Field of the Invention:

The present invention relates to an improved process for the preparation 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 represented by the structural formula-1.

The present invention also provides a novel process for the preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide represented by the structural formula-2 or its acid-addition salts, which are useful intermediates in the synthesis of compound of formula-1.

Background of the Invention:

(lR,5S)-N-[3-amino-l-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(l,l-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 protease inhibitor used in the treatment of hepatitis C. 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".

Boceprevir and its process for preparation were first disclosed in US7012066. The disclosed process involves condensation of compound [A] with compound [B] using (Benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) in presence of N-methylmorpholine (NMM) to provide compound [C], which is deprotected using hydrochloric acid and followed by treating with tert-butylisocyanate to provide compound [D].

The compound [D] is again condensed with compound [E] using l-Ethyl-3-(3-dimethylamino propyl)carbodiimide (EDCI) in presence of Hydroxybenzotriazole (HOBT) and NMM, followed by oxidation provides Boceprevir.

The prior art process for the preparation of Boceprevir is schematically represented as follows:

All the prior art processes for the formation of amide bond involves the usage of coupling agents like EDCI and BOP which are expensive and makes the process uneconomical.

The above problem is solved by the present invention by carrying out the process using simple reagents.

3-amino-4-cyclobutyl-2-hydroxybutanamide is an useful intermediate in the synthesis of Boceprevir. US7012066 disclosed a process for preparation of said intermediate. The disclosed process involves the condensation of tert-butyl l-cyclobutyl-3-oxopropan-2-ylcarbamate with acetone cynohydrin to provide tert-butyl 1 -cyano-3-cyclobutyl-l -hydroxy propan-2-ylcarbamate, which is further hydrolyzed with hydrochloric acid in methanol to provide methyl 3-amino-4-cyclobutyl-2-hydroxybutanoate hydrochloride and then protected with BOC-anhydride, followed by ester hydrolysis with lithium hydroxide and then treated with ammonium chloride in presence of l-ethyl-3 -(3 -dimethyl aminopropyl)carbodiimide (EDCI) and hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBT).

The above process involves cyanation reactions hence not advisable for commercial scale-up due to safety concern. Further, the amidation involves the usage of EDCI and HOOBT. EDCI is costly reagent and HOOBt is classified as a reactive solid which is difficult to handle and storage.

US6992220 also involves the condensation of tert-butyl l-cyclobutyl-3-oxopropan-2-ylcarbamate with acetone cyanohydrin in presence of potassium cyanide. Whereas, the usage of potassium cyanide is difficult to handle and hence not recommended for commercial use.

The present invention overcomes all the above said problems/difficulties by adopting a simple and novel process for the preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide which does not involve cyanation reaction. Hence the present invention is safe and economical friendly process and suitable for commercial level production.

Brief description of the Invention:

The first aspect of the present invention is to provide a novel process for the preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2 or its acid-addition salt.

The second aspect of the present invention is to provide a novel process for the preparation of (S)-3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2S or its acid-addition salt.

The third aspect of the present invention relates to a-halo ketone compound of general formula-7 and a,a-dihalo ketone compound of general formula-8 (or) isomers thereof, which are useful intermediates in the synthesis of 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2 or its acid-addition salt.

The fourth aspect of the present invention is to provide a process for the preparation of alkyl 2-(benzyloxycarbonylamino)-3-cyclobutylpropanoate compound of general formula-5A.

The fifth aspect of the present invention is to provide a process for the preparation of N-protected P-amino-a-hydroxy acid compound of general formula-10.

The sixth aspect of the present invention is to provide a process for the preparation of N-protected P-amino-a-hydroxy acid amide compound of general formula-11.

The seventh aspect of the present invention is to provide an alternative process for the preparation of a,a-dihalo ketone compound of general formula-8.

The eighth aspect of the present invention is to provide a process for the preparation of a-halo ketone compound of general formula-7.

The ninth aspect of the present invention is to provide a process for the preparation of amino acid ester compound of general formula-4.

The tenth aspect of the present invention is to provide an alternative process for the preparation of amino acid ester compound of general formula-4.

The eleventh aspect of the present invention is to provide another alternative process for the preparation of amino acid ester compound of general formula-4.

The twelfth aspect of the present invention is to provide an improved process for the preparation of (1R, 5S)-N-[3 -amino-1 -(cyclobutylmethyl)-2,3 -dioxopropyl]-3 -[2(S)-[[[( 1,1 -dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-l-oxobutyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexan-2(S)-carboxamide compound of formula-1.

The thirteenth aspect of the present invention is to provide an alternative process for the preparation of (1 R,2S,5S)-3-((R)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-29.

Detailed description of the invention:

The main object of the present invention is to provide novel intermediate compounds for the preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2, which in-turn useful in the synthesis of (lR,5S)-N-[3-amino-l-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[ [(1,1 -dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1 -oxobutyl]-6,6-dimethyl-3 -azabicyclo[3.1.0]hexan-2(S)-carboxamide compound of formula-1.

