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WO2014045263A2 - Process for preparation of intermediates of telaprevir - Google Patents

Process for preparation of intermediates of telaprevir Download PDF

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Publication number
WO2014045263A2
WO2014045263A2 PCT/IB2013/058808 IB2013058808W WO2014045263A2 WO 2014045263 A2 WO2014045263 A2 WO 2014045263A2 IB 2013058808 W IB2013058808 W IB 2013058808W WO 2014045263 A2 WO2014045263 A2 WO 2014045263A2
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formula
compound
acid
added
solution
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WO2014045263A3 (en
Inventor
Javed Iqbal
Vilas Hareshwar Dahanukar
Srinivas ORUGANTI
Bhaskar KANDAGATLA
Syam Kumar Unniaran KUNHIMON
Rajeshwar Reddy Sagyam
Babu Ireni
Veera Venkata Satyanarayana Murthy Kondepudi
Murali Mohan Muttavarapu
Ravinder BUCCHIKONDA
Rajendar Reddy GANGIREDDY
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Dr Reddys Laboratories Ltd
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Dr Reddys Laboratories Ltd
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Publication of WO2014045263A3 publication Critical patent/WO2014045263A3/en
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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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/20—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/44—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C223/00—Compounds containing amino and —CHO groups bound to the same carbon skeleton
    • C07C223/02—Compounds containing amino and —CHO groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic
    • C07C35/06—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/30—Compounds having groups
    • C07C43/315—Compounds having groups containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • 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
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic

Definitions

  • the present application relates to novel processes for preparation of (1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1 -carboxylic acid of formula (Vllb) and its derivatives; and their use in preparation of Telaprevir.
  • WO '369 also discloses another process for preparation of (1 S,3aR,6aS)- ethyloctahydrocyclopenta[c]pyrrole-1 -carboxylate (ethyl ester of compound of formula VI lb), in which (1 S,3aR,6aS)-2-benzyl 1 -ethyl-4-oxohexahydrocyclopenta[c]pyrrole- 1 ,2(1 H)-dicarboxylate is reduced using sodiumborohydride to form (1 S,3aR,6aS)-2- benzyl-1 -ethyl-4-hydroxyhexahydrocyclopenta[c]pyrrole-1 ,2(1 H)-dicarboxylate.
  • the hydroxy compound is treated with sodium hydride in presence of carbon disulfide and methyl iodide to form (1 S,3aR,4S,6aS)-2-benzyl-1 -ethyl-4-
  • the (3aS,6aR)-1 , 3a, 4, 5, 6,6a- hexahydrocyclopenta[c]pyrrole exists in the form a dimer or a trimer and is treated with sodium cyanide to from (1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1 -carbonitrile. Subsequent hydrolysis of the nitrile and ester formation using tert-butylmethyl ether yielded (1 S,3aR,6aS)-tert-butyloctahydrocyclopenta[c]pyrrole-1 -carboxylate.
  • the process disclosed in WO '828 is schematically represented in scheme-IV.
  • the object of the present application is to provide novel and industrially advantageous processes for preparation of the (1 S,3aR,6aS)- octahydrocyclopenta[c]pyrrole-1 -carboxylic acid of formula (Vllb).
  • the application provides a process for preparation of (1 S,3aR,6aS)- octahydrocyclopenta[c]pyrrole-1 -carboxylic acid of formula (Vllb), comprising:
  • X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl
  • R is hydrogen or C C 4 alkyl or C5-C12 aralkyl
  • R 1 and R 2 are C C 5 alkyl or both form a cyclic ring
  • the application provides a process for preparation of a compound of formula Vllb, comprising:
  • XX VIII wherein X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl; R is hydrogen or Ci-C alkyl or C5-C 12 aralkyl,
  • R 1 and R 2 are C C 5 alkyl or both form a cyclic ring
  • the present application provides use of compound of formula Vllb prepared by the processes disclosed in the present application in the preparation of telaprevir comprising,
  • the application provides new intermediates and starting materials in the process according to the present invention.
  • the present application provides Telaprevir having purity greater than about 99.5 area % as measured by HPLC.
  • the present application provides Telaprevir having purity greater than about 99.8 area % as measured by HPLC.
  • Fig. 1 is an illustrative example of an XRPD pattern of crystalline telaprevir, prepared in Example 24.
  • Fig. 2 is an illustrative example of an XRPD pattern of crystalline compound of formula IVa, prepared in Example 8. DETAILED DESCRIPRION OF THE INVENTION
  • the present application provides novel processes for preparation of
  • the application provides a process for preparation of
  • X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl
  • R is hydrogen or Ci-C alkyl or C5-C 12 aralkyl
  • R 1 and R 2 are C 1 -C5 alkyl or both form a cyclic ring
  • the step (a) of the process involves reduction of compound of formula XX with a suitable reducing agent to form a compound of formula XIX.
  • the reduction is carried out using a suitable reducing agent in presence of a suitable solvent.
  • Compound of Formula XX may be obtained by any process including processes described in the art, or by a process described in this application.
  • the suitable reducing agent is selected from the group comprising of diisobuyl aluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy)aluminum hydride (Red-AI) triisobuyl aluminum (TIBAL), potassium diisobutyl-tert-butoxyaluminium hydride (PDBBA), lithium diisobutyl-tert-butoxyaluminium hydride (LDBBA), sodium diisobutyl- tert-butoxyaluminium hydride (SDBBA), diisobuyl aluminum butylated oxytoulene (DIBAL-BOT), sodium aluminum hydride (SAH), lithium aluminum hydride (LAH), bis(4- methyl-1 -piperazinyl) aluminum hydride (BMAH).
  • DIBAL-H diisobuyl aluminum hydride
  • Red-AI sodium bis (2-methoxyethoxy)aluminum hydride
  • TIBAL potassium
  • the reducing agent is diisobuyl aluminum hydride (DIBAL-H).
  • the reducing agent is sodium-bis-(2-methoxyethoxy)aluminum hydride (Red-AI).
  • the reducing agent may be used in the form of a solution in a suitable solvent.
  • the quantity of reducing agent may range from about 1 to about 4 moles. In one embodiment the quantity of the reducing agent is about 1 to about 2 moles, per mole of compound of Formula XX.
  • Suitable solvents that can be used for the reaction include, but are not limited to: ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, toluene, 1 ,4- Dioxane, 2-Methyltetrahydrofuran and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; and any mixtures thereof.
  • the solvent used in step (a) is ether such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like.
  • the solvent is hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like.
  • step (a) is suitably carried out at temperatures ranging from about -100°C to about 50°C. In one embodiment the reduction is carried out at temperatures ranging from about -80°C to about 30°C.
  • reaction mixture After completion of the reaction the reaction mixture is quenched with aqueous ammonium chloride or Rochelle's salt, and the salt by-product is removed by filtration.
  • the organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
  • the step (b) of the process involves protection of the aldehyde of the compound of formula XIX with a suitable protecting group in presence of a suitable solvent to form a compound of formula XVIII.
  • the suitable protecting group is selected from the group comprising of trimethylorthoformate, triethylorthoformate, ethylene glycol, propylene glycol, acetic anhydride and propionic anhydride.
  • the quantity of the protecting group may range from about 1 to about 20 moles. In one embodiment the quantity of the reducing agent is about 1 to about 10 moles, per mole of compound of Formula XIX.
  • the protection may be carried out in the presence of an acid and a suitable solvent.
  • the solvent that can be used for the reaction include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; halogenated hydrocarbons such as dichloromethane (DCM), ethylene dichloride, chloroform, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; esters such as ethyl acetate, propyl acetate, and the like; and any mixtures thereof.
  • alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-
  • the solvent used in step (b) is an alcohol such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like.
  • the solvent used in step (b) is hydrocarbons such as toluene, xylene, n- hexane, n-heptane, cyclohexane, and the like;
  • step (b) is suitably carried out at temperatures ranging from about -30°C to about 80°C. In one embodiment the reduction is carried out at temperatures ranging from about 0°C to about 50°C.
  • reaction mixture is diluted with aq.
  • Base such as sodium carbonate or sodium bicarbonate
  • the solution is extracted with a suitable water immiscible solvent.
  • the organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
  • the step (c) of the process involves cyanation of the protected aldehyde of the compound of formula XVIII with a suitable cyanating agent in a suitable solvent.
  • the suitable cyanating agent is selected from the group comprising of Copper cyanide, Sodium cyanide, Potassium cyanide, Zinc cyanide and potassium hexacyanoferroate (K 4 Fe(CN) 6 ).
  • the cyanating agent is Sodium cyanide.
  • the quantity of the cyanating agent may range from about 1 to about 5 moles. In one embodiment the quantity of the cyanating agent is about 1 to about 3 moles per mole of compound of Formula XVIII.
  • the suitable solvent that can be used for cyanation include, but are not limited to: polar aprotic solvents such as Dimethylformamide, Dimethylsulfoxide, Dimethyl acetamide, acetonitrile and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; hydrocarbons such as toluene, xylene, n-hexane, n- heptane, cyclohexane, and the like; and any mixtures thereof.
  • polar aprotic solvents such as Dimethylformamide, Dimethylsulfoxide, Dimethyl acetamide, acetonitrile and the like
  • ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like
  • hydrocarbons such as toluene, xylene, n-hexane, n- hept
  • the solvent used in cyanation is a polar aprotic solvent such as Dimethylformamide, Dimethylsulfoxide, Dimethyl acetamide, acetonitrile and the like;
  • the process of cyanation is suitably carried out at temperatures ranging from about 0°C to about 100°C. In one embodiment the cyanation is carried out at temperatures ranging from about 20°C to about 80°C.
  • reaction mixture may be diluted with water and the solution is extracted with a suitable water immiscible solvent.
  • the organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
  • the step (d) of the process involves reduction of the cyanide of the compound of formula XVII in presence of a suitable catalyst, hydrogen gas, and a suitable solvent.
  • the suitable catalyst is selected from the group comprising of Raney Nickel, Palladium, Platinum, Rhodium, and Ruthenium.
  • the hydrogenation catalyst is Raney-Nickel.
  • the quantity of the catalyst may range from about 0.01 to about 5 moles. In one embodiment the quantity of the catalyst is about 0.1 to about 1 mole per mole of compound of Formula XVII.
  • the suitable solvent that can be used for the catalytic hydrogenation include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert- butanol, and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; hydrocarbons such as toluene, xylene, n-hexane, n- heptane, cyclohexane, and the like; esters such as ethyl acetate, propyl acetate, and the like; water, formic acid, acetic acid and any mixtures thereof.
  • the solvent used in the catalytic hydrogenation is an alcohol such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like;
  • the process of catalytic hydrogenation is suitably carried out at temperatures ranging from about 0°C to about 100°C. In one embodiment the catalytic hydrogenation is carried out at temperatures ranging from about 30°C to about 80°C.
  • the catalyst is isolated from the reaction mixture by way of filtration.
  • the filtrate containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
  • the compound of formula XVI may optionally be protected with and an amine protecting group.
  • the step (e) of the process involves treatment of the amine of the compound of formula XVI or the protected amine with a cyanide to form compound of formula XV.
  • the compound of formula XVI is protected one, before reacting it with cyanide the compound is treated with a suitable acid to deprotect the amine.
  • the suitable acid used in the process of step (e) is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid and acetic acid. In one embodiment the acid used in the process of step (e) is hydrochloric acid.
  • the acid concentration may vary from about 0.1 N to about 10N. In one embodiment the acid concentration is 1 N.
  • the suitable cyanide used in the process of step (e) is selected from the group comprising of Copper cyanide, Sodium cyanide, Potassium cyanide, Zinc cyanide. In one embodiment the cyanide is Potassium cyanide.
  • the quantity of the cyanide used in the process of step (e) may vary from about 1 to about 10 moles. In one embodiment the quantity of the cyanide is about 1 to about 5 moles per mole of compound of Formula XVI.
  • step (e) is suitably carried out at temperatures ranging from about 0°C to about 80°C. In one embodiment the reaction is carried out at temperatures ranging from about 10°C to about 50°C.
  • reaction mixture is diluted with water and may be treated with a base.
  • the resulted solution is extracted with a suitable water immiscible solvent.
  • the solvent containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
  • the step (f) of the process involves hydrolysis of the cyanide of the compound of formula XV in presence of a mineral acid to form compound of formula Vllb.
  • the mineral acid used in the hydrolysis is selected from the group comprising of Hydrochloric acid, Hydrobromic acid, Hydroiodic acid and Sulfuric acid.
  • the mineral acid used in the hydrolysis is Hydrochloric acid.
  • the mineral acid may be used in the form of a solution having a concentration of about 0.1 N to about 10N. In one embodiment the acid concentration is 1 N.
  • the solvent used for the preparation of the mineral acid solution include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert- butanol, and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate, and the like; water, and any mixtures thereof.
  • the solvent used in the preparation of the mineral acid solution is an alcohol such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like.
  • the solvent used in the preparation of the mineral acid solution is water.
  • the reaction mixture is concentrated and the compound of formula Vllb is isolated.
  • the compound of formula Vllb is isolated as an acid addition salt.
  • the compound of formula Vllb or its acid addition salt may be protected to form compound of formula Vila or an acid addition salt.
  • the suitable amine protecting group is selected from the group comprising of 9- Fluorenylmethyloxy carbonyl (FMOC), tert-butyloxycarbonyl (BOC), benzyloxy carbonyl (CBZ), acetyl, trifluoroacetyl, benzyl, triphenylmethyl, and p-toluenesulfonyl.
  • FMOC Fluorenylmethyloxy carbonyl
  • BOC tert-butyloxycarbonyl
  • CBZ benzyloxy carbonyl
  • acetyl trifluoroacetyl
  • benzyl triphenylmethyl
  • p-toluenesulfonyl p-toluenesulfonyl.
  • the amine protecting group is tert-butyloxycarbonyl.
  • Protection of the amine functionality of the compound of formula Vllb is suitably carried out using any process including processes described in the art, or by a process described in this application.
  • the application provides a process for preparation of a compound of formula Vllb, comprising:
  • XX VIII wherein X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl; R is hydrogen or Ci-C alkyl or C5-C 12 aralkyl,
  • R 1 and R 2 are C C 5 alkyl or both form a cyclic ring
  • the step (a) of the process involves reduction of compound of formula XX with a suitable reducing agent to form a compound of formula VIII.
  • the reduction is carried out in presence of a suitable solvent.
  • Compound of Formula XX may be obtained by any process including processes described in the art, or by a process described in this application.
  • the suitable reducing agent is selected from the group comprising of sodium aluminum hydride, sodium borohydride, lithium aluminum hydride, sodium bis (2- methoxyethoxy)aluminumhydride (Red-AI) and bis(4-methyl-1 -piperazinyl) aluminum hydride (BMAH).
  • the reducing agent is lithium aluminum hydride (LAH).
  • the reducing agent is sodium bis (2- methoxyethoxy)aluminumhydride (Red-AI).
  • the quantity of reducing agent may range from about 1 to about 4 moles. In one embodiment the quantity of the reducing agent is about 1 to about 2 moles, per mole of compound of Formula XX.
  • Suitable solvents that can be used for the reaction include, but are not limited to: ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; and any mixtures thereof.
  • the solvent used in step (a) is ether such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like.
  • step (a) is suitably carried out at temperatures ranging from about -30°C to about 50°C. In one embodiment the reduction is carried out at temperatures ranging from about -10°C to about 30°C.
  • reaction mixture may be diluted and the salt by-product can be removed by filtration.
  • the organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
  • the step (b) of the process involves protection of primary hydroxyl functionality of the compound of formula VIII with a suitable hydroxyl protecting group in presence of a suitable solvent to form a compound of formula IX.
  • the primary hydroxyl protection is suitably carried out using known methods. See e.g., T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley and Sons, Inc. (1999).
  • the hydroxyl protecting group is silyl group such as trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl and the like.
  • the hydroxyl protecting group is t-butyldiphenylsilyl (TBDPS).
  • the step (c) of the process involves cyanation of the compound of formula IX with a suitable cyanating agent in a suitable solvent to form compound of formula X.
  • the suitable cyanating agent is selected from the group comprising of Copper cyanide, Sodium cyanide, Potassium cyanide and Zinc cyanide. In one embodiment the cyanating agent is Sodium cyanide.
  • the quantity of the cyanating agent may range from about 1 to about 10 moles. In one embodiment the quantity of the cyanating agent is about 1 to about 3 moles per mole of compound of Formula IX.
  • the suitable solvent that can be used for cyanation include, but are not limited to: polar aprotic solvents such as Dimethylformamide, Dimethylsulfoxide, Dimethyl acetamide, acetonitrile and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; hydrocarbons such as toluene, xylene, n-hexane, n- heptane, cyclohexane, and the like; and any mixtures thereof.
  • the solvent used in cyanation is a polar aprotic solvent such as Dimethylformamide, Dimethylsulfoxide, Dimethyl acetamide, acetonitrile and the like;
  • the process of cyanation is suitably carried out at temperatures ranging from about 0°C to about 100°C. In one embodiment the cyanation is carried out at temperatures ranging from about 20°C to about 80°C.
  • reaction mixture may be diluted with water and the solution is extracted with a suitable water immiscible solvent.
