Claims:1. A process for the preparation of Telaprevir of formula I(a),

comprising the steps of:
a) reacting compound of formula II

with compound of formula III

in presence of propylphosphonic anhydride and organic base in a suitable solvent to obtain compound of formula IV(a)

wherein, the reaction is carried out by addition of compound of formula II to the compound of formula III;
b) reacting compound of formula IV(a) with base in a suitable solvent at a temperature between -25 °C to -5 °C to obtain compound of formula V(a);

c) reacting compound of formula V(a) with compound of formula VI

in presence of propylphosphonic anhydride and organic base to obtain compound of formula VII(a); and

d) oxidizing compound of formula VII(a) using suitable oxidizing agent to obtain compound of formula I(a).

2. A process for the preparation of Telaprevir of formula I(a), comprising the steps of:
a) reacting compound of formula II

with compound of formula III

in presence of propylphosphonic anhydride and organic base in a suitable solvent to obtain compound of formula IV(a)

wherein, the reaction is carried out by adding the compound of formula II to the compound of formula III;
b) converting the compound of formula IV(a) to Telaprevir of formula I(a).

3. The process according to claim 1 and 2, wherein the solvent in step (a) is selected from methylene chloride, ethyl acetate, tetrahydrofuran, toluene, dimethylformamide or mixture thereof.

4. The process according to claim 1, wherein the solvent in step (b) is selected from water, dimethylformamide, dimethylsulfoxide, monoglyme, diglyme or lower alcohols selected from methanol, ethanol, propanol, isopropanol or mixture thereof.

5. A process for the preparation of Telaprevir of formula I(a), comprising the steps of:
a) reacting compound of formula IV(a)

with base to obtain compound of formula V(a);

wherein the reaction is carried out at a temperature between -25 °C to -5 °C;
b) reacting compound of formula V(a) with compound of formula VI

in presence of propylphosphonic anhydride and organic base to obtain compound of formula VII(a); and

c) oxidizing compound of formula VII(a) to obtain compound of formula I(a).

6. The process according to claim 1 and 5, wherein the organic base is N-methylmorpholine or alkylamine.

7. The process according to claim 1 and 5, wherein the base is alkali metal hydroxides, alkaline earth metal hydroxides or ammonium hydroxide.

8. The process according to claim 1 and 5, wherein the reaction of compound of formula IV(a) with base is carried out at -10 °C to -15 °C.

9. The process according to claim 5, wherein the solvent in step (b) is selected from water, dimethylformamide, dimethylsulfoxide, monoglyme, diglyme or lower alcohols selected from methanol, ethanol, propanol, isopropanol or mixture thereof.

10. The process according to claim 1 and 5, wherein the oxidizing agent is selected from Des-Marin-Periodinane (DMP) or 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO).
, Description:Field of the Invention

Present invention relates to an improved process for the preparation of stereoisomerically pure Telaprevir of formula I(a).

Background of the Invention

Telaprevir is an inhibitor of the HCV NS3/4A protease and indicated for the treatment of genotype 1 chronic hepatitis C (CHC).

The IUPAC name of Telaprevir is (1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl} amino)-3,3-dimethylbutanoyl]-N-[(3S)-1(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] pyrrole-1-carboxamide. Its molecular formula is C36H53N7O6 and molecular weight is 679.85.

Telaprevir and a process for the preparation thereof was described in U.S. Patent No. 7,820,671.

Various processes for the preparation of Telaprevir have been also disclosed in US 7,776,887; US 2012/0329704 and US 2015/0038677, etc. Each of these references cited herein are incorporated in their entirety by reference.

However, the processes disclosed in the prior art references yield Telaprevir that requires further column chromatography purifications in order to get the pharmaceutical grade quality. Further, one of the undesired products, (R)-diastereomer of Telaprevir of a formula I(b) is approximately 30-fold less active than Telaprevir. Some of the impurities found in the Telaprevir product obtained by prior art processes are compounds selected from the group comprising of compound of formula IV(b), compound of formula V(b), compound of formula VII(b), and compound of formula I(b).

