DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

INTRODUCTION
Aspects of the present invention relate to processes for preparing Boceprevir and and its intermediates thereof.
BACKGROUND
The drug compound having the adopted name “Boceprevir” has chemical name: (1R,5S)-N-[3-amino-1-(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; and is represented by structure of formula I.

I
The commercial pharmaceutical product VICTRELISTM capsules contain boceprevir as the active ingredient. Boceprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
U.S. Patent No. 7,012,066 discloses boceprevir and its pharmaceutically acceptable salts. Processes for the preparation of boceprevir and its stereoisomers have been disclosed in U.S. Patent Nos. 7,326,795, 7,528,263 and U.S. Patent Application Publication No. 2010/0145013 A1.
US7528263 and WO2012151271 disclose oxidation of hydroxy compound of formula (VII) to boceprevir in presence of various oxidizing agents, catalyst and cocatalyst.
There remains a need for methods of synthesizing compounds which are useful in the preparation of the hepatitis C virus (“HCV”) protease inhibitors.
In view of the importance of hepatitis C virus (“HCV”) protease inhibitors, new, cost-effective, novel methods of making such antagonists are always of interest.

SUMMARY
In first aspect, the present application provides a process for preparation of boceprevir of formula (I) or its stereo isomers and their pharmaceutically acceptable salts

which comprises:
(a) coupling compound of formula (II) or its pharmaceutically acceptable salts with compound of formula (III) in presence of coupling agent and base in an aromatic hydrocarbon, optionally with aprotic polar solvent to provide an azobicyclic compound of formula (IV);

wherein R= C1-C8 alkyl,; X= Cl, Br, I, F
(b) addition of alkali metal or alkaline earth metal hydroxide in the presence of an additive;
(c) treating reaction mass of step (b) with a suitable acid to provide an acid of formula (V);

(d) optionally isolating acid compound of formula (V);
(e) optionally purifying acid compound of formula (V);.
(f) coupling acid compound of formula (V) with a cyclobutyl compound of formula (VI) or its pharmaceutically acceptable salts in presence of suitable coupling agent, base and a suitable solvent to provide a hydroxy compound of formula (VII);

(g) oxidation of hydroxy compound of formula (VII) to provide boceprevir of
formula (I);

(h) optional purification of boceprevir obtained in step (g).

In second aspect, the present application provides a process for preparation of an acid compound of formula (V) or its steroisomers and their pharmaceutically acceptable salts thereof:

which comprises:
(a) coupling compound of formula (II) or its pharmaceutically acceptable salts with compound of formula (III) in presence of coupling agent and base in an aromatic hydrocarbon, optionally with aprotic polar solvent to provide an azobicyclic compound of formula (IV);

wherein R= C1-C8 alkyl,; X= Cl, Br, I, F
(b) addition of alkali metal or alkaline earth metal hydroxide in the presence of an additive;
(c) treating reaction mass of step (b) with a suitable acid to provide an acid compound of formula (V).

The third aspect of the present application provides process for the preparation of boceprevir
which comprises:
(a) oxidation of hydroxy compound of formula (VII) with oxone in presence of one or more catalyst optionally in the presence of cocatalyst;
(b) optional purification of boceprevir obtained in step (a).

The fourth aspect of the present application provides process for preparation of boceprevir
which comprises:
(a) oxidation of hydroxy compound of formula (VII) with permanganate in presence of one or more catalyst optionally in the presence of cocatalyst;
(b) optional purification of boceprevir obtained in step (a).

The fifth aspect of the present application provides pharmaceutical compositions comprising boceprevir of formula (I) or its pharmaceutically acceptable salts prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.