  • the organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
  • the step (d) of the process involves reduction of the cyanide of the compound of formula X in presence of a suitable catalyst, hydrogen gas and a suitable solvent.
  • the suitable catalyst is selected from the group comprising of Raney Nickel, Palladium, Platinum, Rhodium, and Ruthenium.
  • the hydrogenation catalyst is Raney-Nickel.
  • the quantity of the catalyst may range from about 0.01 to about 5 moles. In one embodiment the quantity of the catalyst is about 0.1 to about 1 mole per mole of compound of Formula X.
  • the suitable solvent that can be used for the catalytic hydrogenation include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert- butanol, and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate, and the like; water, formic acid, acetic acid and any mixtures thereof.
  • the solvent used in the catalytic hydrogenation is an alcohol such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like;
  • the process of catalytic hydrogenation is suitably carried out at temperatures ranging from about 0°C to about 100°C. In one embodiment the catalytic hydrogenation is carried out at temperatures ranging from about 10°C to about 50°C.
  • the catalyst is isolated from the reaction mixture by way of filtration.
  • the filtrate containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
  • the step (e) of the process involves deprotection of compound of formula XI using a suitable acid to form a compound of formula XII.
  • the suitable acid that can be used for the deprotection is selected from the group comprising of hydrochloric acid, hydrofluoric acid, hydroiodic acid, hydrobromic acid, tetrabutylammonium fluoride, tetrabutylammonium bromide, acetic acid, and sulfuric acid.
  • the acid used for deprotection of the compound of formula XI is hydrochloric acid.
  • the acid may be used in the form of a solution having a concentration of about 0.1 N to about 10N.
  • the solvent used for the preparation of the acid solution include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert- butanol, and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate, and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK), and the like; water, and any mixtures thereof.
  • the solvent used in the preparation of the mineral acid solution is an alcohol such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like.
  • reaction mixture may be concentrated completely to produce a residue, and the crude may be purified or may be used directly in the next reaction step.
  • the amine functionality of the compound of formula XII may be protected using a suitable protecting group.
  • the amine protection is suitably carried out using known methods. See e.g., T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley and Sons, Inc. (1999).
  • the amine functionality of the compound of formula XII may be protected using tert-butyloxycarbonyl (BOC) protecting group to form compound of formula Xlla.
  • BOC tert-butyloxycarbonyl
  • the step (f) of the process involves oxidation of compound of formula XII or compound of formula Xlla using a suitable oxidizing agent and a suitable solvent to form a compound of formula XIII.
  • the suitable oxidizing agent is selected from the group comprising of Pyridimium chlorochromate (PCC), Pyridimium dichromate (PDC), Dess-Martin periodinane (DMP), (2,2,6,6-Tetramethylpiperidin-1 -yl)oxyl (TEMPO), Aluminum isopropoxide, o- iodoxybenzoic acid (IBX), 2-lodoxybenzenesulfonic acid and diisopropyl azodicarboxylate (DIAD).
  • PCC Pyridimium chlorochromate
  • PDC Pyridimium dichromate
  • DMP Dess-Martin periodinane
  • TEMPO (2,2,6,6-Tetramethylpiperidin-1 -yl)oxyl
  • TEMPO 2,2,6,6-Tetramethylpiperidin-1 -yloxyl
  • IBX o- iodoxybenzoic acid
  • DIAD diisopropyl azodicarboxylate
  • the quantity of the oxidizing agent may range from about 0.1 to about 10 moles. In one embodiment the quantity of the catalyst is about 0.5 to about 3 moles per mole of compound of Formula XII.
  • step (f) is suitably carried out at temperatures ranging from about -30°C to about 100°C.
  • the oxidation is carried out at temperatures ranging from about 0°C to about 50°C.
  • reaction mixture After completion of the oxidation, the reaction mixture is concentrated completely to produce a residue and the residue is dissolved in another solvent or it may be used directly in the next reaction step.
  • the step (g) of the process involves protection of the aldehyde of the compound of formula XIII with a suitable protecting group in presence of a suitable solvent to form a compound of formula XVI.
  • the step (h) of the process involves treatment of the amine of the compound of formula XVI with an acid and a cyanide to form compound of formula XV.
  • step (i) of the process involves hydrolysis of the cyanide of the compound of formula XV in presence of a suitable acid or suitable base to form compound of formula Vllb.
  • the processes of step (g) to step (i) are suitably carried out using the process as described above in this application.
  • the application provides use of the compound of formula Vllb prepared by the processes disclosed in the present application in the preparation of telaprevir comprising:
  • P is an amine protecting group
  • the amine protecting group as used herein is known in the art (see, e.g., T. W. Greene & P.G.M Wutz, "Protective groups in Organic Synthesis", 3 rd edition, John Wiley & Sons, Inc. (1999), and the earlier editions of this book.
  • Step (a) of the process involves coupling of a compound of Formula Vllb or a protected form of compound of formula Vllb or its salt with a compound of Formula Via or its salt in the presence of a suitable coupling reagent to form a compound of formula Va or its salt.
  • the compound of formula Via is used as an acid addition salt.
  • the acid addition salt of compound of formula VI is selected form hydrochloride, hydrobromide, acetate, trifluoroacetate, and hemisulphate.
  • Suitable coupling reagent that may used is selected form the group comprising 1 - (3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), benzotriazol-1 - yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), ((l-H-l,2,3- benzotriazol-l-yloxy)- tris(pyrrolidino)phosphonium tetrafluorophopsphate (PyBOP), bis(2-oxo- 3-oxazolidinyl)phosphinic chloride (BOP-CI), 1 -hydroxybenzotriazole (HOBT), hydroxyazabenzotriazole (HOAT) or mixtures thereof. Quantities of coupling reagent may range from about 1 to about 4 moles, or about 2 to
  • the reaction is effected in the presence of a solvent.
  • the solvent that can be used, include, but or not limited to, a halogenated hydrocarbon solvent such as dichloromethane, ethylene dichloride, chloroform, or the like; ketone solvents such as acetone, methyl isobutyl ketone (MIBK), or the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile or the like; or mixtures thereof.
  • the solvent is N,N- dimethylformamide (DMF).
  • Quantities of solvent used for the process may be from about 1 ml_ to about 30 ml_, per gram of compound of Formula IV.
  • Optional reagents that may used in the amide bond forming reaction include ethyl-2-cyano-2-(hydroxyimino)acetate (oxyma) or active ester reagents such as 1 - hydroxybenzotriazole (HOBT), hydroxyazabenzotriazole (HOAT), hydroxysuccinimide (HOSu) in amounts ranging from about 0.5 to about 5 equivalents.
  • active ester reagents such as 1 - hydroxybenzotriazole (HOBT), hydroxyazabenzotriazole (HOAT), hydroxysuccinimide (HOSu) in amounts ranging from about 0.5 to about 5 equivalents.
  • the reaction is suitably carried out at temperatures ranging from about 0°C to about 80°C, preferably about 10°C to about 50°C.
  • the time required for completion of the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period from about 30 minutes to about 30 hours, preferably from about 3 hours to about 20 hours, is sufficient.
  • Step (b) of the process involves deprotection of the compound of formula Va to provide compound of formula Ilia.
  • a suitable method may be selected depending on the N-protective group.
  • the protective group capable of being deprotected with an acid such as tert-butoxycarbonyl, benzyloxycarbonyl, the reaction of the process may be attained by acid treatment
  • the acid to be used includes, for example, a mineral acid, a sulfonic acid, or a carboxylic acid.
  • the mineral acid is not specifically limited, but includes hydrogen halides such as hydrogen chloride, and hydrogen bromide; sulfuric acid; phosphoric acid.
  • the sulfonic acid is not specifically limited, but includes, for example, methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and 1 -phenylethanesulfonic acid.
  • the carboxylic acid is not specifically limited, but includes, for example, formic acid, acetic acid, trifluoroacetic acid, benzoic acid, and tartaric acid.
  • these acids hydrogen chloride, hydrogen bromide, sulfuric acid, p-toluenesulfonic acid, and benzoic acid that form salts having good crystallinity are preferable; and in particular hydrogen chloride, hydrogen bromide and sulfuric acid are preferable, and hydrogen chloride or sulfuric acid is more preferable.
  • the amount of the acid to be used may be at least a theoretical amount; but the use thereof in a large amount is not economical. Therefore the lower limit of the amount is generally not less than 1 time by mol, and the higher limit is generally not more than 10 times by mol, preferably not more than 3 times by mol, more preferably not more than 2 times by mol relative to the compound of the formula Va.
  • the acid may be added directly as it is, or the aqueous solution or the solution in which the acid is previously dissolved in a solvent mentioned below may be used.
  • concentration of the acid to be added is not specifically limited, but the lower limit is generally 0.1 % by weight, preferably 1 % by weight, more preferably 5% by weight and the higher limit is 100% by weight.
  • the reaction is generally carried out in a solvent.
  • the solvent is not specifically limited, but includes alcohols such as methanol, ethanol, isopropanol, n-propanol; ethers such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1 ,3-dioxolan, 1 ,2- dimethoxy ethane, diethylene glycol dimethyl ether; aliphatic esters such as ethyl acetate, isopropyl acetate, tert-butyl acetate; and halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloethane.
  • the compound is appropriately deprotected according to the type of the protective group, and then is processed with acid according to the above mentioned process to obtain the compound of formula Ilia.
  • Step (c) of the process involves coupling o compound of Formula Ilia or its salt with compound of Formula IVa or its salt in the presence of a suitable coupling reagent to form a compound of formula I la or its salt.
  • a suitable coupling reagent such as copper chloride as taught in International Journal of Peptide and Protein Research 39, 1992, 237-234.
  • the coupling reagent and solvent used in the coupling reaction can appropriately be selected from the above mentioned embodiments.
  • the reaction is suitably carried out at temperatures ranging from about 0°C to about 80°C, preferably about 10°C to about 50°C.
  • reaction is monitored by TLC. After completion of the reaction, water is added to the reaction mixture and the compound of formula lla is isolated by filtration.
  • Step (d) of the process involves oxidation of the compound of formula lla or its salt to form telaprevir or its salt.
  • Suitable oxidizing agent is selected from Dess-Martin periodinane (1 ,1 -dihydro-1 ,1 ,1 -triacetoxy-1 ,2-benzoiodooxol-3(1 H)-one), chromic acid in acetone, sodium hypochlorite in the presence of (2,2,6,6-tetramethyl-piperidin-1 -yl)oxyl (TEMPO) or a TEMPO derivative such as 4-Hydroxy-TEMPO, 4-Amino-TEMPO, 4- Acetamido-TEMPO, 4-(2-Bromoacetamido)-TEMPO, 4-Carboxy-TEMPO, 4-Cyano- TEMPO, 4-Methoxy-TEMPO or 4-Oxo-TEMPO; or potassium permanganate in the presence of TEMPO or a TEMPO derivative.
  • the oxidation is affected in the presence of a solvent.
  • the solvents that can be used include, but are not limited to, ethers such as diethyl ether, tetrahydrofuran (THF) and the like; halogenated solvent such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene and the like; esters such as ethyl acetate methyl acetate, isopropyl acetate and the like or mixtures thereof.
  • the solvent is dichloromethane or ethyl acetate.
  • the oxidation is carried out at a temperature from about -20°C to about 60°C. Preferably from about 0°C to about 30°C.
  • telaprevir prepared by the processes herein described above is having purity greater than about 99 area % as measured by HPLC.
  • the present application provides Telaprevir prepared by the processes herein described above is having purity greater than about 99.5 area % as measured by HPLC.
  • the present application provides Telaprevir prepared by the processes herein described above is having purity greater than about 99.8 area % as measured by HPLC.
  • the present application provides use of Telaprevir having purity greater than about 99.5 area % as measured by HPLC for the manufacture of a pharmaceutical composition.
  • the present application provides use of Telaprevir having purity greater than about 99.8 area % as measured by HPLC for the manufacture of a pharmaceutical composition.
  • vacuum refers to a reduced pressure of below about 150 mm Hg. In another embodiment, the pressure is below about 50 mm Hg. In another embodiment, the pressure is below about 30 mm Hg. As used herein, the term “reduced pressure” refers to a pressure below 760 mm Hg or 1 atmosphere.
  • room temperature refers to a temperature of about 20°C to about 35°C, In another embodiment about 20°C to about 25°C and in another embodiment about 25°C.
  • Alcohol solvent is an organic solvent containing a carbon bound to a hydroxyl group.
  • Alcohol solvents include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, Ci -6 alcohols, or the like.
  • aliphatic or alicyclic hydrocarbon solvent refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution.
  • hydrocarbon solvents include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3- dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3- methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5- Csaliphatic hydrocarbons, petroleum ethers, or mixtures thereof.
  • Aromatic hydrocarbon solvent refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution.
  • aromatic hydrocarbon solvents include, but are not limited to, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-Cioaromatic hydrocarbons, or mixtures thereof.
  • “Ester solvents” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C 3-6 esters, or the like.
  • halogenated hydrocarbon solvent is an organic solvent containing a carbon bound to a halogen.
  • Halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
  • “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3. 6 ket.ones, 4- methyl-pentane-2-one or the like.
  • a "polar aprotic solvent” has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N- dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3- methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane
  • ether solvent is an organic solvent containing an oxygen atom -O- bonded to two other carbon atoms.
  • “Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2- ethoxyethanol, anisole, C 2 - 6 ethers, or the like.
  • oxidizing agent also called an oxidant, oxidizer refers to a chemical compound that readily transfers oxygen atoms or a substance that gains electrons in a chemical reaction.
  • Coupled reagent refers to a chemical compound that react with amino acids to form activated amino acid intermediates which in turn react with the N-terminal amine of the peptide to form the elongated peptide.
  • leaving group refers to an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction.
  • the leaving group is bromide.
  • the leaving group is trimethylamine.
  • the electrophilic nitration of benzene it is H + .
  • the term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates (i.e.
  • Telaprevir and its impurities can be analyzed using HPLC, such as with a liquid chromatograph equipped with a UV detector and the parameters described below:
  • Diisopropylethylamine (2.4 gm) was added to the mixture and stirred for 12 hours at 30°C.
  • reaction mass was filtered and the salt was washed with ethylacetate (20 mL).
  • the ethylacetate layer was concentrated completely under vacuum at below 40°C and cyclohexane (75 mL) was added to the residue and the resulted mixture was agitated for 2 hours at 30°C.
  • the precipitate was filtered and the wet cake was washed with cyclohexane (20 mL) and the solid was dried under vacuum at below 40°C to yield 16.6 gm of title compound.
  • Example 7 Preparation of (S)-methyl 2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3, 3-dimethyl butanoate.
  • reaction mass was filtered and the salt was washed with ethylacetate (10 mL).
  • the ethylacetate layer was washed with 5% aqueous sodium chloride solution and concentrated completely under vacuum at below 40°C.
  • Cyclohexane 25 mL was added to the residue and the resulting mixture was agitated for 1 hour at 28°C.
  • the precipitate was filtered and the wet cake was washed with cyclohexane (5 mL) and the solid was dried under vacuum at 40°C to yield 5.5 gm of title compound.
  • Example 8 Preparation of (S)-2-((f?)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoic acid.
  • Example 10 Preparation of (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoic acid.
  • Example 1 Preparation of (1 S,3af?,6aS)-2-tert-butyl-1 -ethyl-hexahydrocyclopenta
  • Example 13 Preparation of (1 S,3af?,6aS)-2-tert-butoxy carbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxilic acid.
  • the mixture was heated to 55°C and agitated for 5 hours.
  • the reaction mass was distilled off completely under vacuum at 50°C and water (25 mL) was added to the crude and the resulted solution was cooled to 0°C.
  • Aqueous hydrochloric acid solution (10% 42 mL) was added slowly until pH reached to 2.5 and the mixture was agitated for 1 hour at 0°C.
  • the precipitate was filtered and the wet cake was washed with water (15 mL) and the solid dried under vacuum at 45°C to yield 5.6 gm of title compound.
  • Example 14 Preparation of (1 S,3af?,6aS)-2-tert-butoxy carbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxilic acid.
  • the mixture was heated to 55°C and agitated for 3 hours.
  • the reaction mass was distilled off completely under vacuum at 50°C.
  • Water (25 mL) was added to the crude and the resulted solution was cooled to 0°C.
  • Aqueous hydrochloric acid solution (10% 35 mL) was added slowly until pH reached to 2.5 and the mixture was agitated for 1 hour at 28°C.
  • the precipitate was filtered and the wet cake was washed with water (15 mL) and the solid dried under vacuum at 45°C to yield 5.5 gm of title compound.
  • Example 15 Preparation of (1 S,3aR,6aS)-2-tert-butyl 1 -(((3S)-1 -(cyclopropyl amino)-2- hydroxy-1 -oxohexan-3-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2-(1 H)carboxylate
  • Example 16 Preparation of (1 S,3aR,6aS)-2-tert-butyl 1 -(((3S)-1 -(cyclopropyl amino)-2- hydroxy-1 -oxohexan-3-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2-(1 H)carboxylate
  • Example 17 Preparation of (1 S,3aR,6aS)-2-tert-butyl 1 -(((3S)-1 -(cyclopropyl amino)-2- hydroxy-1 -oxohexan-3-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2-(1 H)carboxylate
  • Example 21 Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-1 -(cyclopropyl amino)-2- hydroxy-1 -oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide
  • Example 22 Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-1 -(cyclopropyl amino)-2- hydroxy-1 -oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide
  • Example 23 Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-1 -(cyclopropyl amino)-2- hydrox -1 -oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide
  • TEMPO solution (408 mg of TEMPO in 10 mL of dichloromethane) and 12.5% aqueous sodium hypochlorite (1 1.7 mL) were added to the reaction mixture at 0°C and the reaction mixture was stirred for 2 hours at 5°C.
