Field of the Invention:

The present invention relates to an improved processes for the preparation of intermediate
compounds of (lR,5S)-N-[3-amino- l-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(l, 1-dimethylemyl)arnino]carbonyl]amino]-3,3-dimethyl-l-oxobutyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexan-2(S)-carboxamide which is represented by structural formula-A.

formula-A
(lR,5S)-N-[3-amino- l-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(l, 1 -dimethyl ethyl)amino]carbonyl]amino]-3,3-dimethyl-l-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-A is an inhibitor of the HC V 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 Invention:

Boceprevir and its process for preparation was first disclosed in USRE43298.

USRE43298 discloses the process for the preparation of fragment-C, which involves the usage of toxic and costly reagents like BOP, and also involves the chromatographic purification of its intermediate compound.

There is a need for developing an improved process utilizing reagents which less toxic easily available and also develop techniques which can eliminate the tedious methods like Column chromatography. The present invention involves the method of converting the intermediates into their salts so that they can be isolated without using column chromatography and also increase their purity.

Brief description of the Invention:

The first aspect of the present invention is 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-1.

The second aspect of the present invention provides an improved process for the preparation of methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride compound of formula-2a.
The third aspect of the present invention provides an improved process for the preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride salt compound of formula-3a.

The fourth aspect of the present invention provides a crystalline solid of 2-(tert-butoxy carbonylamino)-3-cyclobutylpropanoic acid compound of formula-16 and its process for preparation.

Brief description of the drawings:
Figure-1: Illustrates the PXRD pattern of crystalline form-M of 2-(tert-butoxycarbonyl amino)-
3-cyclobutylpropanoic acid compound of formula-16.

Formula-2: Illustrates the PXRD pattern of Boceprevir compound of formula-A.
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, p6t.ether, benzene, xylene, 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, propionitrile, 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 or mixtures thereof.

The first 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-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of formula-1, which comprises of:
a) Condensing the (lR,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]
hexane-2-carboxylic acid compound of formula-4 with 3-amino-4-cyclobutyl-2-hydroxy butanamide compound of formula-3 or its acid-addition salt in presence of a suitable condensing agent in a suitable solvent, optionally in presence of a base provides (1R,2S,5S)-tert-butyl 2-(4-amino-1 -cyclobutyl-3-hydroxy-4-oxobutan-2-ylcarbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate compound of formula-5,

b) deprotecting the compound of formula-5 with a suitable deprotecting agent in a suitable
solvent provides (1 R,2S,5 S)-N-(4-amino-1 -cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of formula-6, optionally converting it into its acid-addition salt,

c) condensing the compound of formula-6 or its acid-addition salt with (S)-2-(3-tert-
butylureido)-3,3-dimethylbutanoic acid compound of formula-7 in presence of a suitable
condensing agent in a suitable solvent, optionally in presence of a base provides compound
of formula-1.

Wherein,

In step-(a) & step-(c) 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 dicyclohexyl carbodiimide (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, methane sulfonic anhydride, (Benzotriazol-1-yloxy) tris(dimethylamino) phosphoniumhexafluoro phosphate (BOP), (Benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafiuorophosphate (PyBOP), 0-(7-azabenzotriazol-1 -y1-N,N,N,N,-tetramethyluronium hexafluoro phosphate (HATU); optionally in presence of a catalyst such as 1-hydroxy benzotriazole (HOBt), l-hydroxy-7-azatriazole (HO At), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), (2-(lH-benzotriazol-l-yl) -1,1,3,3-tetra methyl uronium tetrafluoro borate (TBTU).
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 two reactants in the condensation reaction is about 1:1.
The base is selected from inorganic bases such as alkali metal carbonates, bicarbonates and hydroxides; and organic bases such as Iriemylamine, diisopropylamine, diisopropyl ethylamine, pyridine, dimethylaminopyridine, morpholine, imidazole, 1-methylimidazole, 1,2,4-triazole, N-methyl morpholine and the like.
In step-(b) the suitable deprotecting agent is selected from hydrochloric acid, trifluoroacetic acid, tetrabutyl ammonium fluoride, formic acid, aqueous phosphoric acid, BF3-etherate, acetic acid, and p-toluene sulfonic acid.
Further, the first aspect of the present invention is represented schematically as follows: Scheme-I:

In an specific embodiment, 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-1, comprises of:
a) Condensing the (lR,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid compound of formula-4 with 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-3 in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC-HC1), 1-hydroxybenzotriazole (HOBT) and diisopropylethylamine in a mixture of dichloromethane and dimethyl formamide provides (lR,2S,5S)-tert-butyl 2-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-ylcarbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-3-carboxylate compound of formula-5,
b) deprotecting of the compound of formula-5 with isopropanolic-hydrochloride in isopropanol provides (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride compound of formula-6a,
c) condensing the compound of formula-6a with (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-7 in presence of 0-(7-azabenzotriazol-l-yi)-N,N,N,N,-tetramethyl uronium hexafluoro phosphate (HATU) and diisopropylethylamine (DIPEA) in acetonitrile provides compound of formula-1.
The compound of formula-4 of the present invention can be prepared by any of the known methods, for example the process disclosed in Journal of organic chemistry, 1999, 64, 330-331.
The compound of formula-7 is commercially available or can be prepared by the process disclosed in JP60-155968 or WO2009039361.
The compound of formula-3 of the present invention can be prepared by the process disclosed in USRE43298.
The second aspect of the present invention provides an improved process for the preparation of methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride compound of formula-2a, comprising of,
a) Chlorinating the 6,6-dimethyl-3 -azabicyclo[3.1 .Ojhexane compound of formula-8 or its acid-addition salt with sodium hypochlorite in toluene provides 3-chloro-6,6-dimethyl-3-azabicyclo [3.1.0]hexane compound of formula-9, the obtained compound in-situ is treated

