WO2014083582A2

WO2014083582A2 - Novel process for the preparation of (1s,3ar,6as)-2-[(2s)-2-({(2s)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-n-[(3s)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c] pyrrole-1-carboxamide and its intermediates

Info

Publication number: WO2014083582A2
Application number: PCT/IN2013/000722
Authority: WO
Inventors: Srinivasan Thirumalai Rajan; Sajja Eswaraiah; Ghojala Venkat Reddy; Peri Seetha Rama Sarma
Original assignee: Msn Laboratories Limited
Priority date: 2012-11-29
Filing date: 2013-11-28
Publication date: 2014-06-05
Also published as: WO2014083582A3

Abstract

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

Description

Novel process for the preparation of (lS,3aR.6aS)-2-r(2S)-2-r((2S)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyl)amino1acetyl)amino)-3,3-dimethylbutanoyll-N-f(3S)-l-(cvclo propylamino)-l,2-dioxohexan-3-yl|-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta cl pyrrole-l-carboxamide and its intermediates

Related Applications:

This application claims the benefit of priority of our Indian patent application numbers 4976/CHE/20.12 filed on 29^th November 2012 and 3249/CHE/2013 filed on 19^th July 2013 and 5430/CHE/2013 filed on 26 November 2013 which are incorporated herein by reference.

Field of the Invention:

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

Formula- 1

The present invention also provides processes for the preparation of intermediates of compound of formula- 1.

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

Background of the Invention:

( 1 S,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, 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.

Schem -

Telaprevir

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-[(3 S)- l-(cyclopropylamino)- 1 ,2-dioxohexan-3-yl]-3,3a,4,5,6,6a- hexahydro- 1 H-cyclopenta[c]pyrrole- 1 -carboxamide compound of formula- 1.

The second aspect of the present invention is to provide a novel process for the preparation of (1 S,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-5. The third aspect of the present invention is to provide novel intermediate compound of formula-30 which is 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-(cyclopropyl amino)- 1,2-dioxo hexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide compound of formula- 1.

The fourth aspect of the present invention is to provide a process for the preparation of N- ((1 S)-2-((2S)- 1 -( 1 -cyanohexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-3, 3 -dimethyl- 1 -oxobutan-2-yl amino)- l-cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-30. The fifth 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-( yrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5, comprising of hydrolyzing the N-((lS)-2-((2S)-l-(l-cyanohexahydrocyclopenta[c]pyrrol-2(lH)-yl)-3,3- dimethyl- 1 -oxobutan-2-yl amino)- 1 -cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-30 in presence of a suitable acid or a suitable base followed by separating the diastereomers from the obtained compound of formula-32 to provide compound of formula-5.

The sixth aspect of the present invention is to provide a process for the preparation of ( 1 S,3 aR,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-5, comprising of separating the diastereomers from 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3 ,3 -dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-32.

The seventh aspect of the present invention is to provide base-addition salts of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazme-2-carboxamido)acetamido)-3,3-dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5.

The eighth aspect of the present invention is to provide an improved process for the preparation of (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid compound of formula- 10, which is an useful intermediate in the synthesis of compound of formula- 1.

The ninth aspect of the present invention is to provide a process for the preparation of octahydrocyclopenta[c]pyrrole-l-carbonitrile compound of formula- 17. The tenth aspect of the present invention is to provide a process for the preparation of (lS,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-l-carboxylate compound of formula-3 and its hydrochloride compound of formula-3 a.

The eleventh aspect of the present invention is to provide an improved process for the preparation of (S)-tert-butyl l-oxopentan-2-ylcarbamate compound of formula-24, comprising of reducing the (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopentan-2-ylcarbamate compound of formula-23 with vitride in a suitable solvent to provide (S)-tert-butyl l-oxOpentan-2-yl carbamate compound of formula-24. The twelfth aspect of the present invention is to provide a process for the preparation of

(3S)-alkyl 3-amino-2-hydroxyhexanoate hydrochloride salt compound of general formula-26, comprising of reacting the tert-butyl (2S)-l-cyano-l-hydroxypentan-2-ylcarbamate compound of formula-25 with a suitable alcohol in presence of a suitable HC1 source to provide of (3S)-alkyl 3-amino-2-hydroxy hexanoate hydrochloride salt compound of general formula-26.

The thirteenth aspect of the present invention is to provide a process for the preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt of formula-6a.

The fourteenth aspect of the present invention is to provide a 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-[(3 S)- l-(cyclopropylamino)- 1 ,2-dioxohexan-3-yl]-3,3a,4,5,6,6a- hexahydro- 1 H-cyclopenta[c]pyrrole- 1 -carboxamide compound of formula- 1.

The fifteenth aspect of the present invention is to provide crystalline polymorph of (S)-2- ((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3, 3 -dimethyl butanoic acid compound of formula-2.

The sixteenth aspect of the present invention is to provide a process for the preparation of

(3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide compound of formula-6 and its acid- addition salts.

The seventeenth aspect of the present invention is to provide crystalline form of (S)- benzyl-l-chloro-2-oxohexan-3-yl carbamate compound of formula-35a.

The eighteenth aspect of the present invention is to provide crystalline form of (3S)-3-

(tert-butoxycarbonylamino)-2-hydroxyhexanoic acid compound of formula-28a. The nineteenth aspect of the present invention is to provide solid state form of (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-7.

The twentieth aspect of the present invention is to provide crystalline polymorph (herein after designated as crystalline form-N^) of tert-butyl (3 S)-l-(cyclopropylamino)-2 -hydroxy- 1- oxohexan-3-ylcarbamate compound of formula-29a.

The twenty first aspect of the present invention is to provide crystalline polymorph (herein after designated as crystalline form-N₂) of tert-butyl (3S)-l-(cyclopropylamino)-2- hydroxy- 1 -oxohexan-3 -ylcarbamate compound of formula-29a.

The twenty second aspect of the present invention is to provide crystalline polymorph (herein after designated as crystalline form-Ri) of (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide hydrochloride salt compound of formula-6a.

The twenty third aspect of the present invention is to provide crystalline polymorph (herein after designated as crystalline form-R₂) of (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide hydrochloride salt compound of formula-6a.

Brief Description of the Drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form-M of (S)-2-((S)-2-cyclohexyl-2- (pyrazine-2-carboxamido)acetamido)-3 ,3 -dimethyl butanoic acid compound of formula-2.

Figure-2: Illustrates the DSC thermogram of crystalline form-M of (S)-2-((S)-2-cyclohexyl-2-

(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoic acid compound of formula-2.

Figure-3: Illustrates the PXRD pattern of crystalline form-M of (S)-benzyl-l-chloro-2- oxohexan-3-yl carbamate compound of formula-35a.

Figure-4: Illustrates the PXRD pattern of crystalline form-S of (3S)-3-(tert-butoxy carbonylamino)-2-hydroxyhexanoic acid compound of formula-28a.

Figure-5: Illustrates the PXRD pattern of crystalline (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2- cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l- (cyclopropylamino)- 1 ,2-dioxohexan-3 -yl]-3 ,3 a,4,5,6,6a-hexa hydro- 1 H-cyclopenta[c]pyrrole- 1 - carboxamide compound of formula- 1 obtained according to the present invention. Figure-6: Illustrates the PXRD pattern of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine- 2-carboxamido)acetarnido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5.

Figure-7: Illustrates the PXRD pattern of (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-7.

Figure-8: Illustrates the PXRD pattern of crystalline form-Ni of tert-butyl (3S)-l-(cyclopropyl amino)-2-hydroxy-l-oxohexan-3-ylcarbamate compound of formula-29a.

Figure-9: Illustrates the PXRD pattern of crystalline form-N₂ of tert-butyl (3S)-l-(cyclopropyl amino)-2-hydroxy- 1 -oxohexan-3-ylcarbamate compound of formula-29a.

Figure-10: Illustrates the PXRD pattern of form-Ri of (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide hydrochloride salt compound of formula-6a.

Figure-11: Illustrates the PXRD pattern of form-R₂ of (3 S)-3-amino-N-cyclopropyl-2 -hydroxy hexanamide hydrochloride salt compound of formula-6a.

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, pet 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 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; acetic acid 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, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "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 methylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide (LDA), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole and the like; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS); n-butyl lithium 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-[( yrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3- dimethylbutanoyl]-N-[(3 S)- 1 -(cyclopropylamino)- 1 ,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexa hydro- 1 H-cyclopenta[c]pyrrole- 1 -carboxamide compound of formula- 1 , comprising of;

a) Reacting 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- 17 or its acid-addition salt in presence of a suitable coupling agent in a suitable solvent optionally in presence of a suitable base to provide N-((lS)-2-((2S)-l-(l- cyanohexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-3 ,3 -dimethyl- 1 -oxobutan-2-ylamino)- 1 -cyclo hexyl-2-oxoethyl)pyrazine-2-carbpxamide compound of formula-30,

b) converting the compound of formula-30 to its corresponding alkyl ester compound of general formula-31 by reacting it with Ci-C₆ straight chain or branched chain alcohol in presence of a suitable catalyst,

c) hydrolyzing the compound of general formula-31 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- ( yrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole- 1-carboxylic acid compound of formula-32,

d) separating the diastereomers from compound of formula-32 by treating it with a suitable base in a suitable solvent followed by treating the obtained base-addition salt 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-l-carboxylic acid compound of formula-5,

e) reacting the compound of formula-5 with (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide compound of formula-6 or its acid-addition salt in presence of a suitable coupling 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)octahydro cyclopenta[c] pyrrole- 1-carboxamide compound of formula-7,

f) oxidizing the compound of formula-7 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) purifying the compound of formula- 1 to provide pure compound of formula- 1.

Wherein, in step-a) and step-e) the suitable coupling agent is selected from Ν,Ν'- dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropylcarbodiimide (DIC), l-ethyl-3 -(3 -dimethyl aminopropyl)carbodiimide hydrochloride (EDC.HC1), Ν,Ν-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 (DPP A), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-l-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 (HO At), 1-hydroxybenzotriazole (HOBt), 1-hydroxy- lH-l,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol-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, acetyl 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, nitric acid and the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates 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)-l,2,3,4-tetrahydro-l-naphthylamine, (R)-l,2,3,4-tetrahydro-l- 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 chromic acid, sodium hypochlorite

(NaOCl), l,l,l-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- AZ ADO 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-7 of the present invention 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 and the like.

In step-g) the purification of compound of formula- 1 can be carried out by crystallizing the compound from a suitable solvent selected from chloro solvents, hydrocarbon solvents, ester solvents, polar-aprotic solvents, nitrile solvents, ketone solvents, ether solvents, polar solvents or mixtures thereof.

The compound of formula- 1 can also be purified through bisulfite adduct formation. The process comprises extracting the organic layer comprising compound of formula- 1 and one or more organic solvents with an aqueous bisulfite solution thereby forming an aqueous layer comprising bisulfite adduct of the following general formula and optionally isolating the obtained bisulfite adduct as a solid form the reaction mixture.

Telaprevir bisulfite adduct

wherein, M represents an alkali metal such as Na, K, Li and the like.

The pure compound of formula- 1 can be obtained by regenerating the compound of formula- 1 from the bisulfite adduct. The regeneration process preferably comprises treating the reaction mixture comprising bisulfite adduct with a suitable acid such as acetic acid, formic acid, glyoxalic acid and the like.

In the above purification process the bisulfite used to form the adduct include but not limited to Sodium bisulfite, potassium bisulfite and the like.

A preferred embodiment of the present invention provides a 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-[(3 S)- l-(cyclopropylamino)- 1 ,2-dioxohexan-3-yl]-3,3a,4,5,6,6a- hexahydro- 1 H-cyclopenta[c] pyrrole- 1 -carboxamide compound of formula- 1 , comprising of; a) Reacting 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- 17a in presence of N,N-dicyclohexyl carbodiimide/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-30,

b) converting the compound of formula-30 to ethyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3 ,3 -dimethylbutanoyl)octahydrocyclopenta[c]pyrrole- 1 -carboxylate compound of formula-3 la by reacting it with ethanol in presence of thionyl chloride, c) hydrolyzing the compound of formula-3 la 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-l-carboxylic acid of formula-32, d) separating the diastereomers from compound of formula-32 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- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5, e) reacting the compound of formula-5 with (3 S)-3-amino-N-cyclopropyl-2 -hydroxy hexanamide hydrochloride salt compound of formula-6a in presence of N,N-dicyclohexyl carbodiimide/l-hydroxybenzotriazole and diisopropylethyl amine in dichloromethane to provide ( 1 S,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-l -carboxamide compound of formula-7,

f) oxidizing the compound of formula-7 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 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-5, comprising of;

a) Reacting 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- 17 or its acid-addition salt in presence of a suitable coupling agent in a suitable solvent optionally in presence of a suitable base to provide N-((lS)-2-((2S)-l-(l- cyanohexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-3 ,3 -dimethyl- 1 -oxobutan-2-ylamino)- 1 -cyclo hexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-30,

b) hydrolyzing the compound of formula-30 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-32,

c) separating the diastereomers from compound of formula-32 by treating it with a suitable base in a suitable solvent followed by treating the obtained salt compound with a suitable acid to provide (l S,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-5.