  • the organic layer was separated and was quenched with 10% aqueous sodium sulphite solution (60 mL) and the resulted mixture was stirred for 15 minutes.
  • the organic layer was separated and washed with water (60 mL) and the organic layer was dried with anhydrous sodium sulphate and concentrated under vacuum completely.
  • Ethyl acetate (100 mL) was charged into the residue and the resulted solution was stirred for 2 hours at 28°C.
  • the precipitate was filtered and the wet cake was washed with ethyl acetate (20 mL) and the solid was dried under vacuum at 30°C to yield 5.2 gm of telaprevir.
  • Example 25 Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1 -(cyclopropyl amino)-1 -2- dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide (Telaprevir)
  • Example 26 Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1 -(cyclopropyl amino)-1 -2- dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide (Telaprevir)
  • Acetone (375 ml_), Bis(2-methylallyl)-(1 ,5-cyclooctadiene ruthenium (II) (170 mg) and (R)-(+)-(1 ,1 '-Binaphthalene-2,2'-diyl)bis(diphenylphosphine) (R-BINAP, 365 mg) are charged into 1000 ml_ round bottom flask under nitrogen atmosphere. The mixture was sonicated for 20 minutes and cooled to 28°C. 0.2 M methanolic hydrobromide solution (18.9 ml_) was added to the mixture at 28°C and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure at 40°C to Ru-BINAP catalyst.
  • Example 28 The compound obtained in Example 28 (1 g) was charged into a 100 mL round bottom flask and Tetrahydrofuran (15 mL) was added under nitrogen atmosphere. The mixture was cooled to -78°C and Diisobuylaluminum hydride (DIBAL-H, 1 M in Toluene, 5.4 mL) was added over a period of 20 minutes at -78°C and the reaction mixture was stirred for 3 hours at -78°C. The reaction mixture was quenched with methanol (2 mL) at -78°C and Rochelle salt solution (2M aqueous solution, 5 mL) was slowly added to the resulted solution at -78°C.
  • DIBAL-H Diisobuylaluminum hydride
  • Example 29 The compound obtained in Example 29 (150 mg) and Methanol (3 mL) were charged into a 50 mL round bottom flask. Trimethylorthoformate (0.93 mL) and p- Toluene sulfonic acid (5 mg) were added at 30°C and the resulting mixture was stirred for 16 hours at 30°C. Potassium carbonate (50 mg) was added to the reaction mixture and the resulted mixture was concentrated under vacuum at 30°C. Water (5 mL) was added to the residue and the solution was extracted with ethylacetate (2X10 mL). The ethylacetate layers were combined and washed with water (5 mL) and brine solution (5 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum to yield 90 mg of the title product as dark blue oil.
  • Trimethylorthoformate (0.93 mL)
  • p- Toluene sulfonic acid 5 mg
  • Example 29 The compound obtained in Example 29 (150 mg) and Toluene (3 mL) were charged into a 50 mL round bottom flask. Ethylene glycol (0.5 mL) and p-Toluene sulfonic acid (5 mg) were added at 30°C and the resulting mixture was stirred for 16 hours at 30°C. Water (5 mL) and ethylacetate (2X10 mL) were added to the reaction mixture and the organic later was separated. The aqueous layer was extracted with ethylacetate (10 mL). The ethylacetate layers were combined and washed with water (10 mL) and brine solution (10 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum to yield 100 mg of the title product as oil.
  • Example 30 The compound obtained in Example 30 (100 mg) and Dimethylformamide (3 mL) were charged into a 25 mL round bottom flask. Sodium cyanide (103 mg) was added at 30°C. The mixture was heated to 80°C and stirred for 16 hours at 80°C. The reaction mixture was cooled to 30°C and water (20 mL) was added. The resulted solution was extracted with ethylacetate (2X10 mL). The ethylacetate layers were combined and washed with water (10 mL) and brine solution (10 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (10% ethylacetate in hexane) to yield 20 mg of the title product as oil.
  • Example 30 The compound obtained in Example 30 (100 mg) and Dimethylformamide (3 mL) were charged into a 25 mL round bottom flask. Sodium cyanide (102 mg) was added at 30°C. The mixture was heated to 80°C and stirred for 16 hours at 80°C. The reaction mixture was cooled to 30°C and water (20 mL) was added. The resulted solution was extracted with ethylacetate (2X10 mL). The ethylacetate layers were combined and washed with water (10 mL) and brine solution (10 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum to yield 40 mg of the title product as dark blue oil.
  • Example 35 Preparation o -2-(1 ,3-dioxolan-2-yl)cyclopentyl)methanamine
  • the compound obtained in Example 34 (2.5 g) and Methanol (25 mL) were charged into a 100 mL round bottom single neck flask.
  • Raney Nickel (1.5 g) was charged in the mixture under nitrogen atmosphere.
  • Using a balloon hydrogen gas is applied and the reaction mixture is maintained for 16 hours at 27°C.
  • the reaction mixture was filtered through a celite bed and the celite bed was washed with methanol (25 mL). The filtrate was concentrated completely under reduced pressure to get 2.0 g of the title product as pale green syrup.
  • Example 35 The compound obtained in Example 35 (500 mg), 1 N HCI (50 mL) and KCN (760 mg) were charged into a 250 mL round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 30°C. 30% KOH solution (5 mL) was added to the reaction mixture and extracted with dichloromethane (2X25 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (20% ethylacetate in hexane) to yield 200 mg of the title compound as brown liquid.
  • Example 36 The compound obtained in Example 36 (200 mg) and concentrated HCI (2 mL) were charged into a 50 mL round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 100°C.
  • the reaction mixture was concentrated under vacuum and the obtained crude was dissolved in methanol (2 mL), triethylamine (0.4 mL) and di-tert- butyl dicarbonate (B0C 2 O, 400 mg) at 0°C.
  • the resulting mixture was stirred for 2 hours at 30°C and the reaction mixture was concentrated under vacuum and diluted with saturated NaHC03 solution (20 mL) and extracted with ethyl acetate (25 mL).
  • the aqueous solution was acidified using citric acid to pH ⁇ 5 and the aqueous solution was extracted with ethyl acetate (25 mL). Organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum to yield 250 mg of the title compound as a white solid.
  • Example 38 The compound obtained in Example 38 (2.5 g) and Dichloromethane (50 mL) were charged into a 250 mL round bottom flask and the resulted solution was cooled to 0°C. Imidazole (3.5 g) and tert-Butylchlorodiphenylsilane (5.9 g) were added at 0°C and the resulting mixture was stirred for 2 hours at 28°C. Water (100 mL) was added to the reaction mixture and the resulted solution was extracted with Dichloromethane (2 X 50 mL). The organic layers were combined and dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (20% ethylacetate in hexane) to yield 5.7 g of the title product as colorless oil.
  • Example 39 The compound obtained in Example 39 (5 g) and Dichloromethane (100 mL) were charged into a 250 mL round bottom flask and mixture was cooled to 0°C. Triethylamine (4.3 mL) was added to the mixture at 0°C over a period of 10 minutes. Methanesulfonylchloride (1.3 mL) was added to the mixture at 0°C over a period of 20 minutes. The mixture was heated to 28°C and stirred for 2 hours. Water (50 mL) was added to the reaction mixture and stirred for 10 minutes. Organic layer was separated and the aqueous layer was extracted with Dichloromethane (2 X100 mL).
  • Example 40 The compound obtained in Example 40 (5 g) and Dimethylformamide (50 mL) were charged into a 250 mL round bottom flask. Sodium cyanide (1.13 g) was added at 28°C. The mixture was heated to 60°C and stirred for 16 hours at 60°C. The reaction mixture was cooled to 30°C and water (100 mL) was added. The resulted solution was extracted with ethylacetate (2X100 mL). The ethylacetate layers were combined and washed with water (100 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (10% ethylacetate in hexane) to yield 2.5 g of the title product as colorless oil.
  • Example 41 The compound obtained in Example 41 (2.5 g) and Ethanol (25 mL) were charged into a 100 mL round bottom single neck flask. Raney Nickel (1 g) was charged in the mixture under nitrogen atmosphere. Using a balloon hydrogen gas is applied and the reaction mixture is maintained for 16 hours at 27°C. Under nitrogen atmosphere the reaction mixture was filtered through a celite bed and the celite bed was washed with ethanol (25 mL). The filtrate was concentrated completely under reduced pressure to get 2.2 g of the title product as yellowish syrup.
  • Example 42 The compound obtained in Example 42 (2.2 g) and Methanolic hydrochloride (20 mL) was charged into a 100 mL round bottom flask and the resulted mixture was stirred for 2 hours at 28°C. The reaction mixture was evaporated to dryness under reduced pressure. Diethyl ether (25 mL) was added to the obtained crude and the resulted mixture was concentrated under reduced pressure to yield 650 mg of the title product as yellowish syrup.
  • Example 43 The compound obtained in Example 43 (600 mg) and Methanol (6 mL) were charged into a 50 mL round bottom flask. Triethylamine (0.9 mL) was added the mixture at 0°C. Boc anhydride (1.2 mL) was added at 0°C and the resulted mixture was stirred for 1 hour at 28°C. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added to the crude and the obtained solution was extracted with Dichloromethane (2X 50 mL). The combined organic layer was dried over anhydrous sodium sulfate (2 g) and concentrated under reduced pressure. The crude was purified by column chromatography (10% ethylacetate in hexane) to yield 400 mg of the title compound as white solid.
  • Example 44 The compound obtained in Example 44 (200 mg) and Dichloromethane (4 mL) were charged into a 25 mL round bottom flask and the mixture was cooled to 0°C. Dess-Martin Periodinane (DMP, 740 mg) was added and the reaction mixture was stirred at 28°C for 2 hours. Dichloromethane was evaporated under Nitrogen atmosphere. To the residue diethyl ether (15 mL) and hexane (25 mL) were charged and the resulted mixture was stirred for 10 minutes. The precipitation was filtered and the filtrate was concentrated under reduced pressure to yield 150 mg of the title product as brownish oil. The obtained crude material was taken up for next reaction without any further purification.
  • DMP Dess-Martin Periodinane
  • Example 45 The compound obtained in Example 45 (700 mg) and Methanol (7 mL) were charged into a 100 mL round bottom flask. Trimethylorthoformate (3.6 mL) and p-Toluene sulfonic acid (10 mg) were added at 30°C and the resulting mixture was stirred for 16 hours at 30°C. Potassium carbonate (50 mg) was added to the reaction mixture and the resulted mixture was concentrated under vacuum at 30°C. Water (25 mL) was added to the residue and the solution was extracted with dichloromethane (2X25 mL). The organic layer was dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum to yield 700 mg of the title product as colorless liquid. The obtained crude compound was taken up for the next reaction without any further purification.
  • Example 46 The compound obtained in Example 46 (600 mg), 1 N HCI (102 mL) and KCN (570 mg) were charged into a 250 mL round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 30°C. 30% KOH solution (5 mL) was added to the reaction mixture and extracted with ethyl acetate (2X25 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (20% ethylacetate in hexane) to yield 180 mg of the title compound as brown liquid.
  • Example 47 The compound obtained in Example 47 (80 mg) and concentrated HCI (1 mL) were charged into a 25 mL round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 100°C.
  • the reaction mixture was concentrated under vacuum and crude was triturated with diethyl ether (10 mL).
  • the obtained crude was dissolved in methanol (5 mL), triethylamine (0.15 mL) and Boc 2 0 (124 mg) at 30°C.
  • the resulting mixture was stirred for 30 min at 30°C and the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2X25 mL).
  • the organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum to yield 90 mg of the title compound as a white solid.
  • Example 45 The compound obtained in Example 45 (500 mg), 1 N HCI (100 mL) and KCN (520 mg) were charged into a 250 mL round bottom flask at 30°C and the resulting mixture was agitated for 16 hours at 30°C. 30% KOH solution (5 mL) was added to the reaction mixture and extracted with ethyl acetate (2X25 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (20% ethylacetate in hexane) to yield 150 mg of the title compound as brown liquid.
  • Example 50 Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1 -(cyclopropyl amino)-1 -2- dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide (Telaprevir)
  • Telaprevir (35 gm) and dichloromethane (105 mL) were charged into a 500 mL round bottomed flask and stirred to get clear solution and the solution was filtered.
  • Dichloromethane was distilled out completely under vacuum and fresh dichloromethane (35 mL) was added to the residue.
  • Ethylacetate (350 mL) was added to the mass and the resulted mixture was stirred for 30 minutes at 28°C. The precipitation was filtered and the wet cake was washed with ethylacetate (35 mL).
  • the wet material was charged into another 500 mL round bottomed flask, dichloromethane (90 mL) was added and stirred to get clear solution.
  • Telaprevir (24 gm) and dichloromethane (72 mL) were charged into a 500 mL round bottomed flask and stirred to get clear solution and the solution was filtered.
  • Dichloromethane was distilled out completely under vacuum and fresh dichloromethane (24 mL) was added to the residue.
  • Ethylacetate (240 mL) was added to the solution and the resulted mixture was stirred for 30 minutes at 28°C. The precipitation was filtered and the wet cake was washed with ethylacetate (24 mL).
  • the wet material was charged into another 500 mL round bottomed flask dichloromethane (72 mL) was added and stirred to get clear solution.
  • Example 53 The compound obtained in Example 53 (30 g) was charged into a 1000 mL round bottom flask and Toluene (300 mL) was added under nitrogen atmosphere. The mixture was cooled to -78°C and Diisobuylaluminum hydride (DIBAL-H, 1 M in Toluene, 202.5 mL) was added over a period of 30 minutes at -78°C and the reaction mixture was stirred for 2 hours at -78°C. The reaction mixture was quenched with methanol (5 mL) at -78°C and saturated ammonium chloride solution (250 mL) was slowly added to the resulted solution at -78°C.
  • DIBAL-H Diisobuylaluminum hydride
  • Example 54 The compound obtained in Example 54 (24 gm) and Dimethylformamide (144 ml_) and Sodium cyanide (19.9 gm) were charged into a 500 ml_ round bottom flask. The mixture was heated to 65°C and stirred for 16 hours. The reaction mixture was cooled to 30°C and water (250 ml_) was added. The resulted solution was extracted with ethylacetate (2 x 250 ml_). The ethylacetate layers were combined and washed with water (2 x 250 ml_) and brine solution (2 x 150 ml_). The organic layer was dried with anhydrous sodium sulphate (10 gm) and concentrated completely under vacuum and the residue was purified by column chromatography to yield 13 gm of the title product as yellow syrup.
  • Example 55 The compound obtained in Example 55 (13 g) and Methanol (260 ml_) were charged into a 1 L steel vessel. Raney Nickel (3 g) was charged in the mixture under nitrogen atmosphere. The reaction mixture was stirred for 16 hours at 27°C under hydrogen pressure (80 psi) using parr hydrogenator. Under nitrogen atmosphere the reaction mixture was filtered through a celite bed and the celite bed was washed with methanol (200 ml_). The filtrate was taken into a 1000 ml_ round bottom flask, triethylamine (21 .6 ml_) and boc anhydride (16.9 ml_) were added and the resulting mixture was stirred for 2 hours at 28°C.
  • the reaction mass was concentrated completely under reduced pressure and the crude was diluted with water and the solution was extracted with ethylacetate (2 x 250 ml_). The organic layer was washed with 5% citric acid solution to remove excess boc anhydride and washed with brine solution. The organic layer was dried over sodium sulphate (10 g) and concentrated under reduced pressure to get 15.0 g of the title product as pale yellow syrup.
  • Example 56 The compound obtained in Example 56 (14 gm), 2N HCI (3L) and KCN (13.4 gm) were charged into a 5L round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 30°C. 30% KOH solution (1.1 L) was added to the reaction mixture and extracted with dichloromethane (2 x 500 ml_). The organic layer was dried with anhydrous sodium sulphate (10 gm) and concentrated completely under vacuum to give 4 gm of the title compound as colorless syrup.
  • the reaction mixture was concentrated under vacuum and diluted with saturated NaHC03 solution (100 mL) and extracted with ethyl acetate (200 mL).
  • the aqueous solution was acidified using saturated citric acid to pH ⁇ 5 and the aqueous solution was extracted with ethyl acetate (200 mL).
  • Organic layer was dried with anhydrous sodium sulphate (5 gm) and concentrated completely.
  • the obtained crude compound was triturated with hexane for 2 hours and the white solid was filtered and dried under vacuum to give 4.48 gm of the title compound as a white solid.
  • Example 59 The compound obtained in Example 59 (70 g) and Dichloromethane (1.4L) were charged into a 3L round bottom flask and the resulted solution was cooled to 0°C. Imidazole (98 g) and tert-Butylchlorodiphenylsilane (165 g) were added at 0°C and the resulting mixture was stirred for 2 hours at 28°C. Water (1000 mL) was added to the reaction mixture and the resulted solution was extracted with Dichloromethane (2 x 250 mL). The organic layers were combined and washed with brine solution and dried over anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (15% ethylacetate in hexane) to yield 160 g of the title product as colorless oil.