;
;

;

In order to prepare Telaprevir free from undesired products according to prior art processes require several purification steps like column chromatography, which make these processes unfeasible for the industrial scale production of Telaprevir.

Hence, there is a need to develop an alternative process suitable for the industrial scale production of Telaprevir.

Objects of the Invention

One aspect of the present invention is to provide an improved process, which allows industrial scale production of Telaprevir.

Another aspect of the present invention is to provide a process for the preparation of stereoisomerically pure Telaprevir.

Yet another aspect of the present invention is to provide stereoisomerically pure Telaprevir wherein undesired stereoisomer is not detectable.

Summary of the Invention

In one aspect, the present invention is directed to a process for the preparation of Telaprevir of formula I(a),

includes the steps of:
a) reacting compound of formula II

with compound of formula III

in presence of propylphosphonic anhydride and organic base to obtain compound of formula IV(a)

wherein, the reaction is carried out by adding the compound of formula II to the compound of formula III;
b) reacting compound of formula IV(a) with base to obtain compound of formula V(a)

wherein the reaction is carried out at a temperature between -25° to -5° C;
c) reacting compound of formula V(a) with compound of formula VI

in presence of propylphosphonic anhydride and organic base to obtain compound of formula VII(a); and

d) oxidizing compound of formula VII(a) to obtain compound of formula I(a).

In another aspect, the present invention is directed to a process for the preparation of Telaprevir of formula I(a), includes the steps of:
a) reacting compound of formula II

with compound of formula III

in presence of propylphosphonic anhydride and organic base to obtain compound of formula IV(a)

wherein, the reaction is carried out by adding the compound of formula II to the compound of formula III;
b) converting the compound of formula IV(a) to Telaprevir of formula I(a).

In yet another aspect, the present invention is directed to a process for the preparation of Telaprevir of formula I(a), includes the steps of:
a) reacting compound of formula IV(a)

with base to obtain compound of formula V(a);

wherein the reaction is carried out at a temperature between -25° to -5° C;
b) reacting compound of formula V(a) with compound of formula VI

in presence of propylphosphonic anhydride and organic base to obtain compound of formula VII(a); and

c) oxidizing compound of formula VII(a) to obtain compound of formula I(a).

Detailed Description of the Invention

The present invention relates to an improved process for the preparation of Telaprevir of formula I(a), which allows large-scale industrial production of stereoisomerically pure Telaprevir.

The term “stereoisomeric” purity used herein refers to the “enantiomeric” purity and/or “diastereomeric” purity of a compound. The term “stereoisomerically pure" as used herein, is meant to encompass those compounds are substantially free from undesired stereoisomers. The term “stereoisomerically pure" Telaprevir as used herein further meant to encompass Telaprevir having stereoisomeric purity at least 95%, preferably at least 97%, and more preferably at least 99%.

In one aspect of the present invention, compound of the formula II is reacted with compound of the formula III in presence of propylphosphonic anhydride and organic base to obtain compound of the formula IV(a) in a suitable solvent at a suitable temperature. In the preferred aspects, the reaction of compound of the formula III with the compound of the formula II is carried out by addition of compound of the formula II to the compound of the formula III.

The organic base is selected from the group comprising of N-methylmorpholine or alkylamines. The alkylamines are selected from triethylamine, di-isopropyl amine or diisopropyl ethylamine. The suitable solvent is selected from methylene chloride, ethyl acetate, tetrahydrofuran, toluene, dimethylformamide or mixture thereof. The reaction is carried out at -30 ºC to 50 ºC.

In another aspect of the present invention, compound of the formula IV(a) is reacted with base at a temperature in the range between -25 °C to -5 °C. The base is selected from the group comprising of alkali metal hydroxides, alkaline earth metal hydroxides or ammonium hydroxide. The alkali metal hydroxides are selected from lithium hydroxide, sodium hydroxide or potassium hydroxide and the alkaline earth metal hydroxide is selected from magnesium hydroxide or calcium hydroxide. The reaction is carried out in a solvent selected from water, dimethylformamide, dimethylsulfoxide (DMSO), monoglyme, diglyme or lower alcohols selected from methanol, ethanol, propanol, isopropanol or mixture thereof. In the preferred aspects of the present invention, the hydrolysis of compound of formula IV(a) is carried out using 10% aqueous sodium hydroxide.

