Field of the Invention:

The present invention relates to a process and intermediates for the preparation of (lR,5S)-N-[3-amino-l-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(l,l-di methylethyl)amino] carbonyl] amino] -3,3 -dimethyl-1 -oxobutyl] -6,6-dimethyl-3 -aza bicyclo[3.1.0]hexan-2(S)-carboxamide which is represented by the following structural formula-1.

(lR,5S)-N-[3-amino-l-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(l,l-dimethylethyl) amino] carbonyl] amino]-3,3 -dimethyl-1 -oxobutyl] -6,6-dimethyl-3 -azabicyclo[3.1.0]hexan-2(S)-carboxamide is commonly known as "Boceprevir". It is a hepatitis C protease inhibitor used in the treatment of hepatitis C and related disorders. Specifically, the compound of formula-1 is an inhibitor of the HCV NS3/NS4a serine protease. It was developed by Schering-plough, but is now being developed by Merck. It was approved by both FDA and EMEA and marketed under the brand name "Victrelis".

Background of the present invention:

Boceprevir as a compound was first reported in USRE43298. Several processes for preparation of Boceprevir were disclosed in USRE43298, US7326795, US7528263 and US8163937.

Boceprevir is useful in the treatment or prevention or amelioration of one or more symptoms of hepatitis.

In view of the importance of Boceprevir, new, novel methods of making such compound is always preferable.

Brief description of the Invention:

The first aspect of the present invention is to provide a process for the preparation of Boceprevir compound of formula-1, which comprises of:

a) Cyanating the 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene compound of formula-2 to provide 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-3, optionally isolating the compound of formula-3 as an acid-addition salt,

b) condensing the compound of formula-3 or its acid-addition salt with (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-4 to provide 1 -tert-butyl-3-((2S)-l -(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5,

c) converting the compound of formula-5 into 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-8,

d) treating the diastereomeric mixture of compound of formula-8 with an organic amine to provide compound of general formula-9, optionally isolating the compound of general formula-9,

e) treating the compound of general formula-9 with an acid to provide (lR,2S,5S)-3-((S)-2-(3-t-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10,

f) condensing the compound of formula-10 with 3-amino-4-cyclobutyl-2-hydroxybutanamide compund of formula-11 or its acid-addition salt to provide (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3 -tert-butylureido)-3,3 -dimethylbutanoyl) -6,6-dimethyl-3 -azabicyclo [3.1.0] hexane-2-carboxamide compound of formula-12,

g) oxidzing the compound of formula-12 to provide compound of formula-1.

The second aspect of the present invention is to provide a process for diastereomeric resolution of 3-((S)-2-(3-tert-butymreido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-8 with chiral amine to provide (lR,2S,5S)-3-((S)-2-(3-t-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10.

The third aspect of the present invention is to provide novel intermediate compounds, which are useful in the synthesis of Boceprevir.

The fourth aspect of the present invention is to provide a process for the preparation of 1 -tert-butyl-3-((2S)-1 -(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5, comprising of:

a) Cyanating the 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene compound of formula-2 in presence of a suitable cyanating agent in a suitable solvent, optionally in presence of acid or a base to provide 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-3, optionally isolating the compound of formula-3 as an acid-addition salt,

b) condensing the compound of formula-3 or its acid-addition salt with (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-4 in presence of a suitable condensing agent in a suitable solvent, optionally in presence of a base and/or a catalyst to provide compound of formula-5.

The fifth aspect of the present invention is to provide a process for the preparation of 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-8, comprises of:

a) Reacting the l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-3-yl)-3,3 -dimethyl- l-oxobutan-2-yl)urea compound of formula-5 with an alcohol in presence of a catalyst to provide alkyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate compound of general formula-6, wherein"alkyl" represents an alkyl group containing 1 to 4 carbon atoms,

b) hydrolyzing the compound of general formula-6 in presence of aqueous acid or aqueous base in a suitable solvent to provide compound of formula-8.

The sixth aspect of the present invention to provide a process for the preparation of (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-
((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide compound of formula-12, which comprises of condensing the (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10 with 3-amino-4- cyclobutyl-2-hydroxybutanamide compound of formula-11 or its acid-addition salt in presence of dicyclohexylcarbodiimide in a suitable solvent, optionally in presence of a base and/or a catalyst to provide compound of formula-12.