  • Example 60 The compound obtained in Example 60 (160 g) and Dichloromethane (3.2L) were charged into a 5L round bottom flask and mixture was cooled to 0°C. Triethylamine (125 mL) and Methanesulfonylchloride (38 mL) were added to the mixture at 0°C. The mixture was heated to 28°C and stirred for 2 hours. Water (2L) was added to the reaction mixture and stirred for 10 minutes. Organic layer was separated and the aqueous layer was extracted with Dichloromethane (3 x 500 mL). The organic layers were combined and washed with saturated sodium bicarbonate solution (2 x 1 L) followed by washing with brine solution (2 x 1 L). The organic layer was dried with anhydrous sodium sulphate (20 gm) and concentrated completely under vacuum to yield 195 g of the title product as white solid.
  • Example 61 The compound obtained in Example 61 (160 g), Dimethylformamide (960 ml_) and Sodium cyanide (72 g) were charged into a 3L round bottom flask. The mixture was heated to 65°C and stirred for 48 hours at 65°C. The reaction mixture was cooled to 30°C and water (1.5L) was added. The resulted solution was extracted with ethylacetate (3 x 500 ml_). The organic layer was dried with anhydrous sodium sulphate (20 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (7% ethylacetate in hexane) to yield 70 g of the title product as colorless oil.
  • Example 62 The compound obtained in Example 62 (70 g), Methanol (700 mL) and Raney Nickel (1 g) were charged into a 2L steel vessel under nitrogen atmosphere, the reaction mixture was stirred for 16 hours at 27°C under hydrogen pressure (80 psi) using parr hydrogenator. The reaction mixture was filtered through a celite bed and the celite bed was washed with Methanol (500 mL). The filtrate was concentrated completely under reduced pressure to get 65 g of the title product as yellowish syrup.
  • Example 63 The compound obtained in Example 63 (65g) and Methanol (650 mL) were charged into a 2L round bottom flask. HCI gas was passed in to reaction mixture for 4 hours at 0°C. The reaction mixture was basified using Triethylamine (47 mL). Boc anhydride (45 mL) was added at 0°C and the resulted mixture was stirred for 2 hours at 28°C. The reaction mixture was concentrated under reduced pressure. Water (500 mL) was added to the crude and the obtained solution was extracted with Dichloromethane (2 x 500 mL). The combined organic layer was dried over anhydrous sodium sulfate (10 g) and concentrated under reduced pressure. The crude was purified by column chromatography (7% ethylacetate in hexane) to yield 20 mg of the title compound as white solid. Purity: 72.7% by HPLC.
  • Example 64 The compound obtained in Example 64 (20 g) and Dichloromethane (400 ml_) were charged into a 2L round bottom flask and the mixture was cooled to 0°C. Dess- Martin Periodinane (DMP, 74 g) was added and the reaction mixture was stirred at 28°C for 2 hours. Dichloromethane was evaporated under Nitrogen atmosphere. To the residue diethyl ether (450 ml_) and hexane (1 L) were charged and the resulted mixture was stirred for 10 minutes. The resulting solution was filtered through a celite and the filtrate was concentrated under reduced pressure to yield 18 mg of the title product as pale yellow syrup. The obtained crude material was taken up for next reaction without any further purification.
  • DMP Dess- Martin Periodinane
  • Example 65 The compound obtained in Example 65 (18 g), Trimethylorthoformate (93 ml_), p- Toluene sulfonic acid (180 mg) and Methanol (180 ml_) were charged at 30°C and the resulting mixture was stirred for 16 hours at 30°C. Potassium carbonate (10 g) was added to the reaction mixture to adjust pH 9.5 and the resulted mixture was concentrated under vacuum at 30°C. Water (500 ml_) was added to the residue and the solution was extracted with dichloromethane (2 x 250 ml_). The organic layer was dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum to yield 18 g of the title product as yellow liquid. The obtained crude compound was taken up for the next reaction without any further purification.
  • Example 66 The compound obtained in Example 66 (18 g), 1 N HCI (3L) and KCN (17 g) were charged into a 5L round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 30°C. pH was adjusted to 14 with 30% KOH solution (700 ml_) and extracted with dichloromethane (2 x 500 ml_). The organic layer was dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (20% ethylacetate in hexane) to yield 5 g of the title compound as yellow liquid.
  • Example 68 Preparation of (1 S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxylic acid.
  • Example 67 The compound obtained in Example 67 (5 g) and concentrated HCI (25 ml_) were charged into a 250 ml_ round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 100°C.
  • the reaction mixture was concentrated under vacuum and crude was triturated with diethyl ether (10 ml_).
  • the obtained crude was dissolved in methanol (50 ml_), triethylamine (10.2 ml_) and B0C 2 O (9.79 ml_) at 0°C.
  • the resulting mixture was stirred for 2 hours at 30°C.
  • the reaction mixture was concentrated under vacuum and diluted with saturated sodium bicarbonate solution (100 ml_) and extracted with ethyl acetate (250 ml_).
  • the aqueous layer was acidified using saturated citric acid (pH 4.5) and extracted with ethyl acetate (250 ml_).
  • the organic layer was dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum to yield 5 g of the title compound as a white solid.

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Description

PROCESS FOR PREPARATION OF INTERMEDIATES OF TELAPREVIR
FIELD OF THE INVENTION
The present application relates to novel processes for preparation of (1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1 -carboxylic acid of formula (Vllb) and its derivatives; and their use in preparation of Telaprevir.
Figure imgf000002_0001
Formula Vllb
BACKGROUND OF THE INVENTION
(1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1 -carboxylic acid of formula (Vllb) and its derivatives are important intermediates for chemical synthesis of hepatitis C virus (HCV) protease inhibitor telaprevir of formula I.
Figure imgf000002_0002
Formula I
International patent application publication WO 2002018369 (WO '369) discloses a process for preparation of (1 S,3aR,6aS)-tert-butyloctahydrocyclopenta[c]pyrrole-1 - carboxylate (tert-butyl ester of compound of formula Vllb), in which (1 S,3aR,6aS)-tert- butyl 3-oxooctahydrocyclopenta[c]pyrrole-1 -carboxylate is protected with tert- butyloxycarbonyl (boc) and the boc protected compound is reduced with DIBAL-H and subsequent deprotection yielded (1 S,3aR,6aS)-tert-butyl-3- oxooctahydrocyclopenta[c]pyrrole-1 -carboxylate hydrochloride. The process disclosed in WO '369 is schematically represented in scheme-l.
l
Figure imgf000003_0001
Scheme-I
WO '369 also discloses another process for preparation of (1 S,3aR,6aS)- ethyloctahydrocyclopenta[c]pyrrole-1 -carboxylate (ethyl ester of compound of formula VI lb), in which (1 S,3aR,6aS)-2-benzyl 1 -ethyl-4-oxohexahydrocyclopenta[c]pyrrole- 1 ,2(1 H)-dicarboxylate is reduced using sodiumborohydride to form (1 S,3aR,6aS)-2- benzyl-1 -ethyl-4-hydroxyhexahydrocyclopenta[c]pyrrole-1 ,2(1 H)-dicarboxylate. The hydroxy compound is treated with sodium hydride in presence of carbon disulfide and methyl iodide to form (1 S,3aR,4S,6aS)-2-benzyl-1 -ethyl-4-
(((methylthio)carbonothioyl)oxy)hexahydro cyclopenta[c]pyrrole-1 ,2(1 H)-dicarboxylate and subsequent reduction and deprotection yielded (1 S,3aR,6aS)- ethyloctahydrocyclopenta[c]pyrrole-1 -carboxylate. The process is schematically represented in scheme-ll.
Figure imgf000003_0002
Scheme-ll
International patent application publication WO 2007022459 (WO '459) discloses a process for preparation of (1 S,3aR,6aS)-tert-butyloctahydrocyclopenta[c]pyrrole-1 - carboxylate, in which (3aR,6aS)-tert-butyl hexahydrocyclopenta[c]pyrrole-2(1 H)- carboxylate is treated with carbon dioxide in the presence of 3,7-dipropyl-3,7- diazabicylo[3,3,1]nonane and sec-butyllithium to form enriched (1 S,3aR,6aS)- octahydrocyclopenta[c]pyrrole-1 -carboxylic acid. Subsequent resolution of the acid using a chiral base such as (S)-1 ,2,3,4-tetrahydronaphthalen-1 -amine, and tert-butyl ester formation yielded (1 S,3aR,6aS)-tert-butyloctahydrocyclopenta[c]pyrrole-1- carboxylate. The process disclosed in WO '459 is schematically represented in scheme-
Figure imgf000004_0001
Scheme-III
International patent application publication WO 2010008828 (WO '828) discloses a process for preparation of (1 S,3aR,6aS)-tert-butyloctahydrocyclopenta[c]pyrrole-1 - carboxylate, in which (3aR,6aS)-octahydrocyclopenta[c]pyrrole is treated with manoamine oxidase enzyme to yield (3aS,6aR)-1 ,3a, 4, 5, 6, 6a- hexahydrocyclopenta[c]pyrrole. The (3aS,6aR)-1 , 3a, 4, 5, 6,6a- hexahydrocyclopenta[c]pyrrole exists in the form a dimer or a trimer and is treated with sodium cyanide to from (1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1 -carbonitrile. Subsequent hydrolysis of the nitrile and ester formation using tert-butylmethyl ether yielded (1 S,3aR,6aS)-tert-butyloctahydrocyclopenta[c]pyrrole-1 -carboxylate. The process disclosed in WO '828 is schematically represented in scheme-IV.
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
Scheme-IV The prior-art processes herein described above suffer from drawbacks such as low yield and purity. Hence there is a continuing need to develop simplified and improved processes for preparing the compound of formula Vllb which processes are suitable for commercial manufacturing in high purity and yield.
SUMMARY OF THE INVENTION
The object of the present application is to provide novel and industrially advantageous processes for preparation of the (1 S,3aR,6aS)- octahydrocyclopenta[c]pyrrole-1 -carboxylic acid of formula (Vllb).
In an aspect, the application provides a process for preparation of (1 S,3aR,6aS)- octahydrocyclopenta[c]pyrrole-1 -carboxylic acid of formula (Vllb), comprising:
(a) reducing a compound of formula XX with a suitable reducing agent to form a compound of formula XIX
Figure imgf000006_0001
XIX
wherein X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl; R is hydrogen or C C4 alkyl or C5-C12 aralkyl,
(b) protecting the aldehyde functionality of the compound of formula XIX to form a compound of formula XVIII.
Figure imgf000006_0002
wherein R1 and R2 are C C5 alkyl or both form a cyclic ring,
(c) cyanating the compound of formula XVIII with a suitable cyanating agent to form compound of formula XVII
Figure imgf000007_0001
xvm xvii
(d) reducing the compound of formula XVII in the presence of a suitable catalyst to obtain compound of formula XVI,
Figure imgf000007_0002
(e) treating the compound of formula XVI with an acid and an alkali metal cyanide to form compound of formula XV, and
Figure imgf000007_0003
XVT xv
(f) hydrolyzing the compound of formula XV to form compound of formula Vllb or its acid addition salt
Figure imgf000007_0004
XV Vllb
In another aspect, the application provides a process for preparation of a compound of formula Vllb, comprising:
(a) reducing the compound of formula XX with a suitable reducing agent to form a compound of formula VIII
Figure imgf000007_0005
XX VIII wherein X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl; R is hydrogen or Ci-C alkyl or C5-C12 aralkyl,
(b) protecting the primary hydroxyl group of compound of formula VIII to get compound of formula IX,
Figure imgf000008_0001
VIII IX
wherein P is a protecting group,
(c) cyanating the compound of formula IX with a suitable cyanating agent to form compound of formula X
Figure imgf000008_0002
IX X
(d) reducing the compound of formula X in the presence of a suitable catalyst to obtain compound of formula XI,
Figure imgf000008_0003
X XI
(e) optionally, deprotecting the compound of formula XI to form compound of formula XII,
Figure imgf000008_0004
XI XII
(f) oxidizing the compound of formula XII to form compound of formula XIII,
Figure imgf000008_0005
XII ΙΠ (g) optionally, protecting the aldehyde of the compound of formula XIII to form a compound of formula XVI.
Figure imgf000009_0001
XITT XVI
R1 and R2 are C C5 alkyl or both form a cyclic ring,
(h) treating the compound of formula XIII or the compound of formula XVI with an alkali metal cyanide to form a com ound of formula XV and
Figure imgf000009_0002
XVI xv
(i) hydrolyzing the compound of formula XV to form compound of formula Vllb or its acid addition salt
Figure imgf000009_0003
XV Vllb
In another aspect, the present application provides use of compound of formula Vllb prepared by the processes disclosed in the present application in the preparation of telaprevir comprising,
(a) reacting compound of formula Vllb or a protected form of formula Vllb with a compound of formula Via or its salt in the presence of a suitable coupling reagent to form compound of formula Va or its salt,
For
Figure imgf000009_0004
mula Vllb Formula Via
Formula Va
wherein P is an amine protecting group; (b) deprotecting the compound of formula Va or its salt using an acid to form compound of formula Ilia or a salt thereof.
Figure imgf000010_0001
Formula Va Formula Ilia
(c) reacting a compound of formula Ilia or a salt thereof with a compound of formula IVa or a salt thereof in the presence of a suitable coupling reagent to form a compound of formula lla,
Figure imgf000010_0002
(d) oxidizing the compound of Formula lla using a suitable oxidizing reagent to form telaprevir. Oxidation, C JO JC
Figure imgf000010_0003
Telaprevir
In another aspect, the application provides new intermediates and starting materials in the process according to the present invention.
In another aspect, the present application provides Telaprevir having purity greater than about 99.5 area % as measured by HPLC.
In another aspect, the present application provides Telaprevir having purity greater than about 99.8 area % as measured by HPLC.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an illustrative example of an XRPD pattern of crystalline telaprevir, prepared in Example 24.
Fig. 2 is an illustrative example of an XRPD pattern of crystalline compound of formula IVa, prepared in Example 8. DETAILED DESCRIPRION OF THE INVENTION
The present application provides novel processes for preparation of
(1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1 -carboxylic acid of formula (Vllb) and its use in preparation of telaprevir.
In one aspect, the application provides a process for preparation of
(1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1 -carboxylic acid of formula (Vllb), comprising:
(a) reducing a compound of formula XX with a suitable reducing agent to form a compound of formula XIX
Figure imgf000011_0001
xx xix
wherein X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl; R is hydrogen or Ci-C alkyl or C5-C12 aralkyl,
(b) protecting the aldehyde functionality of the compound of formula XIX to form a compound of formula XVIII.
Figure imgf000011_0002
wherein R1 and R2 are C1 -C5 alkyl or both form a cyclic ring,
(c) cyanating the compound of formula XVIII with a suitable cyanating agent to form compound of formula XVII
Figure imgf000011_0003
XVIII XVII
(d) reducing the compound of formula XVII in the presence of a suitable catalyst to obtain compound of formula XVI,
Figure imgf000012_0001
XVII XVI
(e) treating the compound of formula XVI with an alkali metal cyanide to form compound of formula XV, and
Figure imgf000012_0002
XVT xv
(f) hydrolyzing the compound of formula XV to form compound of formula Vllb or its acid addition salt
Figure imgf000012_0003
XV Vllb
The step (a) of the process involves reduction of compound of formula XX with a suitable reducing agent to form a compound of formula XIX. The reduction is carried out using a suitable reducing agent in presence of a suitable solvent.
Compound of Formula XX may be obtained by any process including processes described in the art, or by a process described in this application.
The suitable reducing agent is selected from the group comprising of diisobuyl aluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy)aluminum hydride (Red-AI) triisobuyl aluminum (TIBAL), potassium diisobutyl-tert-butoxyaluminium hydride (PDBBA), lithium diisobutyl-tert-butoxyaluminium hydride (LDBBA), sodium diisobutyl- tert-butoxyaluminium hydride (SDBBA), diisobuyl aluminum butylated oxytoulene (DIBAL-BOT), sodium aluminum hydride (SAH), lithium aluminum hydride (LAH), bis(4- methyl-1 -piperazinyl) aluminum hydride (BMAH). In one embodiment the reducing agent is diisobuyl aluminum hydride (DIBAL-H). In another embodiment the reducing agent is sodium-bis-(2-methoxyethoxy)aluminum hydride (Red-AI). The reducing agent may be used in the form of a solution in a suitable solvent. The quantity of reducing agent may range from about 1 to about 4 moles. In one embodiment the quantity of the reducing agent is about 1 to about 2 moles, per mole of compound of Formula XX.
Suitable solvents that can be used for the reaction include, but are not limited to: ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, toluene, 1 ,4- Dioxane, 2-Methyltetrahydrofuran and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; and any mixtures thereof. In one embodiment the solvent used in step (a) is ether such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like. In another embodiment the solvent is hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like.
The process of step (a) is suitably carried out at temperatures ranging from about -100°C to about 50°C. In one embodiment the reduction is carried out at temperatures ranging from about -80°C to about 30°C.