In one more aspect of the present invention, compound of the formula V(a) is reacted with the compound of the formula VI in presence of propylphosphonic anhydride and organic base in a suitable solvent to obtain compound of the formula VII(a). The organic base is selected from the group comprising of N-methylmorpholine or alkylamines selected from triethylamine, di-isopropyl amine or diisoprpyl ethylamine. The solvent is selected from methylene chloride, ethyl acetate or mixture thereof. In one aspect, the reaction is carried out at -20 °C to 50 °C.

The obtained compound of the formula VII(a) is further purified by crystallization using a suitable solvent selected from the group comprising of ethyl acetate, toluene, cyclohexane, n-heptane, diisopropyl ether, or mixture thereof. Alternatively, compound of formula VII(a) is further purified by acid-base treatment.

In one more aspect, the compound of formula VII(a) is oxidized using suitable oxidizing agents in a suitable solvent to obtain Telaprevir of formula I(a). The oxidizing agent is selected from the group comprising of Des-Marin-Periodinane (DMP) or 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO). The solvent is selected from the group comprising of methylene chloride, toluene, DMSO or mixture thereof.

In one more aspect, the crude Telaprevir is optionally purified by crystallization using suitable solvent to obtain Telaprevir pure. The solvent is selected from the group comprising of ethyl acetate, ethanol, water, isopropanol, methanol, dimethylsulfoxide, acetonitrile, diglyme, monoglyme, heptane, methylene chloride or mixture thereof.

In one more aspect of the present invention, Telaprevir obtained by the process described herein can be used in a pharmaceutical composition.

In one aspect of the present invention, area percentage of the stereoisomeric impurities in Telaprevir and intermediates thereof is carried out by using HPLC method.

Present invention is further illustrated with the following non-limiting examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Examples:

Example-1: Preparation of Ethyl (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta [c]pyrrole-1-carboxylate

Methylene chloride (100 ml) was charged in a flask and compound of formula II (5 gm) was added and then distilled the methylene chloride partially at atmospheric pressure. The reaction mass was cooled to -10 °C to -15 °C. N-methylmorpholine (2.95 gm) and propylphosphonic anhydride solution in ethyl acetate (9.31 ml 50 %) were added to the reaction mass. The obtained reaction mass (RM-1) was stirred. In another flask, methylene chloride (45 ml) was charged and compound of formula III (3.8 gm) was added; then the methylene chloride was distilled partially at atmospheric pressure and cooled to -10 to -15 °C to get reaction mass (RM-2). The above prepared solution of RM-1 was added to the solution of RM-2 at -10 to -15°C and stirred. The obtained reaction mass was washed with brine solution; concentrated under vacuum and dried to get the title compound.
Yield: 3.5 gm.
HPLC purity: 80.62%, Undesired R-isomer: 13.51%.

Example-2: Preparation of Ethyl (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta [c]pyrrole-1-carboxylate

Methylene chloride (25 ml) was charged in a flask and compound of formula II (5 gm) was added. The reaction mass was cooled to -20 °C to -15 °C. N-methyl morpholine (2.95 gm) and propylphosphonic anhydride solution in ethyl acetate (9.5 ml 50 %) were added to the reaction mass. The obtained reaction mass (RM-1) was stirred. In another flask, methylene chloride (25 ml) was charged and compound of formula III (4.37 gm) was added and cooled to -20 to -25 °C to get reaction mass (RM-2). The above prepared solution of solution of RM-1 was added to the solution of RM-2 at -20 to -25°C and stirred the reaction mass. The reaction mass was washed with brine solution; concentrated under vacuum and dried to get the title compound.
Yield: 3.3 gm
HPLC purity: 78.40%, Undesired R-isomer: 13.61%

