WO2014203224A1 - Procédé pour la préparation de télaprévir et d'intermédiaires de télaprévir - Google Patents

Procédé pour la préparation de télaprévir et d'intermédiaires de télaprévir Download PDF

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Publication number
WO2014203224A1
WO2014203224A1 PCT/IB2014/062496 IB2014062496W WO2014203224A1 WO 2014203224 A1 WO2014203224 A1 WO 2014203224A1 IB 2014062496 W IB2014062496 W IB 2014062496W WO 2014203224 A1 WO2014203224 A1 WO 2014203224A1
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Prior art keywords
formula
hydroxy
oxohexan
cyclopropylamino
pyrrole
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Ceased
Application number
PCT/IB2014/062496
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English (en)
Inventor
Satish Kumar
Venugopa l Venkatarama DURVASULA
Parendu Dhirajlal Rathod
Ram Chander Aryan
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Publication of WO2014203224A1 publication Critical patent/WO2014203224A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention provides a process for the preparation of telaprevir and its intermediates.
  • Telaprevir is a serine protease inhibitor disclosed in U.S. Patent No. 7,820,671. It is chemically designated as (15',3ai?,6aS)-2-[(25)-2-( ⁇ (25)-2-cyclohexyl-2-[(pyrazin-2- ylcarbonyl)amino]acetyl ⁇ amino)-3,3-dimethylbutanoyl]-N-[(35)-l-(cyclopropylamino)- l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-l-carboxamide, and has the structure depicted by Formula I.
  • Telaprevir is marketed in the United States under the brand name Incivek and is used for the treatment of hepatitis C, in combination with peginterferon alpha and ribavirin.
  • the present invention provides an alternate, industrially advantageous, efficient, and economical process for the preparation of telaprevir.
  • a first aspect of the present invention provides a process for the preparation of benzyl ⁇ (2S)-1-[(1 S,3aR,6aS)- 1 - ⁇ [(3 S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3- yl]carbamoyl ⁇ hexahydrocyclopenta[c]pyrrol-2( lH)-yl] -3 ,3 -dimethyl- 1 -oxobutan-2- yl ⁇ carbamate of Formula II,
  • a second aspect of the present invention provides a process for the preparation of telaprevir of Formula I,
  • a third aspect of the present invention provides a process for the preparation of telaprevir of Formula I,
  • a fourth aspect of the present invention provides the use of benzyl ⁇ (2S)-1- [( 1 S,3aR,6aS)- 1 - ⁇ [(3 S)- 1 -(cyclopropylamino)-2 -hydroxy- 1 -oxohexan-3-yl] carbamoyl ⁇ hexahydrocyclopenta[c]pyrrol-2(lH)-yl]-3,3-dimethyl-l-oxobutan-2-yl ⁇ carbamate of Formula II
  • a fifth aspect of the present invention provides benzyl ⁇ (2S)-l-[(lS,3aR,6aS)-l- ⁇ [(3 S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3 -yl] carbamoyl ⁇ hexahydrocyclo- penta[c]pyrrol-2(lH)-yl]-3,3-dimethyl-l-oxobutan-2-yl ⁇ carbamate of Formula II.
  • N-[(Benzyloxy)carbonyl] -3 -methyl -L-valine of Formula IV may be prepared according to the process disclosed in WO 2007/022459, which is incorporated herein by reference.
  • (2S)-Cyclohexyl[(pyrazin-2-ylcarbonyl)amino]ethanoic acid of Formula VI may be prepared according to the process disclosed in Chemical Communications, 46(42), p. 7918-7920 (2010).
  • the condensation of the intermediate of Formula III with the intermediate of Formula IV to obtain the intermediate of Formula II is carried out in the presence of a coupling agent, a base, and a solvent at a temperature of about 0°C to about 40°C for about 12 hours to about 2 days.
  • a coupling agent include HATU, HBTU, HDBTU, HOTU, HOBT, EDC, EDC.HC1, BOP, PyBOP, DEPBT, Oxyma, COMU, TNTU, TPTDP, TPTU, TBTU, DIC, DCC, or mixtures thereof.
  • the base may be selected from organic or inorganic bases.
  • organic bases examples include N,N- 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 examples include sodium bicarbonate, potassium bicarbonate, or mixtures thereof.
  • the solvent may be selected from nitriles, chlorinated hydrocarbons, amides, dialkylsulfoxides, or mixtures thereof.
  • nitriles include acetonitrile, propionitrile, butyronitrile, and valeronitrile.
  • chlorinated hydrocarbons include dichloromethane, dichloroethane, chlorobenzene, and chloroform.
  • amides include dimethylformamide, dimethylacetamide, and N- methyl formamide.
  • dialkylsulfoxides include dimethylsulfoxide, diethylsulfoxide, and dibutylsulfoxide.
  • the coupling agent is selected from HOBT, HATU, HBTU, TBTU, EDC, EDC.HC1, or mixtures thereof;
  • the base is selected from N,N-diisopropylethylamine, 4-dimethylaminopyridine, triethyl amine, or N,N-2-trimethyl-2-propanamine; and
  • the solvent is selected from
  • the metal catalyst may be selected from palladium supported on carbon, palladium black, palladium in the presence of barium sulphate, platinum supported on carbon, or raney nickel.
  • the solvent may be selected from alcohols, nitriles, aromatic hydrocarbons, chlorinated hydrocarbons, dialkylsulfoxides, water, or mixtures thereof. Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, and 2-methyl-l-pentanol.
  • nitriles include acetonitrile, propionitrile, butyronitrile, and valeronitrile.
  • aromatic hydrocarbons include toluene and xylene.
  • chlorinated hydrocarbons include dichloromethane, dichloroethane, chlorobenzene, and chloroform.
  • dialkylsulfoxides include dimethylsulfoxide, diethylsulfoxide, and dibutylsulfoxide.
  • the deprotection of benzyl ⁇ (2S)-l-[(lS,3aR,6aS)-l- ⁇ [(3S)-l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3- yl]carbamoyl ⁇ hexahydrocyclopenta[c]pyrrol-2( lH)-yl] -3 ,3 -dimethyl- 1 -oxobutan-2- yl ⁇ carbamate of Formula II is carried out in the presence of methanol at about 10°C to about 30°C for about 1 hour to about 10 hours.
  • Examples of coupling agents include HATU, HBTU, HDBTU, HOTU, HOBT, EDC, EDC.HC1, BOP, PyBOP, DEPBT, Oxyma, COMU, TNTU, TPTDP, TPTU, TBTU, DIC, DCC, or mixtures thereof.
  • the base may be selected from organic or inorganic bases.
  • organic bases examples include N,N- diisopropylethylamine, triethylamine, triisopropylamine, N,N-2-trimethyl-2-propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4- dimethylaminopyridine, l,4-diazabicyclo[2.2.2] octane, l,8-diazabicyclo[5.4.0]undec-7- ene, or mixtures thereof.
  • inorganic bases examples include sodium bicarbonate, potassium bicarbonate, or a mixture thereof.
  • the solvent may be selected from nitriles, chlorinated hydrocarbons, amides, dialkylsulfoxides, or mixtures thereof.
  • nitriles include acetonitrile, propionitrile, butyronitrile, and valeronitrile.
  • chlorinated hydrocarbons include dichloromethane, dichloroethane, chlorobenzene, and chloroform.
  • amides include dimethylformamide, dimethylacetamide, and N- methyl formamide.
  • dialkylsulfoxides include dimethylsulfoxide, diethylsulfoxide, and dibutylsulfoxide.
  • the coupling agent is selected from HOBT, HATU, HBTU, TBTU, EDC, EDC.HC1, or mixtures thereof;
  • the base is selected from N,N-diisopropylethylamine, 4-dimethylaminopyridine, triethyl amine, or N,N-2-trimethyl-2-propanamine; and
  • the solvent is selected from
  • the oxidation of the hydroxy telaprevir of Formula VII to obtain telaprevir of Formula I is carried out in the presence of an oxidizing agent and a solvent.
  • the oxidation is carried out at a temperature of about 0°C to about 20°C for about 1 hour to about 15 hours.
  • oxidizing agents include Dess-Martin periodinane, oxalyl chloride, chromium trioxide, potassium permanganate, or mixtures thereof.
  • a catalytic amount of TEMPO or TPAP may also be added for facilitating the oxidation reaction.
  • the solvent may be selected from nitriles, aromatic hydrocarbons, chlorinated hydrocarbons, dialkylsulfoxides, water, or mixtures thereof.
  • nitriles include acetonitrile, propionitrile, butyronitrile, and valeronitrile.
  • aromatic hydrocarbons include toluene and xylene.
  • chlorinated hydrocarbons include dichloromethane, dichloroethane, chlorobenzene, and chloroform.
  • dialkylsulfoxides include dimethylsulfoxide, diethylsulfoxide, and dibutylsulfoxide.
  • the oxidation of the intermediate of Formula VII is carried out in the presence of Dess-Martin periodinane and dichloromethane at a temperature of about 0°C to about 10°C for about 1 hour to about 5 hours.
  • telaprevir and its intermediates may be carried out by filtration, concentration, decantation, or a combination thereof. In the preferred embodiments of the present invention, the isolation of telaprevir and its intermediates is carried out by concentration.
  • the oil (66 g) was dissolved in ethyl acetate (330 mL) to obtain a solution.
  • (S)-Phenyl ethyl amine (27.6 g) was added to the solution at 20°C to 25°C and the reaction mixture was stirred for 24 hours to 30 hours.
  • the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain an oil.
  • the oil was dissolved in dichloromethane (400 mL) and washed with aqueous hydrochloric acid (40 mL concentrated hydrochloric acid in 400 mL of water). The organic layer was concentrated to provide an oil.
  • the adduct (1 g) was dissolved in isopropyl acetate (10 mL) and heated to a temperature of 60°C to 65°C to obtain a clear solution. The solution was cooled to 55°C to 60°C. A seed crystal of the solid adduct (0.1 g) was added to the reaction mixture followed by cooling to 35°C for 1 hour. The solution was stirred for 2 hours, filtered, washed with isopropyl acetate (5 mL), and dried. The dried solid was dissolved in dichloromethane (10 mL) and washed with IN hydrochloric acid (10 mL).
  • reaction mixture was washed with hydrochloric acid (IN, 2 x 100 mL), sodium bicarbonate solution (5%, 100 mL), and water (100 mL) sequentially.
  • the dichloromethane layer was concentrated at 35°C to 40°C under reduced pressure to obtain a solid residue.
  • the solid residue was slurry- washed with hexane (200 mL), and dried to obtain benzyl (l S,3aR,6aS)- l- ⁇ [(3S)-l- (cyclopropylamino)-2-hydroxy-l-oxohexan-3-yl]carbamoyl ⁇ hexahydrocyclopenta
  • reaction mixture was filtered through a Hyflo® bed and concentrated under reduced pressure to obtain (l S,3aR,6aS)-N-[(3S)-l-(cyclopropylamino)-2 -hydroxy- 1- oxohexan-3 -yl]octahydrocyclopenta[c]pyrrole- 1 -carboxamide .
  • Example 2 Preparation of benzyl ⁇ (2S)- l-r(l S.3aR.6aS)-l- ⁇ r(3S)-l-(cvclopropylamino)- 2-hvdroxy- l-oxohexan-3-yllcarbamoyl ⁇ hexahvdrocvclopentarclpyrrol-2(lH)-yll-3.3- dimethyl-l-oxobutan-2-v carbamate (Formula II)
  • N-[(benzyloxy)carbonyl]-3-methyl-L-valine (Formula IV; 1.7 g) was dissolved in dichloromethane (60 mL).
  • HOBT 0.85 g
  • EDC.HC1 1.25 g
  • the dichloromethane layer was concentrated to obtain benzyl ⁇ (2S)-1-[( 1 S,3aR,6aS)- 1 - ⁇ [(3 S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3- yl]carbamoyl ⁇ hexahydrocyclopenta[c]pyrrol-2( lH)-yl] -3 ,3 -dimethyl- 1 -oxobutan-2- yl ⁇ carbamate.
  • reaction mixture was filtered through a Hyflo ® bed and the filtrate was concentrated under reduced pressure to obtain (lS,3aR,6aS)-2-[(2S)-2-amino-3,3-dimethylbutanoyl]-N-[(3S)-l- (cyclopropylamino)-2 -hydroxy- 1 -oxohexan-3 -yl]octahydrocyclopenta[c]pyrrole- 1 - carboxamide.
  • the temperature of the reaction mixture was raised to 20°C to 25 °C, and the reaction mixture was stirred for 15 hours.
  • the reaction mixture was washed sequentially with IN hydrochloric acid (2 x 25 mL), 5% sodium bicarbonate (25 mL), and water (25 mL).
  • the dichloromethane layer was concentrated at 35°C to 40°C under reduced pressure to obtain hydroxy telaprevir.
  • hydroxy telaprevir (Formula VII; 0.6 g) was dissolved in dichloromethane (15 mL). To the resulting solution, Dess-Martin periodinane (0.72 g) was added at 5°C. The reaction mixture was stirred at 0°C to 5°C for 2 hours. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was quenched with sodium thiosulphate solution (2.4 g in 20 mL water), and washed with sodium bicarbonate solution (1 g in 20 mL water) and water (20 mL). The dichloromethane layer was concentrated under reduced pressure to obtain telaprevir.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyrrole Compounds (AREA)

Abstract

La présente invention concerne un procédé pour la préparation de télaprévir et d'intermédiaires de télaprévir.
PCT/IB2014/062496 2013-06-21 2014-06-20 Procédé pour la préparation de télaprévir et d'intermédiaires de télaprévir Ceased WO2014203224A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1832/DEL/2013 2013-06-21
IN1832DE2013 2013-06-21

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WO2014203224A1 true WO2014203224A1 (fr) 2014-12-24

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018369A2 (fr) 2000-08-31 2002-03-07 Eli Lilly And Company Inhibiteurs peptidomimetiques de protease
WO2007022459A2 (fr) 2005-08-19 2007-02-22 Vertex Pharmaceuticals Incorporated Procedes et intermediaires
WO2008090819A1 (fr) 2007-01-23 2008-07-31 Ajinomoto Co., Inc. Procédé de fabrication d'un composé de proline bicyclique
US20100298568A1 (en) 2006-03-16 2010-11-25 Vertex Pharmaceuticals Incorporated Processes and intermediates for preparing steric compounds
WO2011153423A2 (fr) 2010-06-03 2011-12-08 Vertex Pharmaceuticals Incorporated Procédés et produits intermédiaires

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018369A2 (fr) 2000-08-31 2002-03-07 Eli Lilly And Company Inhibiteurs peptidomimetiques de protease
US7820671B2 (en) 2000-08-31 2010-10-26 Vertex Pharmaceuticals Incorporated Peptidomimetic protease inhibitors
WO2007022459A2 (fr) 2005-08-19 2007-02-22 Vertex Pharmaceuticals Incorporated Procedes et intermediaires
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 (fr) 2007-01-23 2008-07-31 Ajinomoto Co., Inc. Procédé de fabrication d'un composé de proline bicyclique
WO2011153423A2 (fr) 2010-06-03 2011-12-08 Vertex Pharmaceuticals Incorporated Procédés et produits intermédiaires

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANASS ZNABET ET AL: "A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions", CHEMICAL COMMUNICATIONS, vol. 46, no. 42, 1 January 2010 (2010-01-01), pages 7918, XP055027224, ISSN: 1359-7345, DOI: 10.1039/c0cc02823a *
CHEMICAL COMMUNICATIONS, vol. 46, no. 42, 2010, pages 7918 - 7920
YIP Y ET AL: "P4 and P1' optimization of bicycloproline P2 bearing tetrapeptidyl alpha-ketoamides as HCV protease inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 14, no. 19, 4 October 2004 (2004-10-04), pages 5007 - 5011, XP027213215, ISSN: 0960-894X, [retrieved on 20040901] *

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