DESC:PROCESS FOR THE PREPARATION OF MIROGABALIN BESYLATE

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Mirogabalin Besylate with high yield and purity.

BACKGROUND OF THE INVENTION
Mirogabalin Besylate (INN; trade names Tarlige®) is a gabapentinoid medication developed by Daiichi Sankyo. It is approved for the treatment of peripheral neuropathic pain including painful diabetic peripheral neuropathy (DPNP) and postherpetic neuralgia (PHN) in Japan. Mirogabalin Besylate is chemically known as 2-[(1R,5S,6S)-6-(aminomethyl)-3-ethyl-6-bicyclo[3.2.0]hept-3-enyl]acetic acid; benzenesulfonic acid having formula (I):

Mirogabalin Besylate and its synthesis were described in patent US 7947738 of Daiichi Sankyo. The synthesis route used in US ‘738 which comprises resoluting compound of formula (V) by using Chiralpak IC to produce compound of formula (IX). Treating the compound of formula (IX) with Boc anhydride to produce compound of formula (X), followed by treating with HCl to produce Mirogabalin. Treating Mirogabalin with benzenesulfonic acid to produce Mirogabalin Besylate (I).

In the above prior art process, chiral separation by using Chiralpak IC, which makes the process expensive and is not beneficial to industrial scale-up production.

US 8324425B2 describes the process for the preparation of Mirogabalin Besylate, which comprises treating compound of formula (IV) with D-mandelic acid to produce compound of formula (III) mandelate salt by converting the obtained salt into the free form with an aqueous sodium bicarbonate to produce compound of formula (II). Treating the compound of formula (II) with benzenesulfonic acid to produce Mirogabalin Besylate (I).
The above process is schematically shown as below:

In the above prior art process impurities are formed. Removal of these impurities is very difficult and required multiple purification techniques. Hence, above prior-art process is not suitable for commercially in industrial scalable, provide the compound of formula (I) with low purity and not environmentally friendly.
It is therefore essential to develop simplified and an improved process for the preparation of Mirogabalin Besylate, the resulted product is controlled with impurities level. The inventors of the present invention have developed improved process for the preparation of Mirogabalin Besylate. The inventors have worked towards developing a process for preparing Mirogabalin Besylate in good yield and purity.
OBJECT OF THE INVENTION
The one object of the invention is a process for the preparation of Mirogabalin Besylate with high yield and purity.
The second object of the invention is a process for the preparation of Mirogabalin Besylate by using a resolving agent.
The third object of the invention is a purification process of Mirogabalin Besylate (I).

SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Mirogabalin Besylate with high yield and purity.
One embodiment of the present invention provides an improved process for the preparation of Mirogabalin Besylate (I) comprising the steps of,
a) reacting compound of formula (VIII) with compound of formula (VII) in the presence of a base to obtain compound of formula (VI),

b) treating compound of formula (VI) with nitromethane in the presence of a base to obtain the compound of formula (V),

c) reducing compound of formula (V) with reducing agent to obtain the compound of formula (IV) or salt,

d) resoluting compound of formula (IV) or salt with resolving agent in the presence of a solvent to obtain resolving agent salt compound of formula (III), optionally purifying with aqueous alcoholic solvent,

e) treating resolving agent salt compound of formula (III) with base to obtain in-situ compound of formula (II), and

f) treating in-situ compound of formula (II) with benzene sulfonic acid to obtain Mirogabalin Besylate (I).

In the second embodiment of the invention provides a process for the preparation of Mirogabalin Besilate (I) comprising the steps of,
a) resoluting compound of formula (IV) or salt with resolving agent in the presence of a solvent to obtain resolving agent salt compound of formula (III), and

Wherein, the solvent is selected from Methyl tert butyl ether (MTBE), Ethyl methyl ketone (MEK) n-butyl acetate and Methyl isobutyl ketone (MIBK).
b) converting resolving agent salt compound of formula (III) into Mirogabalin Besilate (I).

