WO2014102816A1

WO2014102816A1 - Process for preparation of telaprevir and intermediates

Info

Publication number: WO2014102816A1
Application number: PCT/IN2013/000790
Authority: WO
Inventors: Shekhar Bhaskar Bhirud; Kumar Hari Bhushan; Shekhar Ashok DESHMUKH; Amol Anant KADAM; Prem Chand; Sunil Sudhakar Zope; Sukumar Sinha; Ajit ANERAO; Mangesh TODKAR
Original assignee: Glenmark Pharmaceuticals Limited; Glenmark Generics Limited
Priority date: 2012-12-26
Filing date: 2013-12-23
Publication date: 2014-07-03

Abstract

The present invention relates to a novel process for preparation of telaprevir.

Description

PROCESS FOR PREPARATION OF TELAPREVIR AND INTERMEDIATES

PRIORITY

This application claims the benefit under 35 U.S.C.§ 119 to Indian Provisional Application No. 362 /MUM/2012, filed on Dec 26, 2012, 1380/MUM/2013 filed on April 12, 2013, United States Provisional Application No. 61765005, filed on February 14, 2013, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a novel process for preparation of telaprevir. .

BACKGROUND OF THE INVENTION

Telaprevir is a protease inhibitor belonging to the class of anti-hepatitis C virus drugs represented by compound of Formula I.

Formula I

Telaprevir is currently marketed in the United States under the trade name INCIVEK^® as film coated tablets (375 mg). INCIVEK^® is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated in combination with peginterferon alfa and ribavarin for the treatment of genotype 1 chronic hepatitis C (CHC) in adult patients with compensated liver disease, including cirrhosis, who are treatment naive or who have been previously treated with interferon-based treatment, including prior null responders, partial responders and relapsers.

United States Patent No. 7,820,671 (US'671) discloses process for preparing telaprevir, by oxidizing the compound of Formula VII. O o

CH₃

Formula VII

The process disclosed in US '671 isolates the compound of Formula VII by column chromatography. The compound of Formula VII isolated by column chromatography is then oxidized to give crude compound of formula I which is further purified by column chromatography. The process of US'671 requires use of column chromatography for isolating the intermediate compound of formula VII as well as telaprevir.

United States Patent No. 7,776,887 discloses a process for a preparation of telaprevir via compound of formula VII. The compound of formula VII is not isolated as a solid and is present as a solution in methylene dichloride solution.

Presently, we have developed a novel process wherein the compound of Formula VII is isolated, without column chromatography, as a solid having a purity greater than 99% as determined by high performance liquid chromatography (HPLC). The isolated compound of formula VII in purity greater than 99% can be used to prepare telaprevir, compound of formula I in high purity meeting ICH specifications, without any chromatographic techniques.

The process of the present invention is thus simple, industrially feasible and suited for large scale preparation of telaprevir. Telaprevir possesses six chiral centres and is optically active. The process for synthesis of telaprevir is complex involving chiral intermediates which necessitates controlling the stereoisomeric purity of telaprevir. The sources of potential chemical as well as stereoisomeric impurities in telaprevir may be from residual amounts of raw material, synthetic precursors,^' diastereoisomers, side products, residual solvents and degradation products. The use of excess reagents or various reaction conditions may lead to racemization of one or more intermediates leading to the formation of unwanted diastereoisomers of intermediates or of telaprevir. Without identification of the impurity generated in the process and a synthetic route to make reference standard thereof, it will be impossible to efficiently assay the impurity and monitor its level in the pharmaceutical product

The present invention provides compounds that can be used as reference standard /marker for quantification and identification of impurities present in samples of telaprevir or composition of telaprevir.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of telaprevir, a compound of Formula I

Formula I comprising

(a) reacting a compound of Formula II or salt thereof with a compound of Formula III to

obtain a com ound of Formula IV;

Formula II Formula III Formula IV (b) hydrolyzing the compound of Formula IV to obtain a compound of Formula V;

Formula V

(c) reacting the compound of Formula V with a compound of Formula VI or a salt thereof to obtain a compound of formula VII , wherein the compound of Formula VII is isolated as a solid without column chromatography; and

Formula VI Formula VII

(d) oxidizing the compound of Formula VII, to obtain compound of Formula I.

The present invention provides a process for purification of telaprevir, a compound of formula I, comprising

a. dissolving telaprevir, compound of formula I in a halogenated hydrocarbon to obtain a solution;

b. optionally filtering the solution;

c. adding an antisolvent to the solution to obtain a reaction mass;

d. optionally stirring the reaction mass; and

e. isolating the compound of formula I from the reaction mass.

The present invention provides a process for purification of telaprevir, a compound of formula I, the process comprising recrystallizing telaprevir from a solvent selected from the group consisting of acetonitrile, acetone methylene dichloride and ethyl acetate. The present invention provides telaprevir substantially free of one or more of the compounds of formula A, B or G as determined by HPLC.

The present invention provides a chromatographic method for testing the purity of telaprevir by determining the presence of one or more of compounds of formulae (A) to (H), the method comprising:

(a) preparing a sample solution by dissolving a sample of telaprevir in a solvent ;

(b) preparing a reference marker solution by dissolving a sample of one or more of

compounds of formulae (A) to (H);

(c) subjecting the sample solution and the reference marker solution to a chromatographic technique; and

(d) determining in the sample of telaprevir the presence of one or more of compounds of formulae (A) to (H) by reference to the presence of one or more of compounds of formulae (A) to (H) present in the reference marker solution.

The present invention provides use of one or more of the compounds of formula (A) to (H) as a reference marker or reference standard to analyze the purity of telaprevir, a compound of formula I.

The present invention provides a chiral chromatographic method for testing the purity of telaprevir by determining the presence of one or more of compounds of formulae (I) to (M), the method comprising:

(a) preparing a sample solution by dissolving a sample of telaprevir in a solvent;

compounds of formulae (I) to (M);

(d) determining in the sample of telaprevir the presence of one or more of compounds of formulae (I) to (M) by reference to the presence of one or more of compounds of formulae (A) to (H) present in the reference marker solution.

The present invention provides use of one or more of the compounds of formula (I) to (M) as a reference marker or reference standard to analyze the purity of telaprevir, a compound of formula I. DETAILED DESCRIPTION OF INVENTION

Formula I comprising

a. reacting a compound of Formula II or salt thereof with a compound of Formula III to obtain a compound of Formula IV;

Formula II Formula III Formula IV b. hydrolysing the compound of Formula IV to obtain a compound of Formula V

Formula V

c. reacting the compound of Formula V with a compound of Formula VI or a salt thereof to obtain a compound of formula VII , wherein the compound of Formula VII is isolated as a solid without column chromatography; and

Formula VI Formula VII

d. oxidizing the compound of Formula VII, to obtain compound of Formula I.

In a) of the process directly above, a compound of Formula II or salt thereof is reacted with a compound of Formula III to obtain a compound of Formula IV; wherein the reaction may be carried out in presence of peptide coupling reagents.

Examples of peptide coupling reagents include DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), EDC (l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride), BOP (benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate), PyBOP ((1 -H-l ,2,3-benzotriazol-l-yloxy)-tris(pyrrolidino)phosphonium tetrafluorophopsphate), BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), HOBT (1- hydroxybenzotriazole), FIOAT (hydroxyazabenzotriazole), HOSu (hydroxysuccinimide). The peptide coupling agent may be used singly or in combination. Preferably HOAT (hydroxyazabenzotriazole) and DCC (dicyclohexylcarbodiimide) are used.

The reaction of compound of formula II or salt thereof with compound of formula III may be earned out in an organic solvent for example halogenated hydrocarbons like ethylene dichloride, methylene dichloride and the like.

The reaction of compound of formula II or salt thereof with compound of Formula III may be carried out in the temperature range of about 10°C to 30°C. Preferably the reaction is carried out at temperature of 25°C. Preferably the compound of formula II is used.

Upon completion of reaction, the organic layer containing the compound of formula IV is subjected to acid base purification. In one embodiment, the compound of formula IV obtained by the above process may be used in an isolated form for further reaction.

In one embodiment, further reaction of compound of formula IV is carried out in the same reaction vessel.

In b) of the process directly above, the compound of formula IV may be subjected to hydrolysis to obtain a compound of Formula V. The hydrolysis may be carried out in a presence of an acid or base.

The acid for hydrolysis may be selected from a group consisting of hydrochloric acid, sulfuric acid, nitric acid and the like.

The base for hydrolysis may be selected from a group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide and the like; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate, and the like; metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate; alkali, metal alkoxides such as sodium methoxide, sodium ethoxide, sodium-tert-butoxide, potassium methoxide, potassium ethoxide, potassium-tert-butoxide lithium methoxide, lithium ethoxide, lithium-tert-butoxide and the like.

Preferably a base is used for hydrolysis of compound of formula IV to obtain a compound of formula V. For example, sodium hydroxide is used.

In one embodiment, the compound of formula V is obtained in a purity of at least 99% without column chromatography as determined by high performance liquid chromatography (HPLC).

In one embodiment, the compound of formula V is obtained in a purity of greater than 99% without column chromatography by recrystallization with toluene.

In c) of the process described directly above, the compound of Formula V is reacted with a compound of Formula VI or a salt thereof to

Formula VI obtain a compound of formula VII , wherein the compound of Formula VII is isolated as a solid, without column chromatography.

Formula VII

In one embodiment, the compound of Formula VII is isolated as a solid having a purity greater than about 99% as determined by high performance liquid chromatography (HPLC).

The reaction of compound of formula V with a compound of formula VI may be carried out in a presence of a base.The base may be selected from organic or inorganic base.

