -CH3), 3.043 (6H, -N(CH3)2), 4.794-4.837 (1H, Cyclic -CH), 7.393 (2H Broad signal, Aromatic -NH & HCl), 8.543-8.679 (2H, Primary amine -NH2).
13C NMR (DMSO d6) d ppm: 22.08 (1C, -CH3 group), 36.87 (2C, -N(CH3)2), 57.70 (1C, Chiral carbon), 156.32 (1C, -C=N carbon attached with -NH2), 157.87 (1C, -C=N carbon attached with -N(CH3)2).
Mass (M/Z): 156.1 (M + 1 - HCl).
XRPD: Characteristic peak of 2-theta at about 11.60, 14.70, 16.80, 24.80, 25.40, 26.80 and 27.00 ± 0.2 (2?)
DSC: 251.0-255.0 °C.
Chiral Purity: Not less than 99.85 %.
HPLC Purity: 100%.