Detailed description of the Invention:

The term "suitable solvent" used in the present invention until unless specified is selected from, but not limited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents" such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents" such as toluene, hexane, heptane, pet.ether, benzene, xylene and cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, N-methyl-2-pyrrolidone and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; "nitrile solvents" such as acetonitrile, butyronitrile, isobutyronitrile and the like; polar solvents such as water and also mixtures thereof.

The term "suitable base" used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole and/or mixtures thereof.

The term "acid" wherever necessary is selected from hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid and sulfuric acid.

The term "alkyl" represents aliphatic hydrocarbon group which may be straight or branched. C1-C20 alkyl group means that alkyl group containing 1 to 20 carbon atoms. Few examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.

The term "aryl" represents mono cyclic or multicyclic aromatic ring systems comprising 6 to about 14 carbon atoms. Few examples of aryl include phenyl, substituted phenyl, naphthyl and the like.

The first aspect of the present invention provides a process for the preparation of Boceprevir compound of formula-1, which comprises of
a) Cyanating the 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene compound of formula-2

Formula-2 to provide 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound offormula-3, optionally isolating the compound offormula-3 as an acid-addition salt, b) condensing the compound of formula-3 or its acid-addition salt with (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-4

Formula-4 to provide 1 -tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5,

c) converting the compound of formula-5 into 3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-8,

Formula-8 d) treating the diastereomeric mixture of compound of formula-8 with an organic amine to provide compound of general formula-9, optionally isolating the compound of general formula-9,

Formula-9 e) treating the compound of general formula-9 with an acid to provide (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10,

Formua-10 f) condensing the compound of formula-10 with 3-amino-4-cyclobutyl-2-hydroxybutanamide compund of formula-11

Formula-11 or its acid-addition salt to provide (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3 -((S)-2-(3 -tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of formula-12,

Formula-12 g) oxidizing the compound of formula-12 to provide compound of formula-1.
The first aspect of the present invention is schematically represented as follows: Scheme-I:

The cyanation of compound of formula-2 is carried out in presence of a cyanating agent selected from hydrogen cyanide, acetone cyanohydrin, trimethyl silyl cyanide, metal cyanides of formula MCN (where M=Li, Na, K and the like). The cyanation is optionally carried out in presence of an acid or a base. The acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phophoric acid and the like. The base is selected from inorganic bases such as alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and alkali metal hydroxides, (or) from organic bases selected from triethylamine, diisopropylamine, diisopropyl ethylamine, pyridine, dimethylaminopyridine, morpholine, imidazole, 1-methylimidazole, 1,2,4-triazole, N-methyl morpholine and the like. The acid utilized for the conversion of compound of formula-3 into its acid-addition salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

The condensation of compound of formula-3 or its acid-addition salt with compound of formula-4 is carried out by using a suitable condensing agent selected from alkyl (or) aryl chloroformates such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, isopropenyl chloroformate, phenyl chloroformate, benzyl chloroformate, p-nitrophenyl chloroformate and the like; carbonyldiimidazole (CDI); carbonyl ditriazole; carbodiimides such as dicyclohexylcarbodiimide (DCC), 1 -(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC-hydrochloride), diisopropyl carbodiimide and the like; oxalyl chloride; di phenylphosphoroazidate (DPPA); P2O5; thionyl chloride, methane sulfonyl chloride, benzene sulfonyl chloride, 4-chlorobenzensulfonyl chloride, p-toluene sulfonyl halide; (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy) tripyrrolidino phosphonium hexafluoro phosphate (PyBOP), and 0-(7-azabeiizotriazol-l-yl)-JV,]V,JV'r/V'-tetramethyluronium hexafluoro phosphate (HATU).

Optionally, the condensation reaction includes the addition of catalyst such as 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HOAt), 1-hydroxy-1H-l,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), and (2-(lH-benzotriazol-1-yl) -1,1,3,3-terra methyl uronium tetrafluoro borate (TBTU).