The base may be selected from tertiary amine bases such as triethylamine, diisopropylethyl amine, N-methylmorpholine, 4-Dimethylaminopyridine, pyridine, 2,6-lutidine, 1,4- diazabicyclo[2.2.2]octane (DABCO), trimethylamine, l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 2,6-di-tert-butyl-4-methylpyridine, di-tert butyl pyridine, 4-Dimethylaminopyridine and the like.

The reaction of compound of Formula V with compound of formula VI may be carried out in a presence of peptide coupling reagents. The peptide coupling agents may be selected from the groups as disclosed supra.

In one embodiment, the reaction of compound of Formula V with compound of formula VI may be carried out in presence of N-methylmorpholine and EDC (l-(3-dimethylaminopropyl)-3- ethyl-carbodiimide hydrochloride).

In one embodiment, the present invention provides a compound of Formula VII as a solid, without column chromatography, having a purity greater than 99% as determined by HPLC, obtained by a process comprising isolating the compound of Formula VII from a mixture of ethyl acetate and cyclohexane, cyclohexane, acetonitrile, acetone, dichloromethane and acetonitrile mixture, dichloromethane and acetone mixture. Preferably the compound of Formula VII is isolated from a mixture of ethyl acetate and. cyclohexane.

In one embodiment, the present invention provides a compound of Formula VII as a solid, without column chromatography, having a purity greater than 99% as determined by HPLC obtained by a process comprising stirring the crude compound of Formula VII in a mixture of ethyl acetate and cyclohexane and isolating the compound of formula VII in a purity greater than 99% as determined by HPLC, from the mixture of ethyl acetate and cyclohexane by filtration.

In one embodiment, the present invention provides a process wherein compound of Formula VII is isolated as a solid having a purity greater than 99% as determined by HPLC, without column chromatography, the process comprising recrystallizing the compound of Formula VII from a solvent selected from the group consisting of cyclohexane, acetonitrile, dichloromethane and acetone or mixtures thereof.

In one embodiment, the present invention provides a process wherein compound of Formula VII is isolated as a solid having a purity greater than 99% as determined by HPLC, without column chromatography, the process comprising a. adding cyclohexane to the compound of Formula VII;

b. distilling out cyclohexane;

c. adding ethyl acetate to step b; and

d. isolating the compound of formula VII.

In one embodiment, the present invention provides a process wherein compound of Formula VII is isolated as a solid in a purity greater than 99% as determined by HPLC, without column chromatography, the process comprising a. adding ethyl acetate to the compound of Formula VII and heating the solution;

b. adding cyclohexane to the hot solution; and

c. isolating the compound of formula VII by cooling the solution

The compound of formula VII in ethyl acetate is heated in the temperature range of about 40- 75°C. Preferably the temperature is in the range of about 65-70 °C. The cyclohexane is added to the reaction mass in the temperature range of about 40-75°C, preferably at 65-70 °C. In one embodiment the reaction mixture thus obtained is maintained in the temperature range of about 65-70 °C for a period of about 1-4 hours and stirred. The compound of formula VII is then isolated by cooling the reaction mixture and filtering out the solid.

The compound of Formula VII, obtained by the present invention is oxidized to obtain a compound of Formula I, for example with an oxidizing agent such as Dess martin periodinane, sodium hypochlorite and the like.

In one embodiment, the present invention provides a process for a preparation of compound of Formula I, the process comprising isolating a compound of Formula I from a mixture of ethyl acetate and hydrocarbon solvent.

The hydrocarbon solvent may be selected from the group consisting of hexane, cyclohexane, toluene.

In one embodiment, the present invention provides a . process for isolating compound of formula I, comprising stirring the compound of Formula I in a mixture of ethyl acetate and cyclohexane for a period of about 1 or 2 hours and filtering the compound of formula I.

In one embodiment, the present invention provides a process for purification of telaprevir, a compound of formula I, the process comprising a. dissolving telaprevir, a compound of formula I, in a halogenated hydrocarbon to obtain a solution;

b. optionally, filtering the solution;

c. adding an antisolvent to the solution to obtain a reaction mass;

d. optionally stirring the reaction mass; and

e. . isolating the compound of formula I from the reaction mass.

The halogenated hydrocarbon solvent may be selected from the group consisting of ethylene dichloride, methylene dichloride and the like.

The antisolvent may be selected from the group consisting of ethyl acetate, acetonitrile and acetone or mixtures thereof. In one embodiment, the present invention provides a process for purification of telaprevir, a compound of formula I, the process comprising a. dissolving telaprevir, a compound of formula I, in a halogenated hydrocarbon to obtain a solution;

b. optionally, filtering the solution;

c. adding acetone to the solution to obtain a reaction mass;

d. optionally stirring the reaction mass; and

e. isolating the compound of formula I from the reaction mass.

In one embodiment, the present invention provides a process for preparation of telaprevir substantially free of one or more of the compounds of formula A, B or G as determined by I I LC, the process comprising a. dissolving telaprevir, a compound of formula I, in a halogenated hydrocarbon to obtain a solution;

b. optionally, filtering the solution;

c. adding acetone to the solution to obtain a reaction mass;

d. optionally stirring the reaction mass; and

e. isolating the compound of formula I from the reaction mass.

Compound A Compound B

Compound G In one embodiment, of the present invention the telaprevir obtained has compounds of formula A, B or G to an extent of less than 0.15% w/w relative to the amount of telaprevir, preferably less than 0.05%w/w, more preferably absent.

In one embodiment, the telaprevir obtained by the process of the present invention has compounds of formula A, B or G to an extent of less than 0.15% w/w relative to the amount of telaprevir and is substantially free of diastereoisomeric impurities of compounds of formula I, J, K, L and M.

Compound M

In one embodiment, the present invention provides a process for a purification of telaprevir, a compound of formula I, the process comprising recrystallizing telaprevir from a solvent selected from a group consisting of acetonitrile, acetone, methylene dichloride and ethyl acetate or mixtures thereof. Preferably, acetonitrile or acetone or methylene dichloride.

In one embodiment, the present invention provides telaprevir having a purity greater than 99% as determined by HPLC, preferably greater than 99.5%.In one embodiment the present invention provides telaprevir having a purity of 99.9% as determined by HPLC.

In one embodiment the present invention provides use of One or more of the compounds of formula (A) to (H) as a reference marker or reference standard to analyze the purity of telaprevir, a compound of formula I.

Compound D

Compound E Compound F

Compound G Compound H A compound in a relatively pure state can be used as a "reference standard". A reference standard is similar to a "reference marker", which is used for qualitative analysis only, but is used to quantify the amount of the compound of the reference standard in an unknown mixture, as well. A reference standard is an "external standard," when a solution of a known concentration of the reference standard and an unknown mixture are analysed using the same technique. [Strobel p. 924, Snyder p. 549, Snyder, L. R.; Kirkland, J. J. Introduction to Modern Liquid Chromatography, 2nd ed. (John Wiley &Sons: New York 1979)]. The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response.

The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor", which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined. For this purpose, the reference standard is added directly to the mixture, and is known as an "internal standard

In one embodiment the present invention provides the compounds of Formula A to H in suitable ^' pure form having purity greater than 90% as determined by HPLC.

In one embodiment the present invention provides isolated compounds of Formula A, B, C, D, E, F, G or H.

In one embodiment the present invention provides telaprevir wherein one or more of the compounds of formula A, B, C, D, E, F, G or H, are present below 0.15% relative to the amount of telaprevir as determined by HPLC.

In one embodiment the present invention provides telaprevir wherein one or more of the compounds of formula A, B, C, D, E, F, G or H, are present below 0.1% relative to the amount of telaprevir as determined by HPLC.

In one embodiment the present invention provides telaprevir wherein one or more of the compounds of formula A, B, C, D, E, F, G or H, are present below 0.05% relative to the amount of telaprevir as determined by HPLC. In one embodiment the present invention provides telaprevir wherein one or more of the compounds of formula A, B, C, D, E, F, G or H, are present below 0.01% relative to the amount of telaprevir as determined by HPLC.

In one embodiment the present invention provides telaprevir substantially free of one or more of the compounds of formula A, B, C, D, E, F, G or H as determined by HPLC.

In one embodiment the present invention provides telaprevir substantially free of one or more of the compounds of formula A, B or G as determined by HPLC.

The term substantially free means the compounds of formula A, B or G are present in telaprevir to an extent of less than 0.15% w/w relative to the amount of telaprevir, preferably less than 0.05%w/w, more preferably absent.

In one embodiment the present invention provides telaprevir having one or more of the compounds of formula A, B, or G below 0.1 % w/w relative to the amount of telaprevir as determined by HPLC.

In one embodiment the present invention provides telaprevir having one or more of the compounds of formula A, B, or G below 0.05% w/w relative to the amount of telaprevir as determined by HPLC.

In one embodiment the present invention provides telaprevir wherein one or more of the compounds of formula A, B, or G are absent as determined by HPLC. ^

In one embodiment the present invention provides use of one or more of the compounds of formula A, B, or, G as a reference marker or reference standard to analyze the purity of telaprevir, a compound of formula I.

In one embodiment the present invention provides telaprevir having one or more impurities observed in HPLC at relative retention time (RRT) and having mass m/z value as characterized by mass spectrometry as tabulated below in less than 0.15% w/w relative to the amount of telaprevir as determined by HPLC. Preferably one or more impurities are less than 0.05% w/w relative to the amount of telaprevir, more preferably absent.