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

In step-b) the suitable acid and the suitable base are same as defined in 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 in 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 (l 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-5, comprising of; a) Reacting 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- 17a in presence of N,N-dicyclohexyl carbodiimide/l-hydroxybenzotriazole and sodium bicarbonate in a mixture of dichloromethane and water to provide N-((l S)-2-((2S)-l-(l-cyanohexahydrocyclopenta[c] pyrrol-2( lH)-yl)-3, 3 -dimethyl- 1 -oxobutan-2-ylamino)- 1 -cyclohexyl-2-oxoefhyl)pyrazine-2- carboxamide compound of formula-30,

b) hydrolyzing the compound of formula-30 in presence of conc.HCl to provide 2-((S)-2-((S)-2- cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydro cyclopenta[c]pyrrole-l-carboxylic acid compound of formula-32,

c) separating the diastereomers from compound of formula-32 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-5.

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-5 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 of formula-30 which is 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-(cyclopropyl amino)-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- cyanohexahydrocyclopenta[c]pyrrol-2( 1 H)-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 N-(( 1 S)-2-((2S)- 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-30, comprising of reacting 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- 17 or its acid-addition salt in presence of a suitable coupling agent in a suitable solvent optionally in presence of a suitable base to provide compound of formula-30.

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

A preferred embodiment of the present invention provides a process for the preparation of N-(( 1 S)-2-((2 S)- 1 -( 1 -cyanohexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-3 ,3 -dimethyl- 1 -oxo butan-2-ylamino)-l-cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-30, comprising of reacting 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- 17a in presence of N,N-dicyclohexyl carbodiimide/l-hydroxybenzotriazole and sodium bicarbonate in a mixture of dichloromethane and water to provide compound of formula-30.

The fifth 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-5, comprising of hydrolyzing the N-((l S)-2-((2S)-l-(l-cyanohexahydrocyclopenta[c]pyrrol-2(lH)-yl)-3,3- dimethyl- 1 -oxobutan-2-yl amino)- 1 -cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-30 in presence of a suitable acid or a suitable base followed by separating the diastereomers from the obtained compound of formula-32 to provide compound of formula-5. Wherein, the suitable acid and the suitable base are same as defined in step-c) of the first aspect of the present invention.

A preferred embodiment of the present invention provides a novel process for the preparation of compound of formula-5, comprising of hydrolyzing the compound of formula-30 in presence of conc.HCl to provide 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydro cyclopenta[c]pyrrole-l-carboxylic acid compound of formula-32 and separating the diastereomers from compound of formula-32 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 compound of formula-5

The sixth 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-5, comprising of separating the diastereomers from 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-32 to provide compound of formula-5.

In one embodiment of the present invention, separation of diastereomers from compound of formula-32 involves the treatment of compound of formula-32 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-5.

In the above process, the salt formed by the treatment of compound of formula-32 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 are same as defined in step-d) of the first aspect of the present invention.

A preferred embodiment of the present invention provides a process for the preparation of (1 S,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-5, comprising of; a) treating the 2-((S)-2-((S)-2-cyclohexyl-2-{ yrazine-2-carboxamid )acetamido)-3, 3 -dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l carboxylic acid compound of formula-32 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-5 as a solid,

c) treating the salt compound obtained in step-b) with hydrochloric acid to provide compound of formula-5.

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 seventh aspect of the present invention provides base-addition salts of (lS,3aR,6aS)- 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxarnido)acetamido)-3,3-dimethylbutanoyl)octa hydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5 and stereo isomers thereof, wherein, the base is selected from but not limited to chiral organic amines such as (R)-a-amino ethylbenzene, (S)-a-aminoethylbenzene, (S)-l,2,3,4-tetrahydro-l-naphthylamine, (R)-l,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-butyl amine, 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-carboxarmdo)acetarnido)-3, 3 -dimethyl butanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-5. The reported processes for the preparation of (S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetic acid compound of formula- 10 involves the reaction of pyrazine-2-carboxylic acid compound of formula-8 with alkyl ester of (S)-2-amino-2-cyclohexylacetic acid compound of formula-9 followed by hydrolysis of the obtained compound to provide compound of formula- 10.

In order to decrease the number of steps and increase the yield of the product, the present inventors developed an improved and single step process for the preparation of (S)-2-cyclohexyl- 2-(pyrazine-2-carboxamido)acetic acid compound of formula- 10. The eighth aspect of the present invention provides an improved process for the preparation of (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid compound of formula- 10, comprising of reacting the pyrazine-2-carboxylic acid compound of formula-8 with (S)-2-amino-2-cyclohexylacetic acid compound of formula-9 in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide (S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetic acid compound of formula- 10.

A preferred embodiment of the present invention provides an improved process for the preparation of (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid compound of formula- 10, comprising of reacting the pyrazine-2-carboxylic acid compound of formula-8 with (S)-2-amino-2-cyclohexylacetic acid compound of formula-9 in presence of N,N-carbonyl diimidazole (CDI), triethylamine and trimethylsilyl chloride in tetrahydrofuran to provide (S)-2- cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid compound of formula- 10.

The ninth aspect of the present invention provides a process for the preparation of octahydrocyclopenta[c]pyrrole-l-carbonitrile compound of formula- 17, comprising of reacting the l,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole compound of formula-16 with acetone cyanohydrin in presence of a suitable base in a suitable solvent to provide octahydro cyclopenta[c]pyrrole- 1 -carbonitrile compound of formula- 17. Wherein, the suitable base is selected from inorganic bases, preferably sodium carbonate; the suitable solvent is selected from hydrocarbon solvents, chloro solvents, polar solvents, ether solvents, alcoholic solvents, acetic acid or mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of octahydrocyclopenta[c]pyrrole-l-carbonitrile compound of formula- 17, comprising of reacting the l,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole compound of formula- 16 with acetone cyanohydrin in presence of aq.sodium carbonate in a mixture of dichloromethane and toluene to provide octahydrocyclopenta[c]pyrrole-l-carbonitrile compound of formula-17. The tenth aspect of the present invention provides a process for the preparation of

(lS,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-l-carboxylate compound of formula-3 or its hydrochloride compound of formula-3 a, comprising of;

a) Chlorinating the octahydrocyclopenta[c]pyrrole hydrochloride salt compound of formula- 14a with a suitable chlorinating agent in a suitable solvent to provide 2-chlorooctahydro cyclopenta[c]pyrrole compound of formula- 15,

b) treating the compound of formula- 15 with a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide l,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole compound of formula- 16,

c) reacting the compound of formula- 16 with acetone cyanohydrin in presence of a suitable base in a suitable solvent to provide octahydrocyclopenta[c]pyrrole-l-carbonitrile compound of formula-17,

d) hydrolyzing the compound of formula-17 in presence of a suitable acid to provide octahydro cyclopenta[c]pyrrole-l-carboxylic acid compound of formula- 18,

e) reacting the compound of formula- 18 with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide 2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-

1-carboxylic acid compound of formula- 19,

f) reacting the compound of formula- 19 with a suitable chiral amine in a suitable solvent to provide corresponding chiral amine addition salt compound of general formula-20, g) neutralizing the compound of general formula-20 with a suitable acid in a suitable solvent to provide (1 S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-20, h) reacting the compound of formula-20 with ethanol in presence of a suitable esterification catalyst in a suitable solvent to provide (l S,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-l- carboxylate compound of formula- 3 or its hydrochloride salt of formula-3a. Wherein, in step-a) the suitable chlorinating agent is selected from sodium hypochlorite,

N-chlorosuccinimide, preferably sodium hypochlorite; the suitable solvent is selected from hydrocarbon solvents, ether solvent, ester solvents, chloro solvents or mixtures thereof;

In step-b) the suitable base is selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals; the suitable solvent is selected from hydrocarbon solvents, ether solvent, ester solvents, chloro solvents or mixtures thereof; the suitable catalyst is tetrabutyl ammonium bromide;

In step-c) the suitable base and the suitable solvent are same as defined in eighth aspect of the present invention;

In step-d) the suitable acid is selected form hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like;

In step-e) the suitable base is selected from inorganic bases and the suitable solvent is selected from chloro solvents, ether solvents, polar solvents, hydrocarbon solvents or mixtures thereof;

In step-f) the suitable chiral amine is selected from (R)-l -phenyl ethanamine, (S)-l,2,3,4- tetrahydro-l-naphthylamine and the like, preferably (R)-l-phenylethanamine; the suitable solvent is selected from ester solvents, alcohol solvents, ether solvents, chloro solvents or mixtures thereof;

In step-g) the suitable acid is hydrochloric acid and the suitable solvent is selected from chloro solvents, polar solvents, ether solvents, ester solvents or mixtures thereof;

In step-h) the suitable esterification catalyst is selected form thionyl chloride, conc.sulfuric acid and the like;

The compound of formula-3 of the present invention can be converted to its hydrochloride salt of formula-3 a by treating it with a suitable HC1 source selected from ethyl acetate-HCl, isopropyl alcohol-HCl, ethanolic HC1, aq.HCl, dry HC1 and the like in a suitable solvent such as hydrocarbon solvents, ester solvents, ether solvents, chloro solvents or mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of (lS,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-l-carboxylate hydrochloride compound of formula-3a, comprising of;

a) Chlorinating the octahydrocyclopenta[c]pyrrole hydrochloride salt compound of formula- 14a with sodium hypochlorite in toluene to provide 2-chlorooctahydro cyclopenta[c]pyrrole compound of formula- 15,

b) treating the compound of formula- 15 in-situ with sodium methoxide in presence of tetrabutyl ammonium bromide in dichloromethane to provide l,3a,4,5,6,6a-hexahydrocyclopenta[c] pyrrole compound of formula- 16,

c) reacting the compound of formula- 16 in-situ with acetone cyanohydrin in presence of aq.sodium carbonate to provide octahydrocyclopenta[c]pyrrole- 1 -carbonitrile of formula- 17, d) hydrolyzing the compound of formula- 17 in presence of hydrochloric acid to provide octahydro cyclopenta[c]pyrrole-l-carboxylic acid compound of formula-18,

e) reacting the compound of formula-18 with di-tert.butyl dicarbonate in presence of sodium hydroxide in a mixture of water and toluene to provide 2-(tert-butoxycarbonyl)octahydro cyclopenta[c]pyrrole-l-carboxylic acid compound of formula- 19,

f) reacting the compound of formula- 19 with (R)-l -phenyl ethanamine in a mixture of ethyl acetate and isopropyl alcohol to provide (lS,3aR,6aS)-2-(tert-butoxycarbonyl)octahydro cyclopenta[c]pyrrole-l-carboxylic acid (R)-l-phenylethanamine salt compound of formula-20a,

g) neutralizing the compound of formula-20a with hydrochloric acid in a mixture of dichloromethane and water to provide (lS,3aR,6aS)-2-(tert-butoxycarbonyl)octahydro cyclopenta[c]pyrrole-l-carboxylic acid compound of formula-20,

h) reacting the compound of formula-20 with ethanol in presence of thionyl chloride in toluene to provide (lS,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-l-carboxylate hydrochloride salt compound of formula-3a. US7820671B2 patent discloses a process for the preparation of (S)-tert-butyl 1- oxopentan-2-ylcarbamate compound of formula-24, comprising of reducing the (S)-tert-butyl 1- (methoxy(methyl)amino)-l-oxopentan-2-ylcarbamate compound of formula-23 with lithium aluminium hydride (LAH) to provide compound of formula-24.

Lithium aluminium hydride is pyrophoric in nature and violently reacts with water including atmospheric moisture. Hence, it is not suggestible to use LAH on industrial scale.

The present inventors developed an improved process for the reduction of compound of formula-23 to compound of formula-24 by adopting vitride as a reducing agent. When compared to LAH, vitride is a cost-effective and easy to handle reagent.

The eleventh aspect of the present invention provides an improved process for the preparation of (S)-tert-butyl l-oxopentan-2-ylcarbamate compound of formula-24, comprising of reducing the (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopentan-2-ylcarbamate compound of formula-23 with vitride in a suitable solvent to provide (S)-tert-butyl l-oxopentan-2-ylcarbamate compound of formula-24, wherein the suitable solvent is selected from hydrocarbon solvents, ester solvents, ether solvents, alcohol solvents or mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of (S)-tert-butyl l-oxopentan-2-ylcarbamate compound of formula-24, comprising of reducing the (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopentan-2-ylcarbamate compound of formula-23 with vitride in toluene to provide (S)-tert-butyl l-oxopentan-2-ylcarbamate compound of formula-24.

The twelfth aspect of the present invention is to provide a process for the preparation of (3S)-alkyl 3-amino-2-hydroxyhexanoate hydrochloride salt compound of general formula-26, comprising of reacting the tert-butyl (2S)-l-cyano-l-hydroxypentan-2-ylcarbamate compound of formula-25 with a suitable alcohol in presence of acetyl chloride or thionyl chloride or tri(Ci-C₆ straight chain or branched chain)alkyl silyl halides such as trimethylsilyl chloride (TMSC1) to provide of (3S)-alkyl 3 -amino-2 -hydroxy hexanoate hydrochloride salt compound of general formula-26. Wherein the suitable alcohol is of the general formula R-OH, wherein the group 'R' represents C!-C6 straight chain or branched chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl and the like.