In third embodiment of the invention provides a process for the preparation of pure Mirogabalin Besylate (I) comprising the steps of,
a) treating resolving agent salt compound of formula (III) with inorganic base in the presence of a solvent to obtain in-situ compound of formula (II),
b) reacting in-situ compound formula (II) with benzene sulfonic acid in the presence of a solvent to obtain Mirogabalin Besylate.
c) treating Mirogabalin Besylate with organic amine to obtain Mirogabalin free base, followed by treating with benzene sulfonic acid in the presence of a solvent to obtain Mirogabalin Besylate (I).
In fourth embodiment of the invention provides a purification process of pure Mirogabalin Besylate (I) comprising the steps of,
a) dissolving the Mirogabalin Besylate (I) in a solvent,
b) heating the reaction mixture at suitable temperature,
c) cooling the reaction mixture,
d) adding an anti-solvent to the resulting solution, and
e) isolating the pure Mirogabalin Besylate (I).

In fifth embodiment of the invention provides a purification process resolving agent salt compound of formula (III) by dissolving resolving agent salt compound of formula (III) in aqueous alcoholic solvent and heating the reaction mixture at suitable temperature.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of Mirogabalin Besylate with high yield and purity.
One embodiment of the present invention provides an improved process for the preparation of Mirogabalin Besylate (I) comprising the steps of,
a) reacting compound of formula (VIII) with compound of formula (VII) in the presence of a base to obtain compound of formula (VI),
b) treating compound of formula (VI) with nitromethane in the presence of a base to obtain the compound of formula (V),
c) reducing compound of formula (V) with reducing agent to obtain the compound of formula (IV) or salt,
d) resoluting compound of formula (IV) or salt with resolving agent in the presence of a solvent to obtain resolving agent salt compound of formula (III), optionally purifying with aqueous alcoholic solvent,
e) treating resolving agent salt compound of formula (III) with base to obtain in-situ compound of formula (II), and
f) treating in-situ compound of formula (II) with benzene sulfonic acid to obtain Mirogabalin Besylate (I).

According to the embodiment of the present invention, reacting compound of formula (VIII) with compound of the formula (VII) in presence of a base, carried out at a temperature of 0oC to -25oC for 50-110 min to obtain the compound of formula (VI). Treating compound of formula (VI) with nitromethane in presence of base, carried out at a temperature of 45oC to 75oC for 16-20hrs. to obtain the compound of formula (V). Reducing compound of formula (V) with reducing agent, carried out at a temperature of 55oC to 80oC for 20-24 hrs. to obtain the compound of formula (IV) or salt. resoluting compound of formula (IV) or salt with resolving agent in the presence of a solvent, carried out at a temperature of 45-60°C for 20-80 min to obtain resolving agent salt compound of formula (III), optionally purifying with aqueous alcoholic solvent (alcoholic and water). Treating resolving agent salt compound of formula (III) with a base and a solvent to obtain in-situ compound of formula (II). Treating in-situ compound of formula (II) with benzene sulfonic acid to obtain the Mirogabalin Besylate.

According to the embodiment of the present invention, purifying compound of formula (IV) salt with solvents to obtain crystalline compound of formula (IV) salt (i.e. tert-butyl 2-(6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl) hydrochloride)

In the second embodiment of the invention provides a process for the preparation of Mirogabalin Besilate (I) comprising the steps of,
a) resoluting compound of formula (IV) or salt with resolving agent in the presence of a solvent to obtain resolving agent salt compound of formula (III), and
Wherein, the solvent is selected from Methyl tert butyl ether (MTBE), Ethyl methyl ketone (MEK) n-butyl acetate and Methyl isobutyl ketone (MIBK).
b) converting resolving agent salt compound of formula (III) into Mirogabalin Besilate (I).

According to the embodiment of the present invention, resoluting compound of formula (IV) or salt with resolving agent in the presence of a solvent (i.e. MTBE, MEK, n-butyl acetate and MIBK) to obtain resolving agent salt compound of formula (III), further converting into Mirogabalin Besilate (I).