Ideally, chromatographic separations work with the differential elution of components. As such, elution time corresponds to peak to peak responses. It is well established that the conventional measurement in minutes between injection of the sample on column and elution of the particular component through the detector provides a component's "retention time". Thus, the impurities in telaprevir can be identified by their corresponding elution time in the chromatogram. However, variants, including but not limited to instrumentation, operator, sample preparation and many other factors affect elution time. To circumvent these variances, "relative retention time" is used, where a reference standard is used to normalize the elution time of each component.

"Relative retention time" of a component is its retention time divided by retention time of the reference marker (main peak). Here, Telaprevir is used as the reference marker, which has a retention time of about 35.23 minutes.

HPLC methodology:

Related substances by HPLC: Reagents, Solvents and Standards: Water (Milli Q or equivalent) Acetonitrile (HPLC Grade); Methanol (HPLC Grade); Tris Buffer (GR Grade)

Chromatographic Conditions: Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software. Column: Xterra RP-18, 250 x 4.6mm, 5μ; Column

temperature: 40°C; Mobile Phase A: Buffer; Buffer: 0.01M Tris Buffer [Tris

(hydroxymethyl)aminomethane] in water. Mobile Phase B: Acetonitrile: Methanol (90: 10, v/v)

Time (min.) % Mobile Phase A % Mobile Phase B

0.01 75 25

45 35 65

65 35 65 68 75 25

75 75 25

Diluent: Water: Acetonitrile (20:80, v/v) ; Flow Rate: l .OmL/minute; Detection: UV 270nm; Injection Volume: 20μΙ,

Preparation of Reference solution: Transfer about lOO.Omg of Telaprevir inhouse reference standard, accurately weighed into a 50mL volumetric flask. Add about 25-30ml of diluent and sonicate to dissolve and mix. Make up to the mark with diluent and mix. Dilute 5 mL of this solution to 50 mL with the diluent and mix. Further dilute 1.0 mL of this solution to 100 ml with diluent and mix.

Preparation of Test Solution: Transfer about lOO.Omg of sample, accurately weighed into a 50mL volumetric flask. Add about 25-30ml of diluent and sonicate to dissolve. Make up to the mark with diluent and mix. Procedure: Separately inject the equal volumes of blank solution, six replicate injection of reference solution and then inject test solution in duplicate into the liquid chromatograph. Record the responses eliminating the peaks due to blank. The retention time of main peak i.e. Telaprevir is about 35.23 minutes under these conditions. System suitability test: The relative standard deviation determined from the reference solution in six replicate injections should not be more than 5.0%.

Note: Test solution should be freshly prepared before injection

In one embodiment the present invention provides a chromatographic method for testing the purity of telaprevir by determining the presence of one or more of compounds of formulae (A) to (H), the method comprising:

(b) preparing a reference marker solution by dissolving a sample of one or more of compounds of formulae (A) to (H);

(c) subjecting the sample solution and the reference marker solution to a chromatographic

technique; and

(d) determining in the sample of telaprevir the presence of one or more of compounds of

formulae (A) to (H) by reference to the presence of one or more of compounds of formulae (A) to (H) present in the reference marker solution.

In one embodiment, the present invention provides a chromatographic method for testing the purity of telaprevir by determining the presence of one or more compounds of formula (A) to (H) in the sample of telaprevir, the method comprising comparing the retention time in HPI , of the different components of the sample of telaprevir separated by said chromatographic method with the retention of the compounds of formulae (A) to (H) under the same chromatographic conditions (stationary phase, mobile phase, temperature and pressure).

In one embodiment, the present invention provides a method for assessing the purity of telaprevir, the method comprising using one or more of compounds of formulae (A) to (H) as reference marker to determine the concentration of said one or more compounds of formulae (A) to (H) respectively.

In one embodiment, the present invention provides telaprevir substantially free of diastereoisomeric impurities of compounds of formula I, J, K, L and M.

In one embodiment, the present invention provides telaprevir substantially free of one or more of the compounds of formula A, B or G as determined by HPLC and substantially free of diastereoisomeric impurities of compounds of formula I, J, K, L and M.

In one embodiment, the present invention provides a chiral chromatographic method for testing the purity of telaprevir by determining the presence of one or more of compounds of formulae (I) to (M), the method comprising:

compounds of formulae (I) to (M);

(d) determining in the sample of telaprevir the presence of one or more of compounds of formulae (I) to (M) by reference to the presence of one or more of compounds of formulae (I) to (M) present in the reference marker solution. In one embodiment, the present invention provides use of one or more of the compounds of formula (I) to (M) as a reference marker or reference standard to analyze the purity of telaprevir, a compound of formula I.

In one embodiment, the present invention provides a process for preparing a compound of Formula VIII, from a compound of formula IX, the process comprising

Formula VIII Formula IX hydrolysing a compound of formula IX with acid; then reacting with BOC anhydride to obtain compound of formula VIII;- optionally, converting the compound of formula VIII to a compound of formula II by methods known in the art.

In one embodiment, the present invention provides a process for preparing a compound of Formula VI from a compound of formula X, wherein P is a protecting group such as t- butyloxycarbonyl, benzyloxycarbonyl and the like, the process comprising

Formula VI Formula X treating a compound of formula X with a base, wherein P is t-butyloxycarbonyl; and deprotecting the resulting compound obtained with an acid to obtain compound of formula VI. The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

Examples

Example 1 Preparation of compound of formula IV:

To a mixture of compound of formula III (50g) in dichloromethane (375mL), was added 1- hydroxyazotriazole (23.5g) and dicyclohexyl carbodiimide (DCC) (41.1 g) and the mixture was stirred for about 60min at about 10°C to about 30°C. Compound of formula-II free base in 500mL dichloromethane solution (38 g compound of formula-II. HCl was converted to free base by using aq. ammonia, water and dichloromethane) was slowly added at about 10°C to about 20°C. The reaction mixture was stirred for about 6h at about 10°C to 25°C. Demineralized water was added to the mixture and the mixture was stirred for about 30min. The residue was filtered. The organic layer was separated. The organic layer was washed with 6N aqueous HCl and 5% aqueous sodium bicarbonate solution. Finally, the organic layer was washed with water. The organic layer was concentrated under reduced pressure to completely obtain compound of formula IV. The reaction mass containing compound of formula IV was used per se for further reaction.

Example 2 Preparation of compound of formula IV:

To a mixture of compound of formula III (50g) in dichloromethane (375mL), was added 1- hydroxybenzotriazole (25) and DCC (41.1 g) and the mixture was stirred for about 60min at about 10°C to 30°C. Compound of formula-II free base in 500mL dichloromethane solution (38 g compound of formula-II.HCl was converted to free base by using aq. ammonia, water and dichloromethane) was slowly added at about 10°C to 20°C. The reaction mixture was stirred for about 6h at about 10°C to 25°C. Demineralized water was added to the mixture and the mixture was stirred for about 30min. The residue was filtered. The organic layer was separated. The organic layer was washed with 6N aqueous HCl and 5% aqueous sodium bicarbonate solution. Finally, the organic layer was washed with water. The organic layer was concentrated under reduced pressure to obtain completely compound of formula IV. The reaction mass containing compound of formula IV was used as is for further reaction.

Example 3 Preparation of compound of formula IV: To a mixture of compound of formula III (50g) in dichloromethane (375mL), was added 1- hydroxyazotriazole and l -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC.HC1) (45.0g) and stirred for about 60min at about 10°C to 30°C. Compound of formula-II free base in 500mL dichloromethane solution (38 g compound of formula-II.HCl was converted to free base by using aq. ammonia, water and dichloromethane) was slowly added at about 10°C to 20°C. The reaction mixture was stirred for about 6h at about 10°C to 25°C. Demineralized water was added to the mixture and the mixture was stirred for about 30min. The residue was filtered. The organic layer was separated. The organic layer was washed with 6N aqueous HC1 and 5% aqueous sodium bicarbonate solution. Finally, the organic layer was washed with water. The organic layer was concentrated under reduced pressure to obtain completely compound of formula IV. The reaction mass containing compound of formula IV was used neat for further reaction.

Example 4 Preparation of compound of formula IV:

To a mixture of compound of formula III (50g) in dichloromethane (375mL), was added 1- hydroxybenzotriazole (25g) and EDC.HC1 (45.0g) and stirred for about 60min at about 10°C to about 30°C. Compound of formula-II free base in 500mL dichloromethane solution (38 g compound of formula-II.HCl was converted to a free base by using aq. ammonia, water and dichloromethane) was slowly added at about 10°C to 20°C. The reaction mixture was stirred for about 6h at about 10°C to 25°C. Demineralized water was added to the mixture and the mixture was stirred for about 30min. The residue was filtered. The organic layer was separated. The organic layer was washed with 6N aqueous HC1 and 5% aqueous sodium bicarbonate solution. Finally, the organic layer was washed with water. The organic layer was concentrated under reduced pressure to obtain completely compound of formula IV. The reaction mass containing compound of formula IV was used as is for further reaction.

