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

PROCESS FOR PREPARATION OF MIROGABALIN

INTRODUCTION
Aspects of the present application relates to process for preparation of Mirogabalin or its pharmaceutically acceptable slats thereof.
The drug compound having the adopted name Mirogabalin besylate chemically designated as [(1R, 5S, 6S)-6-(Aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl] acetic acid mono benzenesulfonate and is represented by structure of formula I.

I
Mirogabalin is a gabapentinoid medication which is approved in Japan for the treatment of postherpetic neuralgia and painful diabetic peripheral neuropathy. Mirogabalin has a potent pain-modulating effect with a unique high affinity and prolonged dissociation rate for the a2delta-1 subunit of voltage-gated calcium (Ca2+) channels (VGCCs) on the dorsal root ganglion resulting in more sustained analgesia compared with traditional gabapentinoids.
U.S. Patent No. 7,947,738 discloses Mirogabalin and process for its preparation.
U.S. Patent No. 8,324,425 (‘425 patent) discloses process for preparation of Mirogabalin which involves the use of optically active organic acids as a resolution reagent to get the desire optically pure intermediates.
U.S. Patent No. 9, 206, 104, U.S. Patent No. 9, 394, 235, 5, U.S. Patent No. 9, 035, 103 discloses various processes for preparation optically pure starting material bicyclic compound and its conversion to Mirogabalin. Further, these reported processes starting with optically pure starting material also uses the resolution technique to get the desired optically pure Mirogabalin or its pharmaceutically acceptable slats.
Hence, there is a need for an alternate process for preparation of Mirogabalin or its pharmaceutically acceptable slats by controlling critical impurities or by-products with high yield by employing routinely used simple purification techniques like recrystallization.
The present application provides a process for the preparation of Mirogabalin or its pharmaceutically acceptable slats by controlling critical impurities or by-products which in turn lead to increase in the overall yield and purity.
SUMMARY
In the first embodiment, the present application provides a process for preparation of Mirogabalin besylate, said process comprising:
(a) reacting compound of formula (II) with formula (III) in the presence of
suitable base to give compound of formula (IV)

(b) treating compound of formula (IV) with nitromethane to give mixture of
compound of formula (Va) and formula (Vb)

(c) converting mixture of compound of formula (Va) and formula (Vb) to
compound of formula VI using reducing agent

(d) hydrolysing compound of formula VI with base to provide Mirogabalin;
and
(e) treating Mirogabalin with benzene sulfonic acid to get the Mirogabalin
besylate.
In the second embodiment, the present application provides process for preparation of Mirogabalin or its pharmaceutically acceptable salt comprising ester hydrolysis of compound of formula VI using base.
In the third embodiment, the present application provides substantially pure Mirogabalin or its pharmaceutically acceptable salts free from one or more impurities selected from compound of formula VII, formula VIII and formula IX

In the fourth embodiment, the present application provides substantially pure Mirogabalin or its pharmaceutically acceptable salts having less than 0.01% of one or more impurities selected from compound of formula VII, formula VIII and formula IX

DETAILED DESCRIPTION
In the first embodiment, the present application provides a process for preparation of Mirogabalin besylate, said process comprising:
(a) reacting compound of formula (II) with formula (III) in the presence of
suitable base to give compound of formula (IV)

(b) treating compound of formula (IV) with nitromethane to give mixture of
compound of formula (Va) and formula (Vb)

(c) converting mixture of compound of formula (Va) and formula (Vb) to
compound of formula VI using reducing agent