with sodium methoxide in presence of tetrabutyl ammonium bromide in a mixture of toluene and dichloromethane provides 6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-ene compound of formula-10,
b) reacting the compound of formula-10 in-situ with acetone cyanohydrin in presence of triethyl amine provides 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile compound of formula-11,
c) treating the compound of formula-11 in-situ with ditert-butyldicarbonate provides tert-butyl 2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate compound of formula-12,
d) reacting the compound of formula-12 in-situ with methanol in presence of catalyst such as trimethylsilyl chloride or thionyl chloride provides methyl 6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylate hydrochloride compound of formula-2a.
In a preferred embodiment of the present invention, 6,6-dimethyl-3-azabicyclo[3.1.0] hexane which is starting material is used in the form of its hydrochloride salt compound of formula-8a.
The BOC protection of compound of formula-11 and usage of trimethyl silyl chloride instead of hydrochloric acid enhances the yield and purity of the final compound of formula-2a. The BOC protection of compound of formula-11 also avoids the formation of dimer impurity. The following tables shows the quality and yield improvements through the present invention. Table-1: Yield comparison of compound of formula-2a
Table-2: Yield and purity comparison of compound of formula-2a during conversion of compound of formula-12 to compound of formula-2a.

Formula-2 Formula-12 Formula-11
Formula-2a); HC1 salt
The compound of formula-8 can be prepared by any of the known method (or) by the
process represented in the below scheme.
Scheme-Ill:
Formula-21 Formula-22 Formula-23 £Formula-8a) HC1 salt
The obtained compound of formula-8 can be converted into its acid-addition salt by treating with an acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.
The third aspect of the present invention provides an improved process for the preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride salt compound of formula-3a, which comprises of:

a) Reacting the ethyl 2-(diphenylmethyleneamino)acetate cbmpound of formula-13 or its acid-addition salt with cyclobutylmethylbromide in presence of potassium tert-butoxide in tetrahydrofuran, followed by treating with an aqueous hydrochloric acid to provide ethyl 2-amino-3-cyclobutylpropanoate compound of formula-14,
b) treating the compound of formula-14 in-situ with ditert-butyl dicarbonate in presence of potassium carbonate to provide ethyl 2-(tert-butoxycarbonylamino)-3-cyclobutylpropanoate compound of formula-15,

c) hydrolyzing the compound of formula-15 in-situ in presence of aqueous lithium hydroxide monohydrate provides 2-(tert-butoxycarbonylamino)-3-cyclobutylpropanoic acid compound of formula-16,
d) isolating the compound of formula-16 as a solid using hydrocarbon solvent such as cyclohexane,
e) condensing the 2-(tert-butoxycarbonylamino)-3-cyclobutylpropanoic acid compound of formula-16 with N-methylhydroxylamine hydrochloride in presence of carbonyl diimidazole (CDI) and diisopropyl ethylamine in tetrahydrofuran provides tert-butyl 3-cyclobutyl-l-(methoxy(methyl) amino)- l-oxopropan-2-ylcarbamate compound of formula-17,
f) reducing the compound of formula-17 with vitride in a mixture of toluene and dichloromethane provides tert-butyl l-cyclobutyl-3-oxopropan-2-ylcarbamate compound of formula-18,
g) reacting the compound of formula-18 in-situ with acetone cyanohydrin in presence of triethylamine provides tert-butyl l-cyano-3-cyclobutyl-l-hydroxypropan-2-ylcarbamate compound of formula-19,
h) converting the compound formula-19 to tert-butyl 4-amino-l-cyclobutyl-3-hydroxy-4-oxo butan-2-ylcarbamate compound of formula-20 by treating it with hydrogen peroxide in presence of aqueous sodium hydroxide in dimethylsulfoxide,
i) deprotecting the compound of formula-20 using isopropanolic hydrochloride in isopropanol provides compound of formula-3a.

In the present invention the compound of formula-16 is obtained as a solid, which enhances the purity of the said compound as well as final compound of formula-3a . The purity of compound of formula-3a obtained by the present invention is 99.6%.
The reported literature like USRE43298 discloses the purification of compound of formula-17 by column chromatography using ethyl acetate and hexane. As the chromatographic purification process is tedious and hence not suggestible for commercial purposes. The present invention avoids the chromatographic purification. The compound of formula-17 is purified by using cyclohexane to provide the compound with a purity of 99.9% by HPLC.

USRE43298 disclosed the use of BOP in condensation reaction of compound of formula-16 with N-methyl hydroxylamine. The HMPA bi-product generated when BOP is used in condensation reaction, is carcinogenic and having respiratory toxicity. Hence use of BOP is limited in condensation reaction in large-scale synthesis. Moreover BOP is costly and not suggestible for commercial scale-up.

