DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF GABAPENTINOID

We, LEE PHARMA LIMITED,
a company incorporated under the companies act, 1956 having address at
Sy.No: 257 & 258/1; Door No: 11-6/56-C; Opp: IDPL Factory; Moosapet; Balanagar (Post); Hyderabad, Telangana; 500037- India.

The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Gabapentinoid.

The present invention relates to an improved process for the preparation of Mirogabalin compound of Formula (I),
Formula (I)

The present invention also relates to an improved process for the preparation of chiral Amino acid salts of 2-(3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester enantiomers of Formula (IIIa) and Formula (IIIb) using Amino acid as resolving agent.

wherein R is hydrogen or carboxylic acid protecting group.

The present invention also relates to the amino acid salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or ester of Formula (IIIa).
Formula (IIIa)
wherein R is defined as above.

The present invention specifically relates to the L-proline salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or ester of Formula (IIIp).
Formula (IIIp)
wherein R is defined as above.

The present invention also specifically relates to use of intermediate compound, Chiral Amino acid salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid of Formula (IIIa), in the preparation of Mirogabalin of Formula (I) or its pharmaceutically acceptable salts, specifically besylate salt having the following structure of Formula (Ib).
Formula (Ib)

BACKGROUND OF THE INVENTION
Mirogabalin besylate, an orally administered gabapentinoid that binds and modulates voltage dependent calcium channel a2d-1 subunit widely found in nervous system, is a potent drug for the treatment of peripheral neuropathic pain (PNP), including diabetic PNP and post-herpetic neuralgia.(Drugs, 2019, 79(4), 463-468) Mirogabalin besylate is approved by Japan in 2019 and Korea in 2020 for the treatment of PNP. Chemically Mirogabalin besylate is known as 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid monobenzene sulfnate, and has the following chemical structure.
Formula (Ib)

Daiichi Sankyo’s US 7,947,738 B2 discloses the compound, [(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid and salts thereof, and methods of treating a disease or disorder selected from the group consisting of postherpetic neuralgia, neuropathic pain, diabetic neuropathic pain, and fibromyalgia. This patent also discloses the preparation process of the above compound by optical resolution of carboxylic acid protected 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid using chiral column (CHIRALPAK).

As the compound, 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid, is an important isomer, various resolution procedures have been developed that suitable for industrial production, and high purity API. The basic and complicated step in the Mirogabalin besylate preparation process is separation of stereo-selective isomer of precursor or Mirogabalin compound itself from the racemic mixture.

US 8,324,425 B2 discloses the optical resolution process by dissolving the racemic mixture of carboxylic acid protected 2-(6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate and optically active organic acid in a solvent and then depositing a crystal of carboxylic acid protected 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate. The optically active organic acid is selected from: D-mandelic acid, L-mandelic acid, Di-p-toluoyl-L-tartaric acid, N-Boc-L-proline, (R)-a-methoxyphenylacetic acid, O-acetyl-L-mandelic acid, Di-benzoyl-L-tartaric acid, O-acetyl-D-mandelic acid, N-Boc-L-alanine, (S)-2-(6-methoxy-2-naphthyl)propionic acid, diacetyl-L-tartaric acid, L-tartaric acid, L-malic acid, L-pyroglutamic acid, (+)-camphoric acid, (S)-2-methylglutamic acid, (+)-3-bromocamphor-8-sulfonic acid, (-)-menthoxyacetic acid, and (S)-2-phenoxypropionic acid. The process disclosed in given below schematically.

US 9,469,623 B2 discloses the optical resolution process by dissolving the mixture of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid and 2-((1S,5R,6R)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid to form a salt with an optically active organic amine. The optically active organic amine used is (1R,2R)-trans-1-amino-2-indanol, (S)-2-phenylglycinol, (R)-1-(p-toluyl)ethylamine, (1R,2S)-2-amino-1,2-diphenylethanol, (S)-1-(2-naphthyl)ethylamine, (R)-1-(4-bromophenyl)ethylamine, (1S,2R)-(+)-1-amino-2-indanol, L-phenylalaninol. Further salt dissociation is carried out followed by reduction to obtain 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid, as given below schematically.

