Field of the Invention:

The present invention provides a novel process for the preparation of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c] pyrrole-1-carboxamide compound represented by the following structural formula-1.

Formula-1 The present invention also provides novel intermediate compound useful for the preparation of compound of formula-1.

Background of the Invention:

(lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl} amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide, commonly known as Telaprevir is an inhibitor of the HCV NS3/4A protease and is marketed under the brand names Incivek and Incivo. Telaprevir is a pharmaceutical drug co-developed by Vertex pharmaceuticals and Johnson & Johnson.

Peptidomimetic compounds useful as protease inhibitors such as Telaprevir and process for their preparation is disclosed in US7820671B2. The disclosed process is schematically represented in below scheme-A. Scheme-A:

The disclosed process involves the purification of Telaprevir as well as some of its intermediates using column chromatography. Purification of a compound using chromatography technique is a tedious process and hence not suggestible on commercial scale.

There is still a need in the art to develop a novel process for the preparation of Telaprevir. Also there is a need in the art to develop an improved process for the purification of Telaprevir as well as its intermediate compounds, which avoids the usage of chromatography technique in order to make the process commercially viable.

Brief description of the Invention:

The first aspect of the present invention is to provide a novel process for the preparation of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide compound of formula-1.

The second aspect of the present invention is to provide a novel process for the preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6.

The third aspect of the present invention is to provide novel intermediate compound useful for the preparation of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino] acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1 H-cyclopenta[c]pyrrole-1 -carboxamide compound of formula-1.

The fourth aspect of the present invention is to provide a process for the preparation of octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride salt compound of formula-3a.

The fifth aspect of the present invention is to provide a process for the preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6, comprising of separating the diastereomers of 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5.

The sixth aspect of the present invention is to provide base-addition salts of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydro cyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6.

Detailed description of the Invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; and/or mixtures thereof.

The term "suitable base" used in the present invention refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tertbutoxide; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkaline earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine (DIPEA), diisobutylamine, triethylamine (TEA), tributylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), 2,6-lutidine, lithium diisopropylamide, imidazole; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and/or mixtures thereof.

The first aspect of the present invention provides a novel process for the preparation of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c] pyrrole- 1-carboxamide compound of formula-1, comprising of;

a) Condensing the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoic acid compound of formula-2 with octahydrocyclopenta[c]pyrrole-l-carbonitrile compound of formula-3 or its acid-addition salt in presence of a suitable condensing agent in a suitable solvent optionally in presence of a suitable base to provide N-((lS)-2-((2S)-l-(l-cyanohexahydrocyclopenta[c]pyrrol-2( 1H)-yl)-3,3 -dimethyl-1 -oxobutan-2-ylamino)-1 -cyclo hexyl-2-oxoethyl) pyrazine-2-carboxamide compound of formula-4,

b) converting the compound of formula-4 to its corresponding alkyl ester compound of general formula-9 by reacting it with C1-C4 straight chain or branched chain alcohol in presence of a suitable catalyst,

c) hydrolyzing the compound of general formula-9 in presence of a suitable acid or a suitable base optionally in presence of a suitable solvent to provide 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3 -dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1 -carboxylic acid compound of formula-5,

d) separating the diastereomers of compound of formula-5 by treating it with a suitable base in a suitable solvent followed by treating the obtained salt compound with a suitable acid to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6,

e) condensing the compound of formula-6 with (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide compound of formula-7 or its acid-addition salt in presence of a suitable condensing agent in a suitable solvent optionally in presence of a suitable base to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)-N-((3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl)octahydrocyclopenta[c] pyrrole-1-carboxamide compound of formula-8,

f) oxidizing the compound of formula-8 with a suitable oxidizing agent in a suitable solvent optionally in presence of a suitable catalyst and/or a suitable base to provide compound of formula-1,

g) optionally purifying the compound of formula-1 to provide pure compound of formula-1.

Wherein, in step-a) and step-e) the suitable condensing agent is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride (EDC.HC1), N,N-carbonyldiimidazole (CDI), substituted or unsubstituted alkyl or aryl haloformates such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate, p-nitro phenylchloroformate, benzyl chloroformate and the like, diphenylphosphoroazidate (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), alkyl or aryl sulfonyl halides such as methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and the like optionally in combination with l-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), O-Cbenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N- hydroxy succinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS) and the like; the suitable base is selected from organic or inorganic bases; the suitable solvent is selected from chloro solvents, polar-aprotic solvents, alcoholic solvents, ether solvents, ester solvents, polar solvents, ketone solvents or mixtures thereof;

In step-b) the suitable catalyst is selected from thionyl chloride, dry HC1 gas, tri(Ci-C6 straight chain or branched chain alkyl)silyl halides such as trimethylsilyl chloride (TMSC1) and the like;

In step-c) the suitable acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid and the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and the like; the suitable solvent is selected from alcoholic solvents, ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents or mixtures thereof;

In step-d) the suitable base is selected from inorganic bases and chiral or achiral organic amines; the chiral organic amine is selected from but not limited to (R)-a-aminoethylbenzene, (S)-a-aminoethylbenzene, (S)-1,2,3,4-tetrahydro-1 -naphthylamine, (R)-1,2,3,4-tetrahydro-1 -naphthyl amine, quinine, cinchonine, (lS,2R)-(+)-norephedrine and the achiral organic amine is selected from methyl amine, dimethyl amine, ethyl amine, diethyl amine, n-propyl amine, iso-propyl amine, ethanolamine (2-aminoethanol), n-butylamine, tert.butyl amine, benzylamine and the like;