Example 5 Preparation of compound of formula V:

Methanol (120mL) was added to the reaction mass containing compound of formula IV, and stirred for about lOmin to give a clear solution. 2N aqueous sodium hydroxide solution was slowly added into the reaction mixture. The reaction mixture was stirred for about 2h. Thereafter, the reaction mixture was concentrated completely. Water (210mL) and ethyl acetate were added to the residue and the mixture was stirred. The organic layer and aqueous layer were separated. The aqueous layer was washed with ethyl acetate and the acidity of the aqueous layer was adjusted to a pH of about 1 to 2 with 6N HCl. The reaction mixture was extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the reaction mass was degassed for about 2h at about 50°C to 55°C under reduced pressure. Toluene was added and the reaction mass was heated to about 70°C to 80°C. The reaction mass was maintained for about 30min. The reaction mass was gradually cooled to about 20°C to 30°C and maintained at about the same temperature for about an hour. The solid obtained was filtered and washed with toluene (lOOmL). The product was dried in vacuum tray drier at about 40°C to 45°C for about 12h. Yield: 15.23g (75% wrt compound of formula-Ill; HPLC purity: >99%)

Example 6 Preparation of compound of formula VII:

15. Og of compound of formula V was charged in dichloromethane (150mL). l-(3- dimethylaminopropyl)-3-ethyl-carbodiiiTiide hydrochloride (6.45g) and 1-hydroxybenzotriazole (5.1g) were added and the reaction mass was stirred for about lh. Compound of formula VI free base (6.75g) was added (compound of formula VI HCl was converted to base by using aq. Ammonia, water and dichloromethane (MDC)). The reaction mass was cooled to about 5°C to 10°C. N-methylmorpholine (4.8mL) was slowly added at about 5°C to 10°C. The reaction mass was stirred for about lh. The temperature of the reaction mass was raised to about 20°C to 25 °C and maintained for about 12h. The reaction mass was washed with 50% aq. hydrochloric acid, 10%) aq. potassium carbonate and water. The organic layer was concentrated. Ethyl acetate and cyclohexane mixture (75mL) were added and the reaction mass was stirred for about 30min. The product was filtered; and then dried in vacuum tray drier at about 40°C to 45°C for about 12 h. Yield: 17.5 g (90%); HPLC purity: > 94.0%

Example 7 Preparation of compound of formula VII:

15.0 g of compound of formula V was charged in dichloromethane (150mL).l-(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI.HC1) (6.45g) and hydroxyazabenzotriazole (HOAt) (5.1 g) were added and the reaction mass was stirred for about lh. Compound of formula VI free base (6.75g) was added. (Initially, a compound of formula VI HCl was converted to base form by using aq. Ammonia, water and MDC). The reaction mass was cooled to about 5°C to about 10°C. N-methylmorpholine (4.8 ml) was slowly added at about 5-10°C. The reaction mass was stirred for about lh and the reaction temperature was raised to about 20 to about 25°C and maintained for about 12h. The reaction mass was washed with 50% aq. hydrochloric acid, 10% aq. potassium carbonate and water. The organic layer was concentrated. Ethyl acetate and cyclohexane mixture (75mL) was added and the reaction mass was stirred for about 30min. The solid obtained was filtered and dried in vacuum tray drier at about 40°C to about 45°C for about 12 h. Yield: 17.5g (90%)

Example 8 Preparation of compound of formula VII:

50.0 g of compound of formula V was charged in dichloromethane (500mL). l -(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDO. HQ) (24.16g) and 1 - hydroxybenzotriazole (HOBt) (17 g) was added and the reaction mass was stirred for about lh. The reaction mass was cooled to about 5°C to about 10°C and compound of formula VI.HC1 (26.85g) was added. N-methylmorphiline solution (29.52g dissolved in 50mL dichloromethane) was added by maintaining the reaction mass temperature at about 5°C to about 10°C. The reaction mass was maintained for about 120min at about 20°C to about 25°C. The reaction mass was washed with demineralized water, 50% aq. hydrochloric acid, 10% aq. potassium carbonate and water. The organic layer was concentrated. Cyclohexane (500mL) was added and partly distilled out; then ethyl acetate (50mL) was added. The reaction mass was stirred for about 60min. The solid obtained was filtered and dried in vacuum tray drier at about 40°C to about 45°C for about 12 h. Yield: 55g (83%)

Example 9 Preparation of compound of formula VII:

50. Og of compound of formula V was charged in dichloromethane (500mL). l-(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI.HC1) (24.16g) and 1- hydroxybenzotriazole (HOBt) (20g) was added and the reaction mass was stirred for about lh. The reaction mass was cooled to about 5°C to about 10°C and compound of formula VI.HC1 (26.85 g) was added. N-methylmorphiline solution (29.52g dissolved in 50mL dichloromethane) was added by maintaining the reaction mass temperature at about 5°C to about 10°C. The reaction mass was maintained for about 120min at about 20°C to about 25°C. The reaction mass was washed with demineralized water, 50% aq. hydrochloric acid, 10% aq. potassium carbonate and water. The organic layer was concentrated. Cyclohexane (250mL) was added and cyclohexane (l OOmL) was partly distilled out. Ethyl acetate (50mL) was then added and the reaction mass was stirred for about 60min. The solid obtained was filtered and dried in vacuum tray drier at about 40°C to about 45°C for about 12 h. Yield: 55 g (83%)

Example 10 Preparation of compound of formula VII:

15.0g of compound of formula V was charged in dichloromethane (150mL). Dicyclohexyl carbodiimide (DCC) (5.8g) and 1 -hydroxybenzotriazole (HOBt) (5.1g) was added and the reaction mass was stirred for about lh. Compound of formula VI free base (6.75 g) (compound of formula VI HCl was converted to base by using aq. Ammonia, water and MDC) was then added. The reaction mass was cooled to about 5°C to about 10°C. N-methylmorpholine (4.8mL) was slowly added at about 5°C to about 10°C. The reaction mass was stirred for about lh and the reaction mass temperature was raised to about 2°C 0 to about 25 °C and maintained for about 12h. The reaction mass was washed with demineralized water, 50% aq. hydrochloric acid, 10% aq. potassium carbonate and water. The organic layer was concentrated. : Ethyl acetate and cyclohexane mixture (75mL) was added. The reaction mass was stirred for about 30min. The solid obtained was filtered and dried in vacuum tray drier at about 40°C to about 45°C for about 12 h. Yield: 17.5 g (90%)

Example 11 Preparation of compound of formula VII:

15.0g of compound of formula V was charged in dichloromethane (150mL). Dicyclohexyl carbodiimide DCC (5.8g) and 1 -hydroxybenzotriazole (HOBt) (5.1g) was added and the reaction mass was stirred for about lh. Compound of formula VI HCl was then added. The reaction mass was cooled to about 5°C to about 10°C. N-methylmorpholine (4.8mL) was slowly added at about 5°C to about 10°C. The reaction mass was stirred for about lh and the reaction mass temperature was raised to about 20°C to about 25 °C and maintained for about 12h. The reaction mass was washed with demineralized water, 50% aq. hydrochloric acid, 10% aq. potassium carbonate and water. The organic layer was concentrated. Ethyl acetate and cyclohexane mixture (75mL) was added. The reaction mass was stirred for about 30min. The solid obtained was filtered and dried in vacuum tray drier at about 40°C to about 45°C for about 12 h. Yield: 17.5g (90%)

Example 12 Preparation of compound of formula VII: 15. Og of compound of formula V was charged in dichloromethane (150mL). DCC (5.8g) and hydroxyazabenzotriazole (HO At) (6. lg) was added and the reaction mass was stirred for about lh. Compound of formula VI free base (6.75 g) (compound of formula VI HC1 was converted to base by using aq. Ammonia, water and MDC) was then added. The reaction mass was cooled to about 5°C to about 10°C. N-methylmorpholine (4.8mL) was slowly added at about 5°C to about 10°C. The reaction mass was stirred for about lh and the reaction mass temperature was raised to about 20°C to about 25 °C and maintained for about 12h. The reaction mass was washed with 50% aq. hydrochloric acid, 10% aq. potassium carbonate and water. The organic layer was concentrated. Ethyl acetate and cyclohexane mixture (75mL) was added. The reaction mass was stirred for about 30min, filtered the product. The solid obtained was filtered and dried in vacuum tray drier at about 40°C to about 45°C for about 12 h. Yield: 17.5g (90%)

Example 13 Preparation of compound of formula VII:

15.0g of compound of formula V was charged in dichloromethane (150mL). DCC (5.8g) and hydroxyazabenzotriazole (HO At) (6.1g) was added and the reaction mass was stirred for about lh. Compound of formula VI HC1 was the added. The reaction mass was cooled to about 5°C to about 10°C. N-methylmorpholine (4.8mL) was slowly added at about 5°C to about 10°C. The reaction mass was stirred for about lhr and the reaction mass temperature was raised to about 20°C to about 25°C and maintained for about 12h. The reaction mass was washed with 50% aq. hydrochloric acid, 10% aq. potassium carbonate and water. The organic layer was concentrated. Ethyl acetate and cyclohexane mixture (75mL) was added. The reaction mass was stirred for about 30min, filtered the product. The solid obtained was filtered and dried in vacuum tray drier at about 40°C to about 45°C for about 12 h. Yield: 17.5 g (90%)

Example 14 Purification of compound of formula VII:

A mixture of compound of formula VII (5g) in acetonitrile (50mL) was heated to about 60°C to about 70°C and maintained for about 30min. The reaction mass was gradually cooled to about 20°C to about 30°C and maintained at about the same temperature for about 60min. The solid obtained was filtered, washed with acetonitrile and dried at about 40°C to about 45°C for about 12h. Yield: 3.50g; HPLC purity: >99.0%.

Example 15 Purification of compound of formula VII: A mixture of compound of formula VII (5g) in acetone (20mL) was heated to about 50°C and maintained at about the same temperature for about 60min to give a clear solution. The reaction mass was gradually cooled to about 5°C to about 10°C. The reaction mass was stirred for about 2h at about the same temperature. The solid obtained was filtered, washed with acetone and dried at about 40°C to about 45°C for about 12h. Yield: 3.50g; HPLC purity: >99.0%.

