WO2014033667A1 - Process for the preparation of telaprevir - Google Patents

Process for the preparation of telaprevir Download PDF

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Publication number
WO2014033667A1
WO2014033667A1 PCT/IB2013/058130 IB2013058130W WO2014033667A1 WO 2014033667 A1 WO2014033667 A1 WO 2014033667A1 IB 2013058130 W IB2013058130 W IB 2013058130W WO 2014033667 A1 WO2014033667 A1 WO 2014033667A1
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formula
telaprevir
hydroxy
process according
carried out
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PCT/IB2013/058130
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French (fr)
Inventor
Satish Kumar
Venugopal Venkatarama Durvasula
Parendu Dhirajlal Rathod
Ram Chander Aryan
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Ranbaxy Laboratories Limited
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Publication of WO2014033667A1 publication Critical patent/WO2014033667A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10Tetrapeptides
    • C07K5/1002Tetrapeptides with the first amino acid being neutral
    • C07K5/1016Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention provides a process for the preparation of telaprevir wherein (1 S,3aR,6aS)-N-[(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3- yl]octahydrocyclopenta[c]pyrrole- 1-carboxamide and N- ⁇ (2S)-2-cyclohexyl-2-[(pyrazin- 2-yl-carbonyl)amino]acetyl ⁇ -3-methyl-L-valine are condensed to form hydroxy telaprevir, which is then converted into telaprevir.
  • Telaprevir is chemically known as (lS,3aR,6aS)-2-[(2S)-2-( ⁇ (2S)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyl)amino]acetyl ⁇ amino)-3,3-dimethylbutanoyl]-N-[(3S)- 1 - (cyclopropylamino)- l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole- 1-carboxamide, and has the structure depicted by Formula I:
  • Telaprevir is a serine protease inhibitor disclosed in PCT Publication No. WO 02/18369. Processes for the preparation of telaprevir are disclosed in U.S. Patent No. 7,776,887; U.S. Publication No. 2010/0298568; PCT Publication Nos. WO 02/18369, WO 2008/090819, and WO 201 1/153423; and Chemical Communications 46(42):7918-7920 (2010).
  • PCT Publication No. WO 02/18369 discloses a process for the preparation of telaprevir which involves condensing (l S,3aR,6aS)-2-[(2S)-2-( ⁇ (2S)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyl)amino)acetyl ⁇ amino]-3,3-dimethylbutanoyl]-3,3a,4,5,6,6a- hexahydro-lH-cyclopenta[c]pyrole- l-carboxylic acid with (3S)-3-amino-N-cyclopropyl-2- hydroxyhexanamide in the presence of dichloromethane, PyBOP ([benzotriazole- 1 -yl- oxy]-tripyrrolidinophosphonium hexafluorophosphate), and N,N-diisopropylethylamine leading to the formation of hydroxy telaprevir, which is
  • the present invention provides a process for the preparation of telaprevir of Formula I, comprising the steps of:
  • N- ⁇ (2S)-2-cyclohexyl-2-[(pyrazin-2-yl-carbonyl)amino]acetyl ⁇ -3-methyl-L-valine of Formula IV may be prepared by following the process disclosed in PCT Publication No. WO 02/18369.
  • the condensation in step a) is carried out in the presence of a coupling agent, a base, and a solvent.
  • a coupling agent examples include HATU (2-(lH-7- azabenzotriazol- 1 -yl) ⁇ 1 , 1 ,3,3-tetramethyl uronium hexafluorophosphate
  • HBTU Bisbenzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate
  • HDBTU (2-(3,4-dihydro-4-oxo- l,2,3-benzotriazin-3-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • HOTU (0-[(Ethoxycarbonyl)
  • the base may be selected from weak organic or inorganic bases which facilitate the coupling reagent in carrying out the peptide synthesis.
  • organic bases include ⁇ , ⁇ -diisopropylethylamine, triethylamine, triisopropylamine, N,N-2-trimethyl-2- propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4- dimethylaminopyridine, 1 ,4-diazabicyclo[2.2.2]octane, 1 ,8-diazabicyclo[5.4.0]undec-7- ene, or mixtures thereof.