DETAILED DESCRIPTION
In first aspect, the present application provides a process for preparation of boceprevir of formula (I) or its stereo isomers and their pharmaceutically acceptable salts

which comprises:
(a) coupling compound of formula (II) or its pharmaceutically acceptable salts with compound of formula (III) in presence of coupling agent and base in an aromatic hydrocarbon, optionally with aprotic polar solvent to provide an azobicyclic compound of formula (IV);

wherein R= C1-C8 alkyl,; X= Cl, Br, I, F
(b) addition of alkali metal or alkaline earth metal hydroxide in the presence of an additive;
(c) treating reaction mass of step (b) with a suitable acid to provide an acid compound of formula (V);

(d) optionally isolating acid compound of formula (V);
(e) optionally purifying acid compound of formula (V);
(f) coupling acid compound of formula (V) with a cyclobutyl compound of formula (VI) or its pharmaceutically acceptable salts in presence of suitable coupling agent, base and a suitable solvent to provide a hydroxy compound of formula (VII);

(g) oxidation of hydroxy compound of formula (VII) to provide boceprevir of
formula (I);

(h) optional purification of boceprevir obtained in step (g).

Step (a) may be carried out in one or more coupling agents. Suitable coupling agents that may be used in step (a) include, but are not limited to carbonic or carboxylic mixed anhydrides, carbodiimides but are not limited to dicyclohexyldicarbodiimide (DCC), 1-(3-diemthylaminpropyl)-3-ethylcarbodiimide hydrochloride (EDCI), diisopropyl carbodiimide, N,N'-carbonyldiimidazole, ethyl chloroformate, 2-ethoxyl-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), ethyl chloroformate, isobutyl chloroformate, isopropenyl chloroformate, trimethylacetyl chloride, 2,4,6-trichlorobenzoyl chloride, isobutyl chloroformate, 4-nitrophenzl chloroformate, cyanuric chloride, oxalyl chloride, diethylaminosulfur trifluoride, bis (tetramethylene)fluoroformamidinium hexaflurorophosphate (BPTFFH), dimethylformamide, Vilsmeier's reagent, phosphorus reagents, sulfur reagents, pyridinium salts, phosphonium salts, uronium salts and the like.
Step (a) may be carried out in one or more suitable bases. Suitable base that may be used in step (a) include, but are not limited to organic bases such as, 2,4,6-collidine, 2,6-ditert-butyl-4-methylpyridine, 1-diethylamino-2-propanol, N-ethylamino-2-propanol, N-ethyldiisopropylamine, 4-ethylmorpholine, 1-ethylpiperidine, 2,6-lutidine, N-methylmorpholine, 1-methylpiperidine, tribenzylamine, triethylamine, and the like. Suitable inorganic bases include, but are not limited to alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline earth metal hydroxides, such as, for example, barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like.
The coupling reaction in step (a) optionally includes adding an additive to catalyze activation. Non-limiting examples of additives include 4-dimethylaminopyridine, 1-methylimidazole, 1,2,4-triazole, 4-(1-pyrrolidino)pyridine, N-hydroxysuccinimide, imidazole, 1-hydroxybenzotriazole (HOBt).
Step (a) may be carried out in one or more aromatic hydrocarbon solvent. Suitable aromatic hydrocarbon solvent that may be used in step (a) include, but are not limited to toluene, xylene, benzene, chlorobenzene, ethyl benzene or the like;
Optionally, step (a) may be carried out using one or more suitable polar aprotic solvent along with aromatic hydrocarbon solvent. Suitable polar aprotic solvents that may be used in step (a) include, but are not limited to amides such as dimethylformamide, diethylacetamide or the like; nitriles such as acetonitrile, propionitrile or the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate or the like; ethers such as tetrahydrofuran, 1, 4-dioxane, or the like; ketones such as acetone or the like; sulfoxides such as dimethylsulfoxide or the like.
The ratio of aromatic hydrocarbon solvent to that of polar aprotic solvent may be 1:0.1 to 1:1 v/v or in any ratio.
The temperature at which the above step may be carried out in between about -5 °C and about 70 °C based on the solvent or mixture of solvents used in particular step.