Example 16 Purification of compound of formula VII:

A mixture of compound of formula VII (5g) in cyclohexane (50mL) was heated to about 70°C and at about the same temperature for about 60min. The reaction mass was gradually cooled to about 25°C to about 30°C. The reaction mass was stirred for about 2h at about the same temperature. The solid obtained was filtered, washed with cyclohexane and dried at about 40°C to about 45°C for about 12h. Yield: 3.50g; HPLC purity: >98.0%.

Example 17 Preparation of telaprevir:

To a stirred mixture of compound of formula VII (5g) in dichloromethane (50mL) cooled to about 10°C to about 20°C, was slowly added Dess martin periodinane (DMP) (3.4g) lot wise. The reaction mixture was stirred for about 12h at about 10°C to about 20°C. Ethyl acetate (50mL) and 10% sodium metabisulphite aqueous solution was added to the stirred reaction mixture and the two layers were separated. The organic layer was washed with sodium bicarbonate aqueous solution. The organic layer was concentrated under reduced pressure. A mixture of ethyl acetate and cyclohexane was added to the residue and the mixture was stirred for about 60min at about 20°C to 30°C. The solid obtained was filtered and dried at about 40°C to about 45°C for about 12h. Yield: 3.45g (70%); HPLC purity: >98.5%.

Example 18 Preparation of telaprevir:

To a stirred mixture of compound of formula VII (5g) in dichloromethane (50mL) cooled to about 10°C to about 20°C, was slowly added Dess martin periodinane (DMP) (3.4g) lot wise. The reaction mixture was stirred for about 12h at about 10°C to about 20°C. Ethyl acetate (50mL) and 10% sodium sulphite aqueous solution was added to the stirred reaction mixture and the two layers were separated. The organic layer was washed with 7% sodium bicarbonate aqueous solution. The organic layer was concentrated under reduced pressure. A mixture of ethyl acetate and cyclohexane was added to the residue and the mixture was stirred for about 60min at about 20°C to 30°C. The solid obtained was filtered and dried at about 40°C to about 45°C for about 12h. Yield: 3.45g (70%); HPLC purity: >98.5%.

Example 19 Preparation of telaprevir:

To a stirred mixture of compound of formula VII (5g) in dichloromethane (50mL) cooled to about 10°C to about 20°C, was slowly added Dess martin periodinane (DMP) (3.4g) lot wise. The reaction mixture was stirred for about 12h at about 10°C to about 20°C. Ethyl acetate (50mL) and 10% sodium sulphite aqueous solution was added to the stirred reaction mixture and the two layers were separated. The organic layer was washed with 7% sodium bicarbonate aqueous solution. The organic layer was concentrated under reduced pressure. Acetone (l OmL) was added to the residue and distilled out completely. Dichloromethane (lOmL) was added at about 25°C to about 30°C to the residue and the mixture was stirred for about lOmin to give a clear solution. Acetone (75mL) was added to the mixture at about 25°C to about 30°C and the mixture was heated to about reflux temperature and maintained at about the same temperature for about 60min. The mixture was gradually cooled to about 25°C to about 30°C and maintained at about the same temperature for about 60min. The solid obtained was filtered, washed with acetone and dried at about 40°C to about 45°C for about 12h under vacuum. Yield: 3.75 g (75%); HPLC purity: >99.0%.

Example 20 Preparation of telaprevir:

To a stirred mixture of compound of formula VII (5g) in dichloromethane (50mL) cooled to about 10°C to about 20°C, was slowly added Dess martin periodinane (DMP) (3.4g) lot wise. The reaction mixture was stirred for about 12h at about 10°C to about 20°C. Ethyl acetate (50mL) and 10% sodium sulphite aqueous solution was added to the stirred reaction mixture and the two layers were separated. The organic layer was washed with 7% sodium bicarbonate aqueous solution. The organic layer was concentrated under reduced pressure. Dichloromethane (15mL) was added at about 25°C to about 30°C to the residue and the mixture was stirred for about lOmin to give a clear solution. Acetonitrile (75mL) was added to the mixture at about 25 °C to about 30°C and the mixture was heated to about reflux temperature and maintained at about the same temperature for about 60min. The mixture was gradually cooled to about 25°C to about 30°C and maintained at about the same temperature for about 60min. The solid obtained was filtered, washed with acetonitrile and dried at about 40°C to about 45°C for about 12h under vacuum. Yield: 3.75 g (75%); HPLC purity: >99.0%.

Example 21 Preparation of telaprevir:

To a stirred mixture of compound of formula VII (5g) in dichloromethane (50mL) cooled to about 10°C to about 20°C, was slowly added Dess martin periodinane (DMP) (3.4g) lot wise. The reaction mixture was stirred for about 12h at about 10°C to about 20°C. Ethyl acetate (50mL) and 10% sodium sulphite aqueous solution was added to the stirred reaction mixture and the two layers were separated. The organic layer was washed with 7% sodium bicarbonate aqueous solution. The organic layer was concentrated under reduced pressure. Dichloromethane (lOmL) was added to the residue at about 25 °C to about 30°C and the mixture was stirred for about lOmin to give a clear solution. Ethyl acetate (105mL) was added at about 25°C to about 30°C and the mixture was heated to about reflux temperature and maintained at about the same temperature for about 60min. The mixture was gradually cooled to about 25°C to about 30°C and maintained at about the same temperature for about 60min. The solid obtained was filtered, washed with ethyl acetate (lOmL) and dried at about 40°C to about 45 °C for about 12h under vacuum. Yield: 3.75 g (75%); HPLC purity: >99.0%.

Example 22 Preparation of telaprevir:

To a stirred mixture of compound of formula VII (5g) in dichloromethane (50mL) cooled to about 10°C to about 20°C, was slowly added Dess martin periodinane (DMP) (3.4g) lot wise. The reaction mixture was stirred for about 12h at about 10°C to about 20°C. Ethyl acetate (50mL) and 10% sodium, sulphite aqueous solution was added to the stirred reaction mixture and the two layers were separated. The organic layer was washed with 7% sodium bicarbonate aqueous solution. The organic layer was concentrated under reduced pressure. Acetone (25mL) was added to the residue at about 25°C to about 30°C and the mixture was heated to about reflux temperature and maintained at about the same temperature for about 60min. The mixture was gradually cooled to about 25°C to about 30°C and maintained at about the same temperature for about 60min. The solid obtained was filtered, washed with acetone and dried at about 40°C to about 45°C for about 12h under vacuum. Yield: 4.0g (80%); HPLC purity: >99.0%. Example 23 Preparation of telaprevir:

To a stirred mixture of compound of formula VII (5g) in dichloromethane (50mL) cooled to about 10°C to about 20°C, was slowly added Dess martin periodinane (DMP) (3.4g) lot wise. The reaction mixture was stirred for about 12h at about 10°C to about 20°C. Ethyl acetate (50mL) and 10% sodium sulphite aqueous solution was added to the stirred reaction mixture and the two layers were separated. The organic layer was washed with 7% sodium bicarbonate aqueous solution. The organic layer was concentrated under reduced pressure. Ethyl acetate (25mL) was added at about 25°C to about 30°C to the residue and the mixture was heated to about reflux temperature and maintained at about the same temperature for about 60min. The mixture was gradually cooled to about 25°C to about 30°C and maintained at about the same temperature for about 60min. The solid obtained was filtered, washed with ethyl acetate (lOmL) and dried at about 40°C to about 45°C for about 12h under vacuum. Yield: 4.0g (80%); HPLC purity: >99.0%.

Example 24 Purification of telaprevir:

A mixture of telaprevir (5g) in dichloromethane (lOmL) was stirred for about lOmin at about 20°C to about 25°C to give a clear solution. The reaction mass was filtered and ethyl acetate (105mL) was added to it. The reaction mass was stirred for about 2h at about 20°C to about 25°C. The solid obtained was filtered, washed with ethyl acetate and dried at about 40°C to about 45°C for about 12h. Yield: 3.50g (70%); HPLC purity: >99.6%.

Example 25 Purification of telaprevir:

A mixture of telaprevir (5 g) in dichloromethane (l OmL) was stirred for about lOmin at about 20°C to about 25°C to give a clear solution. The reaction mass was filtered and acetonitriie (105mL) was added at about 20°C to about 25°C. The reaction mass was stirred for about 2h at about the same temperature. The solid obtained was filtered, washed with acetonitriie and dried at about 40°C to about 45°C for about 12h. Yield: 3.50g (70%); HPLC purity: >99.6%.

Example 26 Purification of telaprevir.

A mixture of telaprevir (5g) in acetonitriie (50mL) was heated to about 60°C and maintained at about the same temperature for about 60min. The reaction mass was gradually cooled to about 20°C to about 25°C. The reaction mass was stirred for about 2h at about the same temperature. The solid obtained was filtered, washed with acetonitrile and dried at about 40°C to about 45°C for about 12h. Yield: 3.50g (70%); HPLC purity: >99.6%.

Example 27 Purification of telaprevir:

A mixture of telaprevir (5g) in acetone (25mL) was heated to about reflux temperature and maintained at about the same temperature for about 60min. The reaction mass was gradually cooled to about 20°C to about 25°C. The reaction mass was stirred for about 2h at about the same temperature. The solid obtained was filtered, washed with acetone and dried at about 40°C to about 45°C for about 12h. Yield: 3.50g (70%); HPLC purity: >99.6%.

Example 28 Purification of telaprevir:

To a mixture of dichloromethane and ethyl acetate (0.5:21.0) was added telaprevir (5g) and the mixture was heated to about 40°C and maintained at about the same temperature for about 30min. The reaction mass was gradually cooled to about 20°C to about 25°C. The reaction mass was stirred for about 2h at about the same temperature. The solid obtained was filtered, washed with ethyl acetate and dried at about 40°C to about 45°C for about 12h. Yield: 3.50g (70%); HPLC purity: >99.5%.