  • inorganic bases include sodium bicarbonate and potassium bicarbonate.
  • the reaction is carried out in the presence of an organic base.
  • the organic base is selected from N,N-diisopropylethylamine, 4- dimethylaminopyridine, triethyl amine, or N,N-2-trimethyl-2-propanamine.
  • the solvent is selected from the group comprising of nitriles, chlorinated solvents, amides, dialkylsulfoxides, or mixtures thereof.
  • nitriles include acetonitrile, propionitrile, butyronitrile, or valeronitrile.
  • chlorinated solvents include dichloromethane, dichloroethane, chlorobenzene, or chloroform.
  • amides include dimethylformamide, dimethylacetamide, or N-methyl formamide.
  • dialkylsulfoxides include dimethylsulfoxide, diethylsulfoxide, or dibutylsulfoxide.
  • the solvent is selected from dichloromethane, acetonitrile, or
  • the condensation is carried out at about 0°C to about 20°C. Preferably, the condensation is carried out at about 0°C to about 15°C.
  • the temperature of the reaction mixture may be maintained at about 20°C to about 40°C for about 2 hours to about 20 hours. Preferably, the temperature of the reaction mixture is maintained at about 20°C to about 25°C for about 5 hours to about 10 hours.
  • Isolation of the hydroxy telaprevir of Formula II may be carried out by filtration, concentration, decantation, or combinations thereof. Preferably, the isolation of the hydroxy telaprevir of Formula II is carried out by concentration.
  • the oxidation in step b) is carried out in the presence of an oxidizing agent and a solvent. Examples of oxidizing agents include Dess-Martin Periodinane, oxalyl chloride, chromium trioxide, or potassium permanganate.
  • the oxidizing agents may be used in combination with a catalyst such as TEMPO ((2,2,6,6- tetramethylpiperidin- 1 -yl)oxy), or TPAP (tetrapropylammonium perruthenate).
  • TEMPO ((2,2,6,6- tetramethylpiperidin- 1 -yl)oxy
  • TPAP tetrapropylammonium perruthenate
  • the oxidation is carried out in the presence of Dess-Martin Periodinane.
  • the solvent is selected from the group comprising of nitriles, aromatic hydrocarbons, chlorinated solvents, dialkylsulfoxides, water, or mixtures thereof.
  • nitriles include acetonitrile, propionitrile, butyronitrile, and valeronitrile.
  • aromatic hydrocarbons include toluene and xylene.
  • chlorinated solvents include dichloromethane, dichloroethane, chlorobenzene, and chloroform.
  • dialkylsulfoxides examples include dimethylsulfoxide, diethylsulfoxide, and dibutylsulfoxide.
  • the solvent is selected from dichloromethane or toluene.
  • the oxidation is carried out at about 0°C to about 20°C, preferably at about 0°C to about 10°C.
  • the reaction mixture is stirred at the same temperature for about 30 minutes to about 20 hours.
  • the reaction mixture is maintained at about 0°C to about 5°C for about 1 hour to about 5 hours.
  • Isolation of telaprevir of Formula I may be carried out by filtration, concentration, decantation, or a combination thereof.
  • the isolation of telaprevir of Formula I is carried out by concentration.
  • dichloromethane layer was concentrated to obtain hydroxy telaprevir as a solid residue.
  • telaprevir Form II; 1.05 g
  • dichloromethane 25 mL
  • Dess-Martin Periodinane was added at about 5°C.
  • the reaction mixture was stirred at about 0°C to about 5°C for about 2 hours.
  • the progress of the reaction was monitored by thin layer chromatography.
  • the reaction mixture was quenched with sodium thiosulphate solution and washed with sodium bicarbonate solution (20 mL).
  • the dichloromethane layer was concentrated under reduced pressure to obtain telaprevir as a solid residue.