As used herein the present invention the term "suitable solvent" wherever if necessary is selected from, but not limited to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet.ether, benzene, toluene, xylene and the like; "chloro solvents" such as dichloromethane, dichloroethane, carbon tetrachloride, chloroform and the like; "ester solvents" such as ethyl acetate, methyl acetate, propyl acetate and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, dioxane, acetonitrile and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxy ethane, tetrahydrofuran and the like; "alcoholic solvents" such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "ketone solvents" such as acetone, propanone, methylisobutyl ketone, methylisopropyl ketone and the like; and "polar solvents" such as water; and/or their mixtures.

As used herein the present invention the term "base" wherever if necessary is selected from, but not limited to "inorganic bases" selected from alkali and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; and "organic bases" like diisopropyl amine, diisopropyl ethyl amine, diisobutyl amine, triethyl amine, pyridine, 4-dimethylamino pyridine, N-methyl morpholine and the like.

As used herein the present invention the term "amine protecting group" wherever if necessary is selected from, but not limited to tert-butoxy carbonyl (BOC), benzyloxy carbonyl(CBz), acetyl (Ac), triflouoroacetyl (TFA), benzyl (Bn), dibenzyl, phthalimido, tosyl (Ts), p-methoxybenzylcarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) and benzoyl (Bz).

The "suitable amine protecting agent" is selected such that it is capable of protecting the nitrogen atom with any of the above mentioned amine protecting groups.

The "suitable amine protecting agent" is selected from, but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, alkyl or aryl sulfonyl halides or anhydrides such as mesyl halides, mesyl anhydride, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride and the like.

The suitable deprotecting agent is selected based on the protecting group employed. The "suitable deprotecting agent" is selected from acids like gaseous hydrochloric acid, isoproanolic hydrochloric acid, ethyl acetate-hydrochloric acid, ether-hydrochloric acid, hydrobromic acid, sulfuric acid, periodic acid, trichloroisocyanuric acid and trifluoroacetic acid; hydrogenating agents such as palladium, palladium on carbon and rhodium on carbon under hydrogen pressure; bases like piperidine, ammonia and methylamine; ammonium cerium (IV) nitrate; sodium in liquid ammonia; sodium naphthalenide and the like.

As used herein the present invention the term "suitable halogenating agent" wherever if necessary is selected from, but not limited to phosphorous trichloride, phosphorous penta chloride, phosphorous tribromide, phosphorous penta bromide, N-bromo succinamide, N-chloro succinamide, chlorine, bromine, sulfuryl chloride, copper (II) chloride, copper (II) bromide, ferric chloride, ferric bromide and the like.

The term "suitable condensing agent" used herein the present invention is selected from alkyl (or) aryl chloroformates such as methyl chloroformate, ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, p-nitrophenyl chloroformate and the like, alkyl or aryl sulfonyl halides such as methane sulfonyl chloride, ethane sulfonyl chloride, benzene sulfonyl chloride, toluene sulfonyl chloride, p-toluene sulfonyl halide and the like; and thoinyl chloride optionally in the presence of triazole, benzotriazole and substituted benzotriazole such as hydroxy benzotriazole, l-hydroxy-7-azabenzotriazole and the like.

The term "alkyl" as used herein the present invention refers to a saturated straight or branched hydrocarbon chain comprising C1-C6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and the like.

The term "aryl" as used herein the present invention refers to a carbocyclic ring system containing 6 to 10 carbon atoms forming one or more rings, and wherein the ring may be aromatic or non-aromatic in nature, for example phenyl, naphthyl. The aryl may be substituted with halo, nitro, alkoxy and hydroxy.

The term "alkoxy" used herein the present invention refers to alkyl group as defined above, which is attached via an oxygen atom.

The term "halo" herein the present invention refers to halogen such as chlorine and bromine. The term "acid" used herein the present invention refers to inorganic acid selected from hydrochloric acid, hydrobromic acid and sulfuric acid.

The first aspect of the present invention provides a novel process for the preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2 or its acid-addition salt, comprising of:

a) Reacting ketimide compound of general formula-3 with (halomethyi)cyclobutane in a suitable solvent and in presence of a base, followed by treating with an acid to provide amino acid ester compound of general formula-4,

b) protecting the amine group of general formula-4 with an amine protecting agent in a suitable solvent, optionally in presence of a base to provide N-protected amino acid ester compound of general formula-5,

c) reacting the compound of general formula-5 with a-halo acetic acid salt compound of general formula-6 in a suitable solvent, in presence of alkyl magnesium halide and a base, followed by decarboxylation to provide a-halo ketone compound of general formula-7,

d) halogenating the compound of general formula-7 with a suitable halogenating agent in a suitable solvent, optionally in presence of a catalyst to provide a,a-dihalo ketone compound of general formula-8,

e) treating the compound of general formula-8 with alkali metal hydroxide in a suitable solvent to provide P-amino-a-hydroxy acid compound of formula-9,

f) protecting the amine group of formula-9 with an amine protecting agent in a suitable solvent, optionally in presence of a base to provide N-protected P-amino-a-hydroxy acid compound of general formula-10,

g) reacting the compound of general formula-10 with ammonium chloride in a suitable solvent, in presence of carbonyl diimidazole and a base to provide N-protected p-amino-a-hydroxy acid amide compound of general formula-11,