Step (b) may be carried out in the presence of one or more alkali metal or alkaline earth metal hydroxide. Suitable alkali metal hydroxide that may be used in step (b) include, but are not limited to sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide or the like, Suitable alkaline earth metal hydroxide that may be used in step (b) include, but are not limited to calcium hydroxide, magnesium hydroxide, barium hydroxide, strontium hydroxide or the like.
Step (b) may be carried out in one or more suitable additives. The additive may be a suitable solvent or a suitable reagent based on the reaction condition employed in step (b). Suitable additives that may be used in step (b) include, but are not limited to, alcohol solvents, such as, for example, methanol, ethanol, isopropanol, butanol, propanol or the like; reagents like tetralkyl ammonium hydroxide such as tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide, tetrabutyl ammonium hydroxide or the like.
The temperature at which the above step may be carried out in between about -5 °C and about 70 °C based on the solvent or mixture of solvents used in particular step.
Step (c) may be carried out in the presence of one or more suitable acids. Suitable acids that may be used include, but are not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid or the like.
The temperature at which the above step may be carried out in between about -5 °C and about 80 °C based on the solvent or mixture of solvent used in particular step.
Steps (d) and (e) which involves the isolation and purification of the acid compound of formula (V) can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
The reagents and solvents for step (f) may be selected from one or more suitable reagents and solvents as described in step (a) of the first aspect.
The coupling reaction in step (f) optionally includes adding an additive to catalyze activation. Non-limiting examples of additives include 4-dimethylaminopyridine, 1-methylimidazole, 1,2,4-triazole, 4-(1-pyrrolidino)pyridine, N-hydroxysuccinimide, imidazole, 1-hydroxybenzotriazole (HOBt).
Step (g) may be carried out in one or more suitable oxidizing agents that are reported in the art for preparation of boceprevir.
In an aspect step (g) may be carried out in a suitable oxidizing agent such as but are not limited to DMSO based oxidation, pyridinium chlorochromate (PCC), pyridinium dichromate, oxone in presence of TEMPO, oxone in presence of iodo benzoic acid, permanganate such as sodium permanganate, potassium permanganate or the like in presence of magnesium sulfate, calcium sulfate, barium sulfate, sodium dihydrogen phosphate, sodium hydrogen phosphate, ceric ammonium nitrate or the like.
DMSO oxidation preferably includes the combination of one or more of the following reagents with DMSO: oxalyl chloride with triethylamine, thionyl chloride with triethylamine, cyanuric chloride with triethylamine, DCC, EDCI, acetic anhydride, trifluoroacetic anhydride, sulfur trioxide-pyridine-triethylamine, p-toluenesulfonyl chloride, polyphosphoric acid, phosphorous pentoxide and triethylamine, trichloromethyl chloroformate, methanesulfonic anhydride, and the like.
In an aspect, the present invention also includes the use of one or more catalyst optionally in the presence of one or more co-catalyst along with above described oxidizing agents. The catalyst and co-catalyst may be used as reported in literature for preparation of boceprevir.
Step (g) may be carried out in one or more solvents. Suitable solvent that may be used in step (e) include, but are not limited to ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; water or mixtures thereof.
The temperature at which the above step may be carried out in between about 10 °C and about 70 °C based on the solvent or mixture of solvent used in particular step.
The purification of boceprevir in step (h) according to present invention can be effected, if desired, by any procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
In second aspect, the present application provides a process for preparation of compound of formula (V) or its stereoisomers and their pharmaceutically acceptable salts thereof:

which comprises:
(a) coupling compound of formula (II) or its pharmaceutically acceptable salts with compound of formula (III) in presence of coupling agent and base in an aromatic hydrocarbon, optionally with aprotic polar solvent to provide an azobicyclic compound of formula (IV);

wherein R= C1-C8 alkyl,; X= Cl, Br, I, F
(b) addition of alkali metal or alkaline earth metal hydroxide in the presence of an additive;
(c) treating reaction mass of step (b) with a suitable acid to provide an acid compound of formula (V).
The reagents and solvents for steps (a), (b) and (c) may be selected from one or more suitable reagents and solvents as described in steps (a), (b) and (c) of the first aspect of the present application.
The third aspect of the present application provides process for the preparation of boceprevir
which comprises:
(a) oxidation of hydroxy compound of formula (VII) with oxone in presence of one or more catalyst optionally in the presence of cocatalyst;
(b) optional purification of boceprevir obtained in step (a).
Oxone is potassium peroxomonosulfate and is a commercially available oxidizing agent.
Suitable catalyst that may be used include, but are not limited to TEMPO, 4-methoxy TEMPO, 4-amino TEMPO, iodobenzoic acid and the like
Suitable cocatalyst that may be used include, but are not limited to potassium bromide, sodium bromide, tetrabutyl ammonium bromide and the like.
The catalyst may be used in an amount ranging from 0.1 equivalents to 3 equivalents with respect to hydroxy compound of formula (VII) depending on the nature of catalyst used.
The co-catalyst may be used in an amount ranging from 0.1 equivalents to 2 equivalents with respect to hydroxy compound of formula (VII) depending on the nature of catalyst used.
The purification of boceprevir in step (b) according to present invention can be effected, if desired, by any procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
The fourth aspect of the present application provides process for preparation of boceprevir
which comprises:
(a) oxidation of hydroxy compound of formula (VII) with permanganate in presence of one or more catalyst optionally in the presence of cocatalyst;
(b) optional purification of boceprevir obtained in step (a).
Suitable permanganate that may be used includes, but is not limited to sodium permanganate, potassium permanganate, calcium permanganate, ammonium permanganate or the like.
Suitable catalyst that may be used include, but are not limited to magnesium sulfate, calcium sulfate, barium sulfate, sodium dihydrogen phosphate, sodium hydrogen phosphate or the like.
The catalyst can be used in an amount ranging from 0.1 equivalents to 3 equivalents with respect to hydroxy compound of formula (VII) depending on the nature of catalyst used.
The purification of boceprevir in step (b) according to present invention can be effected, if desired, by any procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
Suitable solvent that may be used in third and fourth aspects of the present application include, but are not limited to ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; water or mixtures thereof.
The temperature at which the third and fourth aspect may be carried out is in between about 10 °C and about 70 °C based on the solvent or mixture of used in particular step.
The processes of the present invention may also include isolation of individual intermediate or processed for further steps without isolation wherever applicable.
The boceprevir and its intermediates prepared according to the present application are having a purity of about 90.0% to about 99.9% by HPLC conditions.
The fifth aspect of the present application provides pharmaceutical compositions comprising boceprevir of formula (I) or its pharmaceutically acceptable salts prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.
Advantages of the invention:
i. The present invention provides an improved process for preparation of boceprevir.
ii. The present invention provides an improved process for preparation of compound of formula (IV) in an aromatic hydrocarbon solvent.
iii. The present invention provides an improved process for preparation of an acid of formula (V) in presence of an additive. The use of additive in the hydrolysis step reduces the reaction time and provides better yield.
iv. The present invention provides process for oxidation of hydroxy compound of formula (VII) to boceprevir using various oxidizing agents, catalyst and cocatalyst.
v. The process of the present invention is environment friendly, offers shorter reaction time, provides better yield and purity and can be practiced on industrial scale.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
A “stereo isomer” is the isomer obtained due to differences in the spatial arrangement of atoms without any differences in connectivity or bond multiplicity between the isomers.
An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcoholic solvents” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, C1-6alcohols, or the like.
A “halogenated hydrocarbon solvent” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbon solvents” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone solvent” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6ketones, 4-methyl-pentane-2-one or the like.