Example 29 Purification of telaprevir:

A mixture of telaprevir (5g) in dichloromethane (lOmL) was stirred at about 20°C to about 25°C to give a clear solution. Acetone (75mL) was added to the clear solution and the reaction mass was heated to about reflux temperature and maintained at about the same temperature for about 60min. The reaction mass was gradually cooled to about 20°C to about 25°C. The reaction mass was stirred for about 2h at about the same temperature. The solid obtained was filtered, washed with acetone and dried at about 40°C to about 45°C for about 12h. Yield: 3.50g (70%); HPLC purity: >99.6%.Particle size distribution dlO: 18 μ; d50: 53μ; d90: 99 μ.

Example 30 Preparation of compound of formula VIII:

To lg of compound of formula IX, 10 ml of hydrochloric acid was added. The reaction mass was heated and stirred for about 2 hours. The reaction was basified and extracted with methylene dichloride. To the methylene dichloride layer was added 0.5 g of BOC -anhydride and the reaction mass was stirred for about 2-3 hours. The organic layer was washed with brine and evaporated to get the compound of formula VIII.

Example 31 Preparation of compound of formula VI: To 1 g of compound of formula X, wherein P is t-butyloxycarbonyl, was added methylene dichloride and potassium hydroxide. The mixture was stirred for about 2-3 hours and the pH was adjusted to neutral. The organic layer was evaporated to dryness. Hydrochloric acid was added to the residue obtained and the compound of formula VII was isolated after completion of reaction.

Example 32 Preparation of (IS, 3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2- ylcarbonyl) amino]acetyl}amino)-3,3- dimethylbutanoyl]octahydrocyclopenta[c]pyrrole-l- carboxamide . compound of formula A:

To 10.0 g of (l S,3aR,6aS)-N-((S)-3-deutero-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl)- 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- ethylbutanoyl)octahydrocyclopenta[c] pyrrole- 1 -carboxamide, 100 ml of MDC was added. The reaction mass was cooled to about 0°C-5°C and triethyl amine (1.28 g ,1.9 mole), was added and the reaction mass was stirred for about 30 min at about 0°C-5°C . Dess martin periodinane (9.5g , 2.0 mol) was added at about 0-5°C and the reaction mass was stirred at about 20-30°C for about 36 hrs .The reaction mass was cooled to about 0-5°C . 10% of (35 ml)of aqueous solution of sodium sulphite was added and the reaction mass was stirred for about 30 min. 50 ml of ethyl acetate was added and the reaction mass was^'stirred for about 15 min and the organic layer was separated and washed with 10% aqueous solution of sodium sulphite followed by washing with 10% aqueous solution of sodium bicarbonate. The organic layer was separated and washed with DM water. The organic layer was distilled at about 35-40°C under vacuum to obtained 6.0 g of compound of formula A which was purified by column chromatography using dichloromethane and methanol.

Example 33 Preparation of (lS,3aR,6aS)-N-[(3S)-l-amino-l,2-dioxohexan-3-yI]-2-[(2S)-2- ({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl] octahydrocyclopenta[c]pyrrole-l-carboxamide, compound of formula B: To 7.0g of (l S,3aR,6aS)-N-((S)-3-deutero-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl)-2-

((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- ethylbutanoyl)octahydrocyclopenta[c]

pyrrole- 1-carboxamide, 70 ml of MDC was added. Dess martin periodinane (7.7 g ,1.5 mol) at 20-25 °C was added and the reaction mass was heated at about 40°C for about 24 hrs. The heating was stopped and the reaction mass was cooled to about 0-5°C. 10% of (35 ml) of aqueous solution of sodium sulphite was added and the reaction mass was stirred for about 30 min. 35 ml of ethyl acetate was added and the reaction mass was stirred for about 15 min and the organic layer was separated and washed with 10% aqueous solution of sodium sulphite followed by washing with 10% aqueous solution of sodium bicarbonate. The organic layer was separated and washed with DM water. The organic layer was distilled at about 35-40°C under vacuum to obtained 6.0 g of compound of formula A which was purified by column chromatography using dichloromethane and methanol.

Example 34 Preparation of Cyclopenta[c]pyrrole-l-carboxamide, (2S)-2-cyclohexyl-N-(2- pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-[(lS)-l-[lR-(acetyloxy)-2- (cyclopropylamino)-2-oxoethyl] butyl] hexahydro-, lS,3aR,6aS), compound of formula E:

To (l S,3aR,6aS)-N-((S)-3-deutero-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl)-2-((S)-2- ((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- ethylbutanoyl)octahydrocyclopenta[c]pyrrole-l- carboxamide, 50 ml of MDC was added. The reaction mass was cooled to about 0°C-5°C and triethyl amine (1.1 1 g ,1.5 mole) was added and stirred the reaction mass for about 30 min at about 0°C-5°C . Acetic anhydride (1.12 g ,1.5 mol) was added at about 0-5°C and the reaction mass further stirred at about 20-25°C for about 16 hrs. The organic layer was washed with water, separated and distilled out under vacuum to obtain 4.5 g of Impurity E which was isolated by preparative HPLC.

Example 35 Preparation of Cyclopenta[c]pyrrole-l-carboxamide, (2S)-2-cyclohexyl-N-(2- pyrazinylcarbonyl)glycyI-3-methyl-L-valyl-N-[(lS)-l-[lS-(acetyloxy)-2-(cyclopropylamino)- 2-oxoethyl]butyl]hexahydro-, (lS,3aR,6aS)- compound of formula F:

To (l S,3aR,6aS)-N-((S)-3-deutero-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl)-2-((S)-2- ((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- ethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxamide 50 ml of MDC was added. The reaction mass was cooled to about 0°C-5°C and triethyl amine (1.1 1 g ,1.5 mole) was added and stirred the reaction mass for about 30 min at about 0°C-5°C . Acetic anhydride (1.12 g , 1.5 mol) was added at about 0-5°C and further stirred the reaction mass at about 20-25°C for about 16 hrs. The organic layer was washed with water, separated and distilled out under vacuum to obtain 4.5 g of Impurity F which was isolated by preparative HPLC.

Example 36 Preparation of (IS, 3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyI-2-[(pyrazin-2- ylcarbonyl)amino] acetyl} amino)-3,3-dimethylbutanoyl] -N- [(2R)-pentan-2- yljoctahydrocyclo penta[c]pyrroIe-l-arboxamide. compound of formula G: To 10.0 g of (l S,3aR,6aS)-N-((S)-3-deutero-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl)-2-((S)-2- ((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- ethylbutanoyl)octahydrocyclopenta[c] pyrrole- 1 -carboxamide, 100 ml of MDC was added. The reaction mass was cooled to about 0°C-5°C and triethyl amine (1.28 g ,1.9 mole) was added and reaction mass was stirred for about 30 min at about 0°C-5°C . Dess martin periodinane (9.5g , 2.0 mol) was added at about 0-5°C and the reaction mass was stirred at about 20-30°C for about 36 hrs . The reaction mass was cooled to about 0-5°C. 10% of aqueous solution of sodium sulphite was added and the reaction mass was stirred for about 30 min.50 ml of ethyl acetate was added and the reaction mass was stirred for about 15 min and the organic layer was separated and washed with 10% aqueous solution of sodium sulphite followed by washing with 10% aqueous solution of sodium bicarbonate. The organic layer was separated and washed with DM water. The organic layer was distilled at about 35-40°C under vacuum to obtained 6.0 g of compound of formula A which was purified by column chromatography using, dichlorome thane and methanol.

Example 37 Cyclopenta[c]pyrrole-l-carboxamide, (2S)-2-cyclohexyl-N-(2- pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-[(lR)-l-[lR-(acetyloxy)-2- (cyclopropylamino)-2-oxoethyl]butyl]hexahydro-, (lS,3aR,6aS)- compound of formula H:

To 12.0 g of compound of formula V was added 120 ml of MDC. l-Hydroxy-7-azabenzotriazole (HOAt) (3.94 ,1.24 mole) and EDCI.HC1(5.43 g ,1.5 mole) was added at 20-25° and the reaction mass was stirred for next 60 min at 20°C-25°C. The reaction mass was cooled to 10-15°C and Hexanamide, 3-amino-N-cyclopropyl- 2-hydroxy-, (3R)- (6.5g ,1.25 mol) was added at 10-15°C and stirred the reaction mass for 10 min at 20-25°C . N-methyl morphiline (7.08 g, 3.0 mol) was added to the reaction mass in 30 min at 10-15 °C. Thereafter the reaction mass was stirred at 20- 25°C for 120 min. On completion of reaction, DM water was Added. The organic layer was separated and washed with 3NHC1 followed by washing with 7% sodium bicarbonate solution and washing with DM water .The organic layer was distilled at 35-40°C under vacuum to obtain crude compound 15.6 g and isolated by column chromatography.

Example 38 Preparation of telaprevir :

To a stirred mixture of compound of formula VII (120g) in dichloromethane (1200mL) sodium acetate (14.43 g) was added and the reaction mass was stirred for 30 min. The reaction mass was cooled to 0-5 °C and slowly 5 lots of Dess martin periodinane (DMP) (22.4g) were added. The reaction mass temperature was raised up to 20-25°C and was stirred for 120 min. The reaction mass was cooled to 10-15°C and 10% sodium sulphite aqueous solution was added to the reaction mixture followed by addition of ethyl acetate (600 ml). The reaction mass was stirred for 20 min and the two layers were separated. The organic layer was washed with 7% sodium bicarbonate aqueous solution. The organic layer was separated and charcoalised with Norit carbon at 25-30°C and the reaction mass was filtered on hyflo bed and washed hyflo bed with dichloromethane. The solvent was distilled off below 50°C under reduced pressure. The reaction mass was degassed under vacuum and cooled the product to 45°C. Acetone (1200 ml) was added and the reaction mass was heated to reflux for 60 min with stirring. The reaction mass was cooled and stirred for 120 min at 20-25°C. The product was filtered and suck dried and the wet cake was washed with acetone. The wet cake was dried in vacuum tray drier at temp 50-55°C under reduced pressure.