In a preferred embodiment of the present invention, ethyl 2-(diphenylmethylene amino)acetate compound of formula-13, a starting material is used in the form of its hydrochloride salt of formula-13 a.

The ethyl 2-(diphenylmethyleneamino)acetate hydrochloride compound of formula-13a can be prepared by reacting the ethyl 2-aminoacetate hydrochloride with benzophenone imine in dichloromethane.
Further, the third aspect of the present invention is schematically represented as follows: Scheme-IV:
Formula-19 Formula-20 Formula-3a
The fourth aspect of the present invention provides a crystalline solid 2-(tert-butoxycarbonyl amino)-3-cyclobutylpropanoic acid compound of formula-16. The crystalline solid herein designated as crystalline form-M. The crystalline form-M is characterized by its powder X-ray diffractogram having peaks at 8.05, 13.7, 13.9, 19.5, 20.4 and 21.3± 0.2 theta. Further the PXRD of crystalline form-M is shown in figure-1.

The fourth aspect also provides a process for the preparation of crystalline form-M of 2-(tert-butoxycarbonylamino)-3-cyclobutylpropanoic acid compound of formula-16, comprises of: a) Suspending the 2-(tert-butoxycarbonylamino)-3-cyclobutylpropanoic acid compound of formula-16 in cyclohexane,

b) stirring the reaction mixture at 25-35°C,
c) cooling the reaction mixture to 10-15°C,
d) stirring the reaction mixture,
e) filtering the solid, washing with cyclohexane and then drying the solid to get crystalline form-M of formula-16.

The compounds-1, 2a, and 3a which are prepared by the present invention are useful in the synthesis of (lR,5S)-N-[3-amino-l-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(l,l-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-l-oxobutyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexan-2(S)-carboxamide compound of formula-A.
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.
HPLC method of analysis:
Tert-butyl 3-cyclobutyl-l-(methoxy(methyl)amino)-l-oxopropan-2-ylcarbamate
compound of formula-17 of the present invention is analyzed by HPLC using the following conditions:
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Cosmicsil Aster XDC18, 100 x 4.6 mm, 3um or equivalent; Flow rate: 1.0 ml/min; wavelength: 210 nm; column temperature: 30°C; Injection volume; 10 uL; Run time: 38 minutes; Needle wash: diluent; Elution: Gradient; Mobile phase-A: Buffer; Mobile phase-B: acetonitrile:water (90:10 v/v); Buffer: Weigh accurately about 1.36 g of potassium dihydrogen ortho phosphate and 1.0 g of 1-Octane sulphonic acid sodium salt anhydrous in 1000 ml of milli-Q water and filter through 0.22μ.m nylon membrane filter paper.
3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride compound of formula-3a is analyzed by HPLC using the following conditions:
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Kromasil CI8, 250 x 4.6 mm, 5μm or equivalent; Flow rate: 1.0 ml/min; wavelength: 200 nm; column temperature: 25°C; Injection volume: 20 μL; Run time: 45 minutes; Needle wash: watenmethanol (1:1 v/v); Diluent: Mobile phase; Elution: isocratic;

Mobile phase: Transfer accurately about 0.5 ml of ortho phosphoric acid and 3.0 g of 1-octane sulphonic acid sodium salt anhydrous in 500 ml of milli-Q water and filter through 0.22μm nylon membrane filter paper.
Methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride compound of formula-2a is analyzed by GC using the following conditions:
Apparatus: A gas chromatographic system is to be equipped with FID (Flame Ionization Detector); Column: Elite capillary column or equivalent with length: 30 mts, ID: 0.53 mm, film thickness: 5.0 μm; Injector temperature: 200°C; Split ratio: 1:10; Detector temperature: 260°C (FID); carrier gas: Heliu,m PSI (Helium); Hydrogen flow: 4. ml/min; air flow: 400ml/ min; make up(N2): 30 ml/min; Diluent: methanol; Injection volume: 1.0 μL; Oven programme: The column temperature is to be programmed according to the following steps: initially keep at 180°C for 10 minutes, then rise to 240°C at the rate of 10°C per minute and hold at 240°C for 18 minutes.
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 (lR,2S,5S)-tert-butyl2-(4-amino-l-cyclobutyl-3-hydroxy-4-oxo
butan-2-ylcarbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (Formula-5)
A mixture of (lR,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid compound of formula-4 (6 g), dichloromethane (90 ml) and dimethyformamide (90 ml) was cooled to 0-5°C. 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-3 (4.9 g) followed by 1-hydroxybenzotriazole (4.7 g), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.7 g) and diisopropylethylamine (12.2 ml) were added to the reaction mixture. The temperature of the reaction mixture was raised to 25-30°C and stirred for 6 hours. After completion of the reaction, water followed dichloromethane was added to the reaction mixture. Both the organic and aqueous layers were separated; the organic layer was treated with hydrochloric acid solution followed by sodium bicarbonate solution and sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure to get the title compound. Yield: 8 gms. Example-2: Preparation of (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-

yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (Formula-6a)
Isopropanolic hydrochloride (12 ml) was added to a mixture of the compound of formula-5 (6 g) and isopropanol (30 ml). The reaction mixture was heated to 60-65°C and stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was concentrated to get title compound. Yield: 4. 9 gms.
Example-3: 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 (Formula-1)
(S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-7 (2 g), followed by 0-(7-azabenzotriazol-l-y1)-N,N,N,N,-tetramethyluroniumhexafluorophosphate (3.92 g) and diisopropyl ethylamine (4.5 ml) were added to a mixture of the compound of formula-6a (3 g) and acetonitrile (60 ml) at 25-30°C and stirred for 5 hours. After completion of the reaction, water followed by ethyl acetate were added to the reaction mixture at 25-3 0°C and stirred for 10 minutes. Both the organic and aqueous layers were separated; the organic layer was washed with sodium bicarbonate solution followed by sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get residue. Co-distillation of the obtained residue with cyclohexane to get title compound. Yield: 4.5 gms. Example-4: Preparation of 3-benzyl-6,6-dimethyl-3-azabicycIo[3.1.0]hexane-2,4-dione (Formula-22)
Benzyl amine (229.5 g) was slowly added to a mixture of caronic anhydride compound of formula-21 (250 g) and methyl tert-butyl ether (500 ml) at 25-30°C and stirred for 45 minutes at the same temperature. After completion of the reaction, the solvent from the reaction mixture was distilled off at a temperature below 70°C. Further the reaction mixture was heated to 135-140°C and stirred for 6 hours under distillation mode. The reaction mixture was cooled to 55-60°C and 5% aqueous isopropanol was added to it, further the reaction mixture was cooled to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with isopropanol and then dried to get title compound. Yield: 330 gms; Melting range: 80-90°C. Example-5: Preparation of 3-benzyl-6,6-dimethyl-3-azabicycIo[3.1.0]hexane (Formula-23)
A solution of the compound of formula-22 (200 g) and toluene (600 ml) was added to a mixture of vitride (1133 g) and toluene (800 ml) at 25-30°C over a period of 3 hours and stirred the reaction mixture for 3 hours. After completion of the reaction, the reaction mixture was

cooled to 0-5°C and quenched with a pre-cooled solution of sodium potassium tartarate (424 g) in water (1640 ml) at a temperature below 20°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 60 minutes. Separated the upper organic layer. Toluene (200 ml) was added to the below two layers. Again separated the upper organic layer. The two separated upper organic layers were combined and taken to the next step without isolation. Example-6: Preparation of 6,6-dimethyI-3-azabicyclo[3.1.0]hexane hydrochloride (FormuIa-8a)
Methanol (850 ml) followed by Pd-C (20 g) was added to the organic layer containing the compound of formula-23 obtained in example-5 under nitrogen atmosphere. Hydrogen gas was passed through the reaction mixture with a pressure of 4.0 kg/cm . The reaction mixture was heated to 40-45°C and stirred for 10 hours. After completion of the reaction, the reaction mixture was cooled to 5-10°C, and filtered through hyflow bed. Hydrochloric acid (200 ml) was added to the filtrate at 25-30°C and stirred for 15 minutes. Distilled off the solvent completely from the reaction mixture under reduced pressure. The reaction mixture was co-distilled with methyl tertiary butyl ether. Isopropanol (100 ml) was added to the reaction mixture at 55-60°C and stirred for 15 minutes. The reaction mixture was cooled to 25-30°C, methyl tertiary butyl ether (700 ml) was slowly added to it over a period of 3 hours and stirred for 1 hour at 25-30°C. Filtered the precipitated solid, washed with methyl tert-butyl ether and then dried to get title compound. Yield: 92 gms; Melting range: 147-157°C. Example-7: Preparation of 3-chIoro-6,6-dimethyI-3-azabicycIo[3.1.0]hexane (Formula-9)
Sodium hypochlorite solution (120 ml) was slowly added to a mixture of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride compound of formula-8a (25 g) and toluene (125 ml) at 30-35°C and stirred for 45 minutes at the same temperature. After completion of the reaction, both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene (25 ml). Both the organic layers were combined, washed with 10% sodium thiosulfate followed by sodium chloride solution. This organic layer containing the title product can be used to next step without isolation. ExampIe-8: Preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-ene (Formula-10)
Sodium methoxide (19.0 g) was added to the organic layer obtained in example-7. A solution of tert-butyl ammonium bromide (0.54 g) in dichloromethane (12.5 ml) was added to the reaction mixture at 25-30°C. The temperature of the reaction mixture was raised to 40-45°C and

stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled to 25-3 0°C
and the reaction mixture was quenched with water. Both the organic and aqueous layers were
separated; the aqueous layer was extracted with toluene. Both the organic layers were combined
and washed with water followed by sodium chloride solution. This organic layer containing the
title compound can be used to next step without isolation. Purity by GC: 96.9%
Example-9: Preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile
(Formula-11)
The organic layer containing compound of formula-10 obtained in example-8 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 containing the title compound was taken to the next step without isolation.
Example-10: Preparation of tert-butyl 2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (Formula-12)
Di tert-butyl dicarbonate (37.0 g) was added to the organic layer containing compound of formula-11 obtained in example-9 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, water was added to the reaction mixture. Both the organic and aqueous layers were separated, washed the organic layer with sodium chloride solution and distilled off the solvent from reaction mixture under reduced pressure to provide title compound as a residue. This residue is taken to the next step without isolation. Purity by GC: 83.18%
Example-11: Preparation of methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (Formula-2a)
Trimethyl silyl chloride (198 g) was slowly added to a solution of the compound of formula-12 obtained in example-10 in methanol (540 ml) at 20-25°C. The reaction mixture was heated to 50-55°C and stirred for 12 hours at the same temperature. After completion of the reaction, the mixture was cooled to 15-20°C and stirred for 45 mins. Filtered the unwanted product, washed with methanol. Distilled off the solvent completely from the filtrate and then co-