In order to improve the yield, product purity, usage of environmental friendly reagents, cost effective and industrial friendly process, different methods have been tried for resolution and subsequent product preparation.

The present inventors have found new improved process for the preparation of Mirogabalin, that involve resolution and separation of precursor compound, 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid using amino acid and further, reduction in order to achieve high yield and pure Mirogabalin compound.

Amino acids are organic compounds that contains both an amino (-NH2) and carboxylic acid (-COOH) functional group, exist as zwitterions, i.e. as dipolar ions with both NH3+ and COO- in charged states hence, can act as both an acid and a base. Carboxylic acid of amino acids protonates in acidic conditions and deprotonates in basc medium, which allows to tune the salt formation and separation with pH adjustment. Moreover, except glycine, all amino acids have chiral center, naturally available, highly biocompatible, safe and easy to handle. It accepts proton transfer from carboxylic group and forms cationic amino acid isomer and anionic Mirogabalin precursor compound leading to the formation of salt. Since, selected amino acid isomer chiral center is always the same, different S and R isomers of the carboxylic anions pack differently that facilitates the separation of isomers.

The process of the present invention enables the use of highly safe, stable, cost-effective, eco-friendly, naturally available chiral Amino acids for the resolution of Mirogabalin precursor compound and also avoids expensive reagents, minimization of impurities by avoiding de-protection step after resolution, in shorter reaction times, cost efficient and with higher productivity and purity than prior art processes. These features make the process of the invention highly suitable for industrial scale up production.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of Mirogabalin compound of Formula (I),
Formula (I)

Another objective of the present invention is to provide an improved process for the separation of intermediate compound, chiral Amino acid salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (IIIA).

Still another objective of the present invention is to provide the reduction of chiral Amino acid salt compound of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (IIIa) followed by deprotection and/or acid treatment or vise versa to obtain 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid of Formula (I).

Another objective of the present invention is to provide the chiral amino acid salt compound of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (IIIa).

Still another preferred objective of the present invention is to provide the specifically L-proline salt compound of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (IIIp).

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of intermediate compound, chiral Amino acid salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid of Formula (IIIa), used in the preparation of Mirogabalin or salts thereof.
Formula (IIIa)

In another embodiment, the present invention provides an improved process for the preparation of chiral Amino acid salts of 2-(3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester enantiomers of Formula (IIIA) and Formula (IIIB) using chiral Amino acid as resolving agent.

In another embodiment, the present invention also provides an improved process for the reduction of chiral Amino acid salt compound of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester of Formula (IIIa) to obtain chiral Amino acid salt of 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester of Formula (Ia) followed by deprotection and/or acid treatment or vise versa to obtain 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid of Formula (I).

or

In another embodiment, the present invention specifically relates to an improved process for the preparation of 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid of Formula (I)
Formula (I)
which comprises:
a) providing the 2-(3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester of Formula (II)
Formula (II)
and reacting with chiral Amino acid in the presence of solvent, to obtain chiral Amino acid salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (IIIa) and chiral Amino acid salt of 2-((1R,5S,6R)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (IIIb),
Formula (IIIa)
Formula (IIIb)
b) separation of the chiral Amino acid salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or ester compound of Formula (IIIa),
Formula (IIIa)
c) reducing the chiral Amino acid salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (IIIa) to produce chiral Amino acid salt of 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (Ia),
Formula (Ia)

followed by deprotecting and/or acid treatment to obtain 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid of Formula (I),
Formula (I)
or

deprotecting and/or treating the chiral Amino acid salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (IIIa) with acid to produce 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid of Formula (III),
Formula (III)

followed by the reduction of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid of Formula (III) to produce 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid of Formula (I),
Formula (I)

In another embodiment, the present invention also provides a compound, chiral Amino acid salt compound of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or ester compound of Formula (IIIa).
Formula (IIIa)

In another embodiment, the present invention specifically relates to the L-proline salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (IIIp).
Formula (IIIp)

In another embodiment, the present invention also provides the use of compound, chiral Amino acid salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid of Formula (IIIa), in the preparation of Mirogabalin of Formula (I) or its pharmaceutically acceptable salts, specifically besylate salt having the following structure of Formula (Ib).
Formula (Ib)

DETAILED DESCRIPTION OF THE INVENTION
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

In a specific embodiment, salt formation of compound of Formula (IIIa) with chiral Amino acid is in a solvent. The reaction may be carried out at a temperature in the range of -15 to 5°C for a duration of 1 to 6 hours. After completion of the reaction, the solids of the compound of Formula (IIIa) filtered and washed with non-polar solvent.