A preferred embodiment of the present invention provides a process for the preparation of (3S)-methyl 3-amino-2-hydroxyhexanoate hydrochloride salt compound of formula-26a, comprising of reacting the tert-butyl (2S)-l-cyano-l-hydroxypentan-2-ylcarbamate compound of formula-25 with methanol in presence of trimethylsilyl chloride to provide of (3S)-methyl 3- amino-2-hydroxyhexanoate hydrochloride salt compound of formula-26a. The thirteenth aspect of the present invention provides a process for the preparation of

(3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of formula-6a, comprising of;

a) Reacting the tert-butyl (2S)-l-cyano-l-hydroxypentan-2-ylcarbamate compound of formula-25 with a suitable Ci-Ce alcohol in presence of acetyl chloride or thionyl chloride or tri(Ci-C6 straight chain or branched chain)alkyl silyl halides such as trimethylsilyl chloride

(TMSC1) to provide (3S)-alkyl 3-amino-2-hydroxy hexanoate hydrochloride salt compound of general formula-26,

b) reacting the compound of general formula-26 with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide (3S)-alkyl 3-(tert-butoxycarbonylamino)-2- hydroxy hexanoate compound of general formula-27,

c) hydrolyzing the compound of general formula-27 in presence of a suitable base to provide (3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanoic acid compound of formula-28a, d) reacting the compound of formula-28a with cyclopropyl amine in presence of a suitable coupling agent in a suitable solvent optionally in presence of a suitable base to provide tert- butyl (3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-ylcarbamate compound of formula-29a,

e) treating the compound of formula-29a with a suitable boc-deprotecting agent in a suitable solvent to provide (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of formula-6a. Wherein, in step-b) the suitable base and the suitable solvent are same as defined in step-e) of the tenth aspect of the present invention;

In step-c) the suitable base is selected from inorganic bases; the suitable solvent is selected from ether solvents, polar solvents, ester solvents, hydrocarbon solvents; ketone solvents or mixtures thereof;

In step-d) the suitable coupling agent, the suitable base and the suitable solvent are same as defined in step-a) of the first aspect of the present invention;

In step-e) the suitable boc-deprotecting agent is selected from ethyl acetate-HCl, isopropyl alcohol-HCl, acetyl chloride/alcohol, ethanol-HCl, methanol-HCI and the like; the suitable solvent is selected from ketone solvents, ether solvents, polar solvents, ester solvents, hydrocarbon solvents, alcohol solvents or mixtures thereof.

A preferred embodiment of the present invention provides a process for preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride saltcompound of formula-6a, comprising of;

a) Reacting the tert-butyl (2S)-l-cyano-l-hydroxypentan-2-ylcarbamate compound of formula-25 with methanol in presence of trimethylsilyl chloride to provide (3S)-methyl 3- amino-2-hydroxy hexanoate hydrochloride salt compound of formula-26a,

b) reacting the compound of formula-26a with di-tert.butyl dicarbonate in presence of potassium carbonate in a mixture of tetrahydrofuran and water to provide (3S)-methyl 3-(tert- butoxycarbonylamino)-2 -hydroxy hexanoate compound of formula-27a,

c) hydrolyzing the compound of formula-27a in presence of aq.lithium hydroxide in tetrahydrofuran to provide (3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanoic acid compound of formula-28a,

d) reacting the compound of formula-28a with cyclopropyl amine in presence of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl)/l-hydroxybenzotriazole (HOBt) in a mixture of ethyl acetate and water to provide tert-butyl (3 S)-l -(cyclopropyl amino)-2-hydroxy-l-oxohexan-3-ylcarbamate compound of formula-29a,

e) treating the compound of formula-29a with ethyl acetate-HCl in acetone to provide (3S)-3- amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of formula-6a. The fourteenth aspect 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-[(3 S)- 1 -(cyclopropylamino)- 1 ,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexa hydro- lH-cyclopenta[c]pyrrole-l-carboxamide compound of formula- 1, comprising of;

a) Reacting the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl butanoic acid compound of formula-2 with (lS,3aR,6aS)-ethyl octahydrocyclopenta[c] pyrrole- 1-carboxylate compound of formula-3 or its acid-addition salt in presence of Ν,Ν'- dicyclohexyl carbodiimide (DCC)/l-hydroxybenzotriazole (HOBt) in presence of a suitable base in a suitable solvent to provide (lS,3aR,6aS)-ethyl 2-((S)-2-((S)-2-cyclohexyl-2- (pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydro cyclopenta[c]pyrrole-

1-carboxylate compound of formula-4,

b) hydrolyzing the compound of formula-4 in presence of a suitable acid or a suitable base in a suitable solvent 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 compound of formula-5,

c) reacting the compound of formula-5 with (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide compound of formula-6 or its acid-addition salt in presence of Ν,Ν'- dicyclohexylcarbodiimide (DCC)/l-hydroxybenzotriazole (HOBt) in presence of a suitable base in a suitable solvent 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- l-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-l-carboxamide compound of formula-7, d) oxidizing the compound of formula-7 with a suitable oxidizing agent in presence of a suitable base in a suitable solvent optionally in presence of a catalyst to provide compound of formula- 1.

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

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

In step-d) the suitable oxidizing agent, the suitable base, the suitable catalyst and the suitable solvent are same as defined in step-f) of the first aspect of the present invention. A preferred embodiment of the present invention provides a 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-hexa hydro- 1 H-cyclopenta[c]pyrrole- 1 -carboxamide compound of formula- 1 , comprising of;

a) Reacting the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-;2-carboxamido)acetamido)-3,3-dimethyl butanoic acid compound of formula-2 with (lS,3aR,6aS)-ethyl octahydrocyclopenta[c] pyrrole- 1-carboxylate hydrochloride compound of formula-3a in presence of Ν,Ν'- dicyclohexylcarbodiimide (DCC)/l-hydroxybenzotriazole (HOBt) in presence of sodium bicarbonate in dichloromethane to provide (l S,3aR,6aS)-ethyl 2-((S)-2-((S)-2-cyclohexyl-2-

(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole- 1-carboxylate compound of formula-4,

b) hydrolyzing the compound of formula-4 in presence of lithium hydroxide in a mixture of acetone and water to provide (l S,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-5,

c) reacting the compound of formula-5 with (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide hydrochloride salt compound of formula-6a in presence of Ν,Ν'- dicyclohexylcarbodiimide (DCC)/l-hydroxybenzotriazole (HOBt) in presence of 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)octahydrocyclopenta[c]pyrrole- 1 - carboxamide compound of formula-7,

d) oxidizing the compound of formula-7 with sodium hypochlorite/TEMPO in presence of sodium bicarbonate and potassium bromide in a mixture of dichloromethane and water to provide compound of formula- 1.

The fifteenth aspect of the present invention provides crystalline polymorph of (S)-2- ((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3, 3 -dimethyl butanoic acid compound of formula-2. The said crystalline polymorph is herein after designated as crystalline form-M and is characterized by its powder X-ray diffraction pattern having peaks at 5.5, 7.3, 10.7, 14.7, 16.7, 17.3, 17.5, 17.8, 18.3, 19.2, 20.7, 21.4, 22.04, 22.21 & 24.7 ± 0.2 degrees of 2-theta. The crystalline form-M of compound of formula-2 is further characterized by its powder X-ray diffraction pattern substantially in accordance with figure- 1 and its DSC endotherm as shown in figure-2. The sixteenth aspect of the present invention provides a process for the preparation of

(3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide compound of formula-6 and its acid- addition salts, comprising of;

a) Reacting the (S)-2-aminopentanoic acid compound of formula-21 with a suitable protecting agent in a suitable solvent optionally in presence of a suitable base to provide compound of general formula-22,

b) esterification of compound of general formula-22 by reacting it with a suitable Ci-C^ alcohol in presence of a suitable esterification catalyst optionally in presence of a suitable solvent to provide compound of general formula-33,

c) reacting the compound of general formula-33 with a-halo acetic acid salt compound of general formula-34 in presence of alkyl magnesium halide and a base in a suitable solvent to provide compound of general formula-35,

d) halogenating the compound of general formula-35 with a suitable halogenating agent in a suitable solvent optionally in presence of a suitable catalyst and a suitable base to provide compound of general formula-36,

e) treating the compound of general formula-36 with alkali metal alkoxide in a suitable solvent to provide (3S)-3-amino-2-hydroxyhexanoic acid compound of formula-37,

f) reacting the compound of formula-37 with a suitable protecting agent in a suitable solvent optionally in presence of a suitable base to provide compound of general formula-28, g) reacting the compound of general formula-28 with cyclopropyl amine in presence of a suitable coupling agent optionally in presence of a suitable base in a suitable solvent to provide compound of general formula-29,

h) deprotecting the compound of general formula-29 to provide (3S)-3-amino-N-cyclopropyl-2- hydroxyhexanamide compound of formula-6,

i) optionally converting the compound of formula-6 into its acid-addition salt by treating it with a suitable acid in a suitable solvent to provide corresponding acid-addition salt of compound of formula-6. Wherein, in step-a) & step-f) the suitable protecting agent is selected such that it is capable of protecting the compound of formula-21 and compound of formula-37 with any of the protecting groups selected from but not limited to methoxy carbonyl, tert-butoxy carbonyl, banzyloxy carbonyl, ethoxy carbonyl, acetyl, trifiouoroacetyl, benzyl, dibenzyl, phthalimido, tosyl, p-methoxybenzyl carbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl and benzoyl. Preferable protecting agents are di-tert.butyl dicarbonate and benzyl chloroformate;

the suitable base is selected form organic and inorganic bases;

in step-b) the suitable esterification catalyst is selected from thionyl chloride and conc.sulfuric acid;

in step-c) the "alkyl magnesium halide" represents C -Ce straight or branched chain alkyl magnesium halides such as methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide and the like; the base is organic base such as triethylamine, diisopropylethylamine and the like; the a-halo acetic acid salt is preferably alkali metal salt such as lithium, sodium and potassium salts of a-halo acetic acid;

in step-d) the suitable halogenating agent is selected from phosphorous trichloride, phosphorous penta chloride, phosphorous tribromide, phosphorous penta bromide, thionyl chloride, N-bromo succinamide, N-chloro succinamide, phosphoryl chloride, oxalyl chloride, cyanuric chloride, chlorine, bromine, thionyl chloride, sulfuryl chloride, copper (II) chloride, copper (II) bromide, ferric chloride, ferric bromide and the like; The suitable catalyst is p-toluene sulfonyl chloride; the suitable base is selected form organic and inorganic bases;

in step-g) the suitable coupling agent, the suitable base are same as defined in step-a) of the first aspect of the present invention;

in step-h) the deprotection step is carried out by hydrogenolysis using metal catalysts like palladium, palladium on carbon and rhodium on carbon under hydrogen pressure; (or) by using acids like hydrochloric acid, hydrobromic acid, sulfuric acid, periodic acid, trichloroisocyanuric acid and trifluoroacetic acid; (or) by using bases like piperidine, ammonia and methylamine; ammonium cerium (IV) nitrate; sodium in liquid ammonia; and sodium naphthalenide;

in step-i) the suitable acid is preferably hydrochloric acid. In step-a) to step-i) the suitable solvent wherever necessary is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar solvents, nitrile solvents, ketone solvents or their mixtures;

^' A preferred embodiment of the present invention provides a process for the preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of formula- 6a, comprising of;

a) Reacting the (S)-2-aminopentanoic acid compound of formula-21 with benzyl chloro formate in presence of aq.sodium hydroxide in 1,4-dioxane to provide (S)^-2-(benzyloxycarbonyl amino)pentanoic acid compound of formula-22b,

b) esterification of compound of formula-22b by reacting it with methanol in presence of thionyl chloride in toluene to provide (S)-methyl 2-(benzyloxycarbonylamino)pentanoate compound of formula-33a,

c) reacting the compound of formula-33a with sodium monochloro acetate compound of formula-34a in presence of tert.butyl magnesium chloride and triethylamine in tetrahydrofuran to provide (S)-benzyl l-chloro-2-oxohexan-3-ylcarbamate compound of formula-35a,

d) chlorinating the compound of formula-35a with sulfuryl chloride in presence of triethylamine in ethyl acetate to provide (S)-benzyl l,l-dichloro-2-oxohexan-3-ylcarbamate compound of formula-36a,

e) treating the compound of formula-36a with aq.sodium hydroxide in toluene to provide (3S)- 3-amino-2-hydroxyhexanoic acid compound of formula-37,

f) reacting the compound of formula-37 with di-tert.butyl dicarbonate in presence of aq.sodium hydroxide in 1,4-dioxane to provide (3S)-3-(tert-butoxycarbonyl amino)-2-hydroxyhexanoic acid compound of formula-28a,

g) reacting the compound of formula-28a with cyclopropyl amine in presence of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole (EDC.HCl/HOBt) in a mixture of ethyl acetate and water to provide tert-butyl (3S)-1- (cyclopropylamino)-2-hydroxy- 1 -oxohexan-3-ylcarbamate compound of formula-29a, h) deprotecting the compound of formula-29a by treating it with ethyl acetate-HCl in ethyl acetate to provide (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of formula-6a. The compound of general formula-29 of the present invention can also be prepared by esterification of compound of general formula-28 with a suitable alcohol in presence of a suitable esterification catalyst followed by reacting the obtained ester compound with cyclopropyl amine in presence of a suitable coupling agent in a suitable solvent optionally in presence of a suitable base to provide compound of general formula-29.