distilled with methyl tert-butyl ether. Isopropanol (126 ml) was added to the reaction mixture at 50-55°C and stirred for 30 mins. The reaction mixture was cooled to 25-30°C and methyl tert-butyl ether (504 ml) was added to it over a period of 2 hours and stirred for 1 hour at 25-30°C. Filtered the precipitated solid, washed with methyl tert-butyl ether and then dried to get title compound. Yield: 20 gms; Melting range: 145-155°C; Purity by GC: 99.43%; [a]D25 = -0.078° (c=l% in methanol at wave length 589 nm).
Example-12: Preparation of ethyl 2-(diphenylmethyleneamino)acetate hydrochloride (Formula-13)
Glycine ethyl ester hydrochloride (38 g) was added to a mixture of benzophenone imine (50 g) and dichloromethane (38 g) and stirred for 5 hours at 25-30°C. After completion of the reaction, water was added to the reaction mixture and stirred for 20 mins. Both the organic and aqueous layers were separated; the solvent from the organic layer distilled off completely to provide title compound as a residue. The residue was taken to the next step. Example-13: Preparation of ethyl 2-amino-3-cyclobutyl propanoate (Formula-14)
The residue obtained in example-12 was dissolved in tetrahydrofuran (150 ml) by heating to 50°C. Cyclobutylmethyl bromide (37 g) followed by a solution of potassium tert-butoxide (28 g) in tetrahydrofuran (150 ml) was added to the reaction mixture under nitrogen atmosphere at 50-55°C and stirred for 6 hours. The reaction mixture was cooled to 5-10°C, a solution of hydrochloric acid (74 ml) in water (148 ml) was added to it at a temperature below 15°C. The temperature of the reaction mixture was raised to 25-3 0°C and stirred for 7 hours. After completion of the reaction, the reaction mixture containing title compound is taken to the next step.
Example-14: Preparation of ethyl 2-(tert-butoxycarbonylamino)-3-cyclobutylpropanoate (Formula-15)
The reaction mixture obtained in example-13 is cooled to 0-5°C. Potassium carbonate (110 g) was added to the reaction mixture in lot wise at 0-5°C. Ditert-butyl dicarbonate (45.2 g) 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 2 hours. After completion of the reaction, the reaction mixture was taken to the next step without isolation.
Example-15: Preparation of 2-(tert-butoxycarbonylamino)-3-cyclobutylpropanoic acid (Formula-16)

A solution of lithium hydroxide monohydrate (50 g) in water (500 ml) was added to the reaction mixture obtained in example-14 at 25-30°C. The reaction mixture was heated to 60-70°C and stirred for 5 hours. After completion of the reaction, the reaction mixture was cooled to 25-3 0°C. Filtered the reaction mixture to remove the by-products and washed with toluene. The filtrate containing the desired product is stirred for 15 mins and both the organic and aqueous layers were separated. Extracted the product traces from the organic layer to aqueous layer. Both the aqueous layers were combined and dichloromethane was added to it and cooled to 5-10°C. pH of the reaction mixture was adjusted to 3 by using aqueous ortho phosphoric acid solution at 0-5°C and stirred for 15 mins. Both the organic and aqueous layers were separated; the aqueous layer was extracted with dichloromethane. Both the organic layers were combined, washed with sodium chloride solution and distilled off the solvent from the organic layer completely and then co-distilled with cyclohexane. Cyclohexane (150 ml) was added to the obtained compound and the reaction mixture was cooled to 25-30°C and stirred for 15 mins. Further the reaction mixture was again cooled to 10-15°C and stirred for 60 mins. Filtered the precipitated solid, washed with cyclohexane and then dried to get title compound. Yield: 40 gms; Melting range: 103-110°C. PXRD of the obtained compound is illustrated in figure-1.
Example-16: Preparation of tert-butyl 3-cycIobutyl-l-(methoxy(methyl)amino)-l-oxopropan-2-ylcarbamate(Formula-17)
A mixture of carbonyl diimidazole (20 g) and tetrahydrofuran (50 ml) was cooled to 0-5°C. A solution of the compound of formula-16 (25 g) in tetrahydrofuran (50 ml) was added slowly to the reaction mixture at 0-5°C and stirred for 3 hours. N,0-dimethyl hydroxylarnine hydrochloride (16 g) followed by diisopropyl ethylamine (16 g) was added to the reaction mixture at 0-5°C and stirred for 2 hours. After completion of the reaction, water followed by ethyl acetate were added to the reaction mixture and stirred for 15 mins. Both the organic and aqueous layers were separated; the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined and cooled to 0-5°C. The organic layer was washed with hydrochloric acid solution followed by sodium bicarbonate solution. Distilled off the solvent completely from the organic layer and then co-distilled with cyclohexane. The crude compound was cooled to 25-3 0°C and cyclohexane (50 ml) was added to the reaction mixture and stirred for 20 mins. The reaction mixture was cooled to 10-15°C and stirred for 60 mins. Filtered the precipitated solid, washed with cyclohexane and then dried to get title compound Yield: 26 gms;