The suitable acid is selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, organic acids such as formic acid, acetic acid, oxalic acid and the like;

The suitable solvent is selected from ester solvents, ether solvents, polar solvents, chloro solvents, alcoholic solvents, hydrocarbon solvents, polar-aprotic solvents or mixtures thereof; preferably a mixture of ethyl acetate and methyl tert.butyl ether.
In step-f) the suitable oxidizing agent is selected from sodium hypochlorite (NaOCl), 1,1,1-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (Dess-Martin periodinane or DMP), oxalyl chloride/dimethylsulfoxide (Swern oxidation), trichloroisocyanuric acid (TCICA), potassium permanganate, pyridinium chlorochromate (PCC), potassium dichromate, manganese dioxide, oxone, chromium trioxide, bis(acetoxy)iodobenzene (BAIB), N-chlorosuccinimide in combination with dimethylsulfide and the like; the suitable catalyst is selected from 2,2,6,6-tetramethyl-piperidin-l-yl)oxyl (TEMPO), 4-methoxy TEMPO, 4-amino TEMPO, 4-acetamido TEMPO, 2-azaadamantane N-Oxyl (AZADO), 1-methyl-AZADO and the like; the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, polar-aprotic solvents, nitrile solvents, ketone solvents or mixtures thereof; the suitable base is selected from inorganic bases, preferably alkali metal carbonates, alkali metal bicarbonates;

The oxidation of compound of formula-8 is carried out optionally in presence of a suitable co-catalyst. The suitable co-catalyst is selected from sodium bromide, potassium bromide, sodium acetate, potassium acetate, ammonium acetate.

A preferred embodiment of the present invention provides a process for the preparation of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c] pyrrole- 1-carboxamide compound of formula-1, comprising of;

a) Condensing the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoic acid compound of formula-2 with octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride salt compound of formula-3a in presence of N,N-dicyclohexylcarbodiimide/l-hydroxybenzotriazole and sodium bicarbonate in a mixture of dichloromethane and water to provide N-(( 1 S)-2-((2S)-1 -(1 -cyanohexahydro cyclopenta[c]pyrrol-2( 1 H)-yl)-3,3-dimethyl-1 -oxobutan-2-ylamino)-l-cyclohexyl-2-oxoethyl) pyrazine-2-carboxamide compound of formula-4,

b) converting the compound of formula-4 to ethyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate compound of formula-9a by reacting it with ethanol in presence of thionyl chloride,

c) hydrolyzing the compound of formula-9a in presence of aqueous lithium hydroxide in acetone to provide 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5,

d) separating the diastereomers of compound of formula-5 by treating it with (R)-a-amino ethylbenzene in a mixture of ethyl acetate and methyl tert.butyl ether followed by treating the obtained (R)-a-aminoethylbenzene salt compound with hydrochloric acid to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6,

e) condensing the compound of formula-6 with (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide hydrochloride salt compound of formula-7a in presence of N,N-dicyclohexyl carbodiimide/1-hydroxybenzotriazole and diisopropylethyl amine in dichloromethane to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl)octahydrocyclo penta[c]pyrrole- 1-carboxamide compound of formula-8,

f) oxidizing the compound of formula-8 with sodium hypochlorite in dichloromethane in presence of 2,2,6,6-tetramethyl-piperidin-l-yl)oxyl (TEMPO), potassium bromide and sodium bicarbonate to provide compound of formula-1,

g) purifying the compound of formula-1 from a mixture of dichloromethane and ethyl acetate to provide pure compound of formula-1.

The (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3 -dimethylbutanoic acid compound of formula-2 utilized in step-a) of the first aspect can be synthesized by any of the processes known in the art such as the process disclosed in US7820671B2. The compound of formula-2 is preferably synthesized by the process described in below scheme-B. Scheme-B:

The (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide compound of formula-7 and its hydrochloride salt compound of formula-7a utilized in step-e) of the first aspect of the present invention can be synthesized by the known processes such as the process disclosed in US7776887B2.

The second aspect of the present invention provides a novel process for the preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6, comprising of; a) Condensing the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoic acid compound of formula-2 with octahydrocyclopenta[c]pyrrole-l-carbonitrile compound of formula-3 or its acid-addition salt in presence of a suitable condensing agent in a suitable solvent optionally in presence of a suitable base to provide N-((lS)-2-((2S)-l-(l-cyanohexahydrocyclopenta[c]pyrrol-2(l H)-yl)-3,3 -dimethyl-1 -oxobutan-2-ylamino)-1 -cyclo hexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-4,

b) hydrolyzing the compound of formula-4 in presence of a suitable acid or a suitable base optionally in presence of a suitable solvent to provide 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3 -dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1 –carboxylic acid compound of formula-5,

c) separating the diastereomers of compound of formula-5 by treating it with a suitable base in a suitable solvent followed by treating the obtained salt compound with a suitable acid to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6.

Wherein, in step-a) the suitable condensing agent, the suitable base and the suitable solvent are same as defined for step-a) of the first aspect of the present invention;

In step-b) the suitable acid and the suitable base are same as defined for step-c) of the first aspect of the present invention;

In step-c) the suitable base, the suitable acid and the suitable solvent are same as defined for step-d) of the first aspect of the present invention.