h) deprotecting the compound of general formula-11 with a suitable deprotecting agent in a suitable solvent to provide 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2 or its acid-addition salt. Wherein, in step-a) the base is inorganic base, preferably potassium tert-butoxide; acid is inorganic acid selected from hydrochloric acid, hydrobromic acid and sulfuric acid; in step-b) & step-f) the base is selected from inorganic base and organic base, preferably inorganic base such as sodium bicarbonate and sodium hydroxide; in step-c) the alkyl magnesium halide is tert-butyl magnesium chloride, tert-butyl magnesium bromide and the like; the base is organic base, preferably triethylamine; the a-halo acetic acid salt is preferably alkali metal salt, such as lithium, sodium and potassium salt of a-halo acetic acid; in step-d) the catalyst is p-toluene sulfonyl chloride; in step-e) alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide; in step-g) the suitable base is inorganic base or organic base, preferably diisopropyl ethylamine; Further, the first aspect of the present invention is represented schematically as below: Scheme-I:

Wherein, P! and P2 both are same or different and independently selected from hydrogen and amine protecting group; R1 is alkyl; X is halogen; and M is an alkali metal such as sodium, potassium and lithium.

The a-halo acetic acid salt compound of general formula-6 used herein the present invention is converted into its corresponding metal enolate before its reaction with compound of general formula-5. The metal enolate of a-halo acetic acid salt is preferably magnesium enolate. The magnesium enolate of a-halo acetic acid salt can be prepared by reacting a-halo acetic acid salt with magnesium compounds like magnesium amide such as chloromagnesium diisopropylamide; Grignard reagent such as alkyl magnesium halide in presence of an amine such as secondary and tertiary amine.

The second aspect of the present invention provides a novel process for the preparation of (S)-3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2S or its acid-addition salt by taking the (S)-amino acid ester compound of general formula-4S as a starting material and the process is schematically represented in below scheme-II.
Scheme-II

Wherein, Pi, P2> R1, M and X are same as defined above.

In the present invention, the compound of formula-2 or compound of formula-2S can be converted into their hydrochloride salts by treating with a hydrochloric acid source such as gaseous hydrochloric acid, dry hydrochloric acid, ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid and ether-hydrochloric acid.

The third aspect of the present invention relates to a-halo ketone compound of general formula-7 and a,a-dihalo ketone compound of general formula-8 (or) isomers thereof,
wherein, Pi; P2 and X are same as defined above, which are useful intermediates in the synthesis of 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2 or its acid-addition salt.

A preferred embodiment of the present invention provides benzyl 4-chloro-l-cyclobutyl-3-oxobutan-2-ylcarbamate compound of formula-7a and benzyl 4,4-dichloro-l-cyclobutyl-3-oxobutan-2-ylcarbamate compound of formula-8a.

In the present invention, the compound of general formula-7 and compound of general formula-8 may be either a racemic mixture or its individual enantiomers.

The fourth aspect of the present invention provides a process for the preparation of alkyl 2-(benzyloxycarbonylamino)-3-cyclobutylpropanoate compound of general formula-5A, comprising of reacting the amino acid ester compound of general formula-4 with benzyloxy carbonyl chloride in a suitable solvent, optionally in presence of a base to provide compound of general formula-5A.

Wherein, R is alkyl; the base is selected from inorganic base or organic base, preferably inorganic base such as sodium bicarbonate.

In the above aspect, the stereo specific enantiomers of compound of formula-5 A can be prepared by taking stereo specific starting material i.e. R or S enantiomer of compound of general formula-4 instead of its racemate.

The fifth aspect of the present invention provides a process for the preparation of N-protected P-amino-a-hydroxy acid compound of general formula-10, comprising of

a) treating a,a-dihalo ketone compound of general formula-8 with alkali metal hydroxide in a suitable solvent to provide P-amino-a-hydroxy acid compound of formula-9,

b) reacting the compound of formula-9 in-situ with a suitable amine protecting agent in a suitable solvent, optionally in presence of a base to provide compound of general formula-10.

In the above aspect, the stereo specific enantiomer of compound of general formula-10 can be prepared from stereo specific starting material i.e. R or S enantiomer of compound of formula-9 instead of its racemate.

The sixth aspect of the present invention provides a process for the preparation of N-protected P-amino-a-hydroxy acid amide compound of general formula-11, comprising of reacting N-protected P-amino-a-hydroxy acid compound of general formula-10 with ammonium chloride in a suitable solvent, in presence of carbonyldiimidazole and a base to provide compound of general formula-11.

In the above aspect, the stereo specific enantiomer of compound of general formula-11 can be prepared from stereo specific starting material i.e. R or S enantiomer of compound of general formula-10 instead of its racemate.