(d) hydrolysing compound of formula VI with base to provide Mirogabalin;
and
(e) treating Mirogabalin with benzene sulfonic acid to get the Mirogabalin
besylate.
Step (a) involves reacting compound of formula (II) with formula (III) in the presence of suitable base to give compound of formula (IV)
Suitable base that may be used in step (a) include but not limited to metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like or metal alkoxides such as sodium methoxide, potassium methoxide, potassium t-butoxide, sodium t-butoxide and the like or metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like;
Suitable solvent that may be used in step (a) include but not limited to hydrocarbons, halogenated hydrocarbons, ethers, polar aprotic solvents, nitriles or mixtures thereof.
Step (a) may be carried out at the reflux temperature of the solvent or mixture of solvents used in step (a) or at a temperature less than less than 80 °C or less than 60 °C or less than 40 °C or less than 20 °C or less than 10 °C or less than 0 °C or any other suitable temperature.
Step (b) involves the treating compound of formula (IV) with nitromethane to give mixture of compound of formula (Va) and formula (Vb)
Suitable base that may be used in step (b) include but not limited to triethylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), Collidine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1-methylmorpholine, 1-methylpiperidine, 1,5-diazabicyclo[4.3.0]non-5-ene, N,N-dimethylpiparazine, N,N-dimethylaniline, 4-(dimethylamino)-pyridine (DMAP), hexamethylenetetramine (HMTA), tetramethylethylenediamine (TMEDA), 2,6-Lutidine, collidine, 2,3,5,6-tetramethylpyridine (TEMP), 1,1,3,3-Tetramethylguanidine and the like.
Suitable solvents that may be used in step (b) include ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or mixtures thereof.
Step (b) may be carried out at the reflux temperature of the solvent or mixture of solvents used in step (b) or at a temperature less than less than 120 °C or less than 80 °C or less than 60 °C or less than 40 °C or less than 20 °C or less than 10 °C or any other suitable temperature.
Step (c) involves converting mixture of compound of formula (Va) and formula (Vb) to compound of formula VI using reducing agent
Suitable reducing agents that may be used in the step (c) including Iron in acidic medium such as Iron & hydrochloric acid, Iron & ammonium chloride, Iron & acetic acid, and the like or catalytic hydrogenation using Raney Nickel, Palladium-on-Carbon and the like or other reagents like sodium dithionate, Stannous chloride and the like or any other suitable reducing agents known in the art.
Suitable solvents that may be used in step (c) include water, alcohols, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or mixtures thereof.
Step (c) may be carried out at the reflux temperature of the solvent or mixture of solvents used in step (c) or at a temperature less than less than 120 °C or less than 80 °C or less than 60 °C or less than 40 °C or less than 20 °C or less than 10 °C or any other suitable temperature.

Step (d) involves ester hydrolysis of compound of formula VI with base to provide Mirogabalin
Inventors of the present application surprisingly found that formation of impurities are significantly controlled in step (d) by converting compound of formula (VI) into corresponding lactam as an in-situ intermediate by treating compound of formula (VI) with base.

Suitable base that may be used in step (d) include but not limited to metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like or metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like or any other suitable base that may be used in the ester hydrolysis.
Suitable solvents that may be used in step (d) include water, alcohols, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or mixtures thereof.
Step (d) may be carried out at the reflux temperature of the solvent or mixture of solvents used in step (d) or at a temperature less than less than 120 °C or less than 80 °C or less than 60 °C or less than 40 °C or less than 20 °C or less than 10 °C or any other suitable temperature.
Step (e) involves treating Mirogabalin with benzene sulfonic acid to get the Mirogabalin besylate.
Suitable solvents that may be used in step (e) include water, alcohols, hydrocarbons, halogenated hydrocarbons, esters, ethers or mixtures thereof.
Mirogabalin or its pharmaceutically acceptable salt or one or more intermediates, in particular compound of formula Va or Formula Vb or Formula VI may be purified using one or more methods selected from slurrying in a solvent, recrystallization from a solvent.
Suitable solvents that may be used for purification of Mirogabalin or its pharmaceutically acceptable salt or one or more intermediates by slurrying in a suitable solvent or recrystallization in a solvent include water, alcohols, ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.
The purification process may be carried out one or more times using one or more purification methods described in the present application to completely remove the impurities or to get the desired purity of Mirogabalin.
In the second embodiment, the present application provides process for preparation of Mirogabalin or its pharmaceutically acceptable salt comprising ester hydrolysis of compound of formula VI using base.
Suitable base that may be used for ester hydrolysis of compound of formula VI include but not limited to metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like or metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like or any other suitable base that may be used in the ester hydrolysis.
Suitable solvents that may be used in ester hydrolysis of compound of formula VI include water, alcohols, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or mixtures thereof.
In the third embodiment, the present application provides substantially pure Mirogabalin or its pharmaceutically acceptable salts free from one or more impurities selected from compound of formula VII, formula VIII and formula IX

In the fourth embodiment, the present application provides substantially pure Mirogabalin or its pharmaceutically acceptable salts having less than 0.01% of one or more impurities selected from compound of formula VII, formula VIII and formula IX