Abstract

Disclosed herein is a process for the preparation of telaprevir wherein (1S,3aR,6a S)-N-[(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl] octahydrocyclopenta[c]pyrrole-1-carboximide and N-{(2S)-2-cyclohexyl-2-[(pyrazin-2-yl- carbonyl)amino]acetyl}-3-methyl-L-valine are condensed to form hydroxy telaprevir, which is then converted into telaprevir.

Description

PROCESS FOR THE PREPARATION OF TELAPREVIR
Field of the Invention
The present invention provides a process for the preparation of telaprevir wherein (1 S,3aR,6aS)-N-[(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3- yl]octahydrocyclopenta[c]pyrrole- 1-carboxamide and N- {(2S)-2-cyclohexyl-2-[(pyrazin- 2-yl-carbonyl)amino]acetyl}-3-methyl-L-valine are condensed to form hydroxy telaprevir, which is then converted into telaprevir.
Background of the Invention
Telaprevir is chemically known as (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyl)amino]acetyl} amino)-3,3-dimethylbutanoyl]-N-[(3S)- 1 - (cyclopropylamino)- l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole- 1-carboxamide, and has the structure depicted by Formula I:
Figure imgf000002_0001
Formula I
Telaprevir is a serine protease inhibitor disclosed in PCT Publication No. WO 02/18369. Processes for the preparation of telaprevir are disclosed in U.S. Patent No. 7,776,887; U.S. Publication No. 2010/0298568; PCT Publication Nos. WO 02/18369, WO 2008/090819, and WO 201 1/153423; and Chemical Communications 46(42):7918-7920 (2010).
PCT Publication No. WO 02/18369 discloses a process for the preparation of telaprevir which involves condensing (l S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyl)amino)acetyl}amino]-3,3-dimethylbutanoyl]-3,3a,4,5,6,6a- hexahydro-lH-cyclopenta[c]pyrole- l-carboxylic acid with (3S)-3-amino-N-cyclopropyl-2- hydroxyhexanamide in the presence of dichloromethane, PyBOP ([benzotriazole- 1 -yl- oxy]-tripyrrolidinophosphonium hexafluorophosphate), and N,N-diisopropylethylamine leading to the formation of hydroxy telaprevir, which is further oxidized using Dess Martin Periodinane to obtain telaprevir.
Chemical Communications 46(42):7918-7920 (2010) discloses the following process of preparation of telaprevir:
Figure imgf000003_0001
K2C03,MeOH
Telaprevir
There remains a need for development of an alternative process for the preparation of telaprevir, which is easier, more economical, and results in a final product with higher purity.
Summary of the Invention
The present invention provides a process for the preparation of telaprevir of Formula I, comprising the steps of:
a) condensing (l S,3aR,6aS)-N-[(3S)-l-(cyclopropylamino)-2-hydroxy- l- oxohexan-3-yl]-octahydrocyclopenta[c]pyrrole- 1 -carboxamide of Formula III
Figure imgf000004_0001
Formula III with N- {(2S)-2-cyclohexyl-2-[(pyrazin-2ylcarbonyl)amino]acetyl}-3-methyl-L-valine of Formula IV
Figure imgf000004_0002
Formula IV to obtain hydroxy telaprevir of Formula II; and
Figure imgf000004_0003
Formula II b) oxidizing the hydroxy telaprevir of Formula II to obtain telaprevir of Formula I.
Figure imgf000005_0001
Formula I
Detailed Description of the Invention
(l S,3aR,6aS)-N-[(3S)- l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3- yl]octahydrocyclopenta[c]pyrrole-l-carboxamide of Formula III may be prepared by the methods disclosed in U.S. Patent No. 8,188,137, and U.S. Publication No. 2010/0292219.
N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-yl-carbonyl)amino]acetyl}-3-methyl-L-valine of Formula IV may be prepared by following the process disclosed in PCT Publication No. WO 02/18369.
The condensation in step a) is carried out in the presence of a coupling agent, a base, and a solvent. Examples of coupling agents include HATU (2-(lH-7- azabenzotriazol- 1 -yl)~ 1 , 1 ,3,3-tetramethyl uronium hexafluorophosphate
methanaminium); HBTU (0-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate); HDBTU (2-(3,4-dihydro-4-oxo- l,2,3-benzotriazin-3-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate; HOTU (0-[(Ethoxycarbonyl)
cyanomethylenamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate); HOBT (N- hydroxybenzotriazole); EDC (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide); EDC. HC1 (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride); BOP
((benzotriazole- 1 -yloxy)tris(dimethylamino) phosphonium hexafluorophosphate); PyBOP (benzotriazole- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate); DEPBT (3- (diethoxy-phosphoryloxy)-3H-benzo[d] [ 1 ,2,3]triazin-4-one); Oxyma (ethyl
(hydroxyimino)cyanoacetate); COMU ((1 -cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate); TNTU (2-(endo-5- norborene-2,3-dicarboxyamido)-l,l,3,3-tetramethyluronium tetrafluoroborate; TPTDP (S- (l-oxo-2-pyridyl)-thio- l,3-dimethylpropyleneuronium tetrafluoroborate); TPTU (0-[l,2- dihydro-2-oxo-l-pyridyl]-N,N, Ν',Ν'-tetramethyluronium tetrafluoroborate); TBTU (O- (Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate); DIC (Ν,Ν'- diisopropylcarbodiimide); DCC (NN'-dicyclohexylcarbodiimide); or mixtures thereof. Preferably, the coupling reagent is selected from HOBT, HATU, HBTU, TBTU, EDC, EDC HC1, or mixtures thereof.
The base may be selected from weak organic or inorganic bases which facilitate the coupling reagent in carrying out the peptide synthesis. Examples of organic bases include Ν,Ν-diisopropylethylamine, triethylamine, triisopropylamine, N,N-2-trimethyl-2- propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4- dimethylaminopyridine, 1 ,4-diazabicyclo[2.2.2]octane, 1 ,8-diazabicyclo[5.4.0]undec-7- ene, or mixtures thereof. Examples of inorganic bases include sodium bicarbonate and potassium bicarbonate. Preferably, the reaction is carried out in the presence of an organic base. Preferably, the organic base is selected from N,N-diisopropylethylamine, 4- dimethylaminopyridine, triethyl amine, or N,N-2-trimethyl-2-propanamine.