The present invention also provides crystalline forms of (S)-benzyl-l-chloro-2-oxohexan- 3-yl carbamate compound of formula-35a and (3S)-3-(tert-butoxycarbonylamino)-2-hydroxy hexanoic acid compound of formula-28a, which are useful intermediates in the synthesis of (3S)- 3-amino-N-cyclopropyl-2-hydroxyhexanamide compound of formula-6 as well as compound of formula- 1.

The seventeenth aspect of the present invention provides crystalline form of (S)-benzyl-

1- chloro-2-oxohexan-3-yl carbamate compound of formula-35a. The said crystalline form is herein after designated as crystalline form-M and is characterized by its powder X-ray diffraction pattern having peaks at 6.7, 8.4, 10.1, 12.6, 16.7, 18.3, 20.0, 22.2, 22.7, 24.0, 26.7, 28.1, 31.0, 32.6 and 35.6 ± 0.2 degrees of 2-theta. The said crystalline form-M is further characterized by its powder X-ray diffraction pattern substantially in accordance with figure-3.

The eighteenth aspect of the present invention provides crystalline form of (3S)-3-(tert- butoxycarbonylamino)-2-hydroxyhexanoic acid compound of formula-28a. The said crystalline form is herein after designated as crystalline form-S and is characterized by its powder X-ray diffraction pattern having peaks at 6.6, 10.9, 13.3, 18.8, 21.9 and 26.9 ± 0.2 degrees of 2-theta. The said crystalline form-S is further characterized by its powder X-ray diffraction pattern substantially in accordance with figure-4.

The nineteenth aspect of the present invention provides solid state form of (lS,3aR,6aS)-

2- ((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3, 3 -dimethyl butanoyl)-N- ((3 S)- 1 -(cyclopropylamino)-2 -hydroxy- 1 -oxohexan-3 -yl)octahydrocyclopenta[c]pyrrole- 1 - carboxamide compound of formula-7. The said solid form of compound of formula-7 is characterized by its PXRD pattern as illustrated in figure-7. The twentieth aspect of the present invention is to provide crystalline polymorph (herein after designated as crystalline forrn-N]) of tert-butyl (3S)-l-(cyclopropylamino)-2-hydroxy-l- oxohexan-3-ylcarbamate compound of formula-29a. The said crystalline form is characterized by its powder X-ray diffraction pattern having peks at 4.7, 5.4, 6.8, 9.4, 10.2, 1 1.0, 15.6, 20.0, 21.2, 24.3, 26.1, 33.2 ± 0.2 degrees of 2-theta. The said crystalline form-N] is further characterized by its powder X-ray diffraction pattern substantially in accordance with figure-8.

The twenty first aspect of the present invention is to provide crystalline polymorph (herein after designated as crystalline form-N₂) of tert-butyl (3S)-l-(cyclppropylamino)-2- hydroxy-1 -oxohexan-3 -ylcarbamate compound of formula-29a. The said crystalline form is characterized by its powder X-ray diffraction pattern having peaks at 4.9, 5.4, 8.0, 8.7, 10.8, 14.1, 14.8, 16.2, 18.7, 19.9, 21.2, 23.7, 27.5, 35.4, 38.2, 46.7 ± 0.2 degrees of 2-theta. The said crystalline form-N₂ is further characterized by its powder X-ray diffraction pattern substantially in accordance with figure-9.

The twenty second aspect of the present invention is to provide crystalline polymorph (herein after designated as crystalline form-R of (3S)-3-amino-N-cyclopropyl-2- hydroxyhexanamide hydrochloride salt compound of formula-6a. The said crystalline form is characterized by its powder X-ray diffraction pattern having peaks at 6.4, 7.7, 10.2, 11.4, 11.8, 15.5, 16.0, 18.4, 20.8, 22.2, 23.8, 24.5, 25.9, 27.5, 31.2, 33.9, 37.0, 39.4 ± 0.2 degrees of 2-theta. The said crystalline form-R₁ is further characterized by its powder X-ray diffraction pattern substantially in accordance with figure- 10.

The twenty third aspect of the present invention is to provide crystalline polymorph (herein after designated as crystalline form-R₂) of (3S)-3-amino-N-cyclopropyl-2- hydroxyhexanamide hydrochloride salt compound of formula-6a. The said crystalline form is characterized by its powder X-ray diffraction pattern having peaks at 6.4, 9.5, 11.8, 16.3, 17.4, 20.0, 21.1, 21.4, 22.3, 23.8, 24.5, 27.4, 27.9, 30.6, 31.6, 33.0, 35.1, 37.0 ± 0.2 degrees of 2-theta. The said crystalline form-R₂ is further characterized by its powder X-ray diffraction pattern substantially in accordance with figure- 11.

The intermediate compounds of the present invention can also be synthesized by the processes described in scheme-7 to scheme- 12 of the present invention.

The compound of formula- 1 of the present invention can also be synthesized by the process described in scheme- 13 of the present invention.

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 μιη or equivalent; Wave length: 210 nm; Flow rate: 1.0 mL/min; Column temperature: 40°C; Injection volume: 10 μΐ,; 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 μιη Nylon membrane filter paper; Mobile phase-A: Buffer; Mobile phase-B: acetonitrile:methanol:water (300:450:250 v/v/v).

The PXRD analysis is carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A⁰ and at a continuous scan speed of 0.03 min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C/min.

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-1

FormuIa-5

ormu a-

Sche

Scheme-3:

FormuIa-2 Formula-12

Scheme-4:

Scheme-5

rin

FormuIa-29a FormuIa-6

6a) HC1 salt

Wherein the group 'R' represents C C₆ straight chain or branched chain alkyl group.

Scheme-6:

CI

28

Wherein, Pi and P₂ both are same (or) different and independently selected from hydrogen and amino protecting group; R is straight or branched chain Ci-C₆ alkyl; "M" is an alkali metal such as Na, K, Li and the like; "X" is halogen such as chlorine, bromine and iodine.

Scheme-7:

Wherein, Pi and P₂ are same as defined above; P is hydroxy protecting group. Scheme-8

lation

Formula-36

Wherein, Pj, P₂, R and X are same as defined above.

Scheme-9:

(ii) HX

Wherein, Pi, P₂, R and X are same as defined above; M is an alkali metal; R₃ and R4 are Ci-C₆ straight or branched chain alkyl.

Scheme-10:

Wherein, R is straight or branched chain C_!-C₆ alkyl; X is halogen such as CI, Br and I; and ?i and P₂ are same as defined above. Scheme-11:

O

OR

(^'

Formula-33

Wherein, R is straight or branched chain Ci-C₆ alkyl; X is halogen such as CI, Br and I; and Pi and P₂ are same as defined above.

Scheme-12:

Wherein, the group 'R' is selected from straight or branched chain Ci-C₆ alkyl groups; 'X' represents halogens such as CI, Br and I; and the base is selected from, but are not limited to alkyllithiums, alkylmagnesium halides, lithium amides, e.g. lithium diisopropylamide, lithium hexamethyldisilazide, etc., and halomagnesium dialkylamides which can be prepared by reacting a Grignard reagent (alkyl magnesium halide) with a secondary amine, e.g. chloromagnesium diisopropylamide, bromomagnesium diisopropylamide and chloromagnesium dicyclohexylamide. These bases can be used independently or in a combination of 2 or more species. Preferred bases are halomagnesium dialkylamides, and particularly preferred base is chloromagnesium diisopropylamide. cheme-13:

The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation to the scope of the invention.

Examples:

Example-1: Preparation of (S)-2-cycIohexyl-2-(pyrazine-2-carboxamido)acetic acid (FormuIa-10)

Trimethylsilyl chloride (5.15 gm) was slowly added to a pre-cooled mixture of (S)-2- amino-2-cyclohexylacetic acid compound of formula-9 (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-8 (5 gm) and N,N-carbonyl diimidazole (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 HCl. 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=1.06%, CHC1₃).

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

A mixture of (S)-2-amino-3,3-dimethylbutanoic acid compound of formula-13 (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-12)

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- 10 (6.0 gm), dichloromethane (36 ml) and (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloride compound of formula-l la (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%; SOR: -2.0° (C=l%, CHC1₃).

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

Lithium hydroxide solution (2.4 gm of LiOH.H₂0 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-12 (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 tert.butyl 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. The PXRD of the obtained compound is shown in figure- 1.

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); MTBE content: 9.5%.

Example-5: Preparation of octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride (Formula-17a)

13% Sodium hypochlorite solution (1552 ml) was slowly added to a solution of octahydrocyclopenta[c]pyrrole hydrochloride compound of formula- 14a (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 25-30°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 25-30°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 25-30°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; MR: 160-165°C.

Example-6: Preparation of octahydrocyclopenta[c]pyrrole-l-carboxylic acid hydrochloride (Formula-18a)

A mixture of conc.HCl (420 ml) and octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride compound of formula- 17 (140 gm) was heated to 60-65°C and stirred for 4 hrs at the same temperature. Another 280 ml of conc.HCl was added to the reaction mixture at 60-65°C and stirred for 10 hrs at the same temperature. After completion of the reaction, distilled off the reaction mixture completely under reduced pressure to get the title compound.

Example-7: Preparation of 2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l- carboxylic acid (Formula-19)

Water (980 ml) was added to the octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride compound of formula- 18 obtained in example-6 at 25-30°C. Sodium hydroxide solution (162 gm of NaOH in 420 ml of water) was slowly added to the reaction mixture at 25- 30°C. A solution of di-tert.butyl dicarbonate (265 gm) in toluene (700 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 10 hrs at the same temperature. After completion of the reaction, both the organic and aqueous layers were separated and dichloromethane was added to the aqueous layer at 25-30°C. Cooled the reaction mixture to 0-5°C and adjusted the pH of the reaction mixture to 2.0 using 5N HC1 solution and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane at 0-5°C. The combined organic layer was washed with water and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.

Example-8: Preparation of (lS,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c] pyrrole-l-carboxylic acid (R)-l-phenylethanamine salt (Formula-20a)

(R)-l-phenylethanamine (88.5 gm) was slowly added to a solution of 2-(tert- butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l -carboxylic acid compound of formula-19 obtained in example-7 in isopropyl alcohol (280 ml) and ethyl acetate (1400 ml) at 25-30°C and stirred the reaction mixture for 8 hrs at the same temperature. Filtered the precipitated solid and washed with ethyl acetate. Isopropyl alcohol (70 ml) and ethyl acetate (1120 ml) were added to the obtained solid at 25-30°C and stirred for 8 hrs at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound.

Yield: 80.0 gm. Example-9: Preparation of (lS,3aR,6aS)-2-(tert-butoxycarbonyI)octahydrocyclopenta[c] pyrrole-l-carboxylic acid (Formula-20) Dichloromethane (980 ml) and water (700 ml) were added to (R)-l-phenylethanamine salt compound of formula-20a (80 gm) and cooled the reaction mixture to 0-5°C. Adjusted the pH of the reaction mixture to 2.0-2.5 using 5N HCl solution at 0-5°C and stirred the reaction mixture for 20 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with n-heptane. Water (420 ml) was added to the obtained solid at 25- 30°C and stirred for 45 min at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 50.0 gm.

ExampIe-10: Preparation of (lS,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-l- carboxylate hydrochloride (Formula-3a)

(lS,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-20 (100 gm) was added to a mixture of toluene (500 ml) and ethanol (200 ml) at 25-30°C. Thionyl chloride (56.7 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 90 min at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 8 hrs at the same temperature. After completion of the reaction, distilled off the excess thionyl chloride completely under reduced pressure and co-distilled the reaction mixture with toluene. 300 ml of toluene was added to the obtained compound at 60-65 °C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with toluene under N₂ atmosphere and dried to get the title compound. Yield: 70.0 gm.

Example-11: Preparation of (S)-2-(tert-butoxycarbonyIamino)pentanoic acid (Fprmula-22a)

(S)-2-aminopentanoic acid compound of formula-21 (200 gm) was added to aqueous sodium carbonate solution (453 gm of sodium carbonate in 2000 ml of water) at 25-30°C. Di- tert.butyl dicarbonate (484 gm) was added to the reaction mixture at 20-25°C and stirred the reaction mixture for 8 hrs at same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C, dichloromethane was added and stirred for 10 min at the same temperature. Adjusted the pH of the reaction mixture to 2-3 using aqueous HCl solution at 0- 5°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 352.0 gm.