Optionally, the condensation also includes the addition of a base which is selected from inorganic bases such as alkali metal hydroxides, carbonates, and bicarbonates, and organic bases such as triethylamine, diisopropylamine, diisopropyl ethylamine, pyridine, dimethylaminopyridine, morpholine, imidazole, 1-methylimidazole, 1,2,4-triazole, N-methyl morpholine, 2,6-lutidine and the like.

The condensation reaction is carried out at a temperature of -20°C to about 80°C, preferably at 10-50°C, more preferably at 20-35°C for about 3-6 hours or until the reaction is complete. The molar ratio of compound-3 to compound-4 is about 1:1.

The compound of formula-4 of the present invention can be prepared by any of the known methods (or) by the process described in our provisional specification IN4346/CHE/2012.

The conversion of compound of formula-5 into compound of formula-8 can be carried out by the following methods;

i) Hydrolysis of compound of formula-5 in presence of an acid or a base to provide compound of formula-8. The acid includes, but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid. The base is selcted from alkali metal hydroxide, carbonate and bicarbonate.

ii) This method includes two steps. First, conversion of compound of formula-5 into compound of general formula-6

Wherein, R represents C1-C4 alkyl,

with an alcohol in presence of catalyst such as dry HC1 gas, HC1 solution, thionyl chloride, tri alkyl silyl halide such as trimethyl silyl chloride, triethyl silyl chloride, tert-butyl dimethyl silyl chloride and the like, and triaryl silyl halide such as triphenyl silyl chloride and the like. Second, hydrolysis of the obtained compound in presence of an aqueous acid or aqueous base provides compound of formula-8. The base includes MOH, M2C03, MHCO3 (where M= Na, K, and Li). The acid used in the hydrolysis is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and the like.

The diastereomeric mixture of compound of formula-8 is treated with an organic amine to provide compound of general formula-9, wherein the organic amine used may be chiral or achiral. The organic amine is selected from, but not limited to 1,2,3,4- tetrahydronaphthalene-l-amine, 2-phenyl glycinol, (S)-1,2,3,4- tetrahydronaphthalene-1 -amine, (R)-1,2,3,4-tetrahdyronaphthalene-1 -amine, (R)-2-phenyl glycinol, (S)-2-phenyl glycinol and the like. Further the obtained compound of general formula-9 is treated with an acid which is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like to provide compound of formula-10.

The condensation reaction of compound of formula-10 with compound of formula-11 or its acid-addition salt is carried out by the condensation method as described in step-b).

The oxidation of compound of formula-12 is carried out by using a suitable oxidizing agent, which is selected from Dess-martin periodinane (DMP), trichloroisocyanuric acid, pyridinium chlorochromate, potassium dichrormate, manganese dioxide, chromium trioxide, manganese dioxide, pyridinium dichromate, aluminium triisopropoxide in acetone, oxalyl chloride in combination with dimethylsulfoxide and a suitable base; quaternary ammonium salt-TEMPO-oxone, N-chloro succinamide in combination with dimethylsulfide and a suitable base, EDC-dichloroacetic acid.

The above oxidation is carried out by using a catalyst such as TEMPO, 4-methoxy TEMPO and 4-amino TEMPO.

The compound of formula-2 used in the present invention can be prepared by the process represented in teh following scheme. Scheme-II:

In a specific embodiment of the present invention provides a process for the preparation of Boceprevir compound of formula-1, comprises of:

a) Cyanating the 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene compound of formula-2 in presence of acetone cyanohydrin, triethylamine in toluene provides 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-3,

b) condensing the compound of formula-3 in-situ with (S)-2-(3-tert-butylureido)-3,3-dimethyl butanoic acid compound of formula-4 in presence of l-(3-dimethylaminopropyl)-3-ethyl carbodimide hydrochloride (EDC-HC1), 2,6-lutidine in toluene provides l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3- azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1 -oxobutan-2-yl) urea compound of formula-5, c) conversion of compound of formula-5 to 3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3 -azabicyclo [3.1.0]hexane-2-carboxylic acid compound of formula-8, by hydrolyzing the compound of formula-5 with an aqueous hydrochloric acid (or) by reacting the compound of formula-5 with methanol in presence of trimethylsilyl chloride or thionyl chloride, followed by treating with water provides methyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-7,