In third embodiment of the invention provides a process for the preparation of pure Mirogabalin Besylate (I) comprising the steps of,
a) treating resolving agent salt compound of formula (III) with inorganic base in the presence of a solvent to obtain in-situ compound of formula (II),
b) reacting in-situ compound formula (II) with benzene sulfonic acid in the presence of a solvent to obtain Mirogabalin Besylate.
c) treating Mirogabalin Besylate with organic amine to obtain Mirogabalin free base, followed by treating with benzene sulfonic acid in the presence of a solvent to obtain Mirogabalin Besylate (I).

According to the embodiment of the present invention, treating resolving agent salt compound of formula (III) with inorganic base in the presence of solvent to obtain in-situ compound of formula (II). Reacting in-situ compound formula (II) with benzene sulfonic acid in the presence of solvent to obtain Mirogabalin besylate. Treating Mirogabalin besylate with organic amine to obtain Mirogabalin free base, followed by treating with benzene sulfonic acid in the presence of a solvent to obtain Mirogabalin Besylate (I).

According to the embodiment of the present invention, in this process positional isomer was controlled around 0.12% in the reaction and the positional isomer was purified by acid and base treatment. The present invention specifically triethyl amine in aqueous medium, and followed by benzene sulfonic acid to get Mirogabalin Besylate. Mirogabalin Besylate was added to mixture of anisole, acetic acid and benzene sulfonic acid monohydrate to get high pure Mirogabalin Besylate (99.95%), Positional isomer was controlled 0.05%.

In fourth embodiment of the invention provides a purification process of pure Mirogabalin Besylate (I) comprising the steps of,
a) dissolving the Mirogabalin Besylate (I) in a solvent,
b) heating the reaction mixture at suitable temperature,
c) cooling the reaction mixture,
d) adding an anti-solvent to the resulting solution, and
e) isolating the pure Mirogabalin Besylate (I).

According to the embodiment of the present invention provides a purification process of Mirogabalin Besylate (I) comprising dissolving the Mirogabalin Besylate (I) in a solvent, reaction mixture is heated at a temperature of 65-70oC for 10-25 min and cool the reaction mass at below 55oC, preferably room temperature (25-30°C). After cooled reaction mass, added anti-solvent to resulting solution and stirred at a temperature of 25-30oC for 2-3 hrs. The resulting solution is filtered wash with solvent to obtain pure Mirogabalin Besylate (I).

According to the embodiment of the present invention, wherein the suitable temperature is between 50 to 70°C, wherein the cooling temperature is between 25 to 55oC.

In fifth embodiment of the invention provides a purification process resolving agent salt compound of formula (III) by dissolving resolving agent salt compound of formula (III) in aqueous alcoholic solvent and heating the reaction mixture at suitable temperature.

According to the embodiment of the present invention, it provides a purification process resolving agent salt compound of formula (III) by dissolving resolving agent salt of compound of formula (III) in aqueous alcoholic solvent (water/solvent) and heated to at a temperature of 60-65°C for 30-60min to get clear solution. The reaction mixture was gradually allowed at a temperature of 25-30°C and stirred at the same temperature for 2-3 hr. The precipitated solid filtered at a temperature of 25-30°C and dried the wet material at a temperature of 55-60° to obtain pure compound of formula (III).

According to the embodiment of the present invention provides purification resolving agent salt compound of formula (III) by aqueous solvent to get resolving agent salt compound of formula (III) with high pure (100%) isomer.

According to an embodiment of the present invention, Mirogabalin Besylate (I) having HPLC purity = 99 %.

According to an embodiment of the present invention, wherein the base is selected from a group consisting of pyridine, diazabicycloundecane (DBU); “organic amine” triethylamine, tert-butylamine; “inorganic base” sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydride, lithium hydroxide, lithium tert-butoxide, Sodium tert-butoxide, potassium tert-butoxide, Cesium hydroxide, potassium carbonate or potassium hydrogen carbonate. According to a more preferred embodiment the base is sodium hydride (NaH), diazabicycloundecane (DBU), triethylamine and sodium hydrogen carbonate or mixtures thereof or other suitable bases.