The seventh aspect of the present invention provides an alternative process for the preparation of a,a-dihalo ketone compound of general formula-8, comprising of:

a) Reacting N-protected amino acid ester compound of general formula-5 with alkyl acetate compound of general formula-12 in a suitable solvent and in presence of a base to provide p-keto ester compound of general formula-13,

a) hydrolyzing the compound of general formula-13 in a suitable solvent and in presence of a base, followed by decarboxylation provides methyl ketone derivative compound of general formula-14,

b) halogenating the compound of general formula-14 with a suitable halogenating agent in a suitable solvent to provide a,a-dihalo ketone compound of general formula-8.
Wherein,

in step-a) the base is selected from inorganic bases and organic bases, in step-b) the base is selected from inorganic bases such as alkali and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates,

in step-c) the suitable halogenating agent is same as defined above in step-(d) of the first aspect. Further, the seventh aspect of the present invention is represented schematically as below:

wherein, P P2,Ri and X are same as defined above. The process described in the above aspect can also be carried out by taking specific enantiomer of N-protected amino acid ester compound of general formula-5 to provide its corresponding enantiomer of a,a-dihalo ketone compound of general formula-8.

The eighth aspect of the present invention is to provide a process for the preparation of a-halo ketone of general formula-7. The process is represented schematically in Scheme-IV:

Wherein, Pi, P2, R1, M and X are same as defined above.

The process described in the above aspect can also be carried out by taking specific enantiomer of N-protected amino acid ester compound of general formula-5 to provide its corresponding enantiomer of a-halo ketone compound of general formula-7.

The ninth aspect of the present invention is to provide a process for the preparation of amino acid ester compound of general formula-4, comprising of:

a) Reacting dialkyl malonate compound of general formula-17 with (halomethyl) cyclobutane in a suitable solvent and in presence of a base to provide dialkyl 2-(cyclobutylmethyl)malonate compound of general formula-18,

b) hydrolyzing the compound of general formula-18 in a suitable solvent and in presence of a base, followed by decarboxylation to provide 3-cyclobutylpropanoic acid compound of formula-19,

c) esterifying the compound of formula-19 with alcohol of formula Ri-OH in presence of an acid or a base, followed by halogenating with a suitable halogenating agent in a suitable solvent to provide alkyl 2-halo-3-cyclobutylpropanoate compound of general formula-20,

d) treating the compound of general formula-20 with ammonia in a suitable solvent to provide amino acid ester compound of general formula-4.

Wherein,

in step-a) & step-b) the base is same as defined in step-a) & step-b) of seventh aspect of the present invention; in step-c) the acid is inorganic acid; the base is inorganic base; and R1 is alkyl.

The ninth aspect of the present invention is represented schematically as below: Scheme-V

In the above aspect, compounds of formulae-18, 20 and 4 are maybe racemic mixture or their enantiomers.

The tenth aspect of the present invention provides an alternative process for the preparation of amino acid ester compound of general formula-4, comprising of:

a) Reacting alkyl 2-halo-acetate compound of general formula-16 with a metal nitrite like silver nitrite in a suitable solvent to provide alkyl 2-nitro-acetate compound of general formula-21,

b) reacting the compound of general formula-21 with (halomethyl)cyclobutane in a suitable solvent and in presence of a base to provide alkyl 3-cyclobutyl-2-nitropropanoate compound of general formula-22,

c) reduction of the compound of general formula-22 in a suitable solvent to provide amino acid ester compound of general formula-4.

Wherein,

in step-b) the base is selected from inorganic base or organic base,

in step-c) the reduction of nitro to amine is carried out by catalytic hydrogenation using metal catalyst like palladium (Pd), Pd on Carbon , palladium hydroxide, palladium acetate, platinum oxide, Raney-Ni under hydrogen pressure; using metals in acid such as Zn-hydrochloric acid, Fe-hydrochloric acid, Fe-acetic acid, Zn-acetic acid; metal catalysts and hydrogen donars like ferrous sulfate-ammonium hydroxide, Pd-C/hydrazine, Pd-C /cyclohexane, Raney-Ni/hydrazine, Pd-C/ammonium formate, Zn-sodium hydroxide, palladium acetate- triethylsilane, ferric chloride-hydrazine hydrate, Pd-C/formic acid and tin chloride-methanol; or sodium borohydride in combination with cobalt (II), copper (II) and rhodium (III), nickel (II) halides; borane-sodium borohydride; sodium borohydride- nickel boride; and pyridine zinc tetrahydroborate.

The eleventh aspect of the present invention provides an alternative process for the preparation of amino acid ester compound of general formula-4, comprising of:

a) Azidating alkyl 2-halo-acetate compound of general formula-16 with metal azide like sodium azide in a suitable solvent to provide alkyl 2-azidoacetate compound of general formula-23, acid ester compound of general formula-4.

wherein,

in step-b) the base is selected from inorganic or organic bases,

in step-c) the reduction of azides to amine is carried out by catalytic hydrogenation using metal catalyst like palladium on carbon, palladium hydroxide, palladium acetate, palladium-barium sulfate, platinum oxide, palladium-calcium carbonate, Ruthenium-calcium and Ruthenium-carbon under hydrogen pressure; (or) by using phosphines such as triphenyl phosphine; metal catalysts and hydrogen donars like palladium hydroxide-hydrazine, Zn-ammonium chloride, Fe-aluminium chloride in ethanol, Pd-C in methanol and Fe-bismuth trichloride in ethanol; (or) borohydrides in combination with metal halides such as sodium borohydride-nickel (II) chloride, Lithium N, N-dimethylaminoborohydride and sodium borohydride-zerconium (IV)chloride; sodium borohydride; lithium aluminium hydride; dichloroindium hydride; Indium-ammonium chloride; and BHCl2-SMe2.