Following gradient HPLC method used to measure the purity of Mirogabalin and the content of impurities in Mirogabalin.
Column : X bridge C18
Column Temperature : 30°C
Injection volume : 10 µL
Diluent : Buffer: Acetonitrile
Test concentration : 1.0 mg/mL
Buffer : Potassium dihydrogen phosphate
Mobile Phase A : Mixture of buffer and Acetonitrile
Mobile Phase B : Mixture of water and Acetonitrile
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, phenol, glycerol and the like.
A “hydrocarbon solvent” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds or aromatic. Examples of “C5-C15 aliphatic or aromatic hydrocarbons” include n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C12 aromatic hydrocarbons and the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole and the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride and the like.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C10 esters” include ethyl acetate, n-propyl acetate, isopropyl Acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate and the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C10 ketones” include acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones and the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include acetonitrile, propionitrile, butanenitrile and the like.
A “polar aprotic solvents” include N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone and the like;
“Free from” as used herein refers to a compound that is having impurities below its limit of detection or not detected as measured by HPLC method or UPLC method or any other analytical method.
“Substantially free” as used herein refers to a compound that is having one or more individual impurities less than about 0.01% or less than about 0.05% or less than about 0.02% or less than about 0.01% or less than about 0.001% or less than about 0.001% or less than about 0.0001% as measured by liquid chromatography method or any other analytical method.
"Substantially pure" as used herein refers to purity of the compound which is at least about 99.5 % or at least about 99.6 % or at least about 99.7 % or at least about 99.8 % or at least about 99.9 % as measured by a liquid chromatography method or any other analytical method.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.
EXAMPLES
Example-1: Preparation of tert-butyl (E)-2-((1R,5S)-3-ethylbicyclo[3.2.0]hept-3-
en-6-ylidene)acetate
Mixture of tert-butyl 2-(dimethoxy phosphoryl)acetate (33.3 g) and toluene (30 mL) was slowly added to the sodium tert-butoxide (13.76 g) in toluene 225 (mL) at -5 °C and stirred for 1 hour at same temperature. (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (15 g) and toluene (30 mL) mixture was slowly added to the reaction mixture at -6 °C and stirred at same temperature for 12 hours. Water (75 mL) was added to the reaction mass and stirred for 30 minutes. Layers were separated, organic layer washed with brine solution (2x45 mL) and concentrated under reduced pressure to afford title compound.
Example-2: Preparation of tert-butyl 2-((1R,5S,6S)-3-ethyl-6-(nitro methyl)bicyclo[3.2.0]hept-3-en-6-yl)acetate
DBU (40.5 g) was charged in to reaction mixture containing tert-butyl (E)-2-((1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene)acetate (25 g) and dimethylsulfoxide (125 mL) at room temperature and stirred for 10 minutes. Nitro methane (16.27 g) was slowly added to the reaction mixture, heated to 55 °C and stirred for 20 hours at same temperature. Aqueous potassium dihydrogen phosphate (250 mL) was added to the reaction mass at 4 °C and stirred for 20 minutes. Charged isopropyl acetate (125 mL) was added to the reaction mixture and stirred for 15 minutes. Layers were separated, aqueous layer extracted with isopropyl acetate (125 mL), combined organic layer washed with water (2x75 mL) and concentrated under reduced pressure to afford title compound.
Example-3: Preparation of tert-butyl 2-((1R,5S,6S)-6-(amino methyl)-3-ethylbicy
clo[3.2.0]hept-3-en-6-yl)acetate