According to an embodiment of the present invention, wherein the solvent is selected from a group of consisting of hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, nitromethane and the like; ether solvents such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether (MTBE), 1,2-dimethoxy ethane, anisole and the like; ester solvents such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and the like; polar-aprotic solvents such as anisole, dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; chloro solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ketone solvents such as methyl ethyl ketone (MEK), acetyl acetone, methyl isobutyl ketone (MIBK) and the like, “anti-solvent” such as acetone; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene glycol-400, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethylether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; polar solvents such as water acetic acid and or mixtures thereof.

According to an embodiment of the present invention, wherein the alcoholic solvents is selected from a group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene glycol-400, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethylether, cyclohexanol, benzyl alcohol, phenol, or glycerol or water and or mixtures thereof.

According to an embodiment of the present invention, wherein the reducing agents selected from a group consisting of cuprous chloride, cupric chloride dihydrate, tin chloride, iron powder, sodium acetoxy borohydride, sodium borohydride, Raney nickel, palladium carbon, sodium cyanoborohydride, lithium aluminium hydride, preferably cuprous chloride, sodium acetoxy borohydride and raney nickel.

According to an embodiment of the present invention, wherein the resolving agent is selected from a group consisting of N-acetyl-L-leucine, N-acetyl-L-tyrosine, D- or L-tartartic acid, di-para-tolyl D-tartratic acid, di-benzoyl D-tartaric acid, (+)-camphor-10-sulfonic acid and (+)-a-phenyl ethylamine, D- or L-mandelic acid, malic acid and the like.

According to an embodiment of the present invention, wherein the acid selected from a group consisting of inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, perchloric acid, carbonic acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, succinic acid, citric acid, uric acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, salicylic acid, oleic acid, octanoic acid, stearic acid, mandelic acid, adepic acid, pivalic acid, camphorsulfonic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and or mixtures thereof.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