The tenth and eleventh aspects of the present invention are represented schematically as below: Scheme-VI

Wherein, R1 is alkyl; and X is halogen.

In the above aspects, the compounds of formula-22, 24 and 4 are either racemates or their individual enantiomers.

The twelfth aspect of the present invention provides an improved process for the preparation of (lR,5S)-N-[3-amino-l-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(l, 1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-l-oxobutyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexan-2(S)-carboxamide compound of formula-1, comprising of:

a) Reacting (S)-2-amino-3,3-dimethylbutanoic acid compound of formula-25 or its ester with 2-methylpropan-2-amine compound of formula-26 or its acid-addition salt in a suitable solvent and in presence of carbonyl diimidazole to provide (S)-2-(3-tert-butylureido)-3,3-dimethyl butanoic acid compound of formula-27,

b) condensing the compound of formula-27 with (lR,2S,5S)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid compound of formula-28 in a suitable solvent, in presence of a suitable condensing agent and/or a base provides (lR,2S,5S)-3-((R)-2-(3-tert-butylureido)-3,3 -dimethylbutanoyl)-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-29,

c) condensing the compound of formula-29 with 3-amino-4-cyclobutyl-2-hydroxybutan amide compound of formula-2 or its acid-addition salt in a suitable solvent, in presence of a suitable condensing agent and/or a base 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-30,

d) oxidizing the compound of formula-30 according to the known methods to provide compound of formula-1.

In the above aspect, the compound of formula-29 can also be condensed with specific enantiomer of 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2 or its acid-addition salt, followed by oxidation provides its corresponding isomer of compound of formula-1.

The compound of formula-29 obtained in step-(b) of twelfth aspect of the present invention is condensed with 3-amino-4-cyclobutyl-2-oxobutanamide compound of formula-31 (or) its acid-addition salt in a suitable solvent, in presence of suitable condensing agent and/or a base to provide compound of formula-1.

In the above aspect, the compound of formula-29 can also be condensed with specific enantiomer of 3-amino-4-cyclobutyl-2-oxobutanamide compound of formula-31 or its acid-addition salt to provide its corresponding isomer of compound of formula-1.

The compound of formula-31 used herein the present invention is obtained by the oxidation of compound of formula-2 as per the process disclosed in the prior art for example US7326795.

The twelfth aspect of the present invention is represented schematically in scheme-VII. Scheme-VII

The thirteenth aspect of the present invention provides an alternative process for the preparation of (1 R,2S,5S)-3-((R)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid compound of formula-29, comprising of:

a) Condensing (S)-2-amino-3,3-dimethylbutanoic acid compound of formula-25 with (lR,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound of formula-2 8 in a suitable solvent, in presence of a suitable condensing agent and/or a base to provide compound of formula-32,

b) reacting the compound of formula-32 with compound of formula-26 in presence of carbonyldiimidazole in a suitable solvent to provide compound of formula-29.

The thirteenth aspect of the present invention is schematically represented below:

The Ketimide compound of formula-3, (S)-amino acid ester compound of general formula-4S, alkyl 2-halo-acetate compound of general formula-16 and dialkyl malonate compound of general formula-17 are commercially available.

The Boceprevir obtained by the present invention can be further micronized or milled to get the desired particle size. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills.

Further, the said Boceprevir can be used in the formation of medicament as an active ingredient for the treatment of hepatitis C.

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 ethyl 2-amino-3-cyclobutylpropanoate (formula-4a)

A mixture of ethyl 2-(diphenylmethyleneamino)acetate compound of formula-3a (250 gms) and tetrahdydrofuran (2000 ml) was cooled to 0-5°C. Potassium tert-butoxide (157.4 gms) was slowly added to the reaction mixture at a temperature below 10°C and stirred for 1 hour at 0-5°C. Cyclobutylmethyl bromide (185 g) was added slowly to the reaction mixture for a period of 30 minutes at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 30 hours. After completion of the reaction, 2N hydrochloric acid was added to the reaction mixture and stirred for 6 hours. After completion of the reaction, dichloromethane was added to the reaction mixture and stirred for 15 minutes. Both the organic and aqueous layers were separated; the aqueous layer was washed with dichloromethane. Dichloromethane was added to the aqueous layer and cooled to 0-5°C. pH of the reaction mixture was adjusted to 12.5 by using 50% sodium hydroxide and stirred for 10 minutes. Both the organic and aqueous layers were separated. The compound was extracted with dichloromethane from the aqueous layer at 0-5°C. The organic layers were combined, dried with sodium sulfate and then distilled off the solvent from the organic layer under reduced pressure to get title compound. Yield: 45 gms.