Ammonium chloride (8.15 g) and iron (36.86 g) was charged in to the reaction mixture containing tert-butyl 2-((1R,5S,6S)-3-ethyl-6-(nitro methyl)bicyclo[3.2.0]hept-3-en-6-yl)acetate (15 g), isopropyl alcohol (150 mL), water (75 mL) at room temperature and the resultant reaction mixture was heated to 63 °C, stirred at same temperature for 21 hours. Reaction mass filtered at room temperature, washed with isopropyl alcohol (45 mL) and the filtrate concentrated up to 4-5 volumes of reaction mass. Isopropyl acetate (150 mL) charged into the reaction mass, stirred for 15 minutes and layers were separated. Aqueous sodium bicarbonate solution (10%; 75 mL) and isopropyl acetate (75 mL) was charged into aqueous layer and stirred for 15 minutes. Layers separated, combined organic layer washed with brine solution (45 mL), concentrated till reaches to 3-4 volumes and the resultant reaction mixture was stirred for 21 hours at room temperature and 2 hours at 10 °C. Separated solid was filtered, washed with isopropyl acetate and dried at 60 °C to afford title compound. The resultant solid was purified using isopropyl acetate (5 volumes) by heating the reaction mass to 54 °C followed by cooled to room temperature.
Purity by HPLC :98.38%; Enantiomer:0.12%
Example-4: Preparation of Mirogabalin
Charged tert-butyl 2-((1R,5S,6S)-6-(amino methyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetate (30 g), methanol (180 mL), water (180 mL) and sodium hydroxide (70 g) into flask, heated to heated to 60 °C and stirred at same temperature for 23 hours. The resultant reaction mass was concentrated under reduced pressure till reaction mass volume reached to 4-5 volumes. Reaction mass pH was slowly adjusted to 6-7 at 3 °C and stirred at same temperature for 60 minutes. Separated solid was filtered, washed with water 30 (mL), followed by isopropyl acetate (90 mL) and dried at 55 °C under reduced pressure to afford title compound.
Purity by HPLC :99.58%; Lactam impurity:0.32%;
Example-5: Preparation of Mirogabalin Besylate
Benzenesulphonic acid (8 g) in isopropyl acetate (40 mL) was slowly added to Mirogabalin (10 g) and isopropyl acetate (100 mL) at 5 °C, stirred for 4 hours, filtered at same temperature and washed with isopropyl acetate (20 mL). Resultant compound, isopropyl acetate(170mL) and water(5mL) charged into flask, heated to 50°C and stirred for 15 minutes. Cooled to 0 °C and stirred for 4 hours at same temperature. Separated solid was filtered, washed with isopropyl acetate(30mL) and dried at 45 °C under reduced pressure to afford title compound.
Purity by HPLC: 99.96%; Enantiomer: 0.06%; Lactam impurity: Not detected; Compound of formula VII: Not detected; Compound of formula VIII: Not detected and Compound of formula IX: Not detected
Example-6: Purification of Mirogabalin Besylate
Mirogabalin Besylate (10 g), ethanol (10 mL) and water (40 mL) charged into flask, heated to 50°C followed by cooled to 5 °C and stirred for 4 hours at same temperature. Separated solid was filtered, washed with water (5 mL) and dried at 45 °C under reduced pressure to purified Mirogabalin besylate.
Example-7: Purification of Mirogabalin Besylate
Mirogabalin Besylate (10 g), methanol (5 mL) and water (25 mL) charged into flask, heated to 50 °C followed by cooled to 5 °C and stirred for 4 hours at same temperature. Separated solid was filtered, washed with water (5 mL) and dried at 45 °C under reduced pressure to afford purified Mirogabalin besylate.
Example-8: Purification of Mirogabalin Besylate
Mirogabalin Besylate (10 g), tert-butyl acetate (100 mL) and water (10 mL) charged into flask, heated to 60 °C followed by cooled to 5 °C and stirred for 4 hours at same temperature. Separated solid was filtered, washed with tert-butyl acetate (10 mL) and dried at 45 °C under reduced pressure to afford purified Mirogabalin besylate.
,CLAIMS:Claims:

1. A process for preparation of Mirogabalin besylate, said process comprising:
(a) reacting compound of formula (II) with formula (III) in the presence of
suitable base to give compound of formula (IV)

(b) treating compound of formula (IV) with nitromethane to give mixture of
compound of formula (Va) and formula (Vb)

(c) converting mixture of compound of formula (Va) and formula (Vb) to
compound of formula VI using reducing agent

(d) hydrolysing compound of formula VI with base to provide Mirogabalin, and
(e) treating Mirogabalin with benzene sulfonic acid to get the Mirogabalin besylate.

2. The process according to claim 1, wherein based used in step (e) is metal hydroxides or metal carbonates.

3. The process according to claim 1, wherein base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or one or two mixtures thereof.

4. The process according to claim 1, wherein base is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.

5. Substantially pure Mirogabalin or its pharmaceutically acceptable salts free from one or more impurities selected from compound of formula VII, formula VIII and formula IX

6. Substantially pure Mirogabalin or its pharmaceutically acceptable salts according to claim 5 having less than 0.01% of one or more impurities selected from compound of formula VII, formula VIII and formula IX