Further, the solvent as used herein is selected from alkane solvents, acyclic and cyclic, saturated and unsaturated alkanes, hexane, heptane, cyclohexane or its mixture; alcohols, ethers.

The compound of formula (II) wherein R is hydrogen is prepared from compound of formula (II) R is carboxylic acid. Deprotection of carboxylic group is carried out in aprotic solvent, water and catalyst. Heat the reaction mass and maintain up to absence of starting material. Add the sodium thiosulfate and extract with MTBE followed by charcoal treatment. Distilled the MTBE layer to get the target compound. The reaction may be carried out in the presence of catalyst such as Iodine.

Further, aprotic solvent as used herein is selected from THF, 2-Me-THF, DMSO, acetone, DMF, CPME, MTBE or its mixture, preferably, THF.

Removal of amino acid from the compound of formula (IIIa or Ia) is carried out by adjusting pH using citric acid and ammonia. The reaction may be carried out at a temperature in the range of -5 oC to 25 oC and 1 to 3 hours. After completion of the reaction, the compound of Formula (III or I) filtered and dried. Further, acid can be used such as oxalic acid, HCl, H2SO4 and H3PO4. And base can be used which are selected from NaOH, KOH, Amines, Ammonia. However, citric acid and ammonia yields high productivity with 45% yield and 99.5% purity of compound of Formula (III or I).

Reduction of nitro compound of Formula (III or IIIa) is carried out by using reducing agent in a solvent under Hydrogen gas pressure up to 4.0 - 5.0 Kg/cm2 at 10 - 50°C for 8 - 24 hours. After completion of reaction, add methanol and filter the reaction mass. Distilled out the solvent and add a halogenated solvent and Water. Filter the solid, the compound of Formula (I or Ia) isolated. The reduction may be carried out using reducing agents such as Pd/C, Pt/C, Rh/C, Raney Ni. However, reduction using Raney Ni at 25-30°C for 8-18 hours and the compound formula (I or Ia) in MTBE and Water solvent produced good yield (45%) and high purity (99.5%) compound of Formula (I or Ia), 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid or L-proline salt of 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid.

Solvent as used herein for reduction is selected from non-polar solvents such as alkanes (pentane, hexane, and heptane), aromatics (benzene, toluene, and xylene), chloroform, diethyl ether, Methyl tert-butyl ether (MTBE) ethyl acetate, methylene chloride, and pyridine and polar solvents such as acetone, acetonitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO), isopropanol, and methanol, and mixture of the both polar and non-polar solvents.

Halogenated solvent is selected from methylene chloride, carbon tetrachloride, chloroform, trichloroethylene, perchloroethylene, trichlorotrifluoroethane, and 1,1,1-trichloroethane.

The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like.

In another preferred embodiment, a process for the preparation of compound of Formula (Ib) which yields the compounds with high chemical purity.

In yet another preferred embodiment, the present invention provides use of intermediate compounds of Formula (IIIa) in the preparation of Mirogabalin or its salts. The intermediates formed in the present invention may or may not be isolated. Any of the above reactions may be carried out in-situ reactions to obtain compound of Formula (I).