Example-2: Preparation of ethyl 2-(benzyloxycarbonylamino)-3-cyclobutyl propanoate (Formula-5a)

A mixture of ethyl 2-amino-3-cyclobutylpropanoate compound of formula-4a (10 g), acetonitrile (30 ml) and water (50 ml) was cooled to 5-10°C. Sodium bicarbonate (9.8 g) was added to the reaction mixture at 5-10°C and stirred for 1 hour at the same temperature. 50%Benzyl chloroformate (20.9 ml) was slowly added to the reaction mixture over a period of 1 hour and stirred for 4 hours at 5-10°C. After completion of the reaction, both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both the organic layers were combined; aqueous sodium chloride solution was added to the reaction mixture and stirred for 10 minutes. Both the organic and aqueous layers were separated, the organic layer was dried with sodium sulfate and then distilled under reduced pressure to get title compound. Yield: 12 gms.

Example-3: Preparation of benzyl 4-chloro-l-cyclobutyl-3-oxobutan-2-ylcarbamate

(Formula-7a)

A mixture of magnesium turnings (4.7 g), iodine (0.02 g) and tetrahydrofuran (15 ml) was taken into a clean RBF at 25-30°C under nitrogen atmosphere and heated to the reaction mixture 55-60°C. A solution of t-butyl chloride (1.51 g) in tetrahydrofuran (2.5 ml), followed by a solution of ethyl bromide (0.1 ml) in tetrahydrofuran (0.5 ml) were added to the reaction mixture and the reaction mixture was stirred for 15 minutes at 55-60°C. Again a solution of t-butyl chloride (13.59 g) in tetrahydrofuran (22.5 ml) was added slowly to the reaction mixture over a period of 1 hour and stirred for 30 minutes to form t-butylmagnesium chloride. The reaction mixture containing t-butylmagnesium chloride was cooled to 25-3 0°C and stored under nitrogen atmosphere. A mixture of ethyl 2-(benzyloxycarbonylamino)-3-cyclobutyl propanoate compound of formula-5a (5 g), sodium mono chloroacetate compound of formula-6a (2.8 g) and toluene (25 ml) was cooled to 0-5°C and triethylamine (3.5 ml) was added to reaction mixture under nitrogen atmosphere. The above t-butyl magnesium chloride solution was added to the reaction mixture at 0-5°C and stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was added to a pre-cooled dilute hydrochloric acid solution at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 15 minutes. Both the organic and aqueous layers were separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with aqueous sodium bicarbonate solution, followed by aqueous sodium chloride solution. The organic layer was dried with sodium sulfate and then distilled off the solvent under reduced pressure to get title compound. Yield: 4.8 gms; MS (MH4): 310.2; IR: 1746.88

Example-4: Preparation of benzyl 4,4-dichloro-l-cyclobutyl-3-oxobutan-2-ylcarbamate (Formula-8a)

Sulfuryl chloride (3.7 ml) was added to a mixture of benzyl 4-chloro-l-cyclobutyl-3-oxobutan-2-ylcarbamate compound of formula-7a (4.8 g) and ethyl acetate (48 ml) at 25-30°C for a period of 30 minutes under nitrogen atmosphere. P-toluene sulfonyl chloride (0.29) was added to the reaction mixture and the reaction mixture was heated to 45-50°C and stirred for 40 hours at 45-50°C. After completion of the reaction, the reaction mixture was cooled to 0-5°C and water was added to the reaction mixture. pH of the reaction mixture was adjusted to 3.5 using aqueous sodium hydroxide solution and stirred the reaction mixture for 15 minutes at 0-5°C. Both the organic and aqueous layers were separated, the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined and washed with aqueous sodium chloride solution. The organic layer was dried with sodium sulfate and then distilled under reduced pressure to get title compound. Yield: 4 gms; MS (MH*): 344.2; IR: 1714.5

Example-5: Preparation of 3-(tert-butoxycarbonylamino)-4-cyclobutyl-2-hydroxybutanoic acid (Formula-l0a)

A solution of sodium hydroxide (2 g) in water (20 ml) was added to a mixture of benzyl 4,4-dichloro-l-cyclobutyl-3-oxobutan-2-ylcarbamate compound of formula-8a (4 g) and toluene (32 ml). The reaction mixture was heated to 45-50°C and stirred for 9 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Both the organic and aqueous layers were separated, the aqueous layer was washed with ethyl acetate. 1,4-dioxane (20 ml) was added to the aqueous layer containing 3-amino-4-cyclobutyl-2-hydroxybutanoic acid compound of formula-9 and the resulting mixture was cooled to 0-5°C. Di-tert-butyl carbonate (2.52 g) was added to the reaction mixture at 0-5°. The temperature of the reaction mixture was raised to 25-30°C and stirred for 12 hours. After completion of the reaction, 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 cooled to 0-5°C and dichloromethane was added to it. pH of the reaction mixture was adjusted to 2.5 using aqueous hydrochloric acid and the reaction mixture was stirred for 15 minutes. Both the organic and aqueous layers were separated, the aqueous layer was extracted with dichloromethane. Both the organic layers were combined, washed with aqueous sodium chloride solution, dried with sodium sulfate and then distilled under reduced pressure to get title compound. Yield: 2.1 gms.