After completion of the reaction the reaction mixture is quenched with aqueous ammonium chloride or Rochelle's salt, and the salt by-product is removed by filtration. The organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
The step (b) of the process involves protection of the aldehyde of the compound of formula XIX with a suitable protecting group in presence of a suitable solvent to form a compound of formula XVIII.
The suitable protecting group is selected from the group comprising of trimethylorthoformate, triethylorthoformate, ethylene glycol, propylene glycol, acetic anhydride and propionic anhydride.
The quantity of the protecting group may range from about 1 to about 20 moles. In one embodiment the quantity of the reducing agent is about 1 to about 10 moles, per mole of compound of Formula XIX.
The protection may be carried out in the presence of an acid and a suitable solvent. The solvent that can be used for the reaction include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; halogenated hydrocarbons such as dichloromethane (DCM), ethylene dichloride, chloroform, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; esters such as ethyl acetate, propyl acetate, and the like; and any mixtures thereof. In one embodiment the solvent used in step (b) is an alcohol such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like. In another embodiment the solvent used in step (b) is hydrocarbons such as toluene, xylene, n- hexane, n-heptane, cyclohexane, and the like;
The process of step (b) is suitably carried out at temperatures ranging from about -30°C to about 80°C. In one embodiment the reduction is carried out at temperatures ranging from about 0°C to about 50°C.
After completion of the reaction, the reaction mixture is diluted with aq. Base such as sodium carbonate or sodium bicarbonate, and the solution is extracted with a suitable water immiscible solvent. The organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
The step (c) of the process involves cyanation of the protected aldehyde of the compound of formula XVIII with a suitable cyanating agent in a suitable solvent.
The suitable cyanating agent is selected from the group comprising of Copper cyanide, Sodium cyanide, Potassium cyanide, Zinc cyanide and potassium hexacyanoferroate (K4Fe(CN)6). In one embodiment the cyanating agent is Sodium cyanide.
The quantity of the cyanating agent may range from about 1 to about 5 moles. In one embodiment the quantity of the cyanating agent is about 1 to about 3 moles per mole of compound of Formula XVIII.
The suitable solvent that can be used for cyanation include, but are not limited to: polar aprotic solvents such as Dimethylformamide, Dimethylsulfoxide, Dimethyl acetamide, acetonitrile and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; hydrocarbons such as toluene, xylene, n-hexane, n- heptane, cyclohexane, and the like; and any mixtures thereof. In one embodiment the solvent used in cyanation is a polar aprotic solvent such as Dimethylformamide, Dimethylsulfoxide, Dimethyl acetamide, acetonitrile and the like; The process of cyanation is suitably carried out at temperatures ranging from about 0°C to about 100°C. In one embodiment the cyanation is carried out at temperatures ranging from about 20°C to about 80°C.
After completion of the reaction, the reaction mixture may be diluted with water and the solution is extracted with a suitable water immiscible solvent. The organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
The step (d) of the process involves reduction of the cyanide of the compound of formula XVII in presence of a suitable catalyst, hydrogen gas, and a suitable solvent.
The suitable catalyst is selected from the group comprising of Raney Nickel, Palladium, Platinum, Rhodium, and Ruthenium. In one embodiment the hydrogenation catalyst is Raney-Nickel.
The quantity of the catalyst may range from about 0.01 to about 5 moles. In one embodiment the quantity of the catalyst is about 0.1 to about 1 mole per mole of compound of Formula XVII.
The suitable solvent that can be used for the catalytic hydrogenation include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert- butanol, and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; hydrocarbons such as toluene, xylene, n-hexane, n- heptane, cyclohexane, and the like; esters such as ethyl acetate, propyl acetate, and the like; water, formic acid, acetic acid and any mixtures thereof. In one embodiment the solvent used in the catalytic hydrogenation is an alcohol such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like;
The process of catalytic hydrogenation is suitably carried out at temperatures ranging from about 0°C to about 100°C. In one embodiment the catalytic hydrogenation is carried out at temperatures ranging from about 30°C to about 80°C.
After completion of the hydrogenation, the catalyst is isolated from the reaction mixture by way of filtration. The filtrate containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
The compound of formula XVI may optionally be protected with and an amine protecting group. The step (e) of the process involves treatment of the amine of the compound of formula XVI or the protected amine with a cyanide to form compound of formula XV.
If the compound of formula XVI is protected one, before reacting it with cyanide the compound is treated with a suitable acid to deprotect the amine. The suitable acid used in the process of step (e) is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid and acetic acid. In one embodiment the acid used in the process of step (e) is hydrochloric acid.
The acid concentration may vary from about 0.1 N to about 10N. In one embodiment the acid concentration is 1 N.
The suitable cyanide used in the process of step (e) is selected from the group comprising of Copper cyanide, Sodium cyanide, Potassium cyanide, Zinc cyanide. In one embodiment the cyanide is Potassium cyanide.
The quantity of the cyanide used in the process of step (e) may vary from about 1 to about 10 moles. In one embodiment the quantity of the cyanide is about 1 to about 5 moles per mole of compound of Formula XVI.
The process of step (e) is suitably carried out at temperatures ranging from about 0°C to about 80°C. In one embodiment the reaction is carried out at temperatures ranging from about 10°C to about 50°C.
After completion of the reaction, the reaction mixture is diluted with water and may be treated with a base. The resulted solution is extracted with a suitable water immiscible solvent. The solvent containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
The step (f) of the process involves hydrolysis of the cyanide of the compound of formula XV in presence of a mineral acid to form compound of formula Vllb.
The mineral acid used in the hydrolysis is selected from the group comprising of Hydrochloric acid, Hydrobromic acid, Hydroiodic acid and Sulfuric acid. In one embodiment the mineral acid used in the hydrolysis is Hydrochloric acid.
The mineral acid may be used in the form of a solution having a concentration of about 0.1 N to about 10N. In one embodiment the acid concentration is 1 N.
The solvent used for the preparation of the mineral acid solution include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert- butanol, and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate, and the like; water, and any mixtures thereof. In one embodiment the solvent used in the preparation of the mineral acid solution is an alcohol such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like. In another embodiment the solvent used in the preparation of the mineral acid solution is water.
After completion of the reaction, the reaction mixture is concentrated and the compound of formula Vllb is isolated. In one embodiment the compound of formula Vllb is isolated as an acid addition salt.
The compound of formula Vllb or its acid addition salt may be protected to form compound of formula Vila or an acid addition salt.
Figure imgf000017_0001
Vila
wherein P is an amine protecting group.
The suitable amine protecting group is selected from the group comprising of 9- Fluorenylmethyloxy carbonyl (FMOC), tert-butyloxycarbonyl (BOC), benzyloxy carbonyl (CBZ), acetyl, trifluoroacetyl, benzyl, triphenylmethyl, and p-toluenesulfonyl. In one embodiment the amine protecting group is tert-butyloxycarbonyl.
Protection of the amine functionality of the compound of formula Vllb is suitably carried out using any process including processes described in the art, or by a process described in this application.
In another aspect, the application provides a process for preparation of a compound of formula Vllb, comprising:
(a) reducing the compound of formula XX with a suitable reducing agent to form a compound of formula XIX
Figure imgf000017_0002
XX VIII wherein X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl; R is hydrogen or Ci-C alkyl or C5-C12 aralkyl,
(b) protecting the primary hydroxyl group of compound of formula VIII to get compound of formula IX,
Figure imgf000018_0001
VIII IX
wherein X is a protecting group,
(c) cyanating the compound of formula IX with a suitable cyanating agent to form compound of formula X
Figure imgf000018_0002
IX X
(d) reducing the compound of formula X in the presence of a suitable catalyst to obtain compound of formula XI,
Figure imgf000018_0003
X XI
(e) deprotecting the compound of formula XI to form compound of formula XII,
Figure imgf000018_0004
XI XII
(f) oxidizing the compound of formula XII to form compound of formula XIII,
Figure imgf000018_0005
(g) optionally, protecting the aldehyde of the compound of formula XIII to form a compound of formula XVI.
Figure imgf000019_0001
XITT XVI
R1 and R2 are C C5 alkyl or both form a cyclic ring,
(h) treating the compound of formula XIII or the compound of formula XVI with an alkali metal cyanide to form a compound of formula XV, and
Figure imgf000019_0002
XVI xv
(i) hydrolyzing the compound of formula XV to form compound of formula Vllb or its acid addition salt
Figure imgf000019_0003
XV Vllb
The step (a) of the process involves reduction of compound of formula XX with a suitable reducing agent to form a compound of formula VIII. The reduction is carried out in presence of a suitable solvent.
Compound of Formula XX may be obtained by any process including processes described in the art, or by a process described in this application.
The suitable reducing agent is selected from the group comprising of sodium aluminum hydride, sodium borohydride, lithium aluminum hydride, sodium bis (2- methoxyethoxy)aluminumhydride (Red-AI) and bis(4-methyl-1 -piperazinyl) aluminum hydride (BMAH). In one embodiment the reducing agent is lithium aluminum hydride (LAH). In another embodiment the reducing agent is sodium bis (2- methoxyethoxy)aluminumhydride (Red-AI). The quantity of reducing agent may range from about 1 to about 4 moles. In one embodiment the quantity of the reducing agent is about 1 to about 2 moles, per mole of compound of Formula XX.
Suitable solvents that can be used for the reaction include, but are not limited to: ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; and any mixtures thereof. In one embodiment the solvent used in step (a) is ether such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like.
The process of step (a) is suitably carried out at temperatures ranging from about -30°C to about 50°C. In one embodiment the reduction is carried out at temperatures ranging from about -10°C to about 30°C.
After completion of the reaction, the reaction mixture may be diluted and the salt by-product can be removed by filtration. The organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
The step (b) of the process involves protection of primary hydroxyl functionality of the compound of formula VIII with a suitable hydroxyl protecting group in presence of a suitable solvent to form a compound of formula IX.
The primary hydroxyl protection is suitably carried out using known methods. See e.g., T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. (1999).
In one embodiment the hydroxyl protecting group is silyl group such as trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl and the like. In another embodiment the hydroxyl protecting group is t-butyldiphenylsilyl (TBDPS).
The step (c) of the process involves cyanation of the compound of formula IX with a suitable cyanating agent in a suitable solvent to form compound of formula X.
The suitable cyanating agent is selected from the group comprising of Copper cyanide, Sodium cyanide, Potassium cyanide and Zinc cyanide. In one embodiment the cyanating agent is Sodium cyanide. The quantity of the cyanating agent may range from about 1 to about 10 moles. In one embodiment the quantity of the cyanating agent is about 1 to about 3 moles per mole of compound of Formula IX.
The suitable solvent that can be used for cyanation include, but are not limited to: polar aprotic solvents such as Dimethylformamide, Dimethylsulfoxide, Dimethyl acetamide, acetonitrile and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; hydrocarbons such as toluene, xylene, n-hexane, n- heptane, cyclohexane, and the like; and any mixtures thereof. In one embodiment the solvent used in cyanation is a polar aprotic solvent such as Dimethylformamide, Dimethylsulfoxide, Dimethyl acetamide, acetonitrile and the like;
The process of cyanation is suitably carried out at temperatures ranging from about 0°C to about 100°C. In one embodiment the cyanation is carried out at temperatures ranging from about 20°C to about 80°C.
After completion of the reaction, the reaction mixture may be diluted with water and the solution is extracted with a suitable water immiscible solvent. The organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
The step (d) of the process involves reduction of the cyanide of the compound of formula X in presence of a suitable catalyst, hydrogen gas and a suitable solvent.
The suitable catalyst is selected from the group comprising of Raney Nickel, Palladium, Platinum, Rhodium, and Ruthenium. In one embodiment the hydrogenation catalyst is Raney-Nickel.
The quantity of the catalyst may range from about 0.01 to about 5 moles. In one embodiment the quantity of the catalyst is about 0.1 to about 1 mole per mole of compound of Formula X.
The suitable solvent that can be used for the catalytic hydrogenation include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert- butanol, and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate, and the like; water, formic acid, acetic acid and any mixtures thereof. In one embodiment the solvent used in the catalytic hydrogenation is an alcohol such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like;
The process of catalytic hydrogenation is suitably carried out at temperatures ranging from about 0°C to about 100°C. In one embodiment the catalytic hydrogenation is carried out at temperatures ranging from about 10°C to about 50°C.
After completion of the hydrogenation, the catalyst is isolated from the reaction mixture by way of filtration. The filtrate containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.
The step (e) of the process involves deprotection of compound of formula XI using a suitable acid to form a compound of formula XII.
The suitable acid that can be used for the deprotection is selected from the group comprising of hydrochloric acid, hydrofluoric acid, hydroiodic acid, hydrobromic acid, tetrabutylammonium fluoride, tetrabutylammonium bromide, acetic acid, and sulfuric acid. In one embodiment the acid used for deprotection of the compound of formula XI is hydrochloric acid.
The acid may be used in the form of a solution having a concentration of about 0.1 N to about 10N. The solvent used for the preparation of the acid solution include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert- butanol, and the like; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate, and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK), and the like; water, and any mixtures thereof. In one embodiment the solvent used in the preparation of the mineral acid solution is an alcohol such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like.
After completion of the deprotection, the reaction mixture may be concentrated completely to produce a residue, and the crude may be purified or may be used directly in the next reaction step.
The amine functionality of the compound of formula XII may be protected using a suitable protecting group. The amine protection is suitably carried out using known methods. See e.g., T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. (1999).
In one embodiment the amine functionality of the compound of formula XII may be protected using tert-butyloxycarbonyl (BOC) protecting group to form compound of formula Xlla.
Figure imgf000023_0001
Xlla
The step (f) of the process involves oxidation of compound of formula XII or compound of formula Xlla using a suitable oxidizing agent and a suitable solvent to form a compound of formula XIII.
The suitable oxidizing agent is selected from the group comprising of Pyridimium chlorochromate (PCC), Pyridimium dichromate (PDC), Dess-Martin periodinane (DMP), (2,2,6,6-Tetramethylpiperidin-1 -yl)oxyl (TEMPO), Aluminum isopropoxide, o- iodoxybenzoic acid (IBX), 2-lodoxybenzenesulfonic acid and diisopropyl azodicarboxylate (DIAD). In one embodiment the oxidizing agent is Dess-Martin periodinane.
The quantity of the oxidizing agent may range from about 0.1 to about 10 moles. In one embodiment the quantity of the catalyst is about 0.5 to about 3 moles per mole of compound of Formula XII.
The process of step (f) is suitably carried out at temperatures ranging from about -30°C to about 100°C. In one embodiment the oxidation is carried out at temperatures ranging from about 0°C to about 50°C.
After completion of the oxidation, the reaction mixture is concentrated completely to produce a residue and the residue is dissolved in another solvent or it may be used directly in the next reaction step.
The step (g) of the process involves protection of the aldehyde of the compound of formula XIII with a suitable protecting group in presence of a suitable solvent to form a compound of formula XVI. The step (h) of the process involves treatment of the amine of the compound of formula XVI with an acid and a cyanide to form compound of formula XV.
The step (i) of the process involves hydrolysis of the cyanide of the compound of formula XV in presence of a suitable acid or suitable base to form compound of formula Vllb. The processes of step (g) to step (i) are suitably carried out using the process as described above in this application.
In another aspect the application provides use of the compound of formula Vllb prepared by the processes disclosed in the present application in the preparation of telaprevir comprising:
(a) reacting compound of formula Vllb or a protected form of formula Vllb with a compound of formula Via or its salt in the presence of a suitable coupling reagent to form compound of formula Va or its salt,
F
Figure imgf000024_0001
Formula Va
wherein P is an amine protecting group;
(b) deprotecting the compound of formula Va or its salt using an acid to form compound of formula Ilia or a salt thereof;
Figure imgf000024_0002
Formula Va Formula Ilia
(c) reacting a compound of formula Ilia or a salt thereof with a compound of formula IVa or a salt thereof in the presence of a suitable coupling reagent to form a compound of formula Ma;
Figure imgf000025_0001
(d) oxidizing the compound of Formula lla using a suitable oxidizing reagent to form telaprevir.
Figure imgf000025_0002
The amine protecting group as used herein is known in the art (see, e.g., T. W. Greene & P.G.M Wutz, "Protective groups in Organic Synthesis", 3rd edition, John Wiley & Sons, Inc. (1999), and the earlier editions of this book.
Step (a) of the process involves coupling of a compound of Formula Vllb or a protected form of compound of formula Vllb or its salt with a compound of Formula Via or its salt in the presence of a suitable coupling reagent to form a compound of formula Va or its salt.
The compound of formula Via is used as an acid addition salt. The acid addition salt of compound of formula VI is selected form hydrochloride, hydrobromide, acetate, trifluoroacetate, and hemisulphate.
Compounds of formula Vllb and formula Via or their salts may be obtained by any processes including processes described in the art, or by a process described in this application.
Suitable coupling reagent that may used is selected form the group comprising 1 - (3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), benzotriazol-1 - yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), ((l-H-l,2,3- benzotriazol-l-yloxy)- tris(pyrrolidino)phosphonium tetrafluorophopsphate (PyBOP), bis(2-oxo- 3-oxazolidinyl)phosphinic chloride (BOP-CI), 1 -hydroxybenzotriazole (HOBT), hydroxyazabenzotriazole (HOAT) or mixtures thereof. Quantities of coupling reagent may range from about 1 to about 4 moles, or about 2 to about 3 moles, per mole of compound of Formula IV.