Example 39 Preparation of compound of formula V:

Methanol (500mL) was added to the reaction mass containing compound of formula IV, and stirred for about 1 Omin to give a clear solution. Aqueous sodium hydroxide solution was slowly added into the reaction mixture. The reaction mixture was stirred for about 2h. Thereafter, the reaction mixture was concentrated completely. Water and Toluene (were added to the residue and the mixture was stirred. The reaction mass was filtered through hyflo bed thereafter organic layer and aqueous layer were separated. The aqueous layer again was washed with toluene and the aqueous layer pH was adjusted to about 1 to 2 with HC1. The reaction mixture was stirred and the product filtered and washed with water and dried at 50-55°C. Toluene was added to the crude compound of formula V and the reaction mass was heated to about 70°C to 80°C. The reaction mass was cooled to about 20°C to 30°C and maintained for about an two hour. The solid obtained was filtered and washed with toluene (lOOmL). The product was dried in vacuum tray drier at about 40°C to 45°C for about 12h. Yield: 40g (HPLC purity: >99%)

Example 40 Preparation of compound of formula VII:

50 g of compound of formula V was charged in dichloromethane (500mL). Hydroxyazabenzotriazole (HO At) (16.42g) and (EDCI.HC1) (22.63g) were added and the reaction mass was stirred for about lh. Compound of formula VI HC1 (27.10g) was added. The reaction mass was cooled to about 0°C to about 10°C. N-methylmorpholine solution (29.52 g dissolved in 50 ml MDC ml) was slowly added at about 5-10°C. The temperature of reaction mass was raised to 25-30 °C. The reaction mass was stirred for about 2h and water and MDC were added to the reaction mass and stirred. The organic layer was separated and washed with aq. hydrochloric acid, aq. sodium bicarbonate and water. The organic layer was treated with activated charcoal & filtered through hyflo bed. The organic layer was concentrated. Ethyl acetate (150ml) was added to the residue & the reaction mass was heated to 65-70°C and cyclohexane (750mL) was added to the reaction mass at 65-70°C .The reaction mass was stirred at 65-70°C for 2h and cooled to 25-30°C and stirred. The solid obtained was filtered and dried in vacuum tray drier at about 50°C to about 55°C for about 12 h. Yield: 47.5-57.5g (0.95-1.15 wrt compound of formula-V; HPLC purity: >99%)

Example 41 Preparation of Telaprevir:

A stirred mixture of compound of formula VII (60g) in dichloromethane (600mL) was cooled to about 0°C to about 5°C. Dess martin periodinane (DMP) (56g) was added lot wise. The temperature of reaction mixture was raised to 20-25°C.The reaction mixture was stirred for about 2hours at about 20°C to about 25°C. Ethyl acetate and 10% sodium sulphite aqueous solution were added to the stirred reaction mixture and the two layers were separated. The organic layer was washed with sodium bicarbonate aqueous solution and finally with, water. The organic layer was charcoaled with activated charcoal & filtered through hyflo bed. The organic layer was concentrated under reduced pressure. Acetone (600mL) was added to the residue. The reaction mass was heated to reflux for 60 min. The reaction mass was cooled to 25-30°C and stirred for about 60min. The solid obtained was filtered washed with acetone and dried in vacuum tray drier at about 50°C to about 55°C for about 12 h. Yield: 42-5 lg ( HPLC purity: >98%)

Example 42 Purification of Crude Telaprevir: A mixture of crude Telaprevir (l OOg) in dichloromethane (500mL) was stirred at about 20°C to about 25 °C to give a clear solution. The clear solution was filtered through micron filter. The filtrate was concentrated under reduced pressure completely. MDC was added and the reaction mass was stirred followed by addition of Acetone (lOOOmL) to the reaction mass. The reaction mass was stirred for about 150 minutes at about the same temperature. The solid obtained was filtered and washed with acetone. The wet product obtained was dissolved in MDC (200ml) and the reaction mass was stirred. Acetone (660mL) was added to the reaction mass. The reaction mass was stirred for about 150Min. at about the same temperature. The solid obtained was filtered, washed with acetone and dried at about 50°C to about 55°C for about 12h. Yield: 45-55g (Telaprevir HPLC purity: 99.75%, Single max impurity NMT 0.05% & Total impurity NMT 0.5%.

Impurity profile: Impurity A=0.01%; B= 0.04%; C= BDL; D = BDL ; E = 0.04%; F=BDL; G= 0.05%; H= 0.05%

Diastereoisomeric impurities: I-M -Each less than 0.15%

Particle size distribution dlO: 18 μ; d50: 53 μ; d90: 99 μ.

Example 43 Preparation of Chiral isome J-(lS,3aR,6aS)-2-[(2R)-2-({(2S)-2-cyclohexyI-2- [(pyrazin-2-ylcarbonyl)amino] acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)- l(cyclopropyIamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole-l-carboxamide.

(R)-2-((S)-2-cycloheyl-2-(pyrazine-2-carboxamido)acetamido)-3,3dimethylbutanoic acid was coupled with (l S,3aR,6aS)-ethyloctahydrocyclopenta[c]pyrrole-l-carboxylate in presence of 1- Hydroxy-7-azabenzotriazole and N.N'-Dicyclohexylcarbodiimide in MDC to obtain Cyclopenta[c]pyrrole-l -carboxylic acid, 2-[(2R)-2-[[(2S)-2-cyclohexyl-2-[(2- pyrazinylcarbonyl)amino] acetyl] amino] -3 ,3 -dimethyl- 1 -oxobutyl] octahydro-ethylester,

(! S,3aR,6aS) which was hydrolyzed by sodium hydroxide in presence of water and methanol to obtain Cyclopenta[c]pyrrole-l-carboxylic acid, 2-[(2R)-2-[[(2S)-2-cyclohexyl-2-[(2-pyrazinyl carbonyl)amino]acetyl]amino]-3,3-dimethyl-l-oxobutyl]octahydro (l S,3aR,6aS) which was recrystallized in toluene and coupled with Hexanamide, 3-amino-N-cyclopropyl- 2-hydroxy- Hydrochloride (1 :1), (3S) by using l-Hydroxy-7-azabenzotriazole and l-Ethyl-3-(3- dimethyllaminopropyl) carbodiimide hydrochloride in dichloromethane and N-methyl morpholine as base followed by recrystallization in ethyl acetate and cyclohexane to obtain (l S,3aR,6aS)-Cyclopenta[C]pyrrole-l-carboxamide,(2S)-2-cyclohexyl-N-(2- pyrazinylcarbonyl)glycyl-3 -methyl -D-valyl-N-[( I S)- 1- [2-(cyclopropylamino)-l-hydroxy-2- oxoethyl]butyl]octahydro which was oxidized with Dess martin periodinane in dichloromethane which was further recrystallized with MDC and acetone mixture to give the title compound.

Example 44 Preparation of Chiral isomer M -(lS,3aR,6aS)-2-[(2R)-2-({(2R)-2-cyclohexyI- 2-[(pyrazin-2-ylcarbonyl)amino] acetyI}amino)-3,3-dimethyIbutanoyl]-N-[(3S)- l(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a_i4,5,6,6a-hexahydro-lH- cyclopenta [c] pyrrole-1 -carboxamide

(R)-2-((R)-2-cycloheyl-2-(pyrazine-2-carboxamido)acetamido-3,3dimethylbutanoic acid was coupled with (l S,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-l-carboxylate in presence of 1 - Hydroxy-7-azabenzotriazole and N, N'-Dicyclohexylcarbodiimide in MDC to obtain cyclopenta[c]pyrrole- 1 -carboxylic acid, 2- [(2R)-2-[[(2R)-2-cyclohexyl-2- [(2-pyrazinyl carbonyl)amino]acetyl]amino]-3,3-dimethyl-l-oxobutyl]octahydro-ethylester,(l S,3aR,6aS), which was hydrolyzed by sodium hydroxide in presence of water and methanol to obtain cyclopenta[c]pyrrole-l -carboxylic acid, 2-[(2R)-2-[[(2R)-2-cyclohexyl-2-[(2- pyrazinylcarbonyl)amino] acetyl] amino] -3 ,3 -dimethyl- 1 -oxobuty 1] octahydro-, ( 1 S ,3 aR,6aS) which was recrystallized from toluene and coupled with Hexanamide, 3-amino-N-cyclopropyl- 2-hydroxy-, Hydrochloride (1 : 1), (3S) by using 1 -Hydroxy-7-azabenzotriazole and l-Ethyl-3-(3- dimethyllaminopropyl) carbodiimide hydrochloride in Dichloromethane and with N-methyl morpholine as base followed by recrystallization in ethyl acetate and cyclohexane to obtain (l S,3aR,6aS)-Cyclopenta[c]pyrrole-l -carboxamide, (2R)-2-cyclohexyl-N-(2- pyrazinylcarbonyl)glycyl-3-methyl-D-valyl-N-[(l S)-l-[2-(cyclopropylamino)-l-hydroxy-2- oxoethyl]butyl]octahydro,which was oxidized with Dess martin periodinane in dichloromethane and further recrystallized with MDC and acetone mixture to give title compound Example 45 Preparation of Chiral isomer I-(lS,3aR,6aS)-2-[(2S)-2-({(2R)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyi)amino] acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)- l(cyclopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole-l-carboxamide