Example-12: Preparation of tert-butyl (2S)-l-cyano-l-hydroxypentan-2-ylcarbamate (Formula-25)

Step-a): Preparation of (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopentan-2-yl carbamate (Formula-23)

Toluene (740 ml) was added to N,N-carbonyldiimidazole (331 gm) at 25-30°C and cooled the reaction mixture to 0-5°C. A solution of (S)-2-(tert-butoxycarbonylamino)pentanoic acid compound of formula-22a (435 gm) in toluene (370 ml) was added to the reaction mixture at 0-5°C and stirred for 3 hrs at the same temperature. Ν,Ο-dimethylhydroxylamine hydrochloride (265 gm) and diisopropylethyl amine (356 ml) were added to the reaction mixture at 0-5°C and stirred for 3 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Combined the organic layers and washed with aq.HCl followed by 10% aq.sodium bicarbonate solution. The obtained organic layer containing (S)-tert- butyl l-(methoxy(methyl)amino)-l-oxopentan-2-yl carbamate compound of formula-23 was utilized in the next step without isolating the product from the reaction mixture.

Step-b): Preparation of (S)-tert-butyl l-oxopentan-2-yIcarbamate (Formula-24)

70% vitride solution (830 ml) was added to the organic layer obtained in the step-a) at - 15° to -10°C and stirred the reaction mixture for 45 min at the same temperature. The reaction mixture was slowly added to pre-cooled aq. sodium potassium tartrate solution (856 gm of sodium potassium tartrate in 1688 ml of water) was slowly added to the reaction mixture at 0- 5°C. Raised the temperature of the reaction mixture to 20-25°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. The combined organic layer was washed with 10% aqueous sodium chloride solution. The obtained organic layer containing (S)-tert-butyl l-oxopentan-2- ylcarbamate compound of formula-24 was utilized in the next step without isolating the product from the reaction mixture.

Step-c): Preparation of tert-butyl (2S)-l-cyano-l-hydroxypentan-2-yl carbamate (Formula-25) The organic layer containing (S)-tert-butyl 1 -oxopentan-2-ylcarbamate compound of formula-24 which is obtained in step-b) was added to aqueous sodium carbonate solution (435 gm of sodium carbonate in 2110 ml of water) at 25-30°C. Acetone cyanohydrin (300 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 2 hrs at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. The combined organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 350 gm.

Example-13: Preparation of tert-butyl (3S)-l-(cyclopropyIamino)-2-hydroxy-l-oxo hexan- 3-yl carbamate (Formula-29a)

Step-a): Preparation of (3S)-methyl 3-amino-2-hydroxyhexanoate hydrochloride (Formula-26a)

Trimethylsilyl chloride (773 ml) was added to a mixture of tert-butyl (2S)-l-cyano-l- hydroxypentan-2-yl carbamate compound of formula-25 (345 gm) and methanol (1725 ml) at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and filtered the reaction mixture. Distilled off the solvent completely from the filtrate. Water and dichloromethane were added to the obtained compound and stirred for 15 min. Both the organic and aqueous layers were separated and the aqueous layer was washed with dichloromethane. The obtained aqueous layer containing (3S)-methyl 3-amino- 2-hydroxyhexanoate hydrochloride was utilized in the next step without isolating the product from the reaction mixture.

Step-b): Preparation of (3S)-methyl 3-(tert-butoxycarbonylamino)-2-hydroxyhexanoate (Formula-27a)

Potassium carbonate (410 gm) and tetrahydrofuran (1035 ml) were added to the aqueous layer obtained in step-a) at 10-15°C. Di-tert.butyl dicarbonate (329 gm) 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 was added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with 5% aq.sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 345 gm. Step-c): Preparation of (3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanoic acid (Formula-28a)

Aq.LiOH solution (164 gm of LiOH in 862 ml of water) was added to a solution of (3S)- methyl 3-(tert-butoxycarbonylamino)-2-hydroxyhexanoate compound of formula-27a (345 gm) in tetrahydrofuran (1725 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 8 hrs at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was cooled to 0-5°C. Distilled off the solvent completely from organic layer, water and above cooled aqueous layer were added to the obtained compound. Toluene was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was washed with toluene. Dichloromethane was added to the aqueous layer and cooled the reaction mixture to 0-5°C. Acidified the reaction mixture with aq.hydrochloric acid solution. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with 5% aq.sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.

Yield: 270 gm.

Step-d): Tert-butyl (3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl carbamate (Formula-29a)

Ethyl acetate (2700 ml) and water (270 ml) were added to (3S)-methyl 3-(tert-butoxy carbonylamino)-2-hydroxyhexanoate compound of formula-28a (270 gm) obtained in step-c) at 25-30°C. Cooled the reaction mixture to 0-5°C. 1-hydroxybenzotriazole (147.5 gm) and 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (251 gm) were added to the reaction mixture at 0-5°C. Cyclopropyl amine (87.2 gm) was added to the reaction mixture at 0-5°C and stirred for 2 hrs at the same temperature. After completion of the reaction, ethyl acetate (1350 ml) and 5% aqueous sodium bicarbonate solution (40.5 gm of sodium bicarbonate in 810 ml of water) were added to the reaction mixture. Heated the reaction mixture to 40-45°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and 5% sodium chloride solution was added to the organic layer. Heated the reaction mixture to 40-45°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer and co-distilled with pet ether under reduced pressure. To the obtained solid, pet ether (810 ml) and ethyl acetate (270 ml) were added. Heated the reaction mixture to 55-60°C and stirred for 1 hr at the same temperature. Slowly cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with pet ether followed by ethyl acetate and dried to get the title compound. The PXRD of the obtained compound is shown in figure-9.

Yield: 232.0 gm; M.R: 130-134°C.

Example-14: Preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride (Formula-6a)

Ethyl acetate- HC1 (636 ml) was added to a mixture of tert-butyl (3S)-1- (cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl carbamate compound of formula-29a (100 gm) and acetone (500 ml) at 25-30°C and stirred the reaction mixture for 8 hrs at the same temperature. Filtered the precipitated solid, washed with a mixture of acetone and ethyl acetate and dried the material to get the title compound.

The PXRD of the obtained compound is shown in figure- 10.

Yield: 60 gm; M.R: 165-170°C.

Example-15: Preparation of (S)-2-(benzyloxycarbonylamino)pentanoic acid (Formula-22b)

Aq.sodium hydroxide solution (102 g of sodium hydroxide in 250 ml of water) was slowly added to a pre-cooled mixture of (S)-2-aminopentanoic acid compound of formula-21 (100 gm) and water (1000 ml) at 0-5°C. 440 ml of benzyl chloroformate (50% in toluene) was slowly added to the reaction mixture at 0-5°C and stirred for 6 hrs at the same temperature. After completion of the reaction, the temperature of the reaction mixture was raised to 20-25°C and both the organic and aqueous layers were separated. The pH of the aqueous layer was adjusted to 1.5 using aq. hydrochloric acid at 0-5°C. Dichloromethane was added to the reaction mixture, temperature of the reaction mixture was raised to 20-25°C. Both the organic and aqueous layers were separated. The solvent from the organic layer was completely distilled off under reduced pressure and then co-distilled with cyclohexane. Cyclohexane (600 ml) was added to the obtained compound at 40-45°C. The reaction mixture was cooled to 10-15°C and then stirred for 60 min. Filtered the precipitated solid and then dried to get title compound.

Yield: 196.0 gm; Purity by HPLC: 97.99%; M.R: 82-84°C; SOR: (-) 16.3° (C=l in methanol at 25°C). Example-16: Preparation of (S)-methyl 2-(benzyloxycarbonyIamino)pentanoate (Formula- 33a)

Thionyl chloride (30 ml) was added to a pre-cooled solution of (S)-2- (benzyloxycarbonylamino)pentanoic acid compound of formula-22b (50 gm) in methanol (250 ml) at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and then stirred for 3 hrs at the same temperature. After completion of the reaction, the solvent from the reaction mixture was completely distilled off under reduced pressure. The reaction mixture was cooled to 25-30°C; dichloromethane, followed by water were added to the reaction mixture and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated; the organic layer was washed with sodium bicarbonate followed by sodium chloride and then distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 51.0 gm; SOR: (-) 27.33° (C=l in methanol at 25°C).

Example-17: Preparation of (S)-benzyl l-chloro-2-oxohexan-3-ylcarbamate (Formula-35a)

A mixture of magnesium (54 gm), iodine (0.2 gm) and tetrahydrofuran (150 ml) was heated to 50-60°C. A solution of tert-butyl chloride (17.4 gm) in tetrahydrofuran (25 ml), followed by a solution of ethyl bromide (1.2 ml) in tetrahydrofuran (5 ml) were added to the above reaction mixture at the same temperature. The reaction mixture was stirred for 15 min at 60-70°C. A solution of tert-butyl chloride (156.6 gm) in tetrahydrofuran (225 ml) was slowly added to the reaction mixture at 60-70°C and stirred for 30 min at the same temperature. The reaction mixture was cooled to 25-30°C; a mixture of toluene (250 ml), (S)-methyl 2- (benzyloxycarbonylamino)pentanoate compound of formula-33a (50 gm), sodium monochloro acetate compound of formula-34a (32.5 gm) and triethyl amine (40 ml)was added to the reaction mixture at 0-10°C and stirred for 2 hrs at the same temperature. After completion of the reaction, the reaction mixture was quenched with aq. hydrochloric acid at a temperature below 10°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 15 min. Both the organic and aqueous layers were separated. The solvent from the organic layer was distilled off completely under reduced pressure and then co-distilled with isopropyl alcohol. Isopropyl alcohol (150 ml) was added to the reaction mixture and the reaction mixture was cooled to 0-5°C and stirred for 30 min at the same temperature. Filtered the precipitated solid and then dried to get the title compound. Yield: 38.0 gm; M.R: 103-106°C; SOR: (-) 33.3° (C=l in methanol at 25°C).

Example-18: Preparation of (S)-benzyl l,l-dichIoro-2-oxohexan-3-ylcarbamate (Formula- 36a)

Sulfuryl chloride (26.4 ml), followed by p-toluene sulfonyl chloride (1.6 gm) were added to a solution of (S)-benzyl l-chloro-2-oxohexan-3-ylcarbamate compound of formula-35a (25 gm) in ethyl acetate (250 ml) under nitrogen atmosphere at 25-30°C. The reaction mixture was heated to 40-45°C and stirred for 36 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5 °C and water was added to it. pH of the reaction mixture was adjusted to 3.2 using 2N NaOH solution at 0-5°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the solvent from the organic layer was completely distilled off to get title compound.

Yield: 26.0 gm; SOR: (-) 26.1° (C=l in methanol at 25°C).

Example-19: Preparation of (3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanoic acid (FormuIa-28a)

A mixture of (S)-benzyl l,l-dichloro-2-oxohexan-3-ylcarbamate compound of formula-

36a (25 gm), toluene (200 ml) and 2M sodium hydroxide solution (200 ml) was heated to 40- 45°C and stirred for 12 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Both the organic and aqueous layers were separated and washed the aqueous layer with ethyl acetate. pH of the aqueous layer was adjusted to 10.5 using 2N NaOH solution. 1,4-dioxane (100 ml) was added to the aqueous layer and the reaction mixture was cooled to 0-5°C. Di-tert-butyl dicarbonate (32.5 gm) was added to the reaction mixture at 0-5°C; the temperature of the reaction mixture was raised to 25-30°C and stirred for 12 hrs at the same temperature. After completion of the reaction, ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated; pH of the aqueous layer was adjusted to 2.5 using aq.hydrochloric acid solution at 0-5°C and dichloromethane was added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C. The organic layers was washed with sodium chloride solution and then the solvent from the organic layer was distilled off at 45°C under reduced pressure to get the title compound.

Yield: 9.0 gm; MR: 102-105°C; SOR: -32.5° (C=l in methanol at 25°C). ExampIe-20: Preparation of tert-butyl (3S)-l-(cyclopropyIamino)-2-hydroxy-l-oxohexan-3- yl carbamate (FormuIa-29a)

Hydroxybenzotriazole (5.3 gm) was added to a mixture of (3S)-3-(tert- butoxycarbonylamino)-2-hydroxyhexanoic acid compound of formula-28a (8 gm) and dichloromethane (40 ml) at 25-30°C under nitrogen atmosphere. The reaction mixture was cooled to 0-5°C. l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (8 gm), followed by cyclopropylamine (5 ml) and diisopropylethyl amine (7 ml) were added to the reaction mixture at 0-5°C and stirred for 2 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture and pH of the reaction mixture was adjusted to 2.5 using aq.hydrochloric acid solution at 0-5°C. Filtered the undissolved solid and washed with dichloromethane. Both the organic and aqueous layers were separated from the filtrate and the organic layer was washed with 5% sodium bicarbonate solution followed by sodium chloride solution. The solvent from organic layer was completely distilled off under reduced pressure and then co-distilled with cyclohexane. Cyclohexane (24 ml) was added to the obtained compound, the reaction mixture was cooled to 0-5°C and stirred for 30 min at the same temperature. Filtered the precipitated solid and then dried to get the title compound.