which is further hydrolyzed in presence of aqueous lithium hydroxide in tetrahydrofuran to provide methyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-aza bicyclo[3.1.0]hexane-2-carboxylate compound of formula-8,

d) treating the diastereomeric mixture of compound of formula-8 with (S)- 1,2,3,4-tetrahydro naphthalene-1 amine in ethyl acetate provides (S)-1,2,3,4- tetrahydronaphthalen-1-amine salt of (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)- 3,3-dimethylbutanoyl)-6,6-dimethyl-3-aza bicyclo[3.1.0] hexane-2- carboxylate compound of formula-9a,

e) treating the compound of formula-9a in-situ with hydrochloric acid to provide (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10,

f) condensing the compound of formula-10 with 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride salt compound of formula-lla in presence of dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBT) and diisopropylethylamine in dichloromethane to provide (lR,2S,5S)-N-(4-amino-1 -cyclobutyl-3 -hydroxy-4-oxobutan-2-yl)-3 -((S)-2-(3-tert-butylureido)-3,3 -dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of formula-12, g) oxidation of compound of formula-12 with Dess-martin periodinane (DMP) in dichloromethane provides Boceprevir compound of formula-1.

The process of the present invention provides the Boceprevir with a purity of 99.3% by HPLC and controls all the impurities to the level which meets ICH requirements.

The second aspect of the present invention provides a process for diastereomeric resolution of 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid compound of formula-8 with chiral amine to provide (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10. Wherein, the suitable chiral amine is selected from (S)-1,2,3,4-tertahydronaphthalene-1 amine, (R)- 1,2,3,4-tertahydronaphthalene-1 amine, (R)-2-phenyl glycinol, (S)-2-phenyl glycinol and the like.

In a specific embodiment, a diastereomeric resolution of (lR,5S)-3-((S)-2-(3-tert-butyl ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-8 with (S)-1,2,3,4-tetrahydronaphthalene-l-amine in .ethyl acetate provides (S)-l,2,3,4-tetrahydronaphthalen-l-amine salt of (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-9a. The obtained compound is in-situ treated with hydrochloric acid to provide compound of formula-10.

The resolution of compound of formula-8 with chiral amine- provides compound of formula-10 having a high purity which meets the requirement of ICH guidelines.

The third aspect of the present invention provides novel intermediate compounds which are useful in the synthesis of Boceprevir. These novel intermediate compounds are represented by the following structural formulas.

and stereo isomers thereof.

The fourth aspect of the present invention provides a process for the preparation of 1 -tert-butyl-3-((2S)-l -(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5, comprising of:

a) Cyanating 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene compound of formula-2 in presence of a suitable cyanating agent in a suitable solvent, optionally in presence of an acid or a base to provide 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-3, optionally isolating the compound of formula-3 as an acid-addition salt,

b) condensing the compound of formula-3 or its acid-addition salt with (S)-2-(3-tert-butyl ureido)-3,3-dimethylbutanoic acid compound of formula-4 in presence of a suitable condensing agent in a suitable solvent, optionally in presence of a base and/or a catalyst to provide compound of formula-5.

Wherein, the suitable cyanating agent and suitable condensing agent are same as defined in the first aspect of teh present invention.

In a specific embodiment, a process for the preparation of l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5, comprising of:

a) Cyanating the 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene compound of formula-2 in presence of acetone cyanohydrin, triethylamine in toluene to provide 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-3,

b) condensing the compound of formula-3 with (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-4 in presence of l-(3-dimethylaminopropyl)-3-ethyl carbodimide hydrochloride (EDC-HC1), 2,6- lutidine in toluene to provide compound of formula-5.

The fifth aspect of the present invention provides a process for the preparation of 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid compound of formula-8, comprises of:

a) Reacting the l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-3-yl)-3,3 -dimethyl- l-oxobutan-2-yl)urea compound of formula-5 with an alcohol in presence of a catalyst to provide alkyl-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate compound of general formula-6, wherein"alkyl" represents an alkyl group containing 1 to 4 carbon atoms,

b) hydrolyzing the compound of general formula-6 in presence of an aqueous acid or aqueous base in a suitable solvent provides compound of formula-8.