The solvent is selected from the group comprising of nitriles, chlorinated solvents, amides, dialkylsulfoxides, or mixtures thereof. Examples of nitriles include acetonitrile, propionitrile, butyronitrile, or valeronitrile. Examples of chlorinated solvents include dichloromethane, dichloroethane, chlorobenzene, or chloroform. Examples of amides include dimethylformamide, dimethylacetamide, or N-methyl formamide. Examples of dialkylsulfoxides include dimethylsulfoxide, diethylsulfoxide, or dibutylsulfoxide.
Preferably, the solvent is selected from dichloromethane, acetonitrile, or
dimethylformamide .
The condensation is carried out at about 0°C to about 20°C. Preferably, the condensation is carried out at about 0°C to about 15°C. The temperature of the reaction mixture may be maintained at about 20°C to about 40°C for about 2 hours to about 20 hours. Preferably, the temperature of the reaction mixture is maintained at about 20°C to about 25°C for about 5 hours to about 10 hours.
Isolation of the hydroxy telaprevir of Formula II may be carried out by filtration, concentration, decantation, or combinations thereof. Preferably, the isolation of the hydroxy telaprevir of Formula II is carried out by concentration. The oxidation in step b) is carried out in the presence of an oxidizing agent and a solvent. Examples of oxidizing agents include Dess-Martin Periodinane, oxalyl chloride, chromium trioxide, or potassium permanganate. Additionally, for rapid oxidation, the oxidizing agents may be used in combination with a catalyst such as TEMPO ((2,2,6,6- tetramethylpiperidin- 1 -yl)oxy), or TPAP (tetrapropylammonium perruthenate).
Preferably, the oxidation is carried out in the presence of Dess-Martin Periodinane.
The solvent is selected from the group comprising of nitriles, aromatic hydrocarbons, chlorinated solvents, dialkylsulfoxides, water, or mixtures thereof.
Examples of nitriles include acetonitrile, propionitrile, butyronitrile, and valeronitrile. Examples of aromatic hydrocarbons include toluene and xylene. Examples of chlorinated solvents include dichloromethane, dichloroethane, chlorobenzene, and chloroform.
Examples of dialkylsulfoxides include dimethylsulfoxide, diethylsulfoxide, and dibutylsulfoxide. Preferably, the solvent is selected from dichloromethane or toluene.
The oxidation is carried out at about 0°C to about 20°C, preferably at about 0°C to about 10°C. The reaction mixture is stirred at the same temperature for about 30 minutes to about 20 hours. Preferably, the reaction mixture is maintained at about 0°C to about 5°C for about 1 hour to about 5 hours.
Isolation of telaprevir of Formula I may be carried out by filtration, concentration, decantation, or a combination thereof. Preferably, the isolation of telaprevir of Formula I is carried out by concentration.
The processes disclosed above are further illustrated in the examples below. These examples are provided as illustrations only, and therefore should not be construed as limiting of the scope of the invention. Thus, specific embodiments, certain modifications, and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
EXAMPLES
Example la: Preparation of Hydroxy Telaprevir (Formula II)
N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}-3-methyl-L-valine (Formula IV; 1.16 g) was dissolved in dichloromethane (30 mL). To this solution, TBTU (1.2 g) was added at 12°C. (l S,3aR,6aS)-N-(3S)- l-(cyclopropylamino)-2-hydroxy-l- oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-l-carboxamide (Formula III; 1.0 g) and N,N-diisopropylethylamine (0.56 mL) were added at 0°C to 5°C. After the addition, the temperature of the reaction mixture was raised from about 23°C to about 25°C, and the reaction mixture was stirred at the same temperature for about 7 hours. The reaction mixture was washed with IN HC1 and 5% sodium bicarbonate solution. The
dichloromethane layer was concentrated to obtain hydroxy telaprevir as a solid residue.
Yield: 1.7 g
Example lb: Preparation of Hydroxy Telaprevir (Formula II)
N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}-3-methyl-L-valine (Formula IV; 1.45 g) was dissolved in dichloromethane (25 mL). To this solution, HOBT (0.5 g) and EDC. HC1 (0.9 g) were added at 12°C. (l S,3aR,6aS)-N-[(3S)-l- (cyclopropylamino)-2-hydroxy- 1 -oxohexan-3-yl]octahydrocyclopenta[c]pyrrole- 1 - carboxamide (Formula III; 1.25 g) and N,N-diisopropylethylamine (1.5 mL) were added at 0°C to 5°C. After the addition, the temperature of the reaction mixture was raised from about 23°C to about 25°C, and the reaction mixture was stirred at the same temperature for about 8 hours. The reaction mixture was washed with IN HC1 and 5% sodium
bicarbonate solution. The dichloromethane layer was concentrated to obtain hydroxy telaprevir as a solid residue.
Yield: 1.8 g
Example II: Preparation of Telaprevir (Formula I)
Hydroxy telaprevir (Formula II; 1.05 g) was dissolved in dichloromethane (25 mL). To the resulting solution, Dess-Martin Periodinane was added at about 5°C. The reaction mixture was stirred at about 0°C to about 5°C for about 2 hours. The progress of the reaction was monitored by thin layer chromatography. After the reaction was complete, the reaction mixture was quenched with sodium thiosulphate solution and washed with sodium bicarbonate solution (20 mL). The dichloromethane layer was concentrated under reduced pressure to obtain telaprevir as a solid residue.
Yield: 0.7 g