Melting range: 95-98°C; Purity by HPLC: 99.9%.
Example-17: Preparation of tert-butyl l-cyclobutyl-3-oxopropan-2-ylcarbamate (Formula-
18)
70% Vitride solution (38.0 ml) was slowly added to a pre-cooled mixture of the compound of formula-17 (25 g) and dichloromethane (125 ml) at -5 to 0°C and stirred for 2 hours. A solution of sodium potassium tartarate (35 g) in water (100 ml) was added to the reaction mixture at temperature below 5°C and stirred for 15 mins. Both the organic layers were separated, the aqueous layer was extracted with dichloromethane. Both the organic layers were combined, washed with water followed by sodium chloride solution. This organic layer containing title compound is used to next step without distillation.
Example-18: Preparation of tert-butyl l-cyano-3-cyclobutyl-l-hydroxypropan-2-ylcarbamate (Formula-19)
Triethylamine (10.9 g) was added to the organic layer containing the compound of formula-18 obtained in example-17. Acetone cyanohydrin (12.5 ml) was added to the reaction mixture at 0-5°C and stirred for 10 hours. After completion of the reaction, the reaction mixture was quenched with 10%sodium carbonate solution. Both the organic and aqueous layers were separated, the aqueous layer was extracted with dichloromethane. Both the organic layers were combined, cooled to 0-5°C and washed with 10% hydrochloric acid followed by 10% sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure to provide title compound as a residue. Yield: 20 gms.
Example-19: Preparation of tert-butyl 4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-ylcarbamate (Formula-20)
A solution of sodium hydroxide (0.6 g) in water (10 ml) was added to a mixture of the compound of formula-19 (25 gms) and dimethyl sulfoxide (100 ml) at 25-3 0°C and stirred for 10 minutes. Hydrogen peroxide (15 ml) was slowly added the reaction mixture at 25-30°C and stirred for 3 hours. After completion of the reaction, water was added to the reaction mixture at a temperature below 10°C and stirred for 60 mins. Filtered the precipitated solid, washed with water and then dried to get title compound. Yield: 20 gms; Melting range: 175-180°C; Purity by HPLC: 90.44%.
ExampIe-20: Preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride (Formula-3a)

Isopropanolic hydrochloride (200 ml) was added to a mixture of the compound of formula-20 (100 g) and isopropanol (300 ml) at 25-30°C. The reaction mixture was heated to 55-60°C and stirred for 3 hours. After completion of the reaction, the reaction mixture was cooled to 25-3 0°C and stirred for 1 hour. Filtered the precipitated solid, washed with isopropanol and then dried to get title compound. Yield: 70 gms; Melting range: 200-210°C; Purity by HPLC: 99.4%. Example-21: Preparation of methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyIate hydrochloride (Formula-2a) using trimethylsilyl chloride and with BOC protection
Trimethyl silyl chloride (198 g) was slowly added to a solution of tert-butyl 2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate compound of formula-12 (115 g) in methanol (540 ml) at 20-25°C. The reaction mixture was heated to 50-55°C and stirred for 12 hours at the same temperature. After completion of the reaction, the mixture was cooled to 15-20°C and stirred for 45 mins. Filtered the unwanted product, washed with methanol. Distilled off the solvent completely from the filtrate and then co-distilled with methyl tert-butyl ether. Isopropanol (126 ml) was added to the obtained residue at 50-55°C and stirred for 30 mins. The reaction mixture was cooled to 25-30°C, methyl tert-butyl ether (504 ml) was added to it over a period of 2 hours and stirred for 1 hour. Filtered the precipitated solid, washed with methyl tert-butyl ether and then dried to get title compound.
Yield: 73 gms; % yield: 73.0%; Purity by GC: 99.14%: Melting range: 149-152°C. ExampIe-22: Preparation of methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (Formula-2a) using methanolic hydrochloric acid

A mixture of compound of formula-12 (20 g) and methanolic hydrochloric acid (80 ml) was heated to 50-55°C and stirred for 6 hours. After completion of the reaction, the reaction mixture was cooled to 25-3 0°C and stirred for 45 mins. Filtered the bi product and distilled off the solvent from the filtrate under reduced pressure and then co-distilled with methyl tert-butyl ether. Isopropanol (28 ml) was added to the obtained residue at 50-55°C and stirred for 30 mins at the same temperature. The reaction mixture was cooled to 25-30°C, added methyl tert-butyl ether (112 ml) to it over a period of 2 hours and stirred for 60 mins. Filtered the solid, washed with methyl tert-butyl ether and then dried to get title compound. Yield: 11.6 gms; % yield: 41.66%; Melting range: 136-139°C; Purity by GC: 48.32%. Example-23: Preparation of methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (Formula-2a) without BOC protection Trimethyl silyl chloride (20 g) was added to a solution of the compound of formula-11 (5 g) in methanol (15 ml) at 25-30°C for about 30-45 minutes. The reaction mixture was heated to 50-5 5°C and stirred for 6 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C and stirred for 45 mins. Filtered the bi-product, washed with methanol and distilled off the solvent from the filtrate under reduced pressure and then co-distilled with methyl tert-butyl ether. Isopropanol (7 ml) was added to the obtained residue at 50-55°C and stirred for 30 mins. The reaction mixture was cooled to 25-30°C. Methyl tert-butyl ether (28 ml) was added to the reaction mixture over a period of 2 hours and stirred for 60 mins. Filtered the solid and dried to get title compound. Yield: 1.3 g; Yield: 29.87%; Melting range: 148-152°C. Example-24: Preparation of (lR,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethyl butanoyI)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyIic acid