The reaction is effected in the presence of a solvent. The solvent that can be used, include, but or not limited to, a halogenated hydrocarbon solvent such as dichloromethane, ethylene dichloride, chloroform, or the like; ketone solvents such as acetone, methyl isobutyl ketone (MIBK), or the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile or the like; or mixtures thereof. Preferably the solvent is N,N- dimethylformamide (DMF). Quantities of solvent used for the process may be from about 1 ml_ to about 30 ml_, per gram of compound of Formula IV.
Optional reagents that may used in the amide bond forming reaction include ethyl-2-cyano-2-(hydroxyimino)acetate (oxyma) or active ester reagents such as 1 - hydroxybenzotriazole (HOBT), hydroxyazabenzotriazole (HOAT), hydroxysuccinimide (HOSu) in amounts ranging from about 0.5 to about 5 equivalents.
The reaction is suitably carried out at temperatures ranging from about 0°C to about 80°C, preferably about 10°C to about 50°C.
The time required for completion of the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period from about 30 minutes to about 30 hours, preferably from about 3 hours to about 20 hours, is sufficient.
Step (b) of the process involves deprotection of the compound of formula Va to provide compound of formula Ilia. For this step, a suitable method may be selected depending on the N-protective group. For example the protective group capable of being deprotected with an acid such as tert-butoxycarbonyl, benzyloxycarbonyl, the reaction of the process may be attained by acid treatment
The acid to be used includes, for example, a mineral acid, a sulfonic acid, or a carboxylic acid. The mineral acid is not specifically limited, but includes hydrogen halides such as hydrogen chloride, and hydrogen bromide; sulfuric acid; phosphoric acid. The sulfonic acid is not specifically limited, but includes, for example, methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and 1 -phenylethanesulfonic acid. The carboxylic acid is not specifically limited, but includes, for example, formic acid, acetic acid, trifluoroacetic acid, benzoic acid, and tartaric acid. Among these acids, hydrogen chloride, hydrogen bromide, sulfuric acid, p-toluenesulfonic acid, and benzoic acid that form salts having good crystallinity are preferable; and in particular hydrogen chloride, hydrogen bromide and sulfuric acid are preferable, and hydrogen chloride or sulfuric acid is more preferable.
The amount of the acid to be used may be at least a theoretical amount; but the use thereof in a large amount is not economical. Therefore the lower limit of the amount is generally not less than 1 time by mol, and the higher limit is generally not more than 10 times by mol, preferably not more than 3 times by mol, more preferably not more than 2 times by mol relative to the compound of the formula Va.
The acid may be added directly as it is, or the aqueous solution or the solution in which the acid is previously dissolved in a solvent mentioned below may be used. The concentration of the acid to be added is not specifically limited, but the lower limit is generally 0.1 % by weight, preferably 1 % by weight, more preferably 5% by weight and the higher limit is 100% by weight.
The reaction is generally carried out in a solvent. The solvent is not specifically limited, but includes alcohols such as methanol, ethanol, isopropanol, n-propanol; ethers such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1 ,3-dioxolan, 1 ,2- dimethoxy ethane, diethylene glycol dimethyl ether; aliphatic esters such as ethyl acetate, isopropyl acetate, tert-butyl acetate; and halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloethane.
In case the protective groups that could not be deprotected by acid, the compound is appropriately deprotected according to the type of the protective group, and then is processed with acid according to the above mentioned process to obtain the compound of formula Ilia.
Step (c) of the process involves coupling o compound of Formula Ilia or its salt with compound of Formula IVa or its salt in the presence of a suitable coupling reagent to form a compound of formula I la or its salt. Optionally, the coupling reaction is carried out using an adduct such as copper chloride as taught in International Journal of Peptide and Protein Research 39, 1992, 237-234.
The coupling reagent and solvent used in the coupling reaction can appropriately be selected from the above mentioned embodiments.
The reaction is suitably carried out at temperatures ranging from about 0°C to about 80°C, preferably about 10°C to about 50°C.
The reaction is monitored by TLC. After completion of the reaction, water is added to the reaction mixture and the compound of formula lla is isolated by filtration.
Step (d) of the process involves oxidation of the compound of formula lla or its salt to form telaprevir or its salt. Suitable oxidizing agent is selected from Dess-Martin periodinane (1 ,1 -dihydro-1 ,1 ,1 -triacetoxy-1 ,2-benzoiodooxol-3(1 H)-one), chromic acid in acetone, sodium hypochlorite in the presence of (2,2,6,6-tetramethyl-piperidin-1 -yl)oxyl (TEMPO) or a TEMPO derivative such as 4-Hydroxy-TEMPO, 4-Amino-TEMPO, 4- Acetamido-TEMPO, 4-(2-Bromoacetamido)-TEMPO, 4-Carboxy-TEMPO, 4-Cyano- TEMPO, 4-Methoxy-TEMPO or 4-Oxo-TEMPO; or potassium permanganate in the presence of TEMPO or a TEMPO derivative.
The oxidation is affected in the presence of a solvent. The solvents that can be used include, but are not limited to, ethers such as diethyl ether, tetrahydrofuran (THF) and the like; halogenated solvent such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene and the like; esters such as ethyl acetate methyl acetate, isopropyl acetate and the like or mixtures thereof. Preferably the solvent is dichloromethane or ethyl acetate.
The oxidation is carried out at a temperature from about -20°C to about 60°C. Preferably from about 0°C to about 30°C.
The reaction is monitored by TLC. After completion of the reaction, the reaction mixture is quenched with dilute aqueous sodium sulphite solution and the organic layer is concentrated to yield crude telaprevir. The crude telaprevir is purified by recrystallizing it from ethylacetate or dichloromethane or a mixture thereof. Telaprevir prepared by the processes herein described above is having purity greater than about 99 area % as measured by HPLC.
In another aspect, the present application provides Telaprevir prepared by the processes herein described above is having purity greater than about 99.5 area % as measured by HPLC.
In another aspect, the present application provides Telaprevir prepared by the processes herein described above is having purity greater than about 99.8 area % as measured by HPLC.
In another aspect, the present application provides use of Telaprevir having purity greater than about 99.5 area % as measured by HPLC for the manufacture of a pharmaceutical composition.
In another aspect, the present application provides use of Telaprevir having purity greater than about 99.8 area % as measured by HPLC for the manufacture of a pharmaceutical composition.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
As used herein, the term "vacuum" refers to a reduced pressure of below about 150 mm Hg. In another embodiment, the pressure is below about 50 mm Hg. In another embodiment, the pressure is below about 30 mm Hg. As used herein, the term "reduced pressure" refers to a pressure below 760 mm Hg or 1 atmosphere.
As used herein, the term "room temperature" refers to a temperature of about 20°C to about 35°C, In another embodiment about 20°C to about 25°C and in another embodiment about 25°C.
An "alcohol solvent" is an organic solvent containing a carbon bound to a hydroxyl group. "Alcohol solvents" include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, Ci-6alcohols, or the like.
An "aliphatic or alicyclic hydrocarbon solvent" refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvents include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3- dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3- methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5- Csaliphatic hydrocarbons, petroleum ethers, or mixtures thereof.
"Aromatic hydrocarbon solvent" refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of aromatic hydrocarbon solvents include, but are not limited to, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-Cioaromatic hydrocarbons, or mixtures thereof.
An "ester solvent" is an organic solvent containing a carboxyl group -(C=0)-0- bonded to two other carbon atoms. "Ester solvents" include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3-6esters, or the like.
A "halogenated hydrocarbon solvent" is an organic solvent containing a carbon bound to a halogen. "Halogenated hydrocarbon solvents" include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A "ketone solvent" is an organic solvent containing a carbonyl group -(C=0)- bonded to two other carbon atoms. "Ketone solvents" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3.6ket.ones, 4- methyl-pentane-2-one or the like. A "polar aprotic solvent" has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N- dimethylformamide (DMF), Ν,Ν-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3- methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, and sulfolane; and sulfoxide-based solvents such as dimethylsulfoxide (DMSO).
An "ether solvent" is an organic solvent containing an oxygen atom -O- bonded to two other carbon atoms. "Ether solvents" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2- ethoxyethanol, anisole, C2-6ethers, or the like.
The term "oxidizing agent" (also called an oxidant, oxidizer) refers to a chemical compound that readily transfers oxygen atoms or a substance that gains electrons in a chemical reaction.
The term "coupling reagent" refers to a chemical compound that react with amino acids to form activated amino acid intermediates which in turn react with the N-terminal amine of the peptide to form the elongated peptide.
"Leaving group" refers to an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction. For example, in the heterolytic solvolysis of benzyl bromide in acetic acid: the leaving group is bromide. In the reaction of Ν,Ν,Ν-trimethyl- 1 -phenylmethanaminium ion with methanethiolate, the leaving group is trimethylamine. In the electrophilic nitration of benzene, it is H+. The term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates (i.e. CH3COO", CF3CO2 ", or (CH3)2CH2COO"), F", water, CI", Br", I", N3 ", SCN", trichloroacetimidate, thiopyridyl, tertiary amines (i.e. trimethylamine), phenoxides (i.e. 0- nitrophenoxide), and sulfonates (/'. e. tosylate, mesylate, or triflate). Powder X-ray Diffraction (PXRD) was performed on an X-ray Powder Diffractometer, equipped with a Cu-anode (λ=1.54 Angstrom), X-ray source operated at 45 kV, 40 mA, and a Ni filter is used to strip K-beta radiation. Two theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range= 2-50° 2Θ, step width=0.017°.
Telaprevir and its impurities can be analyzed using HPLC, such as with a liquid chromatograph equipped with a UV detector and the parameters described below:
Figure imgf000032_0001
Vol. % of mobile phase A 35 35 10 10 35 35
Vol. % of mobile phase B 65 65 90 90 65 65
The invention is further defined by reference to the following examples describing in detail the processes of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example 1 : Preparation of (S)-methyl-2-((S)-2-((tert-butoxycarbonyl)amino)-2- cyclohexylacetamido-3, 3-dimethylbutanoate
Figure imgf000033_0001
(S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (50 gm), tetrahydrofuran (500 mL), 1 -hydroxybenzotriazole (HOBt, 26.3 gm) and 1 -(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCI, 37.2 gm) were charged into a 2000 mL round bottomed flask. The resulted solution was stirred for 30 minutes at 30°C. In another 1000 mL round bottomed flask L-tert-leucine methyl ester (35.3 gm) and tetrahydrofuran (200 mL) were charged, then N,N-dimethylformamide (DMF, 100 mL) and diisopropylethylamine (DIPEA, 50.5 gm) were charged. The resulted solution was stirred for 30 minutes at 30°C and was added to the above (S)-2- ((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid solution at 30°C. The resulted solution was stirred for 20 hours at 30°. The solvent was distilled off completely under vacuum at below 40°C. Water (500 mL) and ethylacetate (500 mL) were added to the crude obtained and the solution was stirred for 15 minutes. The ethyl acetate layer was separated and was washed with 5% aqueous sodium bicarbonate solution (250 mL), 5% aqueous hydrochloric acid solution (250 mL), followed by 5% aqueous sodium chloride solution (250 mL). The ethylacetate layer was concentrated completely under vacuum at 30°C and to the residue n-hexane (500 mL) was added and the resulting mixture was stirred for 2 hours at 30°C. The precipitate was filtered and washed with n- hexane (50 mL) and dried under vacuum at below 30°C to yield 53.8 gm of title compound.
Purity: 99.82% (by HPLC)
Example 2: Preparation of (S)-methyl 2-((S)-2-amino-2-cyclohexylacetamido)-3,3- dimethylbutanoate hydrochloride
Figure imgf000034_0001
(S)-methyl-2-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetamido-3, 3- dimethylbutanoate (5 gm) and dichloromethane (150 mL) were charged into a 500 mL round bottomed flask and the solution was cooled to 0°C. Ethereal hydrochloride (hydrochloride gas dissolved in diethyl ether, 20 mL) was slowly added at 0°C. Temperature raised to 30°C and the mixture was stirred for 15 hours at 30°C. The reaction mixture was concentrated completely under vacuum at 30°C and n-Hexane (40 mL) was added to the residue and the resulting mixture was stirred for 2 hours at 30°C. The precipitate was filtered and wet cake was washed with n-Hexane (10 mL) and the solid dried under vacuum at 30°C to yield 4.0 gm of the title compound.
Purity: 97.61 % (by HPLC).
Example 3: Preparation of (S)-methyl-2-((S)-2-amino-2-cyclohexylacetamido)-3,3- dimethylbutanoate hydrochloride
Figure imgf000034_0002
(S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (10 gm), ethylacetate (100 mL), 1 -hydroxybenzotriazole (HOBt, 6.3 gm), 1 -(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (EDC HCI, 37.2 gm) and L-tert-leucine methyl ester (7 gm) were charged into a 1000 mL round bottomed flask. The resulted solution was agitated for 20 hours at 28°C. Water (100 mL) was added and the solution was agitated for 10 minutes. Layers were separated and the ethylacetate layer was washed with 5% aqueous hydrochloric acid (50 mL) followed by 5% sodium chloride solution (50 mL). The ethylacetate layer was concentrated to 20 mL and a solution of hydrochloric acid dissolved in ethylacetate (40 mL) was added to the crude. The mixture was agitated for 12 hours at 28°C. The precipitate was filtered and the wet cake was washed with ethylacetate (10 mL) and the solid was dried under vacuum at 40°C to yield 1 1.3 gm of the title compound.
Purity: 99.93% (by HPLC).
Example 4: Preparation of (S)-methyl-2-((S)-2-amino-2-cyclohexylacetamido)-3,3- dimethylbutanoate hydrochloride
Figure imgf000035_0001
(S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (10 gm), ethylacetate (100 mL), 1 -hydroxybenzotriazole (HOBt, 6.3 gm), 1 -(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (EDC HCI, 1 1.2 gm), L-tert-leucine methyl ester hydrochloride (7 gm) and diisopropylethylamine (10 gm) were charged into a 1000 mL round bottomed flask. The resulted solution was agitated for 10 hours at 28°C. Water (100 mL) was added and the solution was agitated for 10 minutes. Layers were separated and the ethylacetate layer was washed with 5% sodium chloride solution (50 mL). The ethylacetate layer was concentrated to 28 mL and a solution of hydrochloric acid dissolved in ethylacetate (40 mL) was added to the crude. The mixture was agitated for 10 hours at 28°C. The precipitate was filtered and the wet cake was washed with ethylacetate (10 mL) and the solid was dried under vacuum at 40°C to yield 1 1.3 gm of the title compound.
Purity: 99.93% (by HPLC). Example 5: Preparation of (S)-methyl 2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3, 3-dimethyl butanoate.
Figure imgf000036_0001
(S)-methyl-2-((S)-2-amino-2-cyclohexylacetamido)-3,3-dimethylbutanoate hydrochloride (3 gm), tetrahydrofuran (60 mL), 2-Pyrazine carboxylic acid (1.4 gm), 1 - hydroxybenzotriazole (HOBt, 1.5 gm) and 1 -(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (EDC HCI, 2.16 gm) were charged into a 500 mL round bottomed flask and the resulted mixture was stirred for 15 minutes at 30°C. Diisopropylethylamine (2.4 gm) was added to the mixture and stirred for 12 hours at 30°C. Water (30 mL) and ethylacetate (50 mL) were added to the reaction mixture and the solution was stirred for 15 minutes. The ethyl acetate layer was separated and was washed with 5% aqueous sodium bicarbonate solution (30 mL X 2), 5% aqueous hydrochloric acid solution (15 mL X 2), followed by 5% aqueous sodium chloride solution (30 mL). The ethylacetate layer was concentrated completely under vacuum at 30°C and to the residue n-hexane (30 mL) was added and the resulted mixture was stirred for 2 hours at 30°C. The precipitation was filtered and washed with n-hexane (5 mL) and dried under vacuum at below 30°C to yield 3 gm of title compound.
Purity: 99.98% (by HPLC).
Example 6: Preparation of (S)-methyl 2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3, 3-dimethyl butanoate.
Figure imgf000036_0002
(S)-methyl-2-((S)-2-amino-2-cyclohexylacetamido)-3,3-dimethylbutanoate hydrochloride (15 gm), ethylacetate (300 mL), 2-Pyrazine carboxylic acid (6.4 gm), 1 - hydroxybenzotriazole (HOBt, 6.3 gm), dicyclohexylcarbodiimide (DCC, 14.4 gm) and diisopropylethylamine (DIPEA, 12 gm) were charged into a 1000 mL round bottomed flask and the resulted mixture was agitated for 5 hours at 28°C. The reaction mass was filtered and the salt was washed with ethylacetate (20 mL). The ethylacetate layer was concentrated completely under vacuum at below 40°C and cyclohexane (75 mL) was added to the residue and the resulted mixture was agitated for 2 hours at 30°C. The precipitate was filtered and the wet cake was washed with cyclohexane (20 mL) and the solid was dried under vacuum at below 40°C to yield 16.6 gm of title compound.
Purity: 99.5% (by HPLC).
Example 7: Preparation of (S)-methyl 2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3, 3-dimethyl butanoate.