A preferred embodiment of the present invention provides a novel process for the preparation of (1 S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6, comprising of;

a) Condensing the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoic acid compound of formula-2 with octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride salt compound of formula-3a in presence of N,N-dicyclohexylcarbodiimide/l-hydroxybenzotriazole and sodium bicarbonate in a mixture of dichloromethane and water to provide N-(( 1 S)-2-((2 S)-1 -(1 -cyanohexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-3,3 -dimethyl-1 -oxobutan-2-ylamino)-l -cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-4,

b) hydrolyzing the compound of formula-4 in presence of conc.HCl to provide 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta [c]pyrrole-l-carboxylic acid compound of formula-5,

c) separating the diastereomers of compound of formula-5 by treating it with (R)-a-amino ethylbenzene in a mixture of ethyl acetate and methyl tert.butyl ether followed by treating the obtained salt compound with hydrochloric acid to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclo penta[c]pyrrole-1 -carboxylic acid compound of formula-6.

The (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6 obtained above can be further converted into compound of formula-1 as per the process disclosed in the first aspect of the present invention.

The third aspect of the present invention provides a novel intermediate compound useful in the synthesis of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino] acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide compound of formula-1. The said novel intermediate compound is N-((lS)-2-((2S)-l-(l-cyanohexahydro cyclopenta[c]pyrrol-2(lH)-yl)-3,3 -dimethyl-1 -oxobutan-2-ylamino)-1 -cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide which is represented by the following structural formula;

The fourth aspect of the present invention provides a process for the preparation of octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride salt compound of formula-3a, comprising of;

a) Chlorinating the octahydrocyclopenta[c]pyrrole hydrochloride salt compound of formula-16a by reacting it with a suitable chlorinating agent in a suitable solvent to provide 2-chloro octahydrocyclopenta[c]pyrrole compound of formula-17,

b) dehydrochlorination of compound of formula-17 by treating it in-situ with a suitable base in a suitable solvent optionally in presence of a suitable phase transfer catalyst to provide l,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole compound of formula-18,

c) reacting the compound of formula-18 in-situ with a suitable cyanide source optionally in presence of a suitable base or a suitable acid in a suitable solvent followed by treating the reaction mixture with a suitable HC1 source to provide octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride salt compound of formula-3a.

Wherein, in step-a) the suitable chlorinating agent is selected from sodium hypochlorite, N-chlorosuccinimide (NCS), phosphoryl chloride, sulfuryl chloride; and the suitable solvent is selected from ether solvents, hydrocarbon solvents, chloro solvents, ester solvents, ketone solvents or mixtures thereof;

In step-b) the suitable base is selected from alkali metal hydroxides and alkali metal alkoxides, preferably sodium methoxide; the suitable phase transfer catalyst is selected from tetraalkyl/tetraarylammonium halides/hydroxides, preferably tetrabutylammonium bromide (TBAB); the suitable solvent is selected from hydrocarbon solvents, chloro solvents, alcoholic solvents or mixtures thereof;

In step-c) the suitable cyanide source is selected from alkali metal cyanides such as sodium cyanide, potassium cyanide and acetone cyanohydrin, trimethylsilyl cyanide (TMSCN) and the suitable base is selected from inorganic bases, preferably alkali metal carbonates; the suitable acid is selected from hydrochloric acid, sulfuric acid and the like; the suitable solvent is selected from hydrocarbon solvents, chloro solvents, polar solvents, alcoholic solvents, ether solvents, acetic acid or mixtures thereof;
The suitable HC1 source is selected from ethyl acetate-HCl, dry HC1 gas, aq.HCl, isopropyl alcohol-HCl, ethanolic HC1 and the like.

A preferred embodiment of the present invention provides a process for the preparation of octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride salt compound of formula-3a, comprising of;

a) Chlorinating the octahydrocyclopenta[c]pyrrole hydrochloride salt compound of formula-16a by reacting it with sodium hypochlorite in toluene to provide 2-chlorooctahydrocyclopenta[c] pyrrole compound of formula-17,

b) dehydrochlorination of compound of formula-17 by treating it in-situ with sodium methoxide in a mixture of dichloromethane and toluene in presence of tetrabutylammonium bromide to provide l,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole compound of formula-18,

c) reacting the compound of formula-18 in-situ with acetone cyanohydrin in presence of sodium carbonate followed by treating the reaction mixture with ethyl acetate-HCl to provide octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride salt compound of formula-3a.

The fifth aspect of the present invention provides a process for the preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6, comprising diastereomeric separation of 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5 to provide compound of formula-6.

In one embodiment of the present invention, the diastereomeric separation process involves the treatment of compound of formula-5 with a suitable base in a suitable solvent or mixture of solvents followed by treating the obtained salt compound with a suitable acid to provide optically pure compound of formula-6.

In the above process, the salt formed by the treatment of compound of formula-5 with a base can be optionally isolated from the reaction mixture as a solid and can be further purified from a suitable solvent or mixture of solvents to get pure salt compound.

The suitable base, the suitable acid and the suitable solvent used in the fifth aspect of the present invention are same as defined for step-d) of the first aspect of the present invention.