Example-6: Preparation of tert-butyl 4-amino-l-cycIobutyl-3-hydroxy-4-oxobutan-2-ylcarbamate (Formula-11a)

N,N-carbonyl dimidazole (0.44 g) was added to a mixture of 3-(tert-butoxycarbonyl amino)-4-cyclobutyl-2-hydroxybutanoic acid compound of formula-10a (0.5 g), diisopropyl ethylamine (0.5 ml) and dimethylformamide (10 ml) and stirred for 1 hour at 25-30°C. Ammonium chloride (0.3 g) was added to the reaction mixture and stirred for 12 hours at 25-30°C. After completion of the reaction, water followed by ethyl acetate were added to the reaction mixture and stirred for 10 minutes. Both the organic and aqueous layers were separated, the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined, washed with 10% sodium bicarbonate solution, followed by 10% sodium chloride solution, dried with sodium sulfate and then distilled to get title compound. Yield: 0.3 gms.

ExampIe-7: Preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride (FormuIa-2a)

A mixture of compound of formula-lla (5 g), isopropanol (15 ml) and isopropanolic hydrochloric acid (10 ml) was heated to 60-65°C and stirred for 4 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Filtered the precipitated solid, washed with isopropanol and then dried to get tile compound. Yield: 3.2 gms.

Example-8: Preparation of (S)-2-(3-tert-butyIureido)-3,3-dimethylbutanoicacid (Formula-
27)

Trimethyl silyl chloride (5.0 g) was slowly added to a mixture of (S)-2-amino-3,3-dimethylbutanoic acid compound of formula-25 (5 g), triethylamine (6.42 ml) and dichloromethane (35 ml) at 25-30°C for a period of 30 minutes. The reaction mixture was heated to 40-45°C and stirred for 3 hours. The reaction mixture containing (S)-trimethylsilyl 2-amino-3,3-dimethylbutanoate compound of formula-25a was cooled to 25-30°C. N,N-carbonyl diimidazole (6.8 g) was added to a mixture of 2-methylpropan-2-amine hydrochloride compound of formula-26a (7.5 g) and tetrahydrofuran (15 ml) at 25-30°C and stirred for 3 hours at 25-30°C. This reaction mixture was slowly added to the reaction mixture containing compound of formula-26a at 25-30°C for a period of 30 minutes and stirred for 10 hours at 25-30°C. After completion of the reaction, water followed by dichloromethane were added to the reaction mixture and pH of the reaction mixture was adjusted to 2.5 using 6N hydrochloric acid. The reaction mixture stirred for 15 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both the organic layers were combined, washed with 10% sodium chloride solution, dried with sodium sulfate and then distilled under reduced pressure to get title compound. Yield: 6 gms.

We Claim:

1. A novel process for the preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2 or its acid-addition salt, comprising of:

a) Reacting ketimide compound of general formula-3 with (halomethyl)cyclobutane in a suitable solvent and in presence of a base, followed by treating with an acid to provide amino acid ester compound of general formula-4,

Formula-4; wherein, Ri is alkyl. b) protecting the amino group of general formula-4 with an amine protecting agent in a suitable solvent, optionally in presence of a base to provide N-protected amino acid ester compound of general formula-5,

wherein, R1 is alkyl; Pi and P2 both are same or different and independently selected from hydrogen and amine protecting group, c) reacting the compound of general formula-5 with a-halo acetic acid salt compound of general formula-6 in a suitable solvent, in presence of alkyl magnesium halide and a base, followed by decarboxylation to provide a-halo ketone compound of general formula-7,

wherein, R1 is alkyl; Pi and P2 both are same or different and independently selected from hydrogen and amine protecting group; X is halogen, d) halogenating the compound of general formula-7 with a suitable halogenating agent in a suitable solvent, optionally in presence of a catalyst to provide a,a-dihalo ketone compound of general formula-8,
wherein, Pi and P2 both are same or different and independently selected from hydrogen
and amine protecting group; X is halogen, e) treating the compound of general formula-8 with alkali metal hydroxide in a suitable solvent to provide P-amino-a-hydroxy acid compound of formula-9,

f) protecting the amino group of formula-9 with an amine protecting agent in a suitable solvent, optionally in presence of a base to provide N-protected P-amino-a-hydroxy acid compound of general formula-10,

g) reacting the compound of general formula-10 with ammonium chloride in a suitable solvent, in presence of carbonyl diimdazole and a base to provide N-protected p-amino-a-hydroxy acid amide compound of general formula-11,

h) deprotecting the compound of general formula-11 with a suitable deprotecting agent in a suitable solvent to provide 3-amino-4-cyclobutyl-2-hydroxybutanamide compound of formula-2 or its acid-addition salt.