A mixture of (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid (50 g), (1R,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (49.1 g), 1-hydroxybenzotriazole (5.8 g) and dichloromethane (500 ml) was cooled to 0-5°C. Diisopropylethylamine (45.3 ml) was added to the reaction mixture and stirred for 10 minutes at 0-5°C. A solution of N,N,-Dicyclohexylcarbodiimide (49.2 g) in dichloromethane (150 ml) was added to the reaction mixture. Temperature of the reaction mixture was raised to 25-3 0°C and stirred for 6 hours at the same temperature. After completion of the reaction, filtered the un¬wanted solid and washed the bed with dichloromethane. The filtrate was washed with hydrochloric acid solution followed by sodium bicarbonate solution and sodium chloride solution. Distilled of the solvent from the organic layer to get (lR,2S,5S)-methyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylate as a residue. The temperature of reaction mixture was cooled to 25-3 0°C and the residue was dissolved in tetrahydrofuran (250 ml). A solution of lithium hydroxide monohydrate (14.5 g) and water (250 ml) was added to the reaction mixture 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; dichloromethane was added to the aqueous layer and pH of the reaction mixture was adjusted to below 3 by using dilute hydrochloric acid solution. Both the organic and aqueous layers were separated; the aqueous layer was extracted with dichloromethane. All the organic layers were combined and washed with sodium chloride solution. Distilled off the solvent from the organic layer and then
co-distilled with cyclohexane. The reaction mixture was cooled to 25-30°C, cyclohexane (375 ml) was added to the reaction mixture and stirred for 20 minutes. Filtered the solid and washed with cyclohexnae.

The obtained wet solid was added to a mixture of methyl tertiary butyl ether (250 ml) and cyclohexane (250 ml). The reaction mixture was heated to 65-70°C and stirred for 30 minutes at the same temperature. The reaction mixture was cooled to 10-15°C. Filtered the precipitated solid, washed with cyclohexane and then dried to get title compound as a solid. Yield: 60 gms.

Example-25: Preparation of (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-tert-butyIureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide
1-Hydroxybenzotriazole (1.83 g) followed by 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride salt (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 (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%. Example-26: Preparation of Boceprevir (Formula-A)

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-1 (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. 2-(Tert-butoxycarbonylamino)-3-cyclobutylpropanoic acid as a crystalline solid.

2. A crystalline form-M of 2-(tert-butoxycarbonylamino)-3-cyclobutylpropanoic acid compound of formula-16

Formula-16 characterized by its powder X-ray powder diffractogram having peaks at 8.05, 13.7, 13.9, 19.5, 20.4 and 21.3± 0.2 theta substantially as shown in figure-1.

3. A process for the preparation of crystalline form-M of 2-(tert-butoxycarbonylamino)-3-
cyclobutylpropanoic acid compound of formula-16, comprising of:

a) Suspending the 2-(tert-butoxycarbonylamino)-3-cyclobutylpropanoic acid compound of formula-16 in cyclohexane,

b) stirring the reaction mixture at 25-35°C,

c) cooling the reaction mixture to 10-15°C,

d) stirring the reaction mixture,

e) filtering the solid, washing with cyclohexane and then drying the solid to get crystalline form-M of formula-16.

4. An improved process for the preparation of methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-
2-carboxylate hydrochloride compound of formula-2a,

Formula-2a which comprises of,
a) chlorinating the 6,6-dimethyl-3-azabicyclo[3.1.0]hexane compound of formula-8 or its
acid-addition salt Fourmula-8

with sodium hypochlorite in toluene provides 3-chloro-6,6-dimethyl-3-azabicyclo [3.1.0]hexane compound of formula-9,

Formula-9 the obtained compound in-situ is treated with sodium methoxide in presence of tetrabutyl ammonium bromide in a mixture of toluene and dichloromethane provides 6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-ene compound of formula-10,
Formula-10

b) reacting the compound of formula-10 in-situ with acetone cyanohydrin in presence of
triethyl amine provides 6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carbonitrile
compound of formula-11,
Formula-11

c) treating the compound of formula-11 in-situ with ditert-butyldicarbonate to provide tert-
butyl 2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate compound of
formula-12,

Formula-12
d) reacting the compound of formula-12 in-situ with methanol in presence of catalyst such
as trimethylsilyl chloride or thionyl chloride to provide methyl 6,6-dimethyl-3-azabicyclo
[3.1.0]hexane-2-carboxylate hydrochloride compound of formula-2a.

5. A process for the preparation of (lR,5S)-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride compound of formula-2a, which comprises of reacting the tert-butyl 2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate compound of formula-12 with methanol in presence of trimethylsilyl chloride to provide compound of formula-2a.