A preferred embodiment of the present invention provides a process for the preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6, comprising of;

a) treating the 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5 with (R)-a-aminoethylbenzene in a mixture of ethyl acetate and methyl tert.butyl ether,

b) isolating the (R)-a-aminoethylbenzene salt of compound of formula-6 as a solid,

c) treating the salt compound obtained in step-b) with hydrochloric acid to provide compound of formula-6.

The process disclosed in prior-art such as US7820671B2 involves the purification of Telaprevir as well as its intermediate compounds of almost all the stages using column chromatography, which is not suggestible on industrial scale.

The process of the present invention provides all the intermediate compounds as well as final compound of formula-1 in excellent yield and purity, which is highly advantageous to the inventors. Further the high purity of the said compounds is obtained by simple isolation/ crystallization techniques and doesn't involve any tedious purification processes such as chromatographic purification. Hence the process developed by the present inventors is highly advantageous over prior known processes.

The sixth aspect of the present invention provides base-addition salts of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoyl)octahydro cyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6 and stereo isomers thereof.

Wherein, the suitable base is selected from but not limited to chiral organic amines such as (R)-a-aminoethylbenzene, (S)-a-aminoethylbenzene, (S)-l,2,3,4-tetrahydro-l-naphthylamine, (R)-1,2,3,4-tetrahydro-l-naphthyl amine, quinine, cinchonine, (lS,2R)-(+)-norephedrine and achiral organic amines such as methyl amine, dimethyl amine, ethyl amine, diethyl amine, n-propyl amine, iso-propyl amine, ethanolamine (2-aminoethanol), n-butylamine, tert.butyl amine, benzylamine and the like.

A preferred embodiment of the present invention provides (R)-a-aminoethylbenzene salt of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6.

The compound of formula-1 of the present invention is analyzed by HPLC under the following conditions;

Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector and integrator; Column: X-bridge CI 8, 250x4.6 mm, 5 urn or equivalent; Wave length: 210 nm; Flow rate: 1.0 mL/min; Column temperature: 40°C; Injection volume: 10 uL; Run time: 50 min; Diluent: acetonitrile:methanol (80:20 v/v); Elution: gradient; Buffer: Weigh accurately 3.48 gm of dipotassium hydrogen phosphate and 0.68 gm of potassium dihydrogen phosphate into 1000 ml of milli-Q-water. Adjust the pH to 8.0 with dil.KOH solution. Filtered the solution through 0.22 urn Nylon membrane filter paper; Mobile phase-A: Buffer; Mobile phase-B: acetonitrile:methanol:water (300:450:250 v/v/v).

The particle size distribution of compound of formula-1 of the present invention is measured by using Malvern Mastersizer 2000 instrument.

The compound of formula-1 produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.

The present invention is schematically represented as follows. Scheme-I:

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:

Example-1: Preparation of (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid (Formula-12)

Trimethylsilyl chloride (5.15 gm) was slowly added to a pre-cooled mixture of (S)-2-amino-2-cyclohexylacetic acid compound of formula-11 (6.25 gm), tetrahydrofuran (50 ml) and triethylamine (2.3 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 0-5°C. Tetrahydrofuran (35 ml), pyrazine-2-carboxylic acid compound of formula-10 (5 gm) and N,N-carbonyldiimidazole (6.82 gm) were charged into another clean and dry RBF at 25-30°C and stirred the reaction mixture for 4 hrs at the same temperature. The obtained reaction mixture was slowly added to the above pre-cooled reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hrs at the same temperature. After completion of the reaction, water and ethyl acetate were added to the reaction mixture. Cooled the reaction mixture to 0-5°C and the pH of the reaction mixture was adjusted to below 3.0 using aqueous HC1. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely form the organic layer. To the obtained solid, water was added at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the solid and dried to get the title compound. Yield: 10.7 gm; M.R: 156-161°C; Purity by HPLC: 99.99%; Purity by chiral HPLC: 99.95%; (R)-isomer impurity: 0.05%; Specific optical rotation: +50.9° (C=l .06%, CHC13).

Example-2: Preparation of (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloride (Formula-15a)

A mixture of (S)-2-amino-3,3-dimethylbutanoic acid compound of formula-14 (100 gm) and methanol (400 ml) was heated to 40-45°C. Thionyl chloride (330 ml) was slowly added to the reaction mixture at 40-45°C. Further heated the reaction mixture to 50-55°C and stirred for 18 hrs at the same temperature. After completion of the reaction, distilled off the excess thionyl chloride and methanol from the reaction mixture under reduced pressure. Dichloromethane and water were added to the obtained compound at 10-15°C. Basified the reaction mixture with ammonia solution and stirred for 30 min at 10-15°C. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. Cooled the obtained compound to 10-15°C and ethyl acetate (100 ml) was added. Adjusted the pH of the reaction mixture to below 2.0 with ethyl acetate-HCl (400 ml) at 10-15°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 109.0 gm; M.R: 158-163°C; Specific optical rotation: +16.5° (C=l%, MeOH).

Example-3: Preparation of (S)-methyl 2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoate (Formula-13)

Imidazole (1.71 gm) and 1-hydroxybenzotriazole (1.56 gm) were added to a pre-cooled mixture of (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid compound of formula-12 (6.0 gm), dichloromethane (36 ml) and (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloride compound of formula-15a (4.96 gm) at 0-5°C. Dicyclohexylcarbodiimide solution (5.13 gm of dicyclohexylcarbodiimide dissolved in 25 ml of dichloromethane) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, filtered the reaction mixture and aqueous sodium bicarbonate solution was slowly added to the filtrate at 10-15°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and aqueous hydrochloric acid solution was added to the organic layer at 10-15°C and stirred the reaction mixture for 20 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely form the organic layer under reduced pressure. Methyl tert.butyl ether (36 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the solid and dried to get the title compound.
Yield: 8.5 gm; M.R: 180-185°C; Purity by HPLC: 99.83%; Specific optical rotation: -2.0° (C=l%, CHC13).