Yield: 4.5 gm; M.R: 130-134°C; SOR: (-) 38.7° (C=l in methanol at 25°C).

Example-21: Preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride (Formula-6a)

4N hydrochloric acid solution (10 ml) was added to a mixture of tert-butyl (3S)-1-

(cyclopropylamino)-2-hydroxy-l-oxohexan-3-ylcarbamate compound of formula-29a (2 gm) and 1,4-dioxane (10 ml) at 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, the solvent from the reaction mixture was completely distilled off under reduced pressure at below 50°C and then co-distilled with acetone. Acetone (10 ml) was added to the obtained compound at 25-30°C and stirred for 20 min at the same temperature. The reaction mixture was cooled to 0-5°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with chilled acetone and then dried to get the title compound.

Yield: 1.0 gm; M.R: 200-203°C; SOR: (-) 36.5° (C=l in methanol at 25°C).

Example-22: Preparation of (S)-2-(benzyloxycarbonylamino)pentanoic acid (Formula-22b) 250 gm of (S)-2-aminopentanoic acid compound of formula-21 and 1250 ml of 1,4- dioxane are added to the aqueous sodium hydroxide solution (256 gm of NaOH dissolved in 1500 ml of water) at 0-5°C. To this reaction mixture 875 ml of benzyl chloroformate was added slowly at 0-5°C. Stirred the reaction mixture for 4 hrs at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and water (1175 ml) was added to it. Separated the both aqueous and organic layers and aqueous layer was washed with toluene followed by with ethyl acetate. Cooled the aqueous layer to 0-5°C and acidifying with aqueous hydrochloride at 0-5°C. Ethyl acetate (1000 ml) was added to the reaction mixture and raised the temperature of the reaction mixture to 25-30°C. Separated the both aqueous and organic layers and aqueous layer further extracted with ethyl acetate. Combined the total organic layer and washed with 2.5% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer and co- distilled with cyclohexane (125 ml). Cyclohexane (1500 ml) was added to the reaction mixture and stirred the reaction mixture for 2 hrs at 25-30°C. Filtered the solid and dried the compound to get the title compound.

Yield: 480 gm; MR: 82-84°C.

ExampIe-23: Preparation of (S)-benzyI-l-chloro-2-oxohexan-3-yl carbamate (Formula-35a) Step-a) Thionyl chloride (66 ml) was added to the reaction mixture of (S)-2-(benzyloxycarbonyl amino)pentanoic acid compound of formula-22b (250 gm), toluene (1000 ml) and methanol (187 ml) at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 10-15°Cand water (500 ml) was added to it. Separated the both aqueous and organic layers and the aqueous layer was extracted with toluene (400 ml). 250 ml of water was added to the combined organic layer and the pH of the reaction mixture was adjusted to 6-7 using aqueous carbonate solution at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C. Separated the both aqueous and organic layers and aqueous layer was washed with toluene (250 ml). Organic layer was washed with water (500 ml) and the organic layer was kept aside for further reaction.

Step-b) To 242 grms of magnesium and 0.5 gm of Iodine added 1250 ml of tetrahydrofuran at 25-30°C. Heated the reaction mixture to 40-45°C and added a mixture of t-butyl chloride (744 gm), ethyl bromide (38 ml) in tetrahydrofuran (1250 ml) to the reaction mixture. Heated the reaction mixture to 65-70°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Step-c) To the organic layer obtained in step-a) added sodium mono chloro acetate (175 gm) under nitrogen atmosphere and cooled the reaction mixture to 0-5°C. Triethyl amine (210 ml) and followed by the t-butyl magnesium chloride obtained in step-b) was added to it at 0-5°C. Stirred the reaction mixture for 2 hrs at 0-5°C. This reaction mixture was slowly added to the 0- 5°C pre-cooled aqueous hydrochloric acid(1000 ml of HC1 in 1250 ml of water) and stirred the reaction mixture for 15 min at 20-25°C. Seperated the both aqueous and organic layers and the aqueous layer was extracted with toluene (250 ml). Combined the total organic layer and washed with 5% aqueous sodium bicarbonate solution followed by with 10% sodium chloride solution. Distilled off the solvent completely. Isopropyl alcohol (125 ml) was added to the obtained compound at 40-45°C and distilled off the solvent completely under reduced pressure. Isopropyl alcohol (1000 ml) was added to the obtained compound at 40-45 °C and heated the reaction mixture to 70-75°C. Cooled the reaction mixture to 20-25°C and further cooled to 0-5°C and stirred for 30 min at the same temperature. Filtered the precipitated solid and dried to get the title compound. The PXRD of the obtained compound is shown in figure-3.

Yield: 69.07 gm; MR: 103-106°C.

ExampIe-24: Preparation of (3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanoic acid (Formula-28a)

10 ml of triethyl amine was slowly added to a mixture of (S)-benzyl-l-chloro-2- oxohexan-3-yl carbamate compound of formula-35a (200 gm) and ethyl acetate (2000 ml). Sulfuryl chloride (404.7 gm) was slowly added to the reaction mixture lot wise at 40-45°C and stirred the reaction mixture for 40 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to less than 10°C and the reaction mixture was added to 5-10°C precooled water. Adjusted the pH of the reaction mixture to 3-4 slowly by adding aqueous sodium hydroxide solution at 5-10°C. Separated the both aqueous and organic layers and the aqueous layer was extracted with ethyl acetate at 25-30°C. Combined the total organic layer and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure. To the obtained residue, toluene (1800 ml) was added at 25-30°C and stirred for 15 min at the same temperature. Aq. sodium hydroxide solution (141 gm of NaOH in 1800 ml of water) was added 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. Cooled the reaction mixture to 25-30°C and separated the both organic and aqueous layers. Adjusted the pH of the aqueous layer to 2-3 using aqueous hydrochloric acid. Washed the aqueous layer twice with ethyl acetate followed by toluene. 500 ml of 1,4-dioxane was added to the aqueous layer. 57 gm of sodium hydroxide was added to the reaction mixture at 20-25°C. 308 gm of di-tert.butyl dicarbonate was added to the reaction mixture at 20-25°C. Heated the reaction mixture to 30-35°C and stirred for 2 hrs at the same temperature. 84 gm of NaOH was added lot wise to the reaction mixture at to 30-35°C and stirred for 6 hrs at the same the same temperature. After completion of the reaction, washed the reaction mixture with toluene. Dichloromethane was added to the aqueous layer and adjusted the pH of the reaction mixture to 3-4 using aqueous HCl at 0-5°C. Separated the both aqueous and organic layers. Dichloromethane was added to the aqueous layer and the pH of the reaction mixture was adjusted to 2-3 using aq.HCl solution. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and distilled off the solvent completely from organic layer under reduced pressure and co- distilled with pet ether. 600 ml of pet ether was added to the obtained compound under nitrogen atmosphere and stirred the reaction mixture for 1 hr at 30-35°C. Filtered the precipitated solid, washed with pet ether and dried to get the title compound.

The PXRD of the obtained compound is shown in figure-4.

Yield: 54.0 gm; M.R: 114-116°C. Example-25: Preparation of tert-butyl (3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan- 3-yl carbamate (FormuIa-29a)

15 ml of triethyl amine was added to the mixture of (S)-benzyl-l-chloro-2-oxohexan-3-yl carbamate compound of formula-35a (300 gm) and ethyl acetate (3000 ml). To this reaction mixture added sulfuryl chloride (607.5 gm) lot wise at 40-45°C and stirred the reaction mixture for 40 hrs. Cooled the reaction mixture to less than 10°C. The reaction mixture was added to the precooled water (600 ml) at 5-10°C. Adjusting the pH of the reaction mixture to 3-4 slowly by adding aqueous sodium hydroxide solution at 5-10°C. Separated the both aqueous and organic layers and the aqueous layer was extracted with ethyl acetate (1200 ml) at 25-30°C. Combined the total organic layer and washed with water (600 ml). Distilled off the solvent completely under reduced pressure. To the obtained residue toluene (2700 ml) was added and stirred for 15 min at 25-30°C. Aqueous sodium hydroxide solution (210 gm of NaOH in 2700 ml of water) was added to the reaction mixture at 25-30°C and heated the reaction mixture to 40-45°C. Stirred the reaction mixture for 8 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and separated the both organic and aqueous layers. Adjusted the pH of the aqueous layer to 2-3 using aqueous hydrochloric acid. Washed the aqueous layer twice with ethyl acetate (2x600 ml) and followed by washed with toluene (600 ml). 750 ml of 1,4-dioxane was added to the aqueous layer. 84 gm of sodium hydroxide was added to the reaction mixture at 20-25°C. 460 gm of BOC anhydride was added to the reaction mixture at 20-25 °C and heated the reaction mixture to 30-35°C and stirred for 2 hrs at the same temperature. 126 gm of NaOH was added lot wise to the reaction mixture and stirred the reaction mixture for 6 hrs at 30-35°C. Washed the reaction mixture thrice with toluene. Dichloromethane (900 ml) was added to the aqueous layer and adjusted the pH of the reaction mixture to 3-4 using aqueous HC1 at 0-5°C. Separated the both aqueous and organic layers and aqueous layer was extracted twice with dichloromethane (2x600 ml). Combined the total organic layer and distilled off the solvent completely from organic layer. 900 ml of ethyl acetate and 90 ml of water were added to the obtained compound and cooled the reaction mixture to 0-5°C. 49 gm of HOBt and 83.7 gm of EDC HC1 were added to the reaction mixture at 0-5°C. 29 gm of cyclopropyl amine was added to the reaction mixture at 0-5°C and stirred the reaction mixture for 2 hrs at the same temperature. 450 ml of ethyl acetate was added to the reaction mixture. 5% aqueous sodium bicarbonate solution (13.5 gm in 270 ml) was added to the reaction mixture. Heated the reaction mixture to 40-45°C and stirred for 15 min. Separated the both aqueous and organic layers. Repeated the above sodium bicarbonate washings twice and finally washed with aqueous sodium chloride solution (4.5 gm in 90 ml). Treated the organic layer with 30 gm of activated carbon. Distilled off the solvent completely from the organic layer and co-distilled with pet ether (45 ml). 450 ml of pet ether was added to the obtained compound and stirred the reaction mixture for 2 hrs at 25-30°C. Filtered the precipitated solid and washed with pet ether. Dried the material to get the title compound. The PXRD of the obtained compound is shown in figure-8. Yield: 66 gm; MR: 164-168°C.

Example-26: Preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride (FormuIa-6a) Ethyl acetate-HCl (500 ml) was added to a mixture of tert-butyl (3S)-l-(cyclopropyl amino)-2-hydroxy-l-oxohexan-3-yl carbamate compound of formula-29a (100 gm) and ethyl acetate (500 ml) at 25-30°C. Stirred the reaction mixture for 8 hrs at the same temperature. Filtered the precipitated solid and washed with ethyl acetate (200 ml). Dried the material to get the title compound. The PXRD of the obtained compound is shown in figure- 11.

Yield: 71.0 gm; MR: 200-203 °C.

Example-27: Preparation of (lS,3aR,6aS)-ethyl 2-((S)-2-((S)-2-cycIohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l- carboxylate (Formula-4)

( 1 S,3 aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole- 1 -carboxylate hydrochloride compound of formula-3a (1.75 gm) was added to a mixture of sodium bicarbonate (0.85 gm) and water (2.5 ml) at 25-30°C and stirred for 30 min at the same temperature. Dichloromethane (25 ml) was added to the reaction mixture at 25-30°C and stirred 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 (2.5 gm) was added to the organic layer at 25-30°C. Cooled the reaction mixture to 0-5°C, 1-hydroxybenotriazole (0.45 gm) and a solution of N,N- dicyclohexylcarbodiimide (1.5 gm) in dichloromethane (10 ml) were added. 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 dichloromethane, sodium bicarbonate solution followed by conc.HCl solution. Water was added to the filtrate at 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated, distilled off the solvent completely from the organic layer to get the title compound.

Example-28: Preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cycIohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocycIopenta[c]pyrrole-l- carboxylic acid (FormuIa-5)

Acetone (15 ml) was added to (lS,3aR,6aS)-ethyl 2-((S)-2-((S)-2-cyclohexyl-2-

(pyrazine-2-carboxamido)acetamido)-3 ,3 -dimethylbutanoyl)octahydrocyclopenta[c]pyrrole- 1 - carboxylate compound of formula-4 obtained in example-27 at 25-30°C and stirred for 10 min at the same temperature. Cooled the reaction mixture to 10-15°C and lithium hydroxide solution (0.42 gm of lithium hydroxide hydrate in 15 ml of water) was slowly added. 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. Cooled the reaction mixture to 10-15°C and the pH of the reaction mixture was adjusted to 2-3 using conc.HCl solution. Stirred the reaction mixture for 20 min at 10-15°C and both the organic and aqueous layers were separated. Extracted the aqueous layer with dichloromethane and the combined organic layer was washed with water. Distilled off the solvent completely form the organic layer. Toluene was added to the reaction mixture at 35-40°C, heated the reaction mixture to 70-75°C and stirred for 90 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 6 hrs at the same temperature. Filtered the obtained solid, washed with methyl tert.butyl ether and dried to get the title compound. Yield: 2.2 gm.