EXAMPLES
Example 1:
Preparation of (E)-tert-butyl 2-(3-ethybicyclo [3.2.0] hept-3-en-ylidene) acetate (Formula VI)
60% sodium hydride (64.6g, 1.615 mole) was taken in THF (800 ml) at -10 to-15°C. Solution of 3-ethylbicyclo [3.2.0] hept-3-en-6-one (200g, 1.468 mole) and tert-butyl 2-(dimethoxy phosphoryl) acetate (346g, 1.5432 mole) were dissolved in THF (400 ml) in another RB flask and this solution is added dropwise into above sodium hydride solution at -10 to-15°C. The reaction mass maintained for 60-90 min at same temperature. After completion of the reaction, the reaction was quenched with 20% ammonium chloride solution (1000 ml) and product was extracted with toluene (800 ml). The organic layer was washed with 10% sodium chloride solution (400ml) and distilled organic layer under reduced pressure to get (E)-tert-butyl 2-(3-ethybicyclo [3.2.0] hept-3-en-ylidene) acetate.
Yield: 100% (360g)
Purity by HPLC: 99%
Example 2:
Preparation of tert-butyl 2-(3-ethyl-6-(nitro methyl) bicycle [3.2.0] hept-3-en-6-yl) acetate (Formula V)
3-ethybicyclo [3.2.0] hept-3-en-ylidene) acetate (350gm, 1.49 mole), Nitromethane (273.5gm, 4.48 mole) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (350.5gm, 2.23 mole)were taken into RB flask. The reaction mixture was heated to 55-60°C and maintained the reaction mass for 18 hr at same temperature. After completion of the reaction, the reaction was quenched with water (1750ml) and the product was extracted with toluene (1400 ml). The organic layer was washed with 10% sodium chloride solution (700 ml) and distilled the organic layer under reduced pressure to get tert-butyl 2-(3-ethyl-6-(nitro methyl) bicycle [3.2.0] hept-3-en-6-yl) acetate.
Yield: 92% (406g)
Purity by HPLC: 99%
Example 3:
Preparation of tert-butyl 2-(6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate hydrochloride (Formula IV)
Tert-butyl 2-(3-ethyl-6-(nitro methyl) bicycle [3.2.0] hept-3-en-6-yl) acetate (400gm, 1.354 mole), Iron powder (832gm, 14.896 mole), Ammonium chloride (362.16gm, 6.77 mole) and water (1200ml) were taken in methanol (3200ml). The reaction mixture was heated to 65-70°C and maintained the reaction mass for 22-24hrs at 65-70°C. After completion of the reaction, the reaction mixture was filtered through hyflo bed to remove unreacted Iron powder, filtered and distilled under reduced pressure to get residue material. The obtained residue was dissolved in water (1000 ml) and was washed with hexanes (100 ml) to remove impurities and product was extracted with dichloromethane (1600 ml). The organic layer was washed with 10% sodium chloride (800 ml) and was distilled under reduced pressure to get crude material. The crude material was taken in hexanes (800 ml) and stirred for 60-90 min, then precipitated solid was filtered and dried to get crystalline solid of tert-butyl 2-(6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl) hydrochloride.
Yield: 55% (220g)
Purity by HPLC: 99%
Example 4:
Preparation of tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate D-Mandelate (Formula III)
Tert-butyl 2-(6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate hydrochloride (200 gm) was dissolved in ethyl acetate (1000ml) and was washed with 8% of sodium bicarbonate solution (1300 ml) to get free base. The obtained free base separated the layers and organic layer was concentrated under reduced pressure. Then obtained residue was dissolved in ethyl acetate (400 ml) and D-mandelic acid (120.8gm, 0.794 mole) was added to organic layer and heated to 50-55°C for 30-60min to get mandelate salt. The reaction mixture was gradually cooled to 25-30°C, further allowed to cool at 0-5°C and stirred at same temperature for 2-3 hr at same temperature.
The precipitated solid was filtered at 0-5°C and obtained wet material was taken in aqueous methanol (400 ml) (water/methanol is 2:1). The resultant product was heated to 60-65°C for 30-60min to get a clear solution. The reaction mixture was gradually allowed to 25-30°C and stirred at same temperature for 2-3 hr. The precipitated solid was filtered at 25-30°C and dry the wet material at 55-60°C to get tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate D-Mandelate ((R)-2-hydroxy-2-phenylacetate).
Yield: 30% (80g)
Purity by HPLC: 99%
Example 5:
Preparation of tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate D-Mandelate (Formula III)
Tert-butyl 2-(6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate hydrochloride (100 gm) was dissolved in methyl tert butyl ether (500ml) and washed with 8% of sodium bicarbonate solution (650 ml) to get free base. The obtained free base organic layer separated, add with D-mandelic acid (60.4gm, 0.397 mole) and heated to 50-55°C for 30-60min to get mandelate salt. The reaction mixture was gradually allowed to 25-30°C and stirred at same temperature for 2-3 hr. The precipitated solid was filtered at 25-30°C and dry the wet material at 55-60° to get tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate D-Mandelate ((R)-2-hydroxy-2-phenylacetate).
Yield: 25% (35gm)
Purity by HPLC: 99%
Example 6:
Preparation of tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate D-Mandelate (Formula III)