Example-4: Preparation of (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoic acid (Formula-2)

Lithium hydroxide solution (2.4 gm of LiOH.H2O dissolved in 37.5 ml of water) was slowly added to a pre-cooled solution of (S)-methyl 2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoate compound of formula-13 (7.5 gm) in acetone (37.5 ml) at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 8 hrs at the same temperature. After completion of the reaction, water followed by toluene were added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was cooled to 10-15°C. Adjusted the pH of the aqueous layer to below 3.0 at 10-15°C using aq.HCl solution and stirred the reaction mixture for 1 hr at the same temperature. Filtered the precipitated solid and washed with water. Methyl tertbutyl ether (60 ml) was added to the obtained solid at 25-30°C, heated the reaction mixture to 50-55°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid and dried to get the title compound.

Yield: 7.0 gm; M.R: 184-186°C; Purity by HPLC: 99.9%; Purity by chiral HPLC: 99.88%; SR isomer: 0.02%; RS isomer: 0.03%; Specific optical rotation: +21.7° (C=1.015%, CHC13).

Example-5: Preparation of octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride (Formula-3a)

13%) Sodium hypochlorite solution (1552 ml) was slowly added to a solution of octahydrocyclopenta[c]pyrrole hydrochloride compound of formula-16a (200 gm) in toluene (1000 ml) at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Anhydrous sodium methoxide (151.8 gm) was added to the reaction mixture at 25-30°C. Slowly added tetrabutyl ammonium bromide solution (4.4 gm of tetra butyl ammonium bromide dissolved in 200 ml of dichloromethane) to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 8 hrs at the same temperature. Water was added to the reaction mixture at 25-3 0°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and aqueous sodium carbonate solution (360 gm of sodium carbonate in 1400 ml of water) was added to the organic layer at 25-30°C. Acetone cyanohydrin (230 gm) was slowly added to the reaction mixture at 25-3 0°C and stirred for 12 hrs at the same temperature. After completion of the reaction, both the organic and aqueous layers were separated and the pH of the organic layer was adjusted to below 3.0 using aq.hydrochloric acid solution at 10-15°C. Both the organic and aqueous layers were separated and dichloromethane was added to the aqueous layer. Basified the reaction mixture using 25% NaOH solution at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (600 ml) was added to the obtained compound. Ethyl acetate-HCl (600 ml) was added to the reaction mixture at 25-3 0°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 160.0 gm; M.R: 160-165°C.
Example-6: Preparation of N-((lS)-2-((2S)-l-(l-cyanohexahydrocyclopenta[c]pyrrol-2(lH)- yl)-3,3-dimethyl-l-oxobutan-2-ylamino)-l-cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide (Formula-4) Octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride compound of formula-3a (13.76 gm) and dichloromethane (250 ml) were added to aq.sodium bicarbonate solution (8.36 gm of sodium bicarbonate in 25 ml of water) at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was dried over sodium sulfate. (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoic acid compound of formula-2 (25 gm) was added to the organic layer at 25-30°C and cooled the reaction mixture to 0-5°C. 1-Hydroxybenzotriazole (4.48 gm) followed by N,N-dicyclohexylcarbodiimide solution (15.04 gm of N,N-dicyclohexylcarbodiimide in 100 ml of dichloromethane) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-3 0°C and stirred for 4 hrs at the same temperature. Filtered the reaction mixture and washed the filtrate with sodium bicarbonate solution followed by hydrochloric acid solution. Water was added to the reaction mixture and stirred for 20 min at 25-3 0°C. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer and co-distilled with n-heptane. 250 ml of n-heptane was added to the obtained solid at 25-30°C and stirred for 90 min at the same temperature. Filtered the solid and dried to get the title compound. Yield: 26.3 gm; M.R: 120-125°C.

Example-7: Preparation of ethyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate(Formula-9a)

Thionyl chloride (14.3 gm) was slowly added to a pre-cooled mixture of N-((lS)-2-((2S)-l-(1 -cyanohexahydrocyclopenta[c]pyrrol-2( 1H)-yl)-3,3-dimethyl-1 -oxobutan-2-ylamino)-1 -cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-4 (10 gm) and ethanol (100 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 10 hrs at the same temperature. After completion of the reaction, water was slowly added to the reaction mixture at 0-5°C and stirred for 2 hrs at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with n-heptane. 50 ml of n-heptane was added to the obtained solid at 25-3 0°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 10.0 gm; M.R: 110-115°C.

Example-8: Preparation of 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (Formula-5)

Acetone (30 ml) was added to ethyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylate compound of formula-9a (5 gm) at 25-3 0°C and stirred the reaction mixture for 10 min at the same temperature. Aqueous lithium hydroxide solution was slowly added to the reaction mixture at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hrs at the same temperature. After completion of the reaction, water and toluene were added to the reaction mixture at 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and dichloromethane was added to the aqueous layer. Acidified the reaction mixture using aq.hydrochloric acid solution at 10-15°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer. Toluene (10 ml) was added to the obtained compound at 25-30°C, heated the reaction mixture to 70-75°C and stirred for 90 min at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 6 hrs at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and dried to get the title compound. Yield: 3.5 gm; M.R: 130-140°C.