Wherein, the catalyst is selected from dry hydrochloric acid gas, hydrochloric acid soution, thionyl chloride, trialkyl silyl halides, triaryl silyl halides. The acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and the like. The base is selected from alkali metal hydroxides, carbonates and bicarbonates.

In a preferred embodiment, a process for the preparation of 3-((S)-2-(3-tert-
butyl ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
carboxylicacid compound of formula-8, comprising of:

a) Reacting 1 -tert-butyl-3-((2S)-1 -(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2ryl)urea compound of formula-5 with methanol in presence of thionyl chloride to provide methyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-7,

b) hydrolyzing the compound of formula-7 in presence of aqueous lithium hydroxide in tetrahydrbfuran provides compound of formula-8.

The sixth aspect of the present invention provides a process for the preparation of (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of formula-12, comprising of condensing the (lR,2S,5S)-3- ((S)-2-(3 -tert-butylureido)-3,3 -dimethylbutanoyl)-6,6-dimethyl-3 -azabicyclo [3.1.0] hexane-2-carboxylic acid compound of formula-10 with 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-11 or its acid-addition salt in presence of dicyclohexylcarbodiimide in a suitable solvent, optionally in presence of a base and/or a catalyst to provide compound of formula-12.

Wherein, the catalyst and base for the above reaction is same as defined in step-b) of the first aspect of the present invention. The suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents and/or mixtures thereof.

In a preferred embodiment, a process for the preparation of (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of formula-12, comprising of condensing the (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10 with 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride compound of formula-lla in presence of dicyclohexyl carbodiimide, 1-hydroxy benzotriazole and diisopropyl ethylamine in dichloromethane provides compound of formula-12.

Boceprevir 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 drying of the product.

The impurtities that are formed & controlled during the synthesis of Boceprevir along with their RRT are mentioned in the following table.

The following are the abbreviations used through out the specification:

TEMPO: 2,2,6,6-Tetramethylpiperidinyloxy; EDC: l-(3-dimethylamino propyl)-3-ethyl carbodimide, HOBT: 1-hydroxybenzotriazole; DCC: dicyclohexyl carbodiimide; DIPEA: Diisoporpylethylamine; DCM: dichloromethane; TBAB: tetrabutyl ammonium bromide; DCM: dichloromethane and MTBE: methyl tert-butyl ether.

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

Examples:

Example-1: Preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile
(Formula-3) 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene compound of fonnula-2 (25 g) in toluene (150 ml) was cooled to 0-5°C and triethylamine (47.0 ml) was added to it at 0-5°C. Acetone cyanohydrin (38.6 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 6 hours at the same temperature. After completion of the reaction, water was added to the reaction mixture and stirred for 10 minutes at 0-5°C. Both the organic and aqueous layers were separated, the aqueous layer was extracted with toluene (25.0 ml). The organic layers were combined and washed with water. This organic layer was dried with sodium sulfate and taken to the next step without isolating the title compound from the recation mixture.

Example-2: Preparation of l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3- azabicyclo [3.1.0] hexan-3-yi)-3,3-dimethyl-l-oxobutan-2-yl)urea (Formula-5)

The organic layer containing 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-3 which is obtained in example-1 was cooled to 0-5°C. (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-4 (40 g) followed by l-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (39.8 g), 2,6-lutidine (40.5 ml) were added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was raised to 30-35°C and stirred for 5 hours at 30-35°C. After completion of the reaction, the reaction mixture was cooled to 0-5°C and treating the reaction mixture with 2N hydrochloric acid followed by 10% sodium bicarbonate and 10% sodium chloride solution. Distilled off the solvent completely from the reaction mixture under reduced pressure to provide title compound as a residue. The obtained compound is purified by column chromatography using cyclohexanerethyl acetate (8:2) to get title compound as a solid. Yield: 30 gms; Melting range: 140-150°C; DIP-MS (APCI +) m/z = 349.4.

Example-3: Preparation of methyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Formula-7)
A mixture of l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo [3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5 (10 g) and methanol (100 ml) was cooled to 0-5°C. Thionyl chloride (12.4 ml) was slowly added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 5 hours. After completion of the reaction, the reaction mixture was cooled to 0-5°C and water was added to it. Both the organic and aqueous layers were separated, organic layer was washed with water and the solvent from the organic layer was distilled off completely to get title compound as a solid. Yield: 10 gms; Melting range: 135-140°C; purity by HPLC: 97.5%.