An “ether solvent” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6ethers, or the like.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.
EXAMPLES
Example 1: Preparation of methyl (1R,2S,5S)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (IV)
Methyl -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (II) (50g, 0.024 moles) was added to a mixture of (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid (III) (6.1g, 0.026 moles) in toluene (50ml) and cooled to 0-8°C. EDCI.HCl (6.0g, 0.031 moles) and N-methylmorpholine (6.1g, 0.060 moles) was added into the reaction mixture and stirred for 4-6 hours at 0-10°C. After the completion of reaction, water (200ml) was added to the reaction mixture and extracted with toluene (200ml). The organic layer was washed with 1N HCl and 10% sodium bicarbonate solution and brine solution. The organic layer was distilled under vacuum to provide the title compound.
Yield: 8.17g (88%)
Purity by HPLC: 96.55%
Example 2: Preparation of (1R,2S,5S)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (V)
Methyl -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (II) (20g, 0.0975 moles) was added to a mixture of (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid (III) (22.35g, 0.0972 moles) in 1:1 toluene (100ml) and dimethyl formamide (100ml) and cooled to 0-8°C. EDCI.HCl (24.20g, 0.126 moles) and N-methylmorpholine (24.57g, 0.243 moles) was added to the reaction mixture and stirred for 4-6 hours at 0-10°C. After the completion of reaction, water (200ml) was added to the reaction mixture and extracted with toluene (200ml). To the combined organic layer was added methanol (37ml) and caustic lye solution (11.67g, 0.292 moles) and stirred for 2-4 hours at room temperature. Water (740ml) was added to reaction mixture and the layers were separated. The pH of aqueous layer was adjusted to 1-2 using 2N HCl at 10-15°C and stirred for 45-60 minutes at room temperature. The obtained solid was filtered, washed with water (200ml) and dried under vacuum at 75-85°C to give title compound.
Yield: 30.67g (90.8%)
Purity by HPLC: 95.55%
Example 3: Preparation of (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (VII)
(1R,2S,5S)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (V) (10g, 0.027 moles) and 3-amino-4-cyclobutyl-2-hydroxybutanamide (VI) (6.25g, 0.029 moles) were taken in a mixture of ethyl acetate (50 ml) and dimethylformamide (50ml) and cooled to 0-8°C. EDCI.HCl (6.25, 0.032 moles), N-methylmorpholine (6.25, 0.061 moles) and hydroxy benzotriazole (11g, 0.032 moles) were added into the reaction mixture and stirred for 4-6 hours at 0-10°C. After the completion of reaction, water (100ml) was added to the reaction mixture and extracted with ethyl acetate (200ml). The organic layer was washed with 1N HCl (200ml) and 10% sodium bicarbonate solution (200ml), dried over sodium sulfate and distilled under vacuum to provide the title compound as a solid.
Yield: 12.74 g (90.0%)
Purity by HPLC: 98.04%
Example 4: Preparation of Boceprevir
Saturated solution of magnesium sulfate in water (13ml) and sodium dihydrogen phosphate dihydrate (0.46g, 0.31 moles) was added to a solution of (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (5g, 0.009 moles) in methyl tertiary butyl ether (50ml) and cooled to 10-20°C. Potassium permanganate (1.28g, 0.85 moles) was added to the reaction mixture at 10-20°C. The reaction mixture was stirred at 10-20°C for 5-6 hours. After the completion of reaction, water (50 ml) and ethyl acetate (100ml) was added to the reaction mass and filtered through hyflow bed. The organic layer was washed with water (100ml) and distilled under vacuum to get the title compound.
Yield: 4.2 g (84%)
Example 5: Preparation of Boceprevir
Oxone (3g, 0.009 moles) and 2-iodobenzoic acid (1.34g, 0.0048 moles) was added to a solution of (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (5g, 0.009 moles) in a mixture of acetonitrile and water (2:1, 45ml) and heated at 70°C for 10-12 hours. The reaction mixture was cooled to room temperature. Water (50 ml) and methyl tertiarybutyl ether was added to reaction mixture. The organic layer was separated, washed with 10% sodium bicarbonate solution (50ml) and brine (50ml). The organic layer was dried over sodium sulfate and distilled under vacuum to give the title compound.
Yield: 3.8g (76%)
Example 6: Preparation of Boceprevir
Oxone (5.6g, 0.0189 moles), tetrabutyl ammonium bromide (1.85g, 0.0057 moles) and TEMPO (0.45g, 0.0025 moles) was added to a solution of (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethyl butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (5g, 0.009 moles) in a mixture of acetonitrile and toluene (1: 2, 30ml) and stirred at room temperature for 10-12 hours. Water (30ml) and ascorbic acid (3g) was added to reaction mixture and stirred for one hour. The organic layer was separated, washed with 10% sodium bicarbonate solution (50ml), dried over sodium sulfate and distilled under vacuum to give the title compound.
Yield: 2.1g (64.5%)
,CLAIMS:We Claim:

Claim 1: A process for preparation of boceprevir of formula (I) or its stereo isomers and their pharmaceutically acceptable salts

which comprises:
(a) coupling compound of formula (II) or its pharmaceutically acceptable salts with compound of formula (III) in presence of coupling agent and base in an aromatic hydrocarbon, optionally with aprotic polar solvent to provide an azobicyclic compound of formula (IV);

wherein R= C1-C8 alkyl,; X= Cl, Br, I, F
(b) addition of alkali metal or alkaline earth metal hydroxide in the presence of an additive;
(c) treating reaction mass of step (b) with a suitable acid to provide an acid of formula (V);

(d) optionally isolating acid compound of formula (V);
(e) optionally purifying acid compound of formula (V);.
(f) coupling acid compound of formula (V) with a cyclobutyl compound of formula (VI) or its pharmaceutically acceptable salts in presence of suitable coupling agent, base and a suitable solvent to provide a hydroxy compound of formula (VII);

(g) oxidation of hydroxy compound of formula (VII) to provide boceprevir of
formula (I);

(h) optional purification of boceprevir obtained in step (g).

Claim 2: The coupling agent according to step a) of claim 1 is selected from carbonic or carboxylic mixed anhydrides, carbodiimides, 2-ethoxyl-ethoxycarbonyl-1,2-dihydroquinoline, alkyl or aryl chloroformate, trimethylacetyl chloride, 2,4,6-trichlorobenzoyl chloride, cyanuric chloride, oxalyl chloride, diethylaminosulfur trifluoride, bis (tetramethylene)fluoroformamidinium hexaflurorophosphate, dimethylformamide, Vilsmeier's reagent, phosphorus reagents, sulfur reagents, pyridinium salts, phosphonium salts, uronium salts.

Claim 3: The base according to step a) of claim 1 is selected from organic or inorganic base.

Claim 4: The additive according to step b) of claim 1 is selected from 4-dimethylaminopyridine, 1-methylimidazole, 1,2,4-triazole, 4-(1-pyrrolidino)pyridine, N-hydroxysuccinimide, imidazole, 1-hydroxybenzotriazole (HOBt).

Claim 5: A process for preparation of an acid compound of formula (V) or its steroisomers and their pharmaceutically acceptable salts thereof:

which comprises:
(a) coupling compound of formula (II) or its pharmaceutically acceptable salts with compound of formula (III) in presence of coupling agent and base in an aromatic hydrocarbon, optionally with aprotic polar solvent to provide an azobicyclic compound of formula (IV);

wherein R= C1-C8 alkyl,; X= Cl, Br, I, F
(b) addition of alkali metal or alkaline earth metal hydroxide in the presence of an additive;
(c) treating reaction mass of step (b) with a suitable acid to provide an acid compound of formula (V).

Claim 6: A process for the preparation of boceprevir which comprises:
(a) oxidation of hydroxy compound of formula (VII) with oxone in presence of one or more catalyst optionally in the presence of cocatalyst;
(b) optional purification of boceprevir obtained in step (a).

Claim 7: A process for preparation of boceprevir which comprises:
(a) oxidation of hydroxy compound of formula (VII) with permanganate in presence of one or more catalyst optionally in the presence of cocatalyst;
(b) optional purification of boceprevir obtained in step (a).
Claim 8: The catalyst according to step a) 6 and 7 of claims is selected from TEMPO, 4-methoxy TEMPO, 4-amino TEMPO, iodobenzoic acid.

Claim 9: The cocatalyst according to step a) of claims 6 and 7 is selected from potassium bromide, sodium bromide, tetrabutyl ammonium bromide.

Claim 10: The pharmaceutical compositions comprising boceprevir of formula (I) or its pharmaceutically acceptable salts prepared according to process of any preceding claims together with one or more pharmaceutically acceptable excipient, carrier and diluents.