Example-9: Preparation of 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (Formula-5)

N-((lS)-2-((2S)-l-(l-cyanohexahydrocyclopenta[c]pyrrol-2(lH)-yl)-3,3-dimethyl-l-oxo butan-2-ylamino)-l-cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-4 (20 gm) and conc.HCl (160 ml) were charged into a clean and dry RBF at 25-30°C and stirred for 10 hrs at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 16.6 gm.

Example-10: Preparation of (R)-a-aminoethylbenzene salt of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclo penta[c]pyrrole-l-carboxylic acid

A solution of (R)-a-aminoethylbenzene (4.72 gm) in ethyl acetate (60 ml) was slowly added to a mixture of 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5 (20 gm) and methyl tert.butyl ether (200 ml) at 25-30°C and stirred the reaction mixture for 5 hrs at the same temperature. Filtered the precipitated solid, washed with methyl tert.butyl ether under nitrogen atmosphere and dried to get the title compound. Yield: 10.0 gm.

Example-11: Preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (Formula-6) Water (100 ml) was added to (R)-a-aminoethylbenzene salt of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c] pyrrole-1-carboxylic acid (10 gm) at 25-30°C. Aq.hydrochloric acid solution was slowly added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Filtered the solid, washed with water and dried to get the title compound.

Yield: 6.5 gm; M.R: 135-140°C; Purity by HPLC: 98.13%; Specific optical rotation: -58.0° (C=l%, dichloromethane).

Example-12: Preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (Formula-6)

A solution of (R)-a-aminoethylbenzene (4.72 gm) in ethyl acetate (60 ml) was slowly added to a mixture of 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3 -dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid compound of formula-5 (20 gm) and methyl tert.butyl ether (200 ml) at 25-3 0°C and stirred the reaction mixture for 5 hrs at the same temperature. Filtered the precipitated solid and washed with methyl tert.butyl ether under nitrogen atmosphere. Water (100 ml) was added to the obtained solid at 25-30°C. Aq.hydrochloric acid solution was slowly added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 5.0 gm.

Example-13: Preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-l-carboxamide (Formula-8)

1-hydroxybenzotriazole (13.2 gm) and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride compound of formula-7a (47.7 gm) were added to a pre-cooled mixture of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid compound of formula-6 (100 gm) and dichloromethane (800 ml) at 0-5°C. Diisopropylethylamine (30.2 gm) and N,N-dicyclohexyl carbodiimide solution (44.2 gm of N,N-dicyclohexylcarbodiimide in 200 ml of dichloromethane) were slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. After completion of the reaction, filtered the reaction mixture and washed the filtrate with sodium bicarbonate solution, aq.hydrochloric acid solution followed by with water. Distilled off the solvent completely from the obtained organic layer. Ethyl acetate (900 ml) was added to the obtained compound at 25-3 0°C and stirred for 1 hr at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely from the filtrate and co-distilled with cyclohexane. 500 ml of cyclohexane was added to the obtained solid at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid and dried to get the title compound. Yield: 120.0 gm; MR: 113-118°C; Purity by HPLC: 94.84%.

Example-14: Preparation of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-yl carbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxo hexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide (Formula-1)

0.45 gm of 2,2,6,6-tetramethyl-piperidin-l-yl)oxyl (TEMPO) was slowly added to a pre-cooled mixture of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)-N-((3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl) octahydrocyclopenta[c]pyrrole-l-carboxamide compound of formula-8 (100 gm) and dichloromethane (1000 ml) at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. Potassium bromide (3.4 gm) was added to the reaction mixture at 0-5°C and the reaction mixture was kept aside. Aqueous sodium bicarbonate solution was slowly added to pre-cooled 13% sodium hypochlorite solution (100 ml) in another RBF at 5-10°C and stirred for 30 min at the same temperature. The resulting solution was slowly added to the above reaction mixture at 0-5 °C and stirred for 45 min at the same temperature. After completion of the reaction, both the organic and aqueous layers were separated. Sodium sulfite solution was slowly added to the organic layer at 10-15°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water. Carbon (10 gm) was added to the organic layer and stirred for 15 min. Filtered the reaction mixture through hyflow bed and distilled off the solvent completely from the filtrate and co-distilled with cyclohexane. Ethyl acetate (300 ml) was added to the obtained solid at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid and dried to get the title compound. Yield: 82.0 gm; M.R: 230-235°C; Purity by HPLC: 97.41%; Specific optical rotation: -48.0° (C=l%, CHC13). Particle size distribution: D(0.1) is 4.24, D(0.5) is 44.69 and D(0.9) is 95.97.

Example-15: Purification of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-yl carbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxo hexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide (Formula-1)

Aq. sodium bisulfite solution (1.14 gm of sodium bisulfite dissolved in 50 ml of water) was added to a pre-cooled solution of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-yl carbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxo hexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide compound of formula-1 (5 gm) in dichloromethane (50 ml) at 10-15°C and stirred the reaction mixture for 30 min at the same temperature. Both the organic and aqueous layers were separated, Dichloromethane was added to the aqueous layer and cooled the reaction mixture to 10-15°C. 50% glyoxalic acid solution was slowly added to the reaction mixture at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Both the organic and aqueous layers were separated, distilled off the solvent completely form the organic layer and co-distilled with ethyl acetate. To the obtained solid, ethyl acetate (20 ml) was added at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the pure title compound. Yield: 3.5 gm; Purity by HPLC: 98.96%. Particle size distribution: D(0.1) is 14.31, D(0.5) is 38.80 and D(0.9) is 66.98.