Example-4: Preparation of 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylicacid(Formula-8) Water (70 ml) followed by lithium hydroxide mono hydrate (1.15 gm) was added to a mixture of methyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylate compound of formula-7 (7 g) and tetrahydrofuran (70 ml) and stirred for 6 hours at 25-30°C. After completion of the reaction, water followed by ethyl acetate was added to the reaction mixture and stirred for 15 minutes. Both the organic and aqueous layers were separated; the aqueous layer was acidified with cone. Hydrochloric acid and then extracted twice with dichloromethane, and then washed with sodium chloride solution. Distilled off the solvent from the organic layer to get the title compound as a solid. Yield: 6.0 gms; purity by HPLC: 50.38%; SRSR isomer impurity: 46.25%.

Example-5: Preparation of 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyI)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid (Formula-8)

A mixture of l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5 (20 g) and conc.hydrochloric acid (160 ml) was stirred for 10 hours at 25-3 0°C. After completion of the reaction, water followed by dichloromethane was added to the reaction mixture. Both the organic and aqueous layers were separated; the organic layer was washed with water and then distilled off the solvent completely to get title compound as a residue. Yield: 19 gms.

Example-6: Preparation of (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-
dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid
(Formula-10) (S)-l,2,3,4-tetrahydronaphthalen-l-amine (23.2 g) was added to a mixture of 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-8 (58 g) and ethyl acetate (290 ml) at 25-30°C and stirred for 30 hours at the same temperature. After completion of the reaction, filtered unwanted isomer as a solid, 2N hydrochloric acid (116 ml) was added to the obtained filtrate at 25-30°C and stirred for 20 minutes. After completion of the reaction, both the organic and aqueous layers were separated and the organic layer was washed with sodium chloride solution. Distilled off the solvent from the organic layer to get title compound as a solid.

Yield: 27 gms; Melting range: 130-150°C; Purity by HPLC: 98.62%; SRSR isomer impurity: 0.02%.

Example-7: Preparation of (S)-l,2,3,4-tetrahydronaphthalen-l-amine salt of (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate(Formula-9a) (S)-l,2,3,4-tetrahydronaphthalen-l-amine (23.2 g) was added to a mixture of 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-8 (58 g) and ethyl acetate (290 ml) at 25-30°C and stirred for 30 hours at the same temperature. After completion of the reaction, filtered unwanted isomer as a solid, distilled off the solvent from the filtrate to get title compound. Yield: 54 gms.

Example-8: Preparation of (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyI)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (Formula-12)

1-Hydroxybenzotriazole (1.83 g) followed by 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride salt compound of formula-1 la (6.24 g) and diisopropylethylamine (5.68 ml) was added to a pre-cooled mixture of (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10 (10 g) and dichloromethane (100 ml) at 0-5°C. A solution of N,N'-dicyclohexylcarbodiimide (6.16 g) in dichloromethane (30 ml) was slowly added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 5 hours. After completion of the reaction, filtered the reaction mixture through hyflow bed and washed the bed with dichloromethane. Further the organic layer was treated with dilute hydrochloric acid followed by sodiumbicarbonate solution and then with sodium chloride solution. Distilled off the solvent from the organic layer to get title compound as a solid. Yield: 13 gms.; Melting range: 125-145°C; Purity by HPLC: 99.10%.

ExampIe-9: Preparation of Boceprevir (Formula-1)

A mixture of (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of formula-12 (10 g) and dichloromethane (200 ml) was cooled to 0-5°C. Dess-martin periodinane (10.56 g) 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 2 hours at 25-30°C. After completion of the reaction, filtered the reaction mixture through hyflow bed and washed the bed with dichloromethane. The filtrate was washed with sodium chloride solution and distilled off the solvent from the organic layer completely under reduced pressure to get title compound as a solid. Yield: 8.8 gms; Melting range: 130-140°C; purity by HPLC: 99.3%.