Example-3: Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid

Methanol (34 ml) was charged in a flask and of compound of formula IV(a) (3.4 gm) was added and then the reaction mass was cooled to -5 to -10°C. To the reaction mass 10% aq. NaOH solution (10.2 ml) was added and stirred the reaction mass. 10% aqueous HCl solution was added to the reaction mass. The obtained reaction mass was concentrated under vacuum and then water was added. The reaction mass was stirred and filtered to get the solid, which is dried to get the title compound.
Yield: 3.2 gm
HPLC purity: 84.72%, Undesired R-isomer: 13.62%

Example-4: Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

Methylene chloride (21 ml) was charged in a flask and then added compound of formula V(a) (3 gm) and compound of formula VI (1.95 gm). To the obtained reaction mass added diisopropylethylamine (2.25 gm) and propylphosphonic anhydride solution in Ethyl acetate (4.07 ml 50%) and stirred the reaction mass. The reaction mass was washed with water followed by wash with 1N HCl solution and brine solution. The obtained reaction mass was concentrated under vacuum and dried to get solid of title compound.
Yield: 3.0 gm.
HPLC purity: 91.36%.

Example-5: Preparation of Telaprevir

Methylene chloride (15 ml) was charged in a flask and compound of formula VII(a) (3 gm) was added, followed by addition of TEMPO (0.04 gm) and 5% aqueous sodium bicarbonate solution (12 ml). The obtained reaction mass was cooled to 0°C and slowly added 10-13% sodium hypochlorite solution (3.6 ml). Stirred the reaction mass and layers were separated. Organic layer was washed with water, followed by wash with 1% aqueous sodium sulfite solution and then added acetic acid (0.03 gm). The reaction mass was concentrated under vacuum and added ethyl acetate (24 ml). The obtained reaction mass was stirred, filtered and obtained solid was dried to get title compound.
Yield: 1.3 gm
HPLC purity: 95.63%, Undesired R-isomer: 1.96%

Example-6: Purification of Telaprevir

Ethyl acetate (5 ml) was charged into a flask and above obtained crude Telaprevir (0.5 gm) was added. TO the obtained solution ethyl acetate (5 ml) was added and heated to get clear solution and then methylene chloride (2 ml) and methanol (2 ml) were added. Filtered the clear solution. The obtained reaction mass was partially concentrated under vacuum. Stirred the reaction mass and filtered the solid. The obtained solid was dried to get Telaprevir Pure.
Yield: 0.4 gm
HPLC purity: 97.91%, Undesired R-isomer: Not detected

Comparative Example - 1: Preparation of Ethyl (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl) octahydrocyclopenta[c]pyrrole-1-carboxylate

Methylene chloride (50 ml) was charged in a flask and compound of formula II (5 gm) was added. The reaction mass was cooled to 0 °C to 5 °C. N-methylmorpholine (2.95 gm) and propylphosphonic anhydride solution in ethyl acetate (5.75 ml 50%) were added to the reaction mass. The obtained reaction mass (RM-1) was stirred. In another flask, methylene chloride (50 ml) was charged and compound of formula III (7.0 gm) was added and cooled to 0 °C to 5 °C to get reaction mass (RM-2). The solution of RM-2 was added to the above prepared solution of RM-1 at 0 °C to 5 °C and stirred the reaction mass. The obtained reaction mass was concentrated under vacuum and dried to get the title compound.
Yield: 3.3 gm
HPLC purity: 58.48%, Undesired R-isomer: 18.35%

Comparative Example - 2: (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid

Charged methylene chloride (150ml) in a flask and added compound of formula IV(a) (15 gm) and distilled under atmospheric pressure. Methanol (45 ml) was added to the obtained residue and 10% aqueous sodium hydroxide solution (45 ml) was added at 25 to 30 °C and stirred the reaction mass. Concentrated the reaction mass under vacuum. 20% aqueous HCl solution was added to the reaction mass. The obtained reaction mass was concentrated under vacuum and then water was added. The reaction mass was stirred, washed with ethyl acetate and filtered to get the solid. The obtained solid is dried to get the title compound.
Yield: 4.6 gm
HPLC purity: 67.84%, Undesired R-isomer: 29.85%.