Example-16: Purification of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-yl carbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxo hexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide (Formula-1)

A mixture of dichloromethane (200 ml) and (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino) -l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide compound of formula-1 (100 gm) was stirred for 10 min at 25-30°C. Heated the reaction mixture to 40-45°C and ethyl acetate (500 ml) was slowly added. Further heated the reaction mixture to 65-70°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 82.0 gm; Purity by HPLC: 99.90%; Hydroxy impurity (compound of formula-8): 0.01%; Metabolite impurity ((R)-diastereomer): 0.05%.

Particle size distribution: D(0.1) is 10.83, D(0.5) is 64.65 and D(0.9) is 151.23. Particle size distribution (after pulverization): D(0.1) is 1.37, D(0.5) is 6.60 and D(0.9) is 21.62.

We Claim:

1. Novel process for the preparation of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino] acetyl} amino)-3,3 -dimethylbutanoyl]-N- [(3 S)-1 -(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide compound of formula-1, comprising of;

a) Condensing the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-di methylbutanoic acid compound of formula-2

Formula-2 with octahydrocyclopenta[c]pyrrole-l-carbonitrile compound of formula-3

Formula-3 or its acid-addition salt in presence of a suitable condensing agent in a suitable solvent optionally in presence of a suitable base to provide N-((lS)-2-((2S)-l-(l-cyanohexahydro cyclopenta[c]pyrrol-2( 1 H)-yl)-3,3 -dimethyl-1 -oxobutan-2-ylamino)-1 -cyclohexyl-2-oxo ethyl)pyrazine-2-carboxamide compound of formula-4,
Formula-4 b) converting the compound of formula-4 to its corresponding alkyl ester compound of general formula-9 by reacting it with C1-C4 alcohol in presence of a suitable catalyst,

Formula-9 wherein, 'R' represents C1-C4 straight chain or branched chain alkyl group; c) hydrolyzing the compound of general formula-9 in presence of a suitable acid or a suitable base optionally in presence of a suitable solvent to provide 2-((S)-2-((S)-2-cyclohexyl-2- (pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid compound of formula-5,

Formula-5 d) separating the diastereomers of compound of formula-5 by treating it with a suitable base in a suitable solvent followed by treating the obtained salt compound with a suitable acid to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3 -dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1 -carboxylic acid of formula-6,

Formula-7 or its acid-addition salt in presence of a suitable condensing agent in a suitable solvent optionally in presence of a suitable base to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3 -dimethylbutanoyl)-N-((3 S)-1 -(cyclopropylamino)-2-hydroxy-1 -oxohexan-3 -yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide compound of formula-8,
Formula-8

f) oxidizing the compound of formula-8 with a suitable oxidizing agent in a suitable solvent optionally in presence of a suitable catalyst and a suitable base to provide compound of formula-1,

g) optionally purifying the compound of formula-1 to provide pure compound of formula-1.

2. A process according to claim 1, wherein,

in step-a) and step-e) the suitable condensing agent is selected from N,N'-dicyclohexyl carbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1), N,N-carbonyldiimidazole (CDI), substituted or unsubstituted alkyl or aryl haloformates, thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), alkyl or aryl sulfonyl halides and the like optionally in combination with l-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3 -triazole-4-carboxylate (HOCt), 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyl uroniumtetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxy sulfosuccinimide (Sulfo-NHS);

the suitable base is selected from organic or inorganic bases; and the suitable solvent is selected from chloro solvents, polar-aprotic solvents, alcoholic solvents, ether solvents, ester solvents, polar solvents or their mixtures;

in step-b) the suitable catalyst is selected from thionyl chloride, dry HC1 gas, tri(C1-C6 straight chain or branched chain alkyl)silyl halides;

in step-c) the suitable acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid and the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates; the suitable solvent is selected from alcoholic solvents, ketone solvents, polar solvents or mixtures thereof;

in step-d) the suitable base is selected from inorganic bases and chiral or achiral organic amines; preferably (R)-a-aminoethylbenzene; the suitable acid can be selected from inorganic acids and organic acids, preferably hydrochloric acid and the suitable solvent is selected from ester solvents, ether solvents, polar solvents, chloro solvents, alcohol solvents or mixtures thereof;

in step-f) the suitable oxidizing agent is selected from sodium hypochlorite (NaOCl), Dess-Martin periodinane (DMP), oxalyl chloride/dimethyl sulfoxide (Swern oxidation), trichloroisocyanuric acid (TCICA), bis(acetoxy)iodobenzene (BAIB); the suitable catalyst is selected from 2,2,6,6-tetramethyl-piperidin-l-yl)oxyl (TEMPO), 4-methoxy TEMPO, 4-amino TEMPO, 4-acetamido TEMPO, 2-azaadamantane N-Oxyl (AZADO) and 1-methyl-AZADO;

the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, polar-aprotic solvents, nitrile solvents, ketone solvents or their mixtures; the suitable base is selected from inorganic bases; preferably alkali metal carbonates, alkali metal bicarbonates.