We claim:

1. A process for the preparation of Boceprevir, comprises of;

a) Cyanating the 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene compound of formula-2 in presence of a suitable cyanating agent, optionally in presence of an acid or a base in a suitable solvent to provide 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-3,

optionally isolating the compound of formula-3 as an acid-addition salt, b) condensing the compound of formula-3 or its acid-addition salt with (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-4

in presence of a suitable condensing agent in a suitable solvent, optionally in presence of a base and/or a catalyst to provide l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo [3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5,

c) reacting the compound of formula-5 with an alcohol in presence of a catalyst
provides compound of general formula-6,

wherein, R represents C1-C4 alkyl group, d) hydrolyzing the compound of general formula-6 with an aqueous base or aqueous acid in a suitable solvent provides compound of formula-8,

e) treating the diastereomeric mixture of compound of formula-8 with an organic amine to provide compound of general formula-9, optionally isolating the compound of general formula-9,

wherein, organic amine represents 1,2,3,4-tetrahydronaphthalene-l-amine, (S)-1,2,3,4-tetrahydronaphthalene-1 -amine and (R)-1,2,3,4-tetrahydro naphthalene-1 -amine, f) treating the compound of general formula-9 with an acid to provide (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10,

g) condensing the compound of formula-10 with 3-amino-4-cyclobutyl-2-hydroxybutanamide compund of formula-11 formula-11 or its acid-addition salt in presence of a suitable condensing agent in a suitable solvent, optionally in presence of a base and/or a catalyst to provide (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide compound of formula-12, h) oxidizing the hydroxyl group of compound of formula-12 with a suitbale oxidizing agent in a suitable solvent, optionally in presence of a catalyst provides Boceprevir.

2. The process acording to claim 1, wherein,

In step-a) the suitable cyanating agent is selected from hydrogen cyanide, acetone cyanohydrin, trimethyl silyl cyanide, metal cyanides of formula MCN (where M=Li, Na, and K); the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phophoric acid; the base is selected from inorganic bases such as alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxide and alkali metal hydroxide,and organic bases such as triethylamine, diisopropylamine, diisopropyl ethylamine, pyridine, dimethylamino pyridine, morpholine, imidazole, 1-methyhmidazole, 1,2,4-triazole, and N-methyl morpholine and 2,6-lutidine; The acid utilized for the conversion of compound of formula-3 into its acid- addition salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid;

In step-b) & step-g) the suitable condensing agent is selected from alkyl (or) aryl chloroformates such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, isopropenyl chloroformate, phenyl chloroformate, benzyl chloroformate, p-nitrophenyl chloroformate and the like; carbonyldiimidazole (CDI); carbonyl ditriazole; carbodiimides such as dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC- hydrochloride), diisopropyl carbodiimide and the like; oxalyl chloride; di phenylphosphoroazidate (DPPA); P2O5; thionyl chloride, methane sulfonyl chloride, benzene sulfonyl chloride, 4-chlorobenzensulfonyl chloride, p-toluene sulfonyl halide; (benzotriazol-1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy) tripyrrolidino phosphonium hexafluoro phosphate (PyBOP), and 0-(7-azaberizotriazol-l-yl)-Ar,Af,iV',JV'-tetramethyluronium hexafluoro phosphate (HATU);

the catalyst is selected from 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HOAt), 1 -hydroxy- 1H-1,2,3 -triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), and (2-(lH-benzotriazol-l-yl) -1,1,3,3-tetra methyl uronium tetrafluoro borate (TBTU); the base is selected from inorganic bases and organic bases.

In step-c) the catalyst is selected from dry Hcl gas, Hcl solution, thionyl chloride, trialkyl silyl halides and triaryl silyl halide;

In step-d) the base includes MOH, M2C03, MHCO3 (where M= Na, K, and Li); the acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid;

In step-e) the organic amine is chiral or achiral and selected from, but not limited to 1,2,3,4-tetrahydronaphthalene-l-amine, (S)-l,2,3,4-tetrahydro naphthalene-1-amine, and (R)-1,2,3,4-tetrahdyronaphthalene-l-amine;

In step-f) the acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid;

In step-h) the suitable oxidizing agent is selected from Dess-martin periodinane (DMP), trichloroisocyanuric acid, pyridinium chlorochromate,. potassium dichrormate, manganese dioxide, chromium trioxide, manganese dioxide, pyridinium dichromate, aluminium triisopropoxide in acetone, oxalyl chloride in combination with dimethylsulfoxide and a suitable base; quaternary ammonium salt-TEMPO-oxone, N-chloro succinamide in combination with dimethylsulfide and a suitable base, EDC-dichloroacetic acid; the catalyst is selected from TEMPO, 4-methoxy TEMPO and 4-amino TEMPO.