(S)-2-((R)-2-cycloheyl-2-(pyrazine-2-carboxamido)acetamido-3,3-dimethylbutanoic acid was coupled with(l S,3aR,6aS)-ethyl octahydrocyclopenta [c]pyrrole-l-carboxylate in presence of l-Hydroxy-7-azabenzo.triazole and N,N'-Dicyclohexylcarbodiimide in MDC to obtain

Cyclopenta[c]pyrrole-l-carboxylic acid, 2-[(2S)-2-[[(2R)-2-cyclohexyl-2-[(2-pyrazinyl carbonyl)amino]acetyl]amino]-3,3-dimethyl-l-oxobutyl]octahydro-ethylester, (l S,3aR,6aS) which was hydrolyzed by sodium hydroxide in presence of water and methanol. to obtain Cyclopenta[c] pyrrole- 1 -carboxylic acid, (2R)-2-cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3- methyl-L-valyloctahydro-, (l S,3aR,6aS) which was recrystallized in toluene and coupled with Hexanamide, 3-amino-N-cyclopropyl- 2-hydroxy-, Hydrochloride (1 :1), (3S) by using 1- Hydroxy-7-azabenzotriazole and l-Ethyl-3-(3-dimethyllaminopropyl) carbodiimide

hydrochloride in dichloromethane and using N-methyl morpholine as base followed by recrystallization in ethyl acetate and cyclohexane to obtain (l S,3aR,6aS)-Cyclopenta[c]pyrrole- 1 -carboxamide, (2R)-2-cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-[(l S)-l- [2-(cyclopropylamino)-l -hydroxy-2-oxoethyl]butyl]octahydro which was oxidized with Dess martin periodinane in dichloromethane which is further recrystalize with MDC and acetone mixture to give title compound.

Example 46 Preparation of Chiral isomer K- (IS, 3aR, 6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyl)amino] acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3R)- l(cycIopropylamino)-l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole-l-carboxamide

(2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine was coupled with

(l S,3aR,6aS)-ethyl octahydrocyclopenta [c]pyrrole-l-carboxylate in presence of l-Hydroxy-7- azabenzotriazole and NiN'-Dicyclohexylcarbodiimide in MDC to obtain Cyclopenta[c]pyrrole-l - carboxylic acid, 2-[(2S)-2-[[(2S)-2-cyclohexyl-2-[(2-pyrazinyl carbonyl)amino] acetyl] amino] - 3, 3 -dimethyl- l -oxobutyl]octahydro-ethylester, (l S,3aR,6aS).which was hydrolyzed by sodium hydroxide in presence of water and methanol to obtain Cyclopenta[c]pyrrole-l-carboxylic acid, (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valyloctahydro-, (l S,3aR,6aS) which was recrystallized in toluene and couple dwith Hexanamide, 3-amino-N-cyclopropyl- 2- hydroxy-, Hydrochloride (1 : 1), (3R) by using l-Hydroxy-7-azabenzotriazoIe and l-Ethyl-3-(3- dimethyllaminopropyl) carbodiimide hydrochloride in dichloromethane and use N-methyl morpholine as base followed by recrystallization in ethyl acetate and cyclohexahe to obtain ((l S,3aR,6aS)-Cyclopenta[C]pyrrole-l-carboxamide,(2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl)glycyl-3-methyl-L-valyl-N-[(lR)-l-[2-(cyclopropylamino)-l-hydroxy-2- oxoethyl] butyl] octahydro which was oxidized with Dess martin periodinane in dichloromethane which is further recrystallize with MDC and acetone mixture to give (I S, 3aR, 6aS)-2-[(2S)-2- ({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl) amino] acetyl}amino)-3,3-dimethylbutanoyl]-N- [(3R)-l(cyclopropylamino)-l ,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole-l-carboxamide.

Example 47 Preparation of ((i:l,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2- ylcarbonyl)amino] acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-l(cyclopropylamino)-l,2- dioxohexan-3-yI]-3,3a_»4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide

(2S)-2-cyclohexyl-n-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine was coupled with (l:l,3aR,6aS)-ethyl octahydrocyclopenta [c]pyrrole-l-carboxylate in presence of l-Hydroxy-7- azabenzotriazole and N,N'-Dicyclohexylcarbodiimide in MDC to obtain Cyclopenta[c]pyrrole-l- carboxylic acid, 2-[(2S)-2-[[(2S)-2-cyclohexyl-2-[(2-pyrazinyl carbonyl)amino] acetyl] amino] - 3,3-dimethyl-l-oxobutyl]octahydro-ethylester, (l:l,3aR,6aS) which was hydrolyzed by sodium hydroxide in presence of water and methanol to obtain Cyclopenta[c]pyrrole-l-carboxylic acid, (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valyloctahydro-, (l:l,3aR,6aS) which was recrystallize in toluene and coupled with Hexanamide, 3-amino-N-cyclopropyl- 2- hydroxy-, Hydrochloride (1 : 1), (3S) by using l-Hydroxy-7-azabenzotriazole and l-Ethyl-3-(3- dimethyllaminopropyl) carbodiimide hydrochloride in Dichloromethane and use N-methyl morpholine as base followed by recrystallization in ethyl acetate and cyclohexane to obtain ((l:l,3aR,6aS)-Cyclopenta[C]pyrrole-l-carboxamide,(2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl)glycyl-3 -methyl-L-valyl-N-[( 1 S)- 1 - [2-(cyclopropylamino)- 1 -hydroxy-2- oxoethyl] butyl] octahydro which is oxidized with Dess martin periodinane in dichloromethane which is further recrystallized with MDC and acetone mixture to give ((1:1), 3aR, 6aS)-2-[(2S)- 2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl) amino] acetyl}amino)-3,3-dimethylbutanoyl]- N- [(3 S)- 1 (cyclopropylamino)- 1 ,2-dioxohexan-3 -yl] -3 ,3 a,4,5 ,6 ,6a-hexahydro- 1 H- cyclopenta[c]pyrrole- 1 -carboxamide

Claims

1. A process for the preparation of telaprevir, a compound of Formula I

Formula I

comprising a, reacting a compound of Formula II or salt thereof with a compound of Formula III to obtain a compound of Formula IV;

Formula II Formula III Formula IV

b. hydrolyzing the compound of Formula IV to obtain a compound of Formula V;

Formula V

Formula VI Formula VII

d. oxidizing the compound of Formula VII, to obtain compound of Formula I.

2. The process as claimed in claim 1, wherein the compound of Formula VII is isolated as a solid in purity greater than 99% as determined by HPLC.

3. The process as claimed in claim 2, comprising isolating the compound of Formula VII from a mixture of ethyl acetate and cyclohexane.

4. The process as claimed in claim 3, comprising

a. adding ethyl acetate to the compound of Formula VII and heating the solution;

b. adding cyclohexane to the hot solution; and

c. isolating the compound of formula VII by cooling the solution.

5. The process as claimed in claim 2, comprising isolating the compound of Formula VII by recrystallizing the compound of Formula VII from a solvent selected from the group consisting of cyclohexane, acetonitrile, dichloromethane and acetone or mixtures thereof.

6. The process as claimed in claim 1, wherein compound of Formula IV is subjected to acid base purification.

7. The process as claimed in claim 1, wherein compound of Formula IV is not isolated from the reaction mixture.

8. A process for purification of telaprevir, a compound of formula I, comprising

b. optionally filtering the solution; c. adding an antisolvent to the solution to obtain a reaction mass;

d. optionally stirring the reaction mass; and

e. isolating the compound of formula I from the reaction mass.

The process as claimed in claim 8, wherein the antisolvent is selected from a group consisting of acetonitrile, acetone or mixtures thereof.

The process as claimed in claim 9 wherein the telaprevir obtained is substantially free of or more of the compounds of formula A, B or G as determined by HPLC.

Compound A Compound B

Compound G 1. The process as claimed in claim 10 wherein telaprevir obtained is substantially free of diastereoisomeric impurities of compounds of formula I, J, K, L and M.

Compound I Compound J

Compound M

12. A process for purification of telaprevir, a compound of formula I, the process comprising recrystallizing telaprevir from a solvent selected from the group consisting of acetonitrile, acetone, methylene dichloride and ethyl acetate.

13. Telaprevir substantially free of one or more of the compounds of formula A, B or G as determined by HPLC.

14. Telaprevir as claimed in claim 13 and substantially free of diastereoisomeric impurities of compounds of formula I, J, K, L and M.

15. A chromatographic method for testing the purity of telaprevir by determining the presence of one or more of compounds of formulae (A) to (H), the method comprising:

compounds of formulae (A) to (H);

(e) determining in the sample of telaprevir the presence of one or more of compounds of formulae (A) to (H) by reference to the presence of one or more of compounds of formulae (A) to (H) present in the reference marker solution.

16. Use of one or more of the compounds of formula (A) to (H) as a reference marker or reference standard to analyze the purity of telaprevir, a compound of formula I.

17. A chiral chromatographic method for testing the purity of telaprevir by determining the presence of one or more of compounds of formulae (I) to (M), the method comprising:

compounds of formulae (I) to (M);

(d) determining in the sample of telaprevir the presence of one or more of compounds of formulae (I) to (M) by reference to the presence of one or more of compounds of formulae (I) to (M) present in the reference marker solution.

18. Use of one or more of the compounds of formula (I) to (M) as a reference marker or reference standard to analyze the purity of telaprevir, a compound of formula I.