Example-29: 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-30)

Octahydrocyclopenta[c]pyrrole-l-carbonitrile hydrochloride compound of formula- 17a (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 Ν,Ν-dicyclohexylcarbodiimide solution (15.04 gm of N,N-dicyclohexyl carbodiimide in 100 ml of dichloromethane) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°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 25-30°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-30: Preparation of ethyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate

(Formula-31a)

Thionyl chloride (14.3 gm) was slowly added to a pre-cooled mixture of N-((lS)-2-((2S)- 1 -( 1 -cyanohexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-3,3-dimethyl- 1 -oxobutan-2-ylamino)- 1 - cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-30 (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 25-30°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-31: Preparation of 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrroIe-l-carboxylic acid (Formula-32)

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-31a (5 gm) at 25-30°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-32: Preparation of 2-((S)-2-((S)-2-cyclohexyI-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyI)octahydrocycIopenta [c] pyrrole-l-carboxylic acid (Formula-32)

N-((l S)-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-30 (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-33: 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-32 (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.

Exariiple-34: Preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cycIohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l- carboxylic acid (Formula-5)

Water (100 ml) was added to (R)-a-aminoethylbenzene salt of (l S,3aR,6aS)-2-((S)-2- ((S)-2-cyclohexyl-2-(pyrazme-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydro cyclopenta[c]pyrrole-l-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.

The PXRD of the obtained compound is shown in figure-6.

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

Example-35: 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-5)

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-32 (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 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-36: Preparation of (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethyIbutanoyl)-N-((3S)-l-(cycIopropylamino)-2-hydroxy- l-oxohexan-3-yl)octahy drocyclopenta [c] pyrrole- 1-carboxamide (F or muIa-7)

1-hydroxybenzotriazole (13.2 gm) and (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide hydrochloride compound of formula-6a (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-l -carboxylic acid compound of formula-5 (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 25-30°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. The PXRD pattern of the obtained compound is shown in figure-7.

Yield: 120.0 gm; M.R: 113-118°C; Purity by HPLC: 94.84%. Example-37: Preparation of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cydohexyI-2-[(pyrazin-2-yl carbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l-(cyclopropyIamino)-l,2- dioxohexan-3-yI]-3,3a,4,5,6,6a-hexahydro-lH-cycIopenta[c]pyrroIe-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-((3 S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3 -yl) octahydrocyclopenta[c]pyrrole-l-carboxamide compound of formula-7 (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%; SOR: -48.0° (C=l%, CHC1₃). Particle size distribution: D(0.1) is 4.24 μη , D(0.5) is 44.69 μηι and D(0.9) is 95.97 μηι.

Example-38: Purification of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-yI carbonyI)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

(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-[(pvrazin- 2-yl carbonyl)amino]acetyl} amino)-3,3-dimethylbutanoyl]-N-[(3 S)- 1 -(cyclopropylamino)- 1 ,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 μιη, D(0.5) is 38.80 μπι and D(0.9) is 66.98 μπι.

Example-39: 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- dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrroIe-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- [(3 S)- 1 -(cyclopropyl amino) -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.

The PXRD of the obtained compound is shown in figure-5.

Yield: 82.0 gm; Purity by HPLC: 99.90%; Hydroxy impurity (compound of formula-7): 0.01%; Metabolite impurity ((R)-diastereomer): 0.05%.

Particle size distribution: D(0.1) is 10.83 μπι, D(0.5) is 64.65 μπι and D(0.9) is 151.23 μιη.

Particle size distribution (after pulverization): D(0.1) is 1.37 μπι, D(0.5) is 6.60 μιη and D(0.9) is 21.62 μιη.

Claims

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-[(3S)-l-(cyclopropyl amino)- 1 ,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro- 1 H-cyclopenta[c]pyrrole- 1 - carboxamide compound of formula- 1, comprising of;

a) Reacting the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoic acid compound of formula-2

Formula-2

with octahydrocyclopenta[c]pyrrole- -carbonitrile compound of formula- 17

Formula- 17

or its acid-addition salt in presence of a suitable coupling 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(lH)-yl)-3,3-dimethyl-l-oxobutan-2-ylamino)-l-cyclohexyl-2-oxo ethyl)pyrazine-2-carboxamide compound of formula-30,

Formula-30

b) converting the compound of formula-30 to its corresponding alkyl ester compound of general formula-31 by re presence of a suitable catalyst,

Formula-31

wherein, 'R' represents Q-C6 straight chain or branched chain alkyl group; c) hydrolyzing the compound of general formula-31 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)octahydro cyclopenta[c]pyrrole-l-carboxylic acid compound of formula-32,

Formula-32

d) separating the diastereomers from compound of formula-32 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- 5,

Formula-5

e) reacting the compound of formula-5 with (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide compound of formula-6

Formula-6

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

Formula-7

f) oxidizing the compound of formula-7 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.

A process according to claim 1, wherein,

in step-a) and step-e) the suitable coupling agent is selected from N,N'-dicyclohexyl carbodiimide (DCC), Ν,Ν'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (EDC.HC1), Ν,Ν-carbonyldiimidazole (CDI), substituted or unsubstituted alkyl or aryl haloformates, thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, benzotriazol-l-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP) and alkyl or aryl sulfonyl halides optionally in combination with l-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), l-hydroxy-lH-1,2,3- triazole-4-carboxylate (HOCt), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyl uranium tetrafluoroborate (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 acetyl chloride, thionyl chloride, dry HC1 gas, tr (Ci-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 oxidation step is carried out optionally in presence of a suitable co-catalyst such as sodium bromide, potassium bromide, sodium acetate, potassium acetate, ammonium acetate;

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.

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 -(cyclopropyl amino)-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) Reacting 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- 17a

Formula- 17a

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-30, b) converting the compound of formula-30 to ethyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine- 2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l- carboxylate compound of formula-31a by reacting it with ethanol in presence of thionyl chloride,

Formula-31a

c) hydrolyzing the compound of formula-31a in presence of aqueous lithium hydroxide in acetone to provide 2-((S)-2-((S)-2-cyclohexyI-2-(pyrazine-2-carboxamido)acetamido)- 3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-32,

d) separating the diastereomers from compound of formula-32 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 (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-5,

e) reacting the compound of formula-5 with (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide hydrochloride salt compound of formula-6a in presence of N,N-dicyclohexyl carbodiimide/l-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-l-carboxamide compound of formula-7, f) oxidizing the compound of formula-7 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. 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-5, comprising of;

a) Reacting 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- 17 or its acid-addition salt in presence of a suitable coupling agent in a suitable solvent optionally in presence of a suitable base to provide N-(( 1 S)-2-((2 S)- 1 -( 1 -cyanohexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-3 ,3-dimethyl- 1 -oxo butan-2-ylamino)-l-cyclohexyl-2-oxoethyl)pyrazine-2-carboxamide compound of formula-30,

b) hydrolyzing the compound of formula-30 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-32,

c) separating the diastereomers from compound of formula-32 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)octahydrocyclopenta[c]pyrroIe-l -carboxylic acid compound of formula-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-5, comprising of;

a) Reacting 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- 17a 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-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-30, b) hydrolyzing the compound of formula-30 in presence of conc.HCl to provide 2-((S)-2- ((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octa hydrocyclopenta[c]pyrrole-l-carboxylic acid compound of formula-32,

c) separating the diastereomers from compound of formula-32 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 (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-5.

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-31, comprising of reacting the 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-30 with Ci-C₆ straight chain or branched chain alcohol in presence of a suitable catalyst to provide compound of general formula-31.

The process according to claim 6, wherein suitable catalyst is selected from acetyl chloride, thionyl chloride, dry HC1 gas, tri(C C₆ straight chain or branched chain alkyl)silyl halides.

A process for the preparation of ethyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3 ,3 -dimethylbutanoyl)octahydrocyclopenta[c]pyrrole- 1 -carboxylate compound of general formula-31a, comprising of reacting the 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-30 with ethanol in presence of thionyl chloride to provide compound of formula-31 a.

9. 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-32, comprising of hydrolyzing the N-((lS)-2-((2S)-l-(l-cyano hexahydrocyclopenta[c]pyrrol-2(lH)-yl)-3, 3 -dimethyl- l-oxobutan-2-ylamino)-l -eye lohexyl- 2-oxoethyl)pyrazine-2-carboxamide compound of formula-30 to provide compound of formula-32.

10. Compound having the structural formula

its stereo isomers and pharmaceutically acceptable salts.

11. 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-5, comprising of separating the diastereomers from 2-((S)-2-((S)- 2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclo penta[c]pyrrole-l -carboxylic acid compound of formula-32 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-5.

12. The process according to claim 11, wherein the suitable base is selected from inorganic bases, chiral organic amines such as (R)-a-aminoethylbenzene, (S)-a-aminoethylbenzene, (S)-l,2,3,4-tetrahydro-l-naphthylamine, (R)-l,2,3,4-tetrahydro-l-naphthyl amine, quinine, cinchonine, (lS,2R)-(+)-norephedrine, 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; the suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, organic acids such as formic acid, acetic acid, oxalic acid.

13. 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-5, comprising of separating the diastereomers from 2-((S)-2-((S)- 2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclo penta[c]pyrrole-l -carboxylic acid compound of formula-32 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 with hydrochloric acid to provide compound of formula-5. 14. (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 having the structural formula

15. An improved process for the preparation of (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetic acid compound of formula- 10,

Formula- 10

comprising of reacting the pyrazine-2-carboxylic acid compound of formula-8

Formula-8

with (S)-2-amino-2-cyclohexylacetic acid compound of formula-9

in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid compound of formula- 10.

16. A process according to claim 11, wherein the suitable coupling agent is selected from Ν,Ν'- dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropyl carbodiimide (DIC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), Ν,Ν-carbonyl diimidazole (CDI), alkyl or aryl chloroformates such as ethyl chloroformate, benzyl chloroformate, diphenylphosphoroazidate (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride optionally in combination with l-hydroxy-7-azatriazole (HO At), 1- hydroxybenzotriazole (HOBt), 1 -hydroxy- lH-1, 2,3 -triazole-4-carboxylate (HOCt), O- (benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxy succinimide (HOSu), N-hydroxy sulfosuccinimide (Sulfo-NHS); the suitable base is selected from organic or inorganic bases; the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents or their mixtures. 17. An improved process for the preparation of (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetic acid compound of formula- 10, comprising of reacting the pyrazine-2-carboxylic acid compound of formula-8 with (S)-2-amino-2-cyclohexylacetic acid compound of formula-9 in presence of Ν,Ν-carbonyldiimidazole (CDI), triethylamine and trimethylsilyl chloride in tetrahydrofuran to provide (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid compound of formula- 10.

18. A process for the preparation of (S)-tert-butyl l-oxopentan-2-ylcarbamate compound of formula-24, BocHN-

H

Formula-24

comprising of reducing the (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxo pentan-2- ylcarbamate compound of formula-23

Formula-23

with vitride in a suitable solvent to provide (S)-tert-butyl l-oxopentan-2-ylcarbamate compound of formula-24.

19. A process according to claim 18, wherein the suitable solvent is selected from hydrocarbon solvents, ester solvents, ether solvents, alcohol solvents, ketone solvents or their mixtures.

20. A process for the preparation of (S)-tert-butyl l-oxopentan-2-ylcarbamate compound of formula-24, comprising of reducing the (S)-tert-butyl l-(methoxy(methyI)amino)-l-oxo pentan-2-ylcarbamate compound of formula-23 with vitride in toluene to provide (S)-tert- butyl l-oxopentan-2-ylcarbamate compound of formula-24.

21. A process for the preparation of (3S)-alkyl 3-amino-2-hydroxyhexanoate hydrochloride salt compound of general formula-26,

Formula-26

comprising of reacting the tert-butyl (2S)-l-cyano-l-hydroxypentan-2-ylcarbamate compound of formula-25

Formula-25

with a suitable alcohol in presence of acetyl chloride or thionyl chloride or tri(Ci-C₆ straight chain or branched chain alkyl)silyl halides such as trimethylsilyl chloride to provide of (3S)- alkyl 3-amino-2-hydroxyhexanoate hydrochloride salt compound of general formula-26.

22. A process according to claim 21, wherein the suitable alcohol is of the general formula R-OH in which the group 'R' represents Ci-C₆ straight chain or branched chain alkyl groups.

23. A process for the preparation of (3S)-methyl 3-amino-2-hydroxyhexanoate hydrochloride salt compound of formula-26a,

Formula-26a

comprising of reacting the tert-butyl (2 S)-l-cyano-l -hydroxy pentan-2-ylcarbamate compound of formula-25 with methanol in presence of trimethylsilyl chloride to provide (3S)-methyl 3-amino-2-hydroxyhexanoate hydrochloride salt compound of formula-26a.