3. A process for the preparation of Boceprevir, comprises of:

a) Cyanating the 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene compound of formula-2 in presence of acetone cyanohydrin and triethylamine in toluene provides 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-3,

b) condensing the compound of formula-3 in-situ with (S)-2-(3-tert-butylureido)-3,3-dimethyl butanoic acid compound of formula-4 in presence of l-(3-dimethylaminopropyl)-3-ethyl carbodimide hydrochloride (EDC-HC1) and 2,6-lutidine in toluene to provide l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3 -azabicyclo [3.1.0]hexan-3 -yl)-3,3 -dimethyl-1 -oxobutan-2-yl) urea compound of formula-5,

c) reacting the compound of formula-5 with methanol in presence of thionyl chloride provides methyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-7,

d) hydrolyzing the compound of formula-7 with aqueous lithium hydroxide in tetrahydrofuran to provide compound of formula-8,

e) treating the diastereomeric mixture of compound of formula-8 with (S)-1,2,3,4-tetrahydronaphthalene-l-amine in ethyl acetate provides (S)-1,2,3,4-tetrahydronaphthane-1-amine salt of (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-9a,

f) treating the compound of formula-9a in-situ with hydrochloric acid to provide (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid compound of formula-10,

g) condensing the compound of formula-10 with 3-amino-4-cyclobutyl-2-hydroxy butanamide hydrochloride salt compound of formula-lla in presence of dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBT) and diisopropyl ethylamine in dichloromethane provides (lR,2S,5S)-N-(4-amino-1 -cyclobutyl-3 -hydroxy-4-oxobutan-2-yl)-3 -((S)-2-(3-tert-butylureido)-3,3 -dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of formula-12, h) oxidation of compound of formula-12 with Dess-martin periodinane (DMP) in dichloromethane provides Boceprevir.

4. A process for diastereomeric resolution of 3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid compound of formula-8 with chiral amine selected from (S)-1,2,3,4-tertahydronaphthalene-1 amine, and (R)-l,2,3,4-tertahydronaphthalene-lamine to provide (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10.

5. A compound represented by the sturtural formula and stereoisomers thereof,

6. A process for the preparation of l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo [3.1.0]hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5, comprising of:

a) Cyanating the 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene compound of formula-2 in presence of a suitable cyanating agent in a suitable solvent, optionally in presence of an acid or a base to provide 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-3, optionally isolating the compound of formula-3 as an acid-addition salt,

b) condensing the compound of formula-3 or its acid-addition salt with (S)-2-(3-tert-butyl ureido)-3,3-dimethylbutanoic acid compound of formula-4 in presence of a suitable condensing agent in a suitable solvent, optionally in presence of a base and/or a catalyst to provide compound of formula-5.

7. A compound represented by the structural formula and streoisomers thereof.

8. A process for the preparation of 3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-8, comprises of:

a) Reacting the l-tert-butyl-3-((2S)-l-(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5 with alcohol in presence of catalyst to provide alkyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylate compound of general formula-6, wherein alkyl represents an alkyl group containing 1 to 4 carbon atoms,

b) hydrolyzing the compound of general formula-6 in presence of aqueous acid or aqueous base in a suitable solvent provides compound of formula-8.

9. A process for the preparation of (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy- 4-oxobutan-2-yl)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of formula-12, comprises of condensing the (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-aza bicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-10 with 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-11 or its acid-addition salt in presence of dicyclohexylcarbodiimide and a base in a suitable solvent, optionally in presence of a catalyst provides compound of formula-12.

10. A process for the preparation of 3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-8, comprising of hydrolyzing the l-tert-butyl-3-((2S)-l-(2-cyano-6,6- dimethyl-3-azabicyclo[3.1.0] hexan-3-yl)-3,3-dimethyl-l-oxobutan-2-yl)urea compound of formula-5 in presence of aqueous acid or aqueous base to provide compound of formula- 8.