2. A process according to claim 1, wherein

in step-a) the base is inorganic base;

acid is inorganic acid selected from hydrochloric acid, hydrobromic acid and sulfuric acid;

in step-b) & step-f) the base is selected from inorganic base and organic base;

amino protecting agent is selected from di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl

trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid and trifluoroacetyl chloride;
in step-c) the alkyl magnesium halide is tert-butyl magnesium chloride, tert-butyl magnesium bromide and the like; the base is organic base such as triethylamine, diisopropylethylamine and the like; the a-halo acetic acid salt is preferably alkali metal salt, such as lithium, sodium and potassium salt of a-halo acetic acid;

in step-d) the suitable halogenating agent is selected from phosphorous trichloride,
phosphorous penta chloride, phosphorous tribromide, phosphorous penta bromide, N-bromo succinamide, N-chloro succinamide, chlorine, bromine, sulfuryl chloride, copper (II) chloride, copper (II) bromide, ferric chloride and ferric bromide; the catalyst is p-toluene sulfonyl chloride;

in step-e) alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide;

in step-g) the suitable base is inorganic base or organic base;

in step-h) the base is organic base or inorganic base; the suitable deprotecting agent is sleeted from acids like gaseous hydrochloric acid, isoproanolic hydrochloric acid, ethyl acetate-hydrochloric acid, ether-hydrochloric acid, hydrobromic acid, sulfuric acid, periodic acid, trichloroisocyanuric acid and trifluoroacetic acid; hydrogenating agents such as palladium, palladium on carbon and rhodium on carbon under hydrogen pressure; bases like piperidine, ammonia and methylamine; ammonium cerium (IV) nitrate; sodium in liquid ammonia; and sodium naphthalenide;

in step-a) to step-h) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, ketone solvents, polar solvents and their mixtures;

3. A novel process for the preparation of 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride compound of formula-2a, comprising of:

a) Reacting ethyl 2-(diphenylmethyleneamino)acetate compound of formula-3a with (bromomethyl)cyclobutane in tetrahydrofuran and in presence of potassium ter-butoxide, followed by treating it with hydrochloric acid to provide ethyl 2-amino-3-cyclobutylpropanoate compound of formula-4a,

b) protecting the amino group of formula-4a with benzyl chloroformate in a mixture of acetonitrile and water, in presence of sodium bicarbonate to provide ethyl 2-(benzyloxycarbonylamino)-3-cyclobutylpropanoate compound of formula-5a,

c) reacting the compound of formula-5a with sodium mono chloroacetate compound of formula-6a in a mixture of toluene and tetrahydrofuran, in presence of tert-butyl magnesium chloride and triethylamine, followed by decarboxylation to provide benzyl 4-chloro-l-cyclobutyl-3-oxobutan-2-ylcarbamate compound of formula-7a,

d) chlorinating the compound of formula-7a with sulfuryl chloride in ethyl acetate and in presence of p-toluene sulfonyl chloride to provide benzyl 4,4-dichloro-l-cyclobutyl-3-oxobutan-2-ylcarbamate compound of formula-8a,

e) treating the compound of formula-8a with aqueous sodium hydroxide solution in toluene to provide 3-amino-4-cyclobutyl-2-hydroxybutanoic acid compound of formula-9,

f) protecting the amino group of formula-9 in-situ with di-tert-butyl carbonate in a mixture of 1,4-dioxane and water to provide 3-(tert-butoxycarbonylamino)-4-cyclobutyl-2-hydroxybutanoic acid compound of formula-10a,

g) reacting the compound of formula-10a with ammonium chloride in dimethylformamide, in presence of carbonyl diimidazole and diisopropyl ethylamine to provide tert-butyl 4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-ylcarbamate compound of formula- 11a,

h) deprotecting the compound of formula-lla with isopropanolic hydrochloric acid in isopropanol to provide 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride compound of formula-2a.

4. A process for the preparation of alkyl 2-(benzyloxycarbonylamino)-3-cyclobutyl propanoate compound of general formula-5A, comprising of reacting the amino acid ester compound of general formula-4 with benzyloxy carbonyl chloride in a suitable solvent, optionally in presence of a base to provide compound of general formula-5 A.

5. A process for the preparation of N-protected P-amino-a-hydroxy acid compound of general formula-10, comprising of:

a) Treating a,a-dihalo ketone compound of general formula-8 with alkali metal hydroxide in a suitable solvent to provide P-amino-a-hydroxy acid compound of formula-9,

b) reacting the compound of formula-9 in-situ with a suitable amine protecting agent in a suitable solvent, optionally in presence of a base to provide compound of general formula-10.

6. A process for the preparation of N-protected P-amino-a-hydroxy acid amide compound of general formula-11, comprising of reacting N-protected P-amino-a-hydroxy acid compound of general formula-10 with ammonium chloride in a suitable solvent, in
presence of carbonyldiimidazole and a base to provide compound of general formula-11.

7. The compounds having the following structural formulae:
wherein, Pi and P2 both same or different and independently selected from hydrogen and amine protecting group; X represents halogen.

8. The compounds according to claim 7, are

a) benzyl 4-chloro-l-cyclobutyl-3-oxobutan-2-ylcarbamate; and

b) benzyl 4,4-dichloro-l-cyclobutyl-3-oxobutan-2-ylcarbamate

9. A process for the preparation of a,a-dihalo ketone compound of general formula-8, comprising of halogenating the a-halo ketone compound of general formula-7 with a suitable halogenating agent in a suitable solvent, optionally in presence of a catalyst to provide compound of general formula-8.

10. A process for the preparation of (S)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid compound of formula-27, comprising of reacting the (S)-2-amino-3,3-dimethylbutanoic acid compound of formula-25 (or) its ester with 2-methylpropan-2-amine compound of formula-26 or its acid-addition salt in a suitable solvent and in presence of a suitable condensing agent to provide compound of formula-27.