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

EXAMPLES

Example 1: Preparation of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid L-Proline salt:
To the THF (800 ml) add tert-butyl 6-(nitromethyl)-3-methylbicyclo[3.2.0]hept-3-en-6-yl)acetate (100 g, 0.338 mol), water (catalytic) and Iodine (17.2 g, 0.068 mol). Heat the reaction mass and maintain up to absence of starting material. Add the sodium thiosulfate and extract with MTBE followed by charcoal treatment. Distilled the MTBE layer, add n-heptane and cool to -10 to-8 ° C. Add the L-Proline and maintain the reaction mass at -10 to-8 °C for 2-4 hours. Filter the solid, washed with cold n-heptane, and then dried under reduced pressure at 40°C to obtain the title compound (102.2 g, 85.2%).
HPLC Purity: 97%
SOR: - 119.9o (c = 1.0, methanol)

Example 1a: Preparation of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid L-Proline salt:
To the THF (800 ml) add tert-butyl 6-(nitromethyl)-3-methylbicyclo[3.2.0]hept-3-en-6-yl)acetate (100 g, 0.338 mol), water (catalytic) and Iodine (17.2 g, 0.068 mol). Heat the reaction mass and maintain up to absence of starting material. Add the sodium thiosulfate and extract with MTBE followed by charcoal treatment. Distilled off the MTBE layer, add isopropyl alcohol (300ml) and water (5ml) to residue. Add the L-Proline (35g) and stir the reaction mass at 25°C for 30 mins. Cool the reaction mass to 0-5oC, filtered off the precipitated solid, washed with isopropyl alcohol, and then dried under reduced pressure at 40°C to obtain the title compound (96g, Yield: 75.5%).
HPLC Purity: 99.38%
SOR: ?121.9o (c = 1.0, methanol).

Example 1b: Preparation of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid L-Proline salt:
To the THF (800 ml) add tert-butyl 6-(nitromethyl)-3-methylbicyclo[3.2.0]hept-3-en-6-yl)acetate (100 g, 0.338 mol), water (catalytic) and Iodine (17.2 g, 0.068 mol). Heat the reaction mass and maintain up to absence of starting material. Add the sodium thiosulfate and extract with MTBE (300ml) followed by charcoal treatment. Distilled off the MTBE layer, add Methyl Tertiary Butyl Ether (800ml) to residue. Add the L-Proline (35g) and stir the reaction mass at 25°C for 30 mins. Cool the reaction mass to 0-5oC, filtered off the precipitated solid, washed with MTBE solvent, and then dried under reduced pressure at 40°C to obtain the title compound (60 g, Yield: 43%).
HPLC Purity: 99.59%
SOR: ?124.9o (c = 1.0, methanol)

Example 2: Preparation of 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid:
Raney nickel (30 g), MTBE (1000 ml) and water (50 ml) were added to 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid L-Proline salt (100 g, 0.282 mol). To the reaction solution, apply hydrogen gas and maintained for 10-14 hours. The consumption of the starting materials was confirmed by thin-layer chromatography, add methanol (250 ml) and filter the reaction mass. Distilled out the solvent and add MDC (200 ml) and Water (200 ml). Adjust the pH to 3.5-4.0 using citric acid solution at 0-5°C and further pH adjusted to neutral using ammonia solution. Reaction mass maintained for 2 hours at 0-5°C. Filter the solid, washed with cold MDC, and then dried under reduced pressure at 40°C to obtain the title compound Formula (I) (33.75 g, Yield: 66.43%).
HPLC Purity: 99.42%

Example 2a: Preparation of 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid:
Raney nickel (30 g), Potassium Hydroxide (23.5 g) and water (25 ml) were added to 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid L-Proline salt (100 g, 0.282 mol). To the reaction solution, apply hydrogen gas and maintained for 10-14 hours. The consumption of the starting materials was confirmed by thin-layer chromatography, add methanol (250 ml) and filter the reaction mass. Distilled out the solvent and add MDC (200 ml) and Water (200 ml). Adjust the pH to 3.5-4.0 using citric acid solution at 0-5°C and further pH adjusted to neutral using ammonia solution. Reaction mass maintained for 2 hours at 0-5°C. Filter the solid, washed with cold MDC, and then dried under reduced pressure at 40°C to obtain the title compound Formula (I) (33.1 g, Yield: 65.16%)
HPLC Purity: 99.02%