Tert-butyl 2-(6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate hydrochloride (100 gm) was dissolved in dichloromethane (500ml) and washed with 8% of sodium bicarbonate solution (650 ml) to get free base. The obtained free base layers separated, and organic layer was concentrated under reduced pressure. The obtained residue was dissolved in ethyl methyl ketone (400ml), D-mandelic acid (60.4gm, 0.397 mole) was added to organic layer and heated to 50-55°C for 30-60 min to get mandelate salt. The reaction mixture was gradually allowed to 25-30°C and stirred at same temperature for 2-3 hr. The precipitated solid was filtered at 25-30°C and dry the wet material at 55-60°C to get tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate D-Mandelate ((R)-2-hydroxy-2-phenylacetate).
Yield: 25% (35gm)
Purity by HPLC: 99%
Example 7:
Preparation of tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate D-Mandelate (Formula III)
Tert-butyl 2-(6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate hydrochloride (100 gm) was dissolved in dichloromethane (500ml) and washed with 8% of sodium bicarbonate solution (650 ml) to get free base. The obtained free base organic layer separated, and organic layer was concentrated under reduced pressure. Then obtained residue was dissolved methyl isobutyl ketone (350ml), D-Mandelic acid (60.4gm, 0.397 mole) was added to organic layer and heated to 50-55°C for 30-60min to get mandelate salt. The reaction mixture was gradually allowed to 25-30°C and stirred at same temperature for 2-3 hr. The precipitated solid was filtered at 25-30°C and dry the wet material at 55-60°C to get tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate (D-Mandelate ((R)-2-hydroxy-2-phenylacetate).
Yield: 25% (35gm)
Purity by HPLC: 99%
Example 8:
Preparation of tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate D-Mandelate (Formula III)
Tert-butyl 2-(6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate hydrochloride (100 gm) was dissolved in dichloromethane (500ml) and washed with 8% of sodium bicarbonate solution (650 ml) to get free base. The obtained free base organic layer separated, and organic layer was concentrated under reduced pressure. Then obtained residue was dissolved n-butyl acetate (300ml), D-Mandelic acid (60.4gm, 0.397 mole) was added to organic layer and heated to 50-55°C for 30-60min to get mandelate salt. The reaction mixture was gradually allowed to 25-30°C and stirred at same temperature for 2-3 hr. The precipitated solid was filtered at 25-30°C and dried the wet material at 55-60°C to get tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo [3.2.0] hept-3-en-6-yl) acetate (D-Mandelate ((R)-2-hydroxy-2-phenylacetate).
Yield: 25% (35gm)
Purity by HPLC: 99%
Example 9:
Preparation of Mirogabalin Besylate (I)
Tart-butyl 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate D-mandelate (70gm, 0.1677 mole) was taken in MDC (350 ml) and washed with saturated sodium bicarbonate solution (900ml) and get free base. The organic layer was washed with 10% sodium chloride solution (140 ml) and MDC was removed by distillation. The obtained residue was dissolved in anisole (420 ml) and Benzene sulfonic acid monohydrate (38.38 gm, 0.217 mole) at 25-30°C. The reaction mass was maintained for 36 hr at 25-30°C. After completion of the reaction, filter the precipitated product and wash with Acetone (35 ml).
The obtained above wet material was taken in water (280 ml) and Triethylamine (15.75 g) was added drop wise at 25-30°C to get free base. After that filter the precipitated solid to remove positional isomer and the wet free base solid was dried at 50-55°C to Mirogabalin free base. The obtained Mirogabalin free base was dissolved in mixture of Anisole (280 ml) and acetic acid (22 ml), followed by add with benzene sulfonic acid mono hydrate (23.52 gm) (1.0 equivalent for free base) and maintained reaction mass at 25-30°C for 60-90min. The resultant reaction mixture was allowed to cool at 0-5°C for 3-4 hr. The precipitated solid was filtered, and wet cake was washed with acetone (25 ml) to get crude tile of the compound.
Yield: 65% (40gm)
Example 10:
Preparation of Pure Mirogabalin Besylate (I)
The crude Mirogabalin Besylate (40 gm) was taken in isopropanol (280 ml) and heated to 65-70°C to get a clear solution. The obtained reaction mass was filtered through 0.4µ filter paper and obtained filtrate was taken in RB flask and distilled the solvent under vacuum. The obtained reaction mass was allowed to cool to 55-55, followed by added with acetone (110 ml) to precipitated solid and stirred the reaction mixture at 25-30° for 2-3 hr. The obtained solid was filtered. and washed with acetone (35 ml) and dried the wet material at 50-55°C to get pure Mirogabalin Besylate.
Yield: 87% (35gm)
Purity by HPLC: = 99.80% (Positional isomer 0.05%)
Example 11:
Preparation of Pure Mirogabalin Besylate (I)
The crude Mirogabalin Besylate (40 gm) was taken in isopropanol (280 ml) and heated to 65-70°C to get a clear solution. The obtained reaction mass was filtered through 0.4µ filter paper and obtained filtrate was taken in RB flask and distilled the solvent under vacuum. The obtained reaction mass was allowed to cool to 25-30°C, followed by adding acetone (110 ml) to precipitated solid and stirred the reaction mixture at 25-30°C for 2-3 hr. The obtained solid was filtered. and washed with acetone (35 ml) and dried the wet material at 50-55°C to get pure Mirogabalin Besylate.
Yield: 90% (36gm)
Purity by HPLC: = 99.90%