Claims

We claim:
1. A process for the preparation of telaprevir of Formula I
Figure imgf000009_0001
Formula I
comprising the steps of:
a) condensing (1 S,3aR,6aS)-N-[(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1-
Figure imgf000009_0002
Formula III
oxohexan-3-yl]-octahydrocyclopenta[c]pyrrole- 1 -carboxamide of Formula III with N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}-3- methyl-L-valine of Formula IV
Figure imgf000009_0003
Formula IV
to obtain hydroxy telaprevir of Formula II; and
Figure imgf000010_0001
Formula II
b) oxidizing the hydroxy telaprevir of Formula II to obtain telaprevir of Formula I.
2. The process according to claim 1, wherein the condensation of (l S,3aR,6aS)-N- [(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3-yl]-octahydrocyclopenta[c]pyrrole- 1-carboxamide of Formula III with N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl) amino]acetyl}-3-methyl-L-valine of Formula IV is carried out in the presence of a coupling agent.
3. The process according to claim 2 wherein the coupling agent is selected from the group consisting of HOBT, HATU, HBTU, TBTU, EDC, EDC HCl, or mixtures thereof.
4. The process according to claim 1, wherein the condensation of (l S,3aR,6aS)-N- [(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3-yl]-octahydrocyclopenta[c]pyrrole- 1-carboxamide of Formula III with N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl) amino]acetyl}-3-methyl-L-valine of Formula IV is carried out in the presence of a base selected from Ν,Ν-diisopropylethylamine, 4-dimethylaminopyridine, triethyl amine, or N,N-2-trimethyl-2-propanamine.
5. The process according to claim 1, wherein the condensation of (l S,3aR,6aS)-N- [(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3-yl]-octahydrocyclopenta[c]pyrrole- 1-carboxamide of Formula III with N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl) amino]acetyl}-3-methyl-L-valine of Formula IV is carried out in the presence of a solvent selected from nitriles, chlorinated solvents, amides, dialkylsulfoxides, or mixtures thereof.
6. The process according to claim 4, wherein the solvent is dichloromethane.
7. The process according to claim 1 , wherein the oxidation of the hydroxy telaprevir of Formula II is carried out in the presence of an oxidizing agent selected from Dess-
Martin Periodinane, oxalyl chloride, chromium trioxide, or potassium permanganate.
8. The process according to claim 1, wherein the oxidation is carried out in the presence of a solvent selected from the group comprising of nitriles, aromatic hydrocarbons, chlorinated solvents, dialkylsulfoxides, water, or mixtures thereof.
9. The process according to claim 7, wherein the solvent is dichloromethane.
PCT/IB2013/058130 2012-08-30 2013-08-29 Process for the preparation of telaprevir WO2014033667A1 (en)