3. Novel process for the preparation of (1 S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide compound of formula-1, comprising of;

a) Condensing the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoic acid compound of formula-2 with octahydrocyclopenta[c]pyrrole-l- carbonitrile hydrochloride salt compound of formula-3a
Formula-3a in presence of N,N-dicyclohexylcarbodiimide/l-hydroxybenzotriazole and sodium bicarbonate in a mixture of dichloromethane and water to provide N-((lS)-2-((2S)-l-(l-cyanohexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-3,3 -dimethyl-1 -oxobutan-2-ylamino)-1 -cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-4, b) converting the compound of formula-4 to ethyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate compound of formula-9a by reacting it with ethanol in presence of thionyl chloride,
Formula-9a

c) hydrolyzing the compound of formula-9a in presence of aqueous lithium hydroxide in acetone to provide 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1 -carboxylic acid compound of formula-5,

d) separating the diastereomers of compound of formula-5 by treating it with (R)-a-aminoethylbenzene in a mixture of ethyl acetate and methyl tert.butyl ether followed by treating the obtained (R)-a-aminoethylbenzene salt of formula-6 with hydrochloric acid to provide (1 S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6,

e) condensing the compound of formula-6 with (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide hydrochloride salt compound of formula-7a in presence of N,N-dicyclohexyl carbodiimide/1-hydroxybenzotriazole and diisopropylethyl amine in dichloromethane to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3 -dimethylbutanoyl)-N-((3 S)-1 -(cyclopropylamino)-2-hydroxy-1 -oxohexan-3 -yl)octa hydrocyclopenta[c]pyrrole-1 -carboxamide compound of formula-8,

f) oxidizing the compound of formula-8 with sodium hypochlorite in dichloromethane in presence of 2,2,6,6-tetramethyl-piperidin-l-yl)oxyl (TEMPO), potassium bromide and sodium bicarbonate to provide compound of formula-1,

g) purifying the compound of formula-1 from a mixture of dichloromethane and ethyl acetate to provide pure compound of formula-1.

4. Novel process for the preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6, comprising of;

a) Condensing the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoic acid compound of formula-2 with octahydrocyclopenta[c]pyrrole-l-carbonitrile compound of formula-3 or its acid-addition salt in presence of a suitable condensing agent in a suitable solvent optionally in presence of a suitable base to provide N-(( 1 S)-2-((2S)-1 -(1 -cyanohexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-3,3 -dimethyl-1 -oxo butan-2-ylamino)-1 -cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-4,

b) hydrolyzing the compound of formula-4 in presence of a suitable acid or a suitable base optionally in presence of a suitable solvent to provide 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c] pyrrole-1-carboxylic acid compound of formula-5,

c) separating the diastereomers of compound of formula-5 by treating it with a suitable base in a suitable solvent followed by treating the obtained salt with a suitable acid to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octa hydrocyclopenta[c]pyrrole-1-carboxylic acid compound of formula-6.

5. Novel process for the preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3 - dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1 –carboxylic acid compound of formula-6, comprising of;

a) Condensing the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoic acid compound of formula-2 with octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride salt compound of formula-3a in presence of N,N-dicyclohexyl carbodiimide/1-hydroxybenzotriazole and sodium bicarbonate in a mixture of dichloromethane and water to provide N-((lS)-2-((2S)-l-(l-cyanohexahydrocyclopenta[c] pyrrol-2( 1 H)-yl)-3,3-dimethyl-1 -oxobutan-2-ylamino)-1 -cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-4,

b) hydrolyzing the compound of formula-4 in presence of conc.HCl to provide 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclo penta[c]pyrrole-l-carboxylic acid compound of formula-5,

c) separating the diastereomers of compound of formula-5 by treating it with (R)-a-aminoethylbenzene in a mixture of ethyl acetate and methyl tert.butyl ether followed by treating the (R)-a-aminoethylbenzene salt of compound of formula-6 with hydrochloric acid to provide (1 S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-6.

6. A process for the preparation of alkyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate compound of general formula-9, comprising of reacting the N-((lS)-2-((2S)-l-(l-cyanohexahydro cyclopenta[c]pyrrol-2( 1 H)-yl)-3,3 -dimethyl-1 -oxobutan-2-ylamino)-1 -cyclohexyl-2-oxoethyl) pyrazine-2-carboxamide compound of formula-4 with C1-C4 straight chain or branched chain alcohol in presence of a suitable catalyst to provide compound of general formula-9.

7. A process for the preparation of 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3 -dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1 -carboxylic acid compound of formula-5, comprising of hydrolyzing the N-((lS)-2-((2S)-l-(l-cyanohexahydrocyclo penta[c]pyrrol-2( 1 H)-yl)-3,3 -dimethyl-1 -oxobutan-2-ylamino)-1 -cyclohexyl-2-oxoethyl) pyrazine-2-carboxamide compound of formula-4 to provide compound of formula-5.

8. Compound having the structural formula its stereo isomers and pharmaceutically acceptable salts.

9. A process for the preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3 -dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1 -carboxylic acid compound of formula-6, comprising of separating the diastereomers of 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclo penta[c]pyrrole-l -carboxylic acid compound of formula-5 by treating it with a suitable base in a suitable solvent or mixture of solvents followed by treating the obtained salt compound with a suitable acid to provide compound of formula-6.

10. (R)-a-aminoethylbenzene salt of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid.