FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of (15)-2-((5)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid derivative of formula (I) wherein, R is hydrogen or C1.C4 alkyl.

The compound of formula (I) is the key intermediate in the preparation of Telaprevir of formula II.

BACKGROUND OF THE INVENTION

Telaprevir is chemically known as (15,3a/?,6aS)-2-[(25)-2-({(25)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-Ar-[(3S)-l-(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-1 -carboxamide.

Telaprevir is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. Telaprevir has been approved in combination with Peginterferon alfa and Ribavirin, for the treatment of genotype 1 chronic hepatitis C (CHC), and has been marketed under the brand name Incivek®.

US 7,820,671 disclosed Telaprevir or its pharmaceutically acceptable salts thereof.

According to US '671, the process for the preparation of Telaprevir (II) involves, the condensation of L-cyclohexylglycine methyl ester of formula (III) with pyrazine-2-carboxylic acid of formula (IV) to produce (S)-methyl 2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoate of formula (V), followed by hydrolysis to produce corresponding acid of formula (VI). Compound (VI) is further condensed with 3-azabicyclo[3.3.0]octane-2-carboxylic, methyl ester of formula (VII) to produce (15',3a/?,6a5)-ethyl-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)-acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate of formula (la), followed by hydrolysis to produce corresponding acid of formula (lb), which is further condensed with (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide of formula (VIII) to produce hydroxy Telaprevir of formula (IX). Compound of formula (XI) is oxidized to produce Telaprevir of formula (II). The process is as shown in Scheme-I below:

US 7,776,887 discloses a process for the preparation of Telaprevir (II), by condensation of (lS,3aR,6aS)-t-butyl2-((S)-2-amino-3,3-dimethylbutanoyl)octahydro-cyclopenta[c] pyrrole-1-carboxylate of formula (X) with N-protected (S)-2-amino-2-cyclohexylacetic acid of formula (XI) in presence of a coupling agent to produce N- protected (15,3ai?,6a5)-t-butyl2-((S)-2-((S)-2-amino-2-cyclohexylacetamido)-3,3-dimethyl
butanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylate of formula (XII), followed by deprotection to produce a compound of formula (XIII). Compound (XIII) is condensed with pyrazine-2-carboxylic acid of formula (IV) in presence of a coupling agent to produce (15,3ai?,6aS)-t-butyl2-((5)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate of formula (XIV), followed by hydrolysis to produce compound of formula (lb). Compound (lb) is condensed with (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide of formula (VIII) in presence of a coupling agent to produce hydroxy Telaprevir of formula (IX), followed by oxidation to produce Telaprevir of formula (II). The process is as shown in Scheme-II below:

The major disadvantage of above processes is that the above processes involve large number of steps for the manufacture of Telaprevir of formula (II). In the chemical synthesis, the number of steps is not advisable for the commercialization of the product. The number of steps is more in a chemical process means the lowering of the overall yield and the time cycle of the production is more. This does not make the suitable chemical process.

However, there is always a need for an alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.

Hence, there is a need to develop cost effective and commercially viable process for the preparation of Telaprevir of formula (II).

The present invention is specifically directed towards a simple and cost effective process for the preparation of (15)-2-((5)-2-((5)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3 -dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1 -carboxylic acid derivative of formula (I) with pharmaceutically acceptable limit, which in turn used as such in the preparation of Telaprevir of formula (II).
OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and cost-effective process for the preparation of Telaprevir of formula (II) with high purity on commercial scale.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the preparation of (15,3ai?,6a5)-2-((5)-2-((5)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid derivative of formula (I), wherein, R is hydrogen or C1.C4 alkyl, which comprises:

(i) condensing (lS,3ai?,6aS)-alkyl-2-((5)-2-amino-3,3-dimethylbutanoyl) octahydrocyclopenta[c]pyrrole-l-carboxylate of formula (XV),

with (5)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid of formula (XVI), (ii) isolating the compound of formula (I), (iii) converting the compound of formula (I) to Telaprevir of formula (II).

In another embodiment, the present invention provides a process for the preparation of (15,3a/?,6aS)-alkyl-2-((iS)-2-amino-3,3-dimethylbutanoyl)octahydrocyclopenta [c]pyrrole-l-carboxylate of formula (XV), which comprises: . (i) condensing N-Boc tert-L-leucine of formula (XVII), wherein, R is C1-C4 alkyl, to produce N-Boc(15,3ai?,6a5,)-alkyl-2-((5)-2-amino-3,3-dimethylbutanoyl)-
octahydrocyclopenta [c]pyrrole-l-carboxylate of formula (XIX), (n) de-protecting compound of formula (XIX) to produce compound ot formula (XV).

The process comprises, condensing (l£3ai^6aS)-alkyl-2-((S)-2-amino-3,3-
dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (XV) with (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid of formula (XVI) to produce (15)-2-((iS)-2-((5)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl) octahydrocyclopenta[c] pyrrole-1-carboxylic acid derivative (I).

This condensation reaction is carried out in presence of a coupling agent selected from
DCC (dicyclohexylcarbodiimide), VIC (diisopropylcarbodiimide), di-p-toluoylcarbodiimide, BDP (1 -benzotriazolediethylphosphate-1 -cyclohexyl-3 -(2-morpholinylethyl)carbodiimide), EDC (1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochioride), cyanuric fluoride, cyanuric chloride, TFFH
(tetramethylfluoroformamidiniumhexafluorophosphosphate), DPPA (diphenylphosphorazidate), BOP(benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate), HBTU (O-benzotriazol-1 -yl-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazol-1 -yl-N,N,N',N'-tetramethyluronium tetrafluoroborate), TSTU (0(N-succinimidyl)-N,N,N' ,N'-tetramethyluronium tetrafluoroborate), HATU (N-[(dimethylamino)-1 -H-1,2,3-triazolo[4,5,6]-pyridin-1 -ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide), BOPC1 (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), PyBOP ((l-H-l,2,3-benzotriazol-l-yloxy)-tris(pyrrolidino)phosphonium tetrafluorophopsphate), BrOP (bromotris(dimethylamino) phosphonium hexafluorophosphate), DEPBT (3-10(diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one), or PyBrOP (bromotris(pyrrolidino)phosphonium hexafluorophosphate) and the like.

This condensation step is also carried out in presence of a base and in a solvent. The base used is selected from triethylamine, di-iso-propylethylamine, N-methylmorpholine, 4-dimethylaminopyridine (DMAP), 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) N-methylimidazole and the like. The solvent used is selected from dimethyl sulfoxide (DMSO), JV.Af-dimethylformamide (DMF), JV.N-dimethylacetamide (DMA), Af-methyl-2-pyrrolidone (NMT), methylene dichloride, ethylene dichloride, chloroform or mixtures thereof.

This condensation step is carried out at a temperature of 0°C to 35°C for a time period of 12-24 hrs. After completion of the reaction (15)-2-((5)-2-((5)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]-pyrrole-1-carboxylic acid derivative (I) is isolated by conventional methods such as by removing the solvent under reduced pressure and the residue is dissolved in a solvent selected from ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, eathers such as ethyl acetate isopropyl acetate, ketones such as acetone, alcohols such as methanol, ethanol, isopropanol, N,#-dimethylformamide (DMF), acetonitrile, JV,#-dimethyl sulfoxide (DMSO) or water or mixtures thereof, and washing the resulting solution with aqueous base, followed by removal of solvent.

The isolated compound (I) is subjected to purification either by column chromatography or by crystallization.

The process further comprises, hydrolysis of the compound (I), when R is CM alkyl is carried out using a base selected from alkali or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide magnesium hydroxide, zinc hydroxide, an alkali metal hydrogencarbonates, such as sodium hydrogencarbonate or potassium hydrogencarbonate; alakali metal hydrides such as sodium hydride, potassium hydride and the like or mixture thereof to produce (liS)-2-((5)-2-((5)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1 -carboxylic acid (lb).

The reaction is carried out in a solvent selected from tetrahydrofuran (THF) ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile, dimethyl sulfoxide (DMSO) or mixture thereof; at a temperature of 2Q-30°C for a time period of 2-5 hrs. Compound (la) obtained by this process is isolated by conventional methods such as by removing the solvent under reduced pressure and the residue is dissolved in a solvent selected from ethers such as diethyl ether, THF, dioxane, eathers such as ethyl acetate isopropyl acetate, ketones such as acetone, alcohols such as methanol, ethanol, isopropanol, DMF, acetonitrile, DMSO or water or mixtures thereof, and washing the resulting solution with aqueous base, followed by removal of solvent.

The compound (lb) is isolated as a solid or as such used in next step. Optionally, Compound (lb) is subjected to purification either by column chromatography or by crystallization.

Compound of formula (lb) is converted to Telaprevir (II) by condensing with (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide of formula (VIII) to produce hydroxy Telaprevir of formula (IX) using a coupling agent in presence of a base in a solvent.

The coupling agent and the base used in this reaction is same as defined above and the reaction is carried out at a temperature of 0 to 75°C for a time period of 12-1 4 hrs. After completion of the reaction, Compound (IX) is isolated by conventional methods such as by removing the solvent under reduced pressure and the residue is dissolved in a solvent selected from ethers such as diethyl ether, THF, dioxane, eathers such as ethyl acetate isopropyl acetate, ketones such as acetone, alcohols such as methanol, ethanol, isopropanol, DMF, acetonitrile, DMSO or water or mixtures thereof, and washing the resulting solution with aqueous base, followed by removal of solvent.

Hydroxy Telaprevir of formula (IX) is oxidized using an oxidizing agent selected from sodium hypochlorite, chromic acid, chromium trioxide, pyridinium chlorochromate (PCC), potassium dichromate, oxalyl chloride, Dess-Martin periodinane (1,1-dihydro-l,l,l-triacetoxy-l,2-benzoiodooxol-3(lH)-one) (DMP) to produce Telaprevir of formula (II).

The reaction is carried out at a temperature of 25-55°C for a time period of 1-5 hrs. The reaction mixture was stirred at room temperature for about 30 min. After completion of the reaction, Telaprevir (II) is isolated by conventional methods such as by removing the solvent under reduced pressure and the residue is dissolved in a solvent selected from ethers such as diethyl ether, THF, dioxane, eaters such as ethyl acetate isopropyl acetate, ketones such as acetone, alcohols such as methanol, ethanol, isopropanol, DMF, acetonitrile, DMSO or water or mixtures thereof, and washing the resulting solution with aqueous base, followed by removal of the solvent. Telaprevir (II) is subjected to purification either by column chromatography or by crystallization.

In another embodiment, the present invention provides a process for the preparation of (15',3a/?,6aS)-Alkyl-2-((5)-2-amino-3,3-imethylbutanoyl)octahydrocyclopenta[c]-pyrrole-1-carboxylate (XV).

The process comprises, condensing N-Boc tert-I-leucine (XVII) with 3-azabicyclo (3.3.0)octane-2-carboxylic acid alkyl ester (XVIII) using a coupling agent in presence of a base in a solvent to produce a Compound of Formula (XIX).

The coupling agent and the base used in this reaction is same as defined above and the reaction is carried out at a temperature of 0 to 75°C for a time period of 12-1 4 hrs. After completion of the reaction, Compound (XIX) is isolated by conventional methods such as by removing the solvent under reduced pressure and the residue is dissolved in a solvent selected from ethers such as diethyl ether, THF, dioxane, eathers such as ethyl acetate isopropyl acetate, ketones such as acetone, alcohols such as methanol, ethanol, isopropanol, DMF, acetonitrile, DMSO or water or mixtures thereof, and washing the resulting solution with aqueous base, followed by removal of solvent.

The compound (XIX) is isolated as a solid or as such used in next step. Optionally, Compound (XDQ is subjected to purification either by column chromatography or by crystallization.

De-protection of compound (XIX) is carried out in the presence of an acid selected from organic acids such as formic acid, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid, or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid or mixture threof; in presence of a solvent selected from ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol, a halogenated hydrocarbon, such as methylene chloride, a chloroform; or mixtures of to produce (lS,3afl,6aS)-Alkyl-2-((S)-2-amino-3,3-imethylbutanoyl)- octahydrocyclopenta[c]pyrrole-1 -carboxylate (XV).

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE;

A process for the preparation of Telaprevir:

Step-I: Process for the preparation of methyl (lRJaS,6aM)-2-((R)-2-((tert-butoxycarbonyl)amino-33-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (XlXa):

A solution of N-Boc tert-L-leucine (XVIIa) (lmole.eq, 10 g) in 800 mL dry MDC and 600 mL dry DMF were stirred at 0°C and treated with HATU (1.3 mol.eq, 24 g). The 3-azabicyclo (3.3.0)octane-2-carboxylic acid methyl ester hydrochloride (XVIIIa) (1 mol. eq, 8.9 g) in MDC ( 80 mL) was added dropwise, and then NMM (3.5 mol.eq, 18.5 mL) was added. The mixture was gradually warmed to room temperature and stirred for overnight. All the volatiles removed under reduced pressure and the residue was dissolved in 2 litres of diethyl ether. The organic layer was washed with aqueous IN HC1 (250 mL), aquoues saturated NaHC03, water (250 mL) and brine (250 mL). The organic layer was dried over MgS04 and concentrated under reduced pressure. The residue was purified on silicagel column chromatography, resulted the product (XlXa) 13.8 gin72%yield.

Step-II: Process for the preparation of methyl (l/?3a5,6aif)-2-((/?)-2-amino-3,3-dimethylbutanoyI)octahydrocyclopenta[c]pyrro!e-l-carboxylate(XVa):

A solution of compound (XV)(1 mol.eq, 8.6 g) in 600 mL dry MDC and 250 mL dry DMF were stirred at 0°C and treated with HATU (1.3 mol.eq, 16.2 g). The compound (XVa) (1 mol. Eq, 9.2 g) in MDC (80 mL) was added dropwise and then NMM (3.5 mol.eq, 12.5 mL) was added. The mixture was gradually warmed to room temperature and stirred for overnight. All the volatiles were removed under reduced pressure and the residue was dissolved in 1.5 litres of diethyl ether. The organic layer was washed with aqueous IN HC1 (250 mL), aquoues saturated NaHC03, water (250 mL) and brine (250 mL). The organic layer was dried over MgS04 and concentrated under reduced pressure. The residue was purified on silicagel column chromatography, resulted compound (Ic), 12.8 g in 71% yield.

Step-IV; Process for the preparation of (15,5a^,da5)-2-((S)-2-((5)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-33-dimethylbutanoyI)octahydrocyclopenta [c]pyrrole-l-carboxylic acid (lb):
Lithium hydroxide mono hydrate (2.5mol.eq, 2.5g) was added to a solution of compound (Ic) (1 mol.eq, 12.5g) in 450 mL of THF: H20: MeOH (1:1:1) solution. The reaction mixture was stirred at room temperature for about 3 h until no more starting material was detected by TLC analysis. The mixture was concentrated under reduced pressure and the residue was partitioned between MDC (600 mL) and aqueous IN HC1 (20 mL). The aqueous layer was back extracted with MDC (2X150 mL). The combined organic layer was dried over MgSO-j, filtered and concentrated under reduced pressure. The obtained residue not required further purification for resulted compound (lb), 12.8 g in 71% yield.

Step-V; Process for the preparation of W-(if/S)-l-cyclohexyI-2-(((2S)-l-((lS,Ja/?,6aS)-l-(N-(2-(cyclopropylamino)-l-hydroxy-2-oxoxethyl)-N-propylglycyl)hexahydro cyclopenta[c]pyrrol-2(l//)-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-2-oxoethyl)pyrazine-2-carboxamide(IX)

A solution of compound (lb) (1 mol.eq, 11.2 g) in 800 mL dry MDC and 600 mL dry DMF were stirred at 0°C and treated with HATU (1.3 mol.eq, 10.4 g). The compound (VIII) (1 mol. eq, 9.2 g) in MDC ( 80 mL) was added dropwise and then NMM (3.5 mol.eq, 8.2 mL) was added. The mixture was gradually warmed to room temperature and stirred overnight. All the volatiles removed under reduced pressure and the residue was dissolved in 1.5 litres of diethyl ether. The organic layer was washed with aqueous IN HC1 (200 mL), aquoues saturated NaHC03, water (200 mL) and brine (200 mL). The organic layer was dried over MgSC>4 and concentrated under reduced pressure. The residue was purified on silicagel column chromatography, resulted compound (IX), 11.3 gin 71% yield.

Step-VI; Process for the preparation of Telaprevir (II)

A solution of compound (IX) (1 mol.eq, 11.3 g) in 200 mL of dry MDC was treated •with DMP (2 mol.eq, 13.8 g). The reaction mixture was stirred at room temperature for about 30 min. The reaction mixture was treated with 1M sodium thiosulphate solution (200mL) and stirred for 5 min. Aqueous saturated NaHCC>3 solution (300 mL) was also added and stirring was continued for further 20 min. The mixture was extracted with MDC (3X200mL). The combined organic layer was dried over MgSC>4 and concentrated under reduced pressure. The residue was purified by silicagel column chromatography gives Telaprevir (II), 9.5 g in 85% yield.