24. A process for the preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of fo of;

Formula-6a

a) Reacting the tert-butyl (2S)-l-cyano-l-hydroxypentan-2-ylcarbamate compound of formula-25 with a suitable alcohol in presence of acetyl chloride or thionyl chloride or tri(C!-C6 straight chain or branched chain alkyl)silyl halides such as trimethylsilyl chloride to provide (3S)-alkyl 3-amino-2-hydroxy hexanoate hydrochloride salt compound of general formula-26,

b) reacting the compound of general formula-26 with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide (3S)-alkyl 3-(tert-butoxy carbonylamino)- 2-hydroxy hexanoate compound of general formula-27,

Formula-27

c) hydrolyzing the compound of general formula-27 in presence of a suitable base to provide (3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanoic acid of formuIa-28a,

Formula-28a

d) reacting the compound of formula-28a with cyclopropyl amine in presence of a suitable coupling agent in a suitable solvent optionally in presence of a suitable base to provide tert-butyl (3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-ylcarbamate compound of formula-29a,

Formula-29a

e) treating the compound of formula-29a with a suitable boc-deprotecting agent in a suitable solvent to provide (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanarnide hydrochloride salt compound of formula-6a.

25. A process according to claim 24, wherein

in step-a) the suitable alcohol is of the general formula R-OH in which the group 'R' represents Ci-C^ straight chain or branched chain alkyl groups;

in step-b) the suitable base is selected from inorganic bases and the suitable solvent is selected from chloro solvents, ether solvents, polar solvents, hydrocarbon solvents or their mixtures;

in step-c) the suitable base is inorganic base; the suitable solvent is selected from ether solvents, polar solvents, ester solvents, hydrocarbon solvents, ketone solvents or their mixtures;

in step-d) the suitable coupling agent is selected from but not limited to Ν,Ν'- dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), N,N-carbonyldiimidazole (CDI), alkyl or aryl chloroformates such as ethyl chloroformate, benzyl chloroformate, thionyl chloride, oxalyl chloride, benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluoro phosphate (PyBOP), methane sulfonyl chloride optionally in combination with 1- hydroxy-7-azatriazole (HO At), 1-hydroxybenzotriazole (HOBt), O-(benzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxy succinimide (HOSu); the suitable base is selected from organic or inorganic bases; the suitable solvent, is selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, polar solvents or their mixtures;

in step-e) the suitable boc-deprotecting agent is selected from ethyl acetate-HCl, isopropyl alcohol-HCl, acetyl chloride, ethanol-HCl, methanol-HCl; the suitable solvent is selected from ketone solvents, ether solvents, polar solvents, ester solvents, hydrocarbon solvents, alcoholic solvents or mixtures thereof.

26. A process for the preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of formula-6a, comprising of;

a) Reacting the tert-butyl (2S)-l-cyano-l-hydroxypentan-2-ylcarbamate compound of formula-25 with methanol in presence of trimethylsilyl chloride to provide (3S)-methyl 3-amino-2-hydroxy hexanoate hydrochloride salt compound of formula-26a, b) reacting the compound of formula-26a with di-tert.butyl dicarbonate in presence of aq.potassium carbonate in tetrahydrofuran to provide (3S)-methyl 3-(tert-butoxy carbonylamino)-2-hydroxy hexanoate compound of formula-27a,

Formula-27a

d) reacting the compound of formula-28a with cyclopropyl amine in presence of l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1)/1 -hydroxybenzotriazole (HOBt) in a mixture of ethyl acetate and water to provide tert-butyl (3 S)-l -(cyclopropyl amino)-2-hydroxy-l-oxohexan-3-ylcarbamate compound of formula-29a,

e) treating the compound of formula-29a with ethyl acetate- HC1 in acetone to provide (3S)- 3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride compound of formula-6a. A process for the preparation of (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2- ylcarbonyl)amino] acetyl} amino)-3,3-dimethyl butanoyl]-N-[(3S)- 1 -(cyclopropylamino)- 1 ,2- dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxarnide compound of formula- 1, comprising of;

a) Reacting the (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoic acid compound of formula-2 with (lS,3aR,6aS)-ethyl octahydro cyclopenta[c]pyrrole- 1 -carboxylate hydrochloride compound of formula-3a

Formula-3a

in presence of Ν,Ν'-dicyclohexylcarbodiimide (DCC)/1 -hydroxybenzotriazole (HOBt) in presence of sodium bicarbonate in dichloromethane to provide (!S,3aR,6aS)-ethyl 2-((S)- 2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl) octahydro cyclopenta[c]pyrrole-l-carboxylate compound of formula-4,

Formula-4

b) hydrolyzing the compound of formula-4 in presence of aq.LiOH in acetone to provide (lS,3aR,6aS)-2-((S)-2-((S)-2_^cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid of formula-5, c) reacting the compound of formula-5 with (3S)-3-amino-N-cyclopropyl-2-hydroxy hexanamide hydrochloride salt compound of formula-6a in presence of Ν,Ν'- dicyclohexylcarbodiimide (DCC)/l-hydroxybenzotriazole (HOBt) and diisopropylethyl amine in dichloromethane to provide (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2- (pyrazine-2-carboxarnido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-l-(cyclopropyl amino)-2-hydroxy- 1 -oxohexan-3-yl)octahydrocyclopenta[c]pyrrole- 1 -carboxamide compound of formula-7,

d) oxidizing the compound of formula-7 with sodium hypochlorite/TEMPO in presence of sodium bicarbonate and potassium bromide in a mixture of dichloromethane and water to provide compound of formula- 1,

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

28. Crystalline form-M of (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoic acid compound of formula-2, characterized by;

a) its powder X-ray diffraction pattern having peaks at 5.5, 7.3, 10.7, 14.7, 16.7, 17.3, 17.5, 17.8, 18.3, 19.2, 20.7, 21.4, 22.04, 22.21 & 24.7 ± 0.2 degrees of 2-theta, and

b) its powder X-ray diffraction pattern substantially in accordance with figure- 1 ,

c) its DSC endotherm substantially in accordance with figure-2.

29. A process for the preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of formula-6a, comprising of; a) Reacting the (S)-2-aminopentanoic acid compound of formula-21

Formula-21

with benzyl chloroformate in presence of aq.sodium hydroxide in 1,4-dioxane to provide (S)-2-(benzyloxycarbonylamino)pentanoic acid compound of formula-22b,

O

CbzHNv

OH

Formula-22b

c) reacting the compound of formula-33a with sodium monochloro acetate compound of formula-34a

O

"O Na⁺

Formula-34a

in presence of tert.butyl magnesium chloride and triethylamine in tetrahydrofuran to provide (S)-benzyl l-chloro-2-oxohexan-3-ylcarbamate compound of formula-35a,

O

CbzH L ,C\

Formula-35a d) chlorinating the compound of formula-35a with sulfuryl chloride in presence of triethylamine in ethyl acetate to provide (S)-benzyl l,l-dichloro-2-oxohexan-3- ylcarbamate compound of formula-36a,

Formula-36a

e) treating the compound of formula-36a with aq.sodium hydroxide in toluene to provide

(3S)-3-amino-2-hydroxyhexanoic acid compound of formula-37,

Formula-37

f) reacting the compound of formula-37 with di-tert.butyl dicarbonate in presence of aq.sodium hydroxide in 1,4-dioxane to provide (3S)-3-(tert-butoxycarbonyl amino)-2- hydroxyhexanoic acid compound of formula-28a,

g) reacting the compound of formula-28a with cyclopropyl amine in presence of l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole (EDC.HCl/HOBt) in a mixture of ethyl acetate and water to provide tert-butyl (3S)-1- (cyclopropylamino)-2-hydroxy-l-oxohexan-3-ylcarbamate compound of formula-29a, h) deprotecting the compound of formula-29a by treating it with ethyl acetate-HCl in ethyl acetate to provide (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of formula-6a. A process for the preparation of (S)-benzyl-l-chloro-2-oxohexan-3-yl carbamate compound of formula-35a, comprising of;

a) esterifying the compound of formula-22b with methanol in presence of thionyl chloride in toluene to provide (S)-methyl 2-(benzyloxycarbonylamino)pentanoate compound of formula-33a,

b) reacting the compound of formula-33a in-situ with sodium monochloroacetate compound of formula-34a in presence of t-butyl magnesium chloride and triethylamine in tetrahedrofuran followed by decarboxylation to provide (S)-benzyl-l-chloro-2-oxohexan- 3-yl carbamate compound of formula-35a.

31. A process for the preparation of (3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanoic acid compound of formula-28a, comprising of;

a) Chlorinating the compound of formula-35a with sulfuryl chloride in presence of triethyl amine in ethyl acetate to provide (S)-benzyl l,l-dichloro-2-oxohexan-3-ylcarbamate compound of formula-36a,

b) treating the compound of formula-36a in-situ with aqueous sodium hydroxide in toluene to provide β-amino-a- hydro y carboxylic acid compound of formula-37,

c) reacting the compound of formula-37 in-situ with di-tert-butyl dicarbonate (Boc anhydride) in presence of aqueous sodium hydroxide in 1,4-dioxane to provide (3S)-3- (tert-butoxycarbonylamino)-2-hydroxyhexanoic acid compound of formula-28a. 32. A process for the preparation of tert-butyl (3S)-l-(cyclopropylamino)-2-hydroxy-l- oxohexan-3-yl carbamate compound of formuIa-29a, comprising of reacting the (3S)-3-(tert- butoxycarbonylamino)-2-hydroxyhexanoic acid compound of formula-28a with cyclopropyl amine in presence of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HC1) and 1 -hydroxy benzotriazole in a mixture of ethyl acetate and water to provide tert-butyl (3 S)-l-(cyclopropylamino)-2 -hydroxy- l-oxohexan-3-yl carbamate compound of formula-29a.

33. Solid state form of (S)-benzyl-l-chloro-2-oxohexan-3-yl carbamate compound of formula-35 a.

34. A compound as claimed in claim 33, characterized by;

a) its powder X-ray diffraction pattern having peaks at 6.7, 8.4, 10.1, 12.6, 16.7, 18.3, 20.0, 22.2, 22.7, 24.0, 26.7, 28.1, 31.0, 32.6 and 35.6 ± 0.2 degrees of 2-theta, and

b) its powder X-ray diffraction pattern substantially in accordance with figure-3.

35. Solid state form of (3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanoic acid compound of formula-28a.

36. A compound as claimed in claim 35, characterized by;

a) its powder X-ray diffraction pattern having peaks at 6.6, 10.9, 13.3, 18.8, 21.9 and 26.9 ± 0.2 degrees of 2-theta, and

b) its powder X-ray diffraction pattern substantially in accordance with figure-4.

37. Amorphous ( 1 S,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)octahydro cyclopenta[c]pyrrole- 1 -carboxamide.

38. Crystalline form-N_t of tert-butyl (3S)-l-(cyclopropylamino)-2-hydro y-l-oxohexan-3- ylcarbamate compound of formula-29a, characterized by;

a) its powder X-ray diffraction pattern having peaks at 4.7, 5.4, 6.8, 9.4, 10.2, 1 1.0, 15.6, 20.0, 21.2, 24.3, 26.1, 33.2 ± 0.2 degrees of 2-theta, and

b) its powder X-ray diffraction pattern substantially in accordance with figure-8.

39. Crystalline form-N₂ of tert-butyl (3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl carbamate compound of formula-29a, characterized by;

a) its powder X-ray diffraction pattern having peaks at 4.9, 5.4, 8.0, 8.7, 10.8, 14.1, 14.8, 16.2, 18.7, 19.9, 21.2, 23.7, 27.5, 35.4, 38.2, 46.7 ± 0.2 degrees of 2-theta, and

b) its powder X-ray diffraction pattern substantially in accordance with figure-9.

40. Crystalline form-R._! of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of formula-6a, characterized by;

a) its powder X-ray diffraction pattern having peaks at 6.4, 7.7, 10.2, 1 1.4, 1 1.8, 15.5, 16.0, 18.4, 20.8, 22.2, 23.8, 24.5, 25.9, 27.5, 31.2, 33.9, 37.0, 39.4 ± 0.2 degrees of 2-theta, and b) its powder X-ray diffraction pattern substantially in accordance with figure- 10.

41. Crystalline form-R₂ of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride salt compound of formula-6a, characterized by;

a) its powder X-ray diffraction pattern having peaks at 6.4, 9.5, 1 1.8, 16.3, 17.4, 20.0, 21.1,

21.4, 22.3, 23.8, 24.5, 27.4, 27.9, 30.6, 31.6, 33.0, 35.1, 37.0 ± 0.2 degrees of 2-theta, and b) its powder X-ray diffraction pattern substantially in accordance with figure- 11.

42. Use of amorphous (lS,3a ,6aS)-2-((S)-2-((S)-2rcyclohexyl-2-(pyrazine-2-carboxamido) acetamido) 3,3-dimethylbutanoyl)-N-((3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3- yl)octahydro cyclopenta[c]pyrrole-l-carboxamide in the preparation of Telaprevir.

43. Use of 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 compound of formula-30 in the preparation of Telaprevir.

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