Example 2b: Preparation of 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid:
Raney nickel (30 g), Ethanol (1000 ml) and water (1000 ml) were added to 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid L-Proline salt (100 g, 0.282 mol). To the reaction solution, apply hydrogen gas and maintained for 10-14 hours. The consumption of the starting materials was confirmed by thin-layer chromatography, add methanol (250 ml) and filter the reaction mass. Distilled out the solvent and add MDC (200 ml) and Water (200 ml). Adjust the pH to 3.5-4.0 using citric acid solution at 0-5°C and further pH adjusted to neutral using ammonia solution. Reaction mass maintained for 2 hours at 0-5°C. Filter the solid, washed with cold MDC, and then dried under reduced pressure at 40°C to obtain the title compound Formula (I) (16 g, Yield: 26.5%).
HPLC Purity: 99.04%

Example 3: Preparation of 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid monobenzene sulfonate (Mirogabalin Besylate):
To a solution of benzene sulfonic acid (75.5g) in water (500ml), add 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid ( 100g) slowly at 25oC. Raise the temperature of reaction mass to 50-55oC and stirred 30-45mins to get a clear solution. Charge Pencarb (N) carbon at 50-55°C and stir the mass for 5-10mins and filtered. The filtrate is cooled to 2-5oC and stirred for 30mins, filtered off the solid and dried under vacuum at 50-55oC for 6-8 hours to afford the Mirogabalin Besylate. (143g, Yield: 82%)
HPLC purity: 99.84%
Chiral purity ee: 99.98%). ,CLAIMS:We Claim:

1. Novel process for the preparation of compound of Formula (I)

wherein the process comprising the steps of:

a) treating the compound of Formula (II)

wherein R is hydrogen or carboxylic acid protecting group with a chiral Amino acid in a solvent to obtain compound of formula (IIIa)

b) converting the compound of Formula (IIIa) to compound of formula (I).

2. The process for the preparation of compound of Formula (I) as claimed in claim 1 wherein the process comprises

a) treating the compound of Formula (II)

wherein R is hydrogen or carboxylic acid protecting group with a chiral Amino acid in a solvent to obtain compound of formula (IIIa),

b) reducing the compound of Formula (IIIa) using reducing agent in a solvent to obtain compound of formula (Ia),

c) desalifying the compound of formula (Ia) in aprotic solvent, to obtain compound of formula (I) and
d) optionally converting the compound of formula (I) to its pharmaceutically acceptable salts.

3. The process for the preparation of compound of Formula (I) as claimed in claim 1 wherein the process comprises

a) treating the compound of Formula (II)

wherein R is hydrogen with a chiral Amino acid in a solvent to obtain compound of formula (IIIa)

b) desalifying the compound of formula (IIIa) in aprotic solvent, to obtain compound of formula (III).

c) reducing the compound of Formula (III) using reducing agent in a solvent to obtain compound of formula (I), and
d) optionally converting the compound of formula (I) to its pharmaceutically acceptable salts.

4. The process as claimed in claims 1-3 wherein the solvent used in step (a) is selected from alcohols, ethers, alkane solvents, acyclic and cyclic, saturated and unsaturated alkanes, hexane, heptane, cyclohexane or its mixtures.

5. The process as claimed in claims 2 and 3 wherein the reducing agent is selected from Pd/C, Pt/C, Rh/C, Raney Ni.

6. The process as claimed in claims 2 and 3 wherein the aprotic solvent is selected from THF, 2-Me-THF, DMSO, acetone, DMF, CPME, MTBE or its mixture.

7. The process as claimed in claims 2 and 3 wherein the catalyst is Iodine.

8. The process as claimed in claims 2 and 3 wherein the solvent used in reduction is non-polar solvents such as alkanes (pentane, hexane, and heptane), aromatics (benzene, toluene, and xylene), chloroform, diethyl ether, Methyl tert-butyl ether (MTBE) ethyl acetate, methylene chloride, and pyridine and polar solvents such as acetone, acetonitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO), isopropanol, and methanol, and mixture of the both polar and non-polar solvents.

9. The process for the preparation of compound of Formula (I) as claimed in claim 1 wherein the process relates to the use of L-proline salt of 2-((1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid or their ester compound of Formula (IIIp).
Formula (IIIp)

Dated this Fourteenth (14th) day of September, 2024
_________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883