WE CLAIM:

1. A process for the preparation of (lS)-2-((5)-2-((5)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl) octahydrocyclopenta[c]pyrrole-1 -carboxylic acid derivative of formula (I), wherein, R is hydrogen or C1.C4 alkyl, which comprises: (i) condensing(lS,3ai?,6aS)-alkyl-2-((5)-2-amino-3,3-dimethylbutanoyl) octahydrocyclopenta[c]pyrrole-l-carboxylate of formula (XV), with (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid of formula (XVI), (ii) isolating the compound of formula (I), (iii) converting the compound of formula (I) to Telaprevir of formula (II).

2. The process according to claim 1, wherein the condensation reaction in step-(i) is carried out in presence of a coupling agent.

3. The process according to claim 2, wherein the coupling agent comprises DCC (dicyclohexylcarbodiimide), DIG (diisopropylcarbodiimide), di-p-toluoylcarbodiimide, BDP (1 -benzotriazolediethylphosphate-1 -cyclohexyl-3 -(2-morpholinylethyl)carbodiimide), EDC (1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochioride), cyanuric fluoride, cyanuric chloride, TFFH (tetramethylfluoroformamidiniumhexafluorophosphosphate), DPPA (diphenyl phosphorazidate), BOP (benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorophosphate), HBTU (O-benzotriazol-1 -yl-N,N,N^N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazol-1 -yl-N,N,N\N'-tetramethyluronium tetrafluoroborate), TSTU (0(N-succinimidyl)-N,N,N',N*-tetramethyluronium tetrafluoroborate), HATU (N-[(dimethylamino)-1 -H-1,2,3-triazolo[4,5,6]-pyridin-1 -ylmethylene]-N-methylmethanaminium hexafluoro phosphateN-oxide), BOPC1 (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), PyBOP ((1-H-1,2,3-benzotriazol-1-yloxy)-tris(pyrrolidino)phosphoniumtetrafluoro phopsphate), BrOP (bromotris (dimethylamino)phosphoniumhexafluorophosphate), DEPBT (3-10(diethoxy phosphoryloxy)-l,2,3-benzotriazin-4(3H)-one), or PyBrOP (bromotris(pyrrolidino) phosphonium hexafluorophosphate) and the like.

4. The process according to claim 1, wherein the condensation step-(i) is carried out in presence of a base and in a solvent.

5. The process according to claim 4, wherein the base comprises triethylamine, di-iso- ropylethylamine, N-methylmorpholine, 4-Dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec7-ene (DBU), l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO) N-methylimidazole or mixture thereof.

6. The process according to claim 4, wherein the solvent comprises dimethyl sulfoxide (DMSO), AA-dimethylformamide (DMF), Jv",JV-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMT), methylene dichloride, ethylene dichloride, chloroform or mixtures thereof.

7. A process for the preparation of (15,3a/?,6aS)-alkyl-2-((5)-2-amino-3,3-dimethylbutanoyl)octahydrocyclopenta [c]pyrrole-l-carboxylate of formula (XV), which comprises:
(i) condensing N-Boc tert-L-leucine of formula (XVII),

with 3-azabicyclo (3.3.0)octane-2-carboxylic acid alkyl ester of formula (XVIII) or a salt, wherein, R is C1.C4 alkyl, to produce N-Boc (lS,,3a/?,6a5)-alkyl-2-((5)-2-amino-3,3-dimethylbutanoyl)-
octahydrocyclopenta[c]pyrrole-l-carboxylate of formula (XIX), (ii) de-protecting the compound of formula (XIX) to produce compound of formula (XV).

8. The process according to claim 7, wherein the condensation step-(i) is carried out in presence of a coupling agent and a base.

9. The process according to claim 8, wherein the coupling agent and the base used in this reaction is same as defined above.

10. The process according to claim 7, wherein the de-protection of compound (XIX) is carried out in the presence of an acid comprises organic acids such as formic acid, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid, or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid or mixture thereof; in presence of a solvent comprises ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol, a halogenated hydrocarbon, such as methylene chloride, chloroform or mixtures thereof.