,CLAIMS:WE CLAIM:
1. An improved process for the preparation of Mirogabalin Besylate (I) comprising the steps of,
a) reacting compound of formula (VIII) with compound of formula (VII) in the presence of a base to obtain compound of formula (VI),

b) treating compound of formula (VI) with nitromethane in the presence of a base to obtain the compound of formula (V),

c) reducing compound of formula (V) with reducing agent to obtain compound of formula (IV) or salt,

d) resoluting compound of formula (IV) or salt with resolving agent in the presence of a solvent to obtain resolving agent salt compound of formula (III), optionally purifying with aqueous alcoholic solvent,

e) treating resolving agent salt compound of formula (III) with base to obtain in-situ compound of formula (II), and

f) treating in-situ compound of formula (II) with benzene sulfonic benzene sulfonic acid to obtain Mirogabalin Besylate (I).

2. The process as claimed in claim 1, wherein the base is selected from a group consisting of pyridine, diazabicycloundecane (DBU); organic amine triethylamine, tert-butylamine; inorganic base sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydride, lithium hydroxide, lithium tert-butoxide, Sodium tert-butoxide, potassium tert-butoxide, Cesium hydroxide, potassium carbonate or potassium hydrogen carbonate. According to a more preferred embodiment the base is sodium hydride (NaH), diazabicycloundecane (DBU), triethylamine and sodium hydrogen carbonate or mixtures thereof or other suitable bases.

3. The process as claimed in claim 1, wherein the reducing agents selected from a group consisting of cuprous chloride, cupric chloride dihydrate, tin chloride, iron powder, sodium acetoxy borohydride, sodium borohydride, raney nickel, palladium carbon, sodium cyanoborohydride, lithium aluminium hydride, preferably cuprous chloride, sodium acetoxy borohydride and raney nickel.

4. The process as claimed in claim 1, wherein the solvent is selected from a group of consisting of hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, nitromethane and the like; ether solvents such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether (MTBE), 1,2-dimethoxy ethane, anisole and the like; ester solvents such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and the like; polar-aprotic solvents such as anisole, dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; chloro solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ketone solvents such as methyl ethyl ketone (MEK), acetyl acetone, methyl isobutyl ketone (MIBK) and the like, “anti-solvent” such as acetone; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene glycol-400, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethylether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; polar solvents such as water acetic acid and or mixtures thereof.

5. The process as claimed in claim 1, wherein the resolving agent is selected from a group consisting of N-acetyl-L-leucine, N-acetyl-L-tyrosine, D- or L-tartartic acid, di-para-tolyl D-tartratic acid, di-benzoyl D-tartaric acid, (+)-camphor-10-sulfonic acid and (+)-a-phenyl ethylamine, D- or L-mandelic acid, malic acid and the like.

6. A purification process of pure Mirogabalin Besylate (I) comprising the steps of,
a) dissolving the Mirogabalin Besylate (I) in a solvent,
b) heating the reaction mixture at suitable temperature,
c) cooling the reaction mixture,
d) adding an anti-solvent to the resulting solution, and
e) isolating the pure Mirogabalin Besylate (I).

7. The process as claimed in claim 6, wherein the solvent is selected from a group of consisting of hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, nitromethane and the like; ether solvents such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether (MTBE), 1,2-dimethoxy ethane, anisole and the like; ester solvents such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and the like; polar-aprotic solvents such as anisole, dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; chloro solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ketone solvents such as methyl ethyl ketone (MEK), acetyl acetone, methyl isobutyl ketone (MIBK) and the like, anti-solvent such as acetone; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene glycol-400, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethylether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; polar solvents such as water acetic acid and or mixtures thereof.
8. The process as claimed in claim 6, wherein the suitable temperature is between 50 to 70°C, wherein the cooling temperature is between 25 to 55oC.