6. An improved process for the preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride salt compound of formula-3a, which comprises of:

a) Reacting the ethyl 2-(diphenylmethyleneamino)acetate compound of formula-13 or its
acid-addition salt
Formula-13

with cyclobutylmethylbromide in presence of potassium tert-butoxide in tetrahydrofuran,
followed by treating with an aqueous hydrochloric acid to provide ethyl 2-amino-3-
cyclobutylpropanoate compound of formula-14,

Formula-14
b) treating the compound of formula-14 in-situ with ditert-butyl dicarbonate in presence of potassium carbonate to provide ethyl 2-(tert-butoxycarbonylamino)-3-cyclobutyl propanoate compound of formula-15,

c) hydrolyzing the compound of formula-15 in-situ in presence of aqueous lithium hydroxide monohydrate provides 2-(tert-butoxycarbonylamino)-3-cyclobutyl propanoic acid compound of formula-16,
Formula-16

d) isolating the compound of formula-16 as a solid using hydrocarbon solvent such as
cyclohexane,

e) condensation of 2-(tert-butoxycarbonylamino)-3-cyclobutylpropanoic acid compound of
formula-16 with N-methylhydroxylamine hydrochloride in presence of carbonyl
diimidazole (CDI) and diisopropyl ethylamine in tetrahydrofuran to provide tert-butyl 3-
cyclobutyl-l-(methoxy(methyl) amino)-l-oxopropan-2-ylcarbamate compound of
formula-17,

Formula-17

f) reducing the compound of formula-17 with vitride in a mixture of toluene and
dichloromethane provides tert-butyl l-cyclobutyl-3-oxopropan-2-ylcarbamate compound
of formula-18,

Formula-18

g) reacting the compound of formula-18 in-situ with acetone cyanohydrin in presence of
triethylamine provides tert-butyl l-cyano-3-cyclobutyl-l-hydroxypropan-2-ylcarbamate
compound of formula-19,

Formula-19 h) converting the compound formula-19 to tert-butyl 4-amino-l-cyclobutyl-3-hydroxy-4-oxo butan-2-ylcarbamate compound of formula-20 ormula-20 by treating it with hydrogen peroxide in presence of aqueous sodium hydroxide in dimethylsulfoxide, i) deprotecting the compound of formula-20 using isopropanolic hydrochloride in isopropanol provides compound of formula-3a.

7. 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-1,

Formula-1
comprising of condensation of ((lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-
oxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of
formula-6 or its acid-addition salt

Formula-6 with (S)-2-(3-tert-butylureido)-3,3-dimethyl butanoic acid compound of formula-7

Formula-7
in presence of a suitable condensing agent in a suitable solvent, optionally in presence of a base provides compound of formula-1.

8. 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-aza
bicycle[3.1.0] hexane-2-carboxamide compound of formula-1, comprising of:

a) Condensing the (lR,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid compound of formula-4
Formula-4 with 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-3


Formula-3 or its acid-addition salt in presence of a suitable condensing agent in a suitable solvent, optionally in presence of a base provides (lR,2S,5S)-tert-butyl 2-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-ylcarbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate compound of formula-5,

Formula-5
b) deprotection of the compound of formula-5 with a suitable deprotecting agent in a suitable solvent provides (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compound of formula-6, optionally converting it into its acid-addition salt,

c) condensing the compound of formula-6 or its acid-addition salt with (S)-2-(3-tert-butylureido)-3,3-dimethyl butanoic acid compound of formula-7 in presence of a suitable condensing agent in a suitable solvent, optionally in presence of a base provides compound of formula-1.

9. The process according to claim 8, wherein,
In step-(a) & step-(c) the suitable condensing agent is selected from alkyl (or) aryl chloroformates; carbonyldiimidazole (CDI); carbonyl ditriazole; carbodiimides; oxalyl chloride; di phenylphosphoroazidate (DPPA); P2O5; thionyl chloride, methane sulfonyl . chloride, benzene sulfonyl chloride, methane sulfonic anhydride, (Benzotriazol-1-yloxy)tris(dimethylamino) phosphoniumhexafluoro phosphate (BOP), (Benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), 0-(7-azabenzotriazol-l-yl)-AVVV-tetramethyluronium hexafluoro phosphate (HATU) which can be optionally in presence of a catalyst selected from 1-hydroxy benzotriazole (HOBt), l-hydroxy-7-azatriazole (HOAt), l-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), (2-(lH-benzotriazol-l-yl) -1,1,3,3-tetra methyl uronium tetrafluoro borate (TBTU); the base is selected from inorganic bases or organic bases; and

In step-(b) the suitable deprotecting agent is selected from hydrochloric acid, trifluoroacetic acid, tetrabutyl ammonium fluoride, formic acid, aqueous phosphoric acid, BF3-etherate, acetic acid, andp-toluene sulfonic acid.

10. 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-aza bicyclo[3.1.0] hexane-2-carboxamide compound of formula-1, which comprises of:

a) Condensation of (lR,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid compound of formula-4 with 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-3 in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC-HC1), 1-hydroxybenzo triazole (HOBT) and diisopropylethylamine in a mixture of dichloromethane and dimethyl formamide provides compound of formula-5,

b) deprotection of the compound of formula-5 with isopropanolic-hydrochloride in isopropanol provides compound of formula-6a,

Formula-6a

c) condensation of compound of formula-6a with (S)-2-(3-tert-butylureido)-3,3-
dimethylbutanoic acid compound of formula-7 in presence of 0-(7-azabenzotriazol-l-yl)-
JV,AfJV',Jvt-tetramethyl uronium hexafluoro phosphate (HATU) and diisopropylethylamine
(DIPEA) in acetonitrile to provide compound of formula-1.