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US20060276404A1 (en) * 2005-06-02 2006-12-07 Anima Ghosal Medicaments and methods combining a HCV protease inhibitor and an AKR competitor
WO2008090819A1 (en) 2007-01-23 2008-07-31 Ajinomoto Co., Inc. Process for production of bicyclic proline compound
US7776887B2 (en) 2005-08-19 2010-08-17 Vertex Pharmaceuticals Incorporated Processes and intermediates
US20100292219A1 (en) 2007-02-26 2010-11-18 Achillion Pharmaceuticals, Inc. Tertiary amine substituted peptides useful as inhibitors of hcv replication
US20100298568A1 (en) 2006-03-16 2010-11-25 Vertex Pharmaceuticals Incorporated Processes and intermediates for preparing steric compounds
WO2011153423A2 (en) 2010-06-03 2011-12-08 Vertex Pharmaceuticals Incorporated Processes and intermediates
US8188137B2 (en) 2008-08-15 2012-05-29 Avila Therapeutics, Inc. HCV protease inhibitors and uses thereof
WO2013120871A1 (en) * 2012-02-13 2013-08-22 Dipharma Francis S.R.L. Process for the preparation of a viral protease inhibitor and its intermediates
WO2013131978A1 (en) * 2012-03-07 2013-09-12 Dipharma Francis S.R.L. Process for the preparation of intermediates useful in the preparation of a viral protease inhibitor

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Publication number Priority date Publication date Assignee Title
WO2002018369A2 (en) 2000-08-31 2002-03-07 Eli Lilly And Company Peptidomimetic protease inhibitors
US20060276404A1 (en) * 2005-06-02 2006-12-07 Anima Ghosal Medicaments and methods combining a HCV protease inhibitor and an AKR competitor
US7776887B2 (en) 2005-08-19 2010-08-17 Vertex Pharmaceuticals Incorporated Processes and intermediates
US20100298568A1 (en) 2006-03-16 2010-11-25 Vertex Pharmaceuticals Incorporated Processes and intermediates for preparing steric compounds
WO2008090819A1 (en) 2007-01-23 2008-07-31 Ajinomoto Co., Inc. Process for production of bicyclic proline compound
US20100292219A1 (en) 2007-02-26 2010-11-18 Achillion Pharmaceuticals, Inc. Tertiary amine substituted peptides useful as inhibitors of hcv replication
US8188137B2 (en) 2008-08-15 2012-05-29 Avila Therapeutics, Inc. HCV protease inhibitors and uses thereof
WO2011153423A2 (en) 2010-06-03 2011-12-08 Vertex Pharmaceuticals Incorporated Processes and intermediates
WO2013120871A1 (en) * 2012-02-13 2013-08-22 Dipharma Francis S.R.L. Process for the preparation of a viral protease inhibitor and its intermediates
WO2013131978A1 (en) * 2012-03-07 2013-09-12 Dipharma Francis S.R.L. Process for the preparation of intermediates useful in the preparation of a viral protease inhibitor

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Title
CHEMICAL COMMUNICATIONS, vol. 46, no. 42, 2010, pages 7918 - 7920

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