Figure imgf000037_0001
(S)-methyl-2-((S)-2-amino-2-cyclohexylacetamido)-3,3-dimethylbutanoate hydrochloride (5 gm), ethylacetate (100 mL), 2-Pyrazine carboxylic acid (6.4 gm), 1 - hydroxybenzotriazole (HOBt, 2.1 gm), dicyclohexylcarbodiimide (DCC, 3.9 gm) and diisopropylethylamine (DIPEA, 4 gm) were charged into a 500 mL round bottomed flask and the resulting mixture was agitated for 5 hours at 28°C. The reaction mass was filtered and the salt was washed with ethylacetate (10 mL). The ethylacetate layer was washed with 5% aqueous sodium chloride solution and concentrated completely under vacuum at below 40°C. Cyclohexane (25 mL) was added to the residue and the resulting mixture was agitated for 1 hour at 28°C. The precipitate was filtered and the wet cake was washed with cyclohexane (5 mL) and the solid was dried under vacuum at 40°C to yield 5.5 gm of title compound.
Purity: 99.03% (by HPLC).
Example 8: Preparation of (S)-2-((f?)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoic acid.
Figure imgf000038_0001
(S)-methyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3, 3- dimethyl butanoate (30 gm) and terf-Butanol (360 mL) were charged into a 1000 mL round bottomed flask and the solution was cooled to 0°C. Aqueous sodium hydroxide solution (6.2 gm of sodium hydroxide was dissolved in 60 mL of water) was added slowly in to the reaction mixture at 0°C. Temperature raised to 30°C and the reaction mixture was stirred for 12 hours at 30°C. te/t-Butanol was distilled off completely under vacuum at 30°C and water (300 mL) was added to the crude and the resulted solution was cooled to 0°C. 0.5N aqueous hydrochloric acid solution was added slowly until pH reached to 2.5 and the mixture was stirred for 1 hour at 0°C. The precipitate was filtered and the wet cake was washed with water (30 mL) and the solid dried under vacuum at 45°C to yield 26.8 gm of title compound.
Purity: 98.51 % (by HPLC).
Example 9: Preparation of (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoic acid.
Figure imgf000038_0002
(S)-methyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethyl butanoate (1 gm), te/t-Butanol (10 mL) and 20% aqueous tetrabutyl ammonium hydroxide were charged into a 100 mL round bottomed flask and the mixture was agitated for 12 hours at 28°C. te/t-Butanol was distilled off completely under vacuum at below 40°C and water (20 mL) was added to the crude and the resulted solution was cooled to 0°C. 10% aqueous hydrochloric acid solution was added slowly until pH reached to 2.5 and the mixture was stirred for 1 hour at 0°C. The precipitate was filtered and the solid dried under vacuum at below 45°C to yield 0.86 gm of title compound. Purity: 99.43% (by HPLC); XRD pattern: Figure 2.
Example 10: Preparation of (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoic acid.
Figure imgf000039_0001
(S)-methyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethyl butanoate (0.5 gm), te/t-Butanol (5 mL) and tetrabutyl ammonium hydroxide (3.3 gm) were charged into a 100 mL round bottomed flask and the mixture was agitated for 8 hours at 27°C. te/t-Butanol was distilled off completely under vacuum at below 40°C and water (10 mL) was added to the crude and the resulted solution was cooled to 0°C. 10% aqueous hydrochloric acid solution was added slowly until pH reached to 2 and the mixture was stirred for 1 hour at 0°C. The precipitate was filtered and the solid dried under vacuum at 45°C to yield 0.45 gm of title compound.
Purity: 99.54% (by HPLC); PXRD pattern: similar to figure 2.
Example 1 1 : Preparation of (1 S,3af?,6aS)-2-tert-butyl-1 -ethyl-hexahydrocyclopenta
[c]pyrrole-1 ,2- -dicarboxylate.
Figure imgf000039_0002
(1 S,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-1 -carboxylate hydrochloride (5 gm) and dichloromethane (50 mL) were charged into 1000 mL round bottomed flask and the solution was cooled to 0°C. Di-tert-butyl dicarbonate (1 1.6 gm), dimethylaminopyridine (4 gm) and triethylamine (3.45 gm) were added at 0°C. The reaction mixture was maintained for 15 minutes at 0°C and temperature raised slowly to 30°C and the reaction mixture was stirred for 20 hours at 30°C. 5% aqueous sodium bicarbonate solution (50 mL) was added to the reaction mixture and stirred for 15 minutes. Dichloromethane layer was separated and washed with 5% aqueous sodium bicarbonate solution (50 mL), 5% aqueous hydrochloric acid solution (50 mL X 2), followed by 5% aqueous sodium chloride solution (30 mL X 2). The organic layer was concentrated completely under vacuum at 30°C to yield 6 gm of title compound.
Purity: 93.96% (by HPLC)
Example 12: Preparation of (1 S,3af?,6aS)-2-tert-butoxy carbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxilic acid
Figure imgf000040_0001
(1 S,3af?,6aS)-2-tert-butyl-1 -ethyl-hexahydrocyclopenta [c]pyrrole-1 ,2-(1 H)- dicarboxylate (5 gm) and methanol (50 mL) were charged into a 500 mL round bottomed flask and the solution was cooled to 0°C. Aqueous sodium hydroxide solution (1.5 gm of sodium hydroxide was dissolved in 10 mL of water) was added slowly in to the reaction mixture at 0°C. Temperature was raised to 30°C and the reaction mixture stirred for 20 hours at 30°C. Methanol was distilled off completely under vacuum at 30°C and water (50 mL) added to the crude and the resulted solution was cooled to 0°C. Aqueous hydrochloric acid solution (25%, 8 mL) was added slowly until pH reached to 2.5 and the mixture stirred for 1 hour at 0°C. The precipitate was filtered and the wet cake was washed with water (10 mL) and the solid dried under vacuum at 45°C to yield 3.5 gm of title compound.
Purity: 100% (by HPLC).
Example 13: Preparation of (1 S,3af?,6aS)-2-tert-butoxy carbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxilic acid.
Figure imgf000040_0002
(1 S,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-1 -carboxylate hydrochloride (5 gm) and methanol (20 mL), sodium bicarbonate (2.09 gm) and Di-tert-butyl dicarbonate (5.97 gm) were charged into a 200 mL round bottomed flask. The reaction mixture was maintained for 2 hours at 30°C. The reaction mixture was filtered and the salt was washed methanol (10 mL). Aqueous sodium hydroxide solution (2.27 gm of sodium hydroxide was dissolved in 4.72 mL of water) was slowly added to the methanol layer. The mixture was heated to 55°C and agitated for 5 hours. The reaction mass was distilled off completely under vacuum at 50°C and water (25 mL) was added to the crude and the resulted solution was cooled to 0°C. Aqueous hydrochloric acid solution (10% 42 mL) was added slowly until pH reached to 2.5 and the mixture was agitated for 1 hour at 0°C. The precipitate was filtered and the wet cake was washed with water (15 mL) and the solid dried under vacuum at 45°C to yield 5.6 gm of title compound.
Purity: 99.57% (by HPLC).
Example 14: Preparation of (1 S,3af?,6aS)-2-tert-butoxy carbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxilic acid.
Figure imgf000041_0001
(1 S,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-1 -carboxylate hydrochloride (5 gm) and methanol (15 mL), sodium bicarbonate (2.48 gm) and Di-tert-butyl dicarbonate (5.97 gm) were charged into a 100 mL round bottomed flask. The reaction mixture was maintained for 2 hours at 28°C. The reaction mixture was filtered and the salt was washed methanol (10 mL). Aqueous sodium hydroxide solution (2.73 gm of sodium hydroxide was dissolved in 5.52 mL of water) was slowly added to the methanol layer. The mixture was heated to 55°C and agitated for 3 hours. The reaction mass was distilled off completely under vacuum at 50°C. Water (25 mL) was added to the crude and the resulted solution was cooled to 0°C. Aqueous hydrochloric acid solution (10% 35 mL) was added slowly until pH reached to 2.5 and the mixture was agitated for 1 hour at 28°C. The precipitate was filtered and the wet cake was washed with water (15 mL) and the solid dried under vacuum at 45°C to yield 5.5 gm of title compound.
Purity: 99.78% (by HPLC).
Example 15: Preparation of (1 S,3aR,6aS)-2-tert-butyl 1 -(((3S)-1 -(cyclopropyl amino)-2- hydroxy-1 -oxohexan-3-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2-(1 H)carboxylate
Figure imgf000042_0001
(1 S,3af?,6aS)-2-tert-butoxy carbonyl)octahydrocyclopenta [c]pyrrole-1 - carboxilic acid (15 gm) and tetrahydrofuran (300 mL) were charged into a 1000 mL round bottomed flask and the solution was cooled to 0°C. 1 -hydroxybenzotriazole (HOBt, 7.93 gm) and 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCI, 12.5 gm) were added and the resulted mixture was stirred for 15 minutes at 0°C. In another 500 mL round bottomed flask tetrahydrofuran (75 mL), (3S)-3-amino-N- cyclopropyl-2-hydroxyhexanamide hydrochloride (19.62 gm) and N,N- Dimethylformamide (30 mL) were charged and mixture was cooled to 5°C. Diisopropylethylamine (19.7 gm) was added and the mixture was added to the above1000 mL flask at 0°C. Temperature of the resulted mixture was raised to 30°C and stirred for 14 hours. Tetrahydrofuran was distilled off completely under vacuum at 40°C and the mass was cooled to 25°C. Water (100 mL) and ethylacetate (200 mL) were charged and stirred for 30 minutes. The organic layer was washed with 5% aqueous sodium bicarbonate solution (90 mL X 2), 5% aqueous hydrochloric acid solution (90 mL X 2), followed by 5% aqueous sodium chloride solution (90 mL X 2). The organic layer was concentrated completely under vacuum at 40°C to yield 22.1 gm of title compound.
Purity by HPLC : 75.3% (S-isomer), 24.32% (R-isomer).
Example 16: Preparation of (1 S,3aR,6aS)-2-tert-butyl 1 -(((3S)-1 -(cyclopropyl amino)-2- hydroxy-1 -oxohexan-3-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2-(1 H)carboxylate
Figure imgf000043_0001
(1 S,3af?,6aS)-2-tert-butoxy carbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxilic acid (5 gm), ethylacetate (50 mL) 1 -hydroxybenzotriazole (HOBt, 2.6 gm), 1 -(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCI, 4.13 gm), triethylamine (4.35 gm), (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride (4.57 gm) and ethylacetate (25 mL)were charged into a 500 mL round bottomed flask and the mixture was agitated for 3 hours. Water (50 mL) and ethylacetate (25 mL) were added and the mixture was heated to 40°C. Layers were separated and the aqueous layer was extracted with ethylacetate (20 mL). Combined organic layer was washed with 2% aqueous hydrochloric acid solution (20 mL) and 2% aqueous sodium bicarbonate solution (20 mL), followed by 5% aqueous sodium chloride solution (20 mL). The organic layer was concentrated completely under vacuum at 40°C and cyclohexane (75 mL) was added to the crude and the mixture was agitated for 30 minutes. The precipitate was filtered and the wet cake was washed with cyclohexane (25 mL) and wet material was dried under vacuum at 40°C to yield 7.5 gm of title compound.
Example 17: Preparation of (1 S,3aR,6aS)-2-tert-butyl 1 -(((3S)-1 -(cyclopropyl amino)-2- hydroxy-1 -oxohexan-3-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2-(1 H)carboxylate
Figure imgf000043_0002
(1 S,3af?,6aS)-2-tert-butoxy carbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxilic acid (10 gm), ethylacetate (150 mL) 1 -hydroxybenzotriazole (HOBt, 5.26 gm), 1 -(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCI, 1 1.23 gm), triethylamine (12 mL), (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride (8.7 gm) were charged into a 500 mL round bottomed flask and the mixture was agitated for 5 hours. Water (90 mL) and ethylacetate (150 mL) were added and the mixture was agitated for 10 minutes. Layers were separated and the aqueous layer was extracted with ethylacetate (50 mL). Combined organic layer was washed with 2% aqueous citric acid solution (50 mL) and 2% aqueous sodium bicarbonate solution (50 mL), followed by 5% aqueous sodium chloride solution (50 mL). The organic layer was concentrated to 120 mL and used in the next step.
Example 18: Preparation of (1 S,3aR,6aS)-N-((3S)-1 -(cyclopropyl amino)-2-hydroxy-1 - oxohexan-3-yl)carbamoyl)octahydrocyclopenta[c]pyrrole-1 -carboxamide hydrochloride
Figure imgf000044_0001
(1 S,3aR,6aS)-2-tert-butyl-1 -(((3S)-1 -(cyclopropylamino)-2-hydroxy-1 - oxohexan-3-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2-(1 H)carboxylate (25 gm) and dichloromethane (500 mL) were charged into a 1000 mL round bottomed flask and the solution was cooled to 0°C. Ethereal hydrochloride (hydrochloride gas dissolved in diethyl ether, 100 mL) was slowly added at 0°C. Temperature was raised to 30°C and the mixture was stirred for 12 hours at 30°C. The reaction mixture was concentrated completely under vacuum at 30°C to yield 20.6 gm of the title compound.
Purity by HPLC: 60.5% (S-isomer), 30.9% (R-isomer).
Example 19: Preparation of (1 S,3aR,6aS)-N-((3S)-1 -(cyclopropyl amino)-2-hydroxy-1 - oxohexan-3-yl)carbamoyl)octahydrocyclopenta[c]pyrrole-1 -carboxamide hydrochloride
Figure imgf000044_0002
(1 S,3aR,6aS)-2-tert-butyl-1 -(((3S)-1 -(cyclopropylamino)-2-hydroxy-1 - oxohexan-3-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2-(1 H)carboxylate (5 gm), methanol (2 mL) and ethylacetate (15 mL) were charged into a 100 mL round bottomed flask and the solution was cooled to 0°C. Ethylacetate hydrochloride (hydrochloride gas dissolved in ethylacetate, 17 mL) was slowly added at 0°C. The mixture was heated to 30°C and agitated for 4 hours. Ethylacetate (25 mL) was added to the reaction mixture and agitated for 1 hour to 0°C. The mixture was filtered and the wet material was washed with ethylacetate (5 mL). The compound was dried under vacuum at 40°C to yield 4.0 gm of the title compound.
Purity by HPLC: 67.42% (S-isomer): 30.14% (R-isomer)
Example 20: Preparation of (1 S,3aR,6aS)-N-((3S)-1 -(cyclopropyl amino)-2-hydroxy-1 - oxohexan-3-yl)carbamoyl)octahydrocyclopenta[c]pyrrole-1 -carboxamide hemisulphate
Organic layer obtained from the example 17 (120 mL) and methanol (8.5 mL) were charged into a 500 mL round bottomed flask and the solution was cooled to 0°C. Sulfuric acid (2.5 mL) was slowly added at 0°C. The mixture was heated to 40°C and agitated for 8 hours. Ethylacetate (165 mL) was added to the reaction mixture and agitated for 1 hour to 5°C and the precipitate was filtered. The wet material, ethyl acetate (140 mL) and methanol (7 mL) were charged into a 500 mL round bottomed flask and the mixture was agitated for 1 hour. The precipitate was filtered was washed with ethylacetate (40 mL). The compound was dried under vacuum at 60°C to yield 12.7 gm of the title compound.
Purity by HPLC: 58.46% (S-isomer), 40.54% (R-isomer).
Example 21 : Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-1 -(cyclopropyl amino)-2- hydroxy-1 -oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide
Figure imgf000046_0001
(1 S,3aR,6aS)-N-((3S)-1 -(cyclopropyl amino)-2-hydroxy-1 -oxohexan-3- yl)carbamoyl)octahydrocyclopenta[c]pyrrole-1 -carboxamide hydrochloride (0.95 gm) and N,N-dimethylformamide (10 mL) were charged into a 250 mL round bottomed flask. 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCI, 1 .0 gm) and dimethylaminopyridine (0.3 gm) were charged and the reaction mixture was stirred for 30 minutes at 28°C. The reaction mixture cooled to 2°C and N,N-dimethylformamide solution of (S)-2-((f?)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoic acid (1.0 gm in 10 mL of Ν,Ν-dimethylformamide) was added and the reaction mixture was stirred for 3 hours at 5°C. Temperature was raised to 28°C and stirred for 15 hours. The reaction mixture was cooled to 0°C and water (20 mL) added and stirred for 30 minutes at 5°C. The precipitation was filtered and the wet cake was washed with water (5 mL) and dried the compound in vacuum at 30°C to yield 1.1 gm of title compound.
Purity by HPLC: 56.1 % (S-isomer), 24.9% (R-isomer).
Example 22: Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-1 -(cyclopropyl amino)-2- hydroxy-1 -oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide
Figure imgf000047_0001
(1 S,3aR,6aS)-N-((3S)-1 -(cyclopropyl amino)-2-hydroxy-1 -oxohexan-3- yl)carbamoyl)octahydrocyclopenta[c]pyrrole-1 -carboxamide hydrochloride (10 gm) and N,N-dimethylformamide (60 mL) were charged into a 500 mL round bottomed flask and cooled to 0°C. Copper(ll) chloride dihydrate (4.7 gm), dicyclohexylcarbodiimide (6 gm), triethylamine (4.6 mL) and (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoic acid (1 1.5 gm) were added and the reaction mixture was agitated for 10 hours at 0°C. Ethylacetate (100 mL) was added to the reaction mixture and heated to 28°C and stirred for 15 minutes. The reaction mixture was filtered and the salt was washed with ethylacetate (100 mL). Water (100 mL) was added to the ethylacetate layer and the resulted solution was agitated for 10 minutes. Layers were separated and the aqueous layer was extracted with ethylacetate (100 mL). The ethylacetate layers were combined and washed with 20% aqueous ammonium chloride (200 mL), 5% aqueous hydrochloric acid solution (100 mL) and 5% aqueous sodium bicarbonate solution (100 mL) followed by 10% aqueous sodium chloride solution (100 mL) and the ethylacetate layer was concentrated under vacuum. Diisopropyl ether (50 mL) was added to the crude and agitated for 30 minutes at 28°C. The precipitation was filtered and the wet cake was washed with diisopropyl ether (30 mL) and dried the compound in vacuum at 30°C to yield 15.4 gm of title compound. Purity by HPLC: 64.57% (S-isomer), 22.49% (R-isomer). Example 23: Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-1 -(cyclopropyl amino)-2- hydrox -1 -oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide
Figure imgf000048_0001
(1 S,3aR,6aS)-N-((3S)-1 -(cyclopropyl amino)-2-hydroxy-1 -oxohexan-3- yl)carbamoyl)octahydrocyclopenta[c]pyrrole-1 -carboxamide (5 gm) and dichloromethane (30 mL) were charged into a 500 mL round bottomed flask. Copper(ll) chloride dihydrate (1.6 gm) was added and the mixture was cooled to 5°C. Dicyclohexylcarbodiimide (3.1 gm), triethylamine (2.4 mL) and (S)-2-((S)-2-cyclohexyl-2- (pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoic acid (5.5 gm) were added and the reaction mixture was agitated for 8 hours at 15°C. The reaction mixture was filtered and the salt was washed with dichloromethane (30 mL). The organic layer was washed with 5% EDTA (2 X 50 mL) and concentrated under vacuum. Methanol (10 mL) and sodium hydroxide (0.5 gm) were added to the crude and agitated for 30 minutes at 28°C and concentrated under vacuum. Ethylacetate (50 mL) was added to the crude and agitated for 10 minutes. Water (50 mL) was added to the crude and agitated for 10 minutes. Layers were separated and the organic layer was washed with 10% aqueous sodium chloride solution (50 mL) and the organic layer was concentrated under vacuum. Diisopropylether (25 mL) was added to the crude and agitated for 30 minutes. The precipitation was filtered and the wet cake was washed with diisopropyl ether (15 mL) and dried the compound in vacuum at 60°C to yield 7.6 gm of title compound.
Purity by HPLC: 56.01 % (S-isomer), 31.46% (R-isomer) Example 24: Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1 -(cyclopropyl amino)-1 -2- dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide (Telaprevir)
Figure imgf000049_0001
(1 S,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)-octa hydrocyclopenta[c]pyrrole-1 -carboxamide (12 gm), dichloromethane (180 mL) and 15% aqueous sodium bromide solution (7.57 mL) were charged into 1000 mL round bottomed flask and 7.5% aqueous sodium bicarbonate solution (30.3 mL) was added to the reaction mixture and the mixture was cooled to 5°C. TEMPO solution (408 mg of TEMPO in 10 mL of dichloromethane) and 12.5% aqueous sodium hypochlorite (1 1.7 mL) were added to the reaction mixture at 0°C and the reaction mixture was stirred for 2 hours at 5°C. The organic layer was separated and was quenched with 10% aqueous sodium sulphite solution (60 mL) and the resulted mixture was stirred for 15 minutes. The organic layer was separated and washed with water (60 mL) and the organic layer was dried with anhydrous sodium sulphate and concentrated under vacuum completely. Ethyl acetate (100 mL) was charged into the residue and the resulted solution was stirred for 2 hours at 28°C. The precipitate was filtered and the wet cake was washed with ethyl acetate (20 mL) and the solid was dried under vacuum at 30°C to yield 5.2 gm of telaprevir.
Purity: 96.7 (by HPLC); PXRD pattern: Figure 1.
Example 25: Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1 -(cyclopropyl amino)-1 -2- dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide (Telaprevir)
Figure imgf000050_0001
(1 S,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)-octa hydrocyclopenta[c]pyrrole-1 -carboxamide (10 gm) and dichloromethane (100 mL) were charged into a 500 mL round bottomed flask and cooled to 0°C. Potassium bromide (0.34 gm), sodium bicarbonate (9.8 gm) and N-Acetamido-TEMPO (0.31 gm) were added to the reaction mixture and the mixture is agitated for 10 minutes. 10% aqueous sodium hypochlorite (13.1 mL) was slowly added to the reaction mixture at 0°C and the reaction mixture was agitated for 2 hours at 10°C. The reaction mixture was filtered and washed with dichloromethane (30 mL). 10% aqueous hypo solution (100 mL) was added to the organic layer and the solution was agitated for 10 minutes. Layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). Organic layers were combined and washed with 10% aqueous sodium chloride solution (100 mL) and the organic layer was concentrated under vacuum completely. Ethyl acetate (50 mL) was added to the residue and the resulted solution was stirred for 2 hours at 28°C. The precipitate was filtered and the wet cake was washed with ethyl acetate (20 mL) and the solid was dried under vacuum at 30°C to yield 7.0 gm of telaprevir.
Purity: 96.5 (by HPLC); XRD pattern: similar to figure 1.
Example 26: Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1 -(cyclopropyl amino)-1 -2- dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide (Telaprevir)
Figure imgf000050_0002
(1 S,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)-octa hydrocyclopenta[c]pyrrole-1 -carboxamide (5 gm) and ethylacetate (50 ml_) were charged into a 500 ml_ round bottomed flask. Potassium bromide (0.18 gm), sodium bicarbonate (3.7 gm) and N-Acetamido-TEMPO (0.15 gm) were added to the reaction mixture and cooled to 0°C and the mixture is agitated for 10 minutes. 10% aqueous sodium hypochlorite (5.5 ml_) was slowly added to the reaction mixture at 0°C and the reaction mixture was agitated for 2 hours at 0°C. Water (50 ml_) was added to the reaction mixture and the resulted solution was agitated for 10 minutes. Layers were separated and the organic layer was concentrated under vacuum completely. A mixture of acetonitrile and water (9:1 , 10 ml_) was added to the residue and the resulted solution was stirred for 30 minutes at 28°C. The precipitate was filtered and the wet cake was washed with acetonitrile (5 ml_) and the solid was dried under vacuum at 43°C to yield 3.2 gm of telaprevir.
Purity: 96.99% (by HPLC); XRD pattern: similar to Figure 1.
Example 27: Preparation of (1 R,2R)-methyl 2-hydroxycyclopentanecarboxylate
Figure imgf000051_0001
Acetone (375 ml_), Bis(2-methylallyl)-(1 ,5-cyclooctadiene ruthenium (II) (170 mg) and (R)-(+)-(1 ,1 '-Binaphthalene-2,2'-diyl)bis(diphenylphosphine) (R-BINAP, 365 mg) are charged into 1000 ml_ round bottom flask under nitrogen atmosphere. The mixture was sonicated for 20 minutes and cooled to 28°C. 0.2 M methanolic hydrobromide solution (18.9 ml_) was added to the mixture at 28°C and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure at 40°C to Ru-BINAP catalyst.
The above freshly prepared Ru-BINAP catalyst, 2-Methoxycarbonyl cyclopentanone (150 g), methanol (1050 ml_) are charged into autoclave at 28°C. The autoclave was flushed three times with nitrogen and one time with hydrogen. The vessel was filled with hydrogen pressure at 1 1 kg/cm2, and then heated to 65°C. The reaction mixture was stirred for 5 hours under hydrogen pressure at 65°C. The reaction mixture was cooled to 28°C and unloaded from autoclave. The mixture was concentrated under reduced pressure at 50°C. The crude was distilled under reduced pressure at 130°C to get 135 g of the title compound as colorless oil.
1H NMR (400 MHz, CDCI3) : δ 1.57-1.69 (m, 2H), 1.71 -1.81 (m, 2H), 1.92-2.05 (m, 2H), 2.42 (brs,1 H), 2.64 (m, 1 H), 3.70 (s,3H) 3.71 ( m, 1 H) 4.35 (m, 1 H)
Example 28: Preparation of (1 R,2R)-methyl-2-((methylsulfonyl)oxy)cyclopentene carboxylate
Figure imgf000052_0001
(1 R,2R)-methyl 2-hydroxycyclopentanecarboxylate (5 g) and Dichloromethane (50 mL) were charged into a 100 mL round bottom flask and mixture was cooled to 0°C. Triethylamine (9.6 mL) was added to the mixture at 0°C over a period of 10 minutes. Methanesulfonylchloride (2.9 mL) was added to the mixture at 0°C over a period of 10 minutes. The mixture was heated to 30°C and stirred for 2 hours. Water (50 mL) was added to the reaction mixture and stirred for 10 minutes. Organic layer was separated and the aqueous layer was extracted with Dichloromethane (2X25 mL). The organic layers were combined and dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum. The resulted residue was purified by column chromatography to yield 5.2 g of the title product as yellow oil.
1H NMR (400 MHz, CDCI3): δ 1.73-1.85 (m, 3H), 1.94-2.01 (m, 2H), 2.10-2.18 (m, 2H), 3.01 (s, 3H), 3.05 (m, 1 H), 3.72 (s, 3H), 5.27 (m, 1 H).
Example 29: Preparation of (1 R,2R)-2-formylcyclopentyl methanesulfonate
Figure imgf000052_0002
The compound obtained in Example 28 (1 g) was charged into a 100 mL round bottom flask and Tetrahydrofuran (15 mL) was added under nitrogen atmosphere. The mixture was cooled to -78°C and Diisobuylaluminum hydride (DIBAL-H, 1 M in Toluene, 5.4 mL) was added over a period of 20 minutes at -78°C and the reaction mixture was stirred for 3 hours at -78°C. The reaction mixture was quenched with methanol (2 mL) at -78°C and Rochelle salt solution (2M aqueous solution, 5 mL) was slowly added to the resulted solution at -78°C. The resulted solution was slowly heated to 30°C and filtered through a celite bed. Organic layer was separated and the aqueous layer was extracted with ethylacetate (3X15 mL). The organic layers were combined, and washed with water (20 mL) and brine solution (10 mL). The organic layer was dried with anhydrous sodium sulphate (2 gm) and concentrated completely under vacuum to yield 500 mg of the title product. The obtained crude material was taken up for the next reaction without any further purification.
Example 30: Preparation of 1 R,2R)-2-(dimethoxymethyl)cyclopentyl methanesulfonate
Figure imgf000053_0001
The compound obtained in Example 29 (150 mg) and Methanol (3 mL) were charged into a 50 mL round bottom flask. Trimethylorthoformate (0.93 mL) and p- Toluene sulfonic acid (5 mg) were added at 30°C and the resulting mixture was stirred for 16 hours at 30°C. Potassium carbonate (50 mg) was added to the reaction mixture and the resulted mixture was concentrated under vacuum at 30°C. Water (5 mL) was added to the residue and the solution was extracted with ethylacetate (2X10 mL). The ethylacetate layers were combined and washed with water (5 mL) and brine solution (5 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum to yield 90 mg of the title product as dark blue oil.
Example 31 : Preparation of (1 R,2R)-2-(1 ,3-dioxolan-2-yl)cyclopentyl methanesulfonate
Figure imgf000053_0002
The compound obtained in Example 29 (150 mg) and Toluene (3 mL) were charged into a 50 mL round bottom flask. Ethylene glycol (0.5 mL) and p-Toluene sulfonic acid (5 mg) were added at 30°C and the resulting mixture was stirred for 16 hours at 30°C. Water (5 mL) and ethylacetate (2X10 mL) were added to the reaction mixture and the organic later was separated. The aqueous layer was extracted with ethylacetate (10 mL). The ethylacetate layers were combined and washed with water (10 mL) and brine solution (10 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum to yield 100 mg of the title product as oil.
Example 32: Preparation of (1 R,2R)-2-(1 ,3-dioxolan-2-yl)cyclopentyl methanesulfonate
Figure imgf000054_0001
(1 R,2R)-methyl-2-((methylsulfonyl)oxy)cyclopentene carboxylate (30 g) was charged into a 1000 mL round bottom flask and Toluene (300 mL) was added under nitrogen atmosphere. The mixture was cooled to -78°C and Diisobuylaluminum hydride (DIBAL-H, 1 M in Toluene, 202.5 mL) was added over a period of 3 hours at -78°C and the reaction mixture was stirred for 2 hours at -78°C. The reaction mixture was quenched with methanol (5 mL) at -78°C. Saturated NH4CI solution (250 mL) was slowly added to the mixture at -78°C and the resulted solution was slowly heated to 30°C and filtered through a celite bed. The bed was washed with toluene (200 mL). The organic layer was separated and washed with saturated NaHC03 solution (500 mL). The organic layer was dried with anhydrous sodium sulphate (20 gm) and the organic layer was charged into a 1000 mL round bottom flask. Ethylene glycol (150 mL) and p- Toluene sulfonic acid (3.4 g) were added at 30°C and the resulting mixture was stirred for 16 hours at 30°C. Water (300 mL) was added to the reaction mixture and the resulted solution was stirred for 10 minutes. The organic later was separated and washed with saturated NaHC03 solution (2X250 mL). The organic layer was dried with anhydrous sodium sulphate (20 g) and concentrated completely under vacuum to yield 14 g of the title product as pale yellow syrup.
Example 33: Preparation of (1 S,2R)-2-(dimethoxymethyl)cyclopentanecarbonitrile
Figure imgf000055_0001
The compound obtained in Example 30 (100 mg) and Dimethylformamide (3 mL) were charged into a 25 mL round bottom flask. Sodium cyanide (103 mg) was added at 30°C. The mixture was heated to 80°C and stirred for 16 hours at 80°C. The reaction mixture was cooled to 30°C and water (20 mL) was added. The resulted solution was extracted with ethylacetate (2X10 mL). The ethylacetate layers were combined and washed with water (10 mL) and brine solution (10 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (10% ethylacetate in hexane) to yield 20 mg of the title product as oil.
Example 34: Preparation of (1 S,2R)-2-(1 ,3-dioxolan-2-yl)cyclopentanecarbonitrile
Figure imgf000055_0002
The compound obtained in Example 30 (100 mg) and Dimethylformamide (3 mL) were charged into a 25 mL round bottom flask. Sodium cyanide (102 mg) was added at 30°C. The mixture was heated to 80°C and stirred for 16 hours at 80°C. The reaction mixture was cooled to 30°C and water (20 mL) was added. The resulted solution was extracted with ethylacetate (2X10 mL). The ethylacetate layers were combined and washed with water (10 mL) and brine solution (10 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum to yield 40 mg of the title product as dark blue oil.
Example 35: Preparation o -2-(1 ,3-dioxolan-2-yl)cyclopentyl)methanamine
Figure imgf000055_0003
The compound obtained in Example 34 (2.5 g) and Methanol (25 mL) were charged into a 100 mL round bottom single neck flask. Raney Nickel (1.5 g) was charged in the mixture under nitrogen atmosphere. Using a balloon hydrogen gas is applied and the reaction mixture is maintained for 16 hours at 27°C. Under nitrogen atmosphere the reaction mixture was filtered through a celite bed and the celite bed was washed with methanol (25 mL). The filtrate was concentrated completely under reduced pressure to get 2.0 g of the title product as pale green syrup.
Example 36: Preparation o aS)-octahydrocyclopenta[c]pyrrole-1 -carbonitrile
Figure imgf000056_0001
The compound obtained in Example 35 (500 mg), 1 N HCI (50 mL) and KCN (760 mg) were charged into a 250 mL round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 30°C. 30% KOH solution (5 mL) was added to the reaction mixture and extracted with dichloromethane (2X25 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (20% ethylacetate in hexane) to yield 200 mg of the title compound as brown liquid.
1H NMR (400 MHz, CDCI3): δ 1.29-1.42 (m, 2H), 1.44-1.51 (m, 1 H), 1 .61 -1.70 (m, 1 H), 1.83-1.97 (m, 2H), 2.68 (m, 1 H), 2.78 (dd, 1 H, J = 9.8 Hz, 2 Hz), 3.24 (dd, 1 H, J = 10 Hz, 7.6 Hz), 3.68 (d,1 H, J = 2 Hz).
Example 37: Preparation of (1 S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxylic acid
Figure imgf000056_0002
The compound obtained in Example 36 (200 mg) and concentrated HCI (2 mL) were charged into a 50 mL round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 100°C. The reaction mixture was concentrated under vacuum and the obtained crude was dissolved in methanol (2 mL), triethylamine (0.4 mL) and di-tert- butyl dicarbonate (B0C2O, 400 mg) at 0°C. The resulting mixture was stirred for 2 hours at 30°C and the reaction mixture was concentrated under vacuum and diluted with saturated NaHC03 solution (20 mL) and extracted with ethyl acetate (25 mL). The aqueous solution was acidified using citric acid to pH ~5 and the aqueous solution was extracted with ethyl acetate (25 mL). Organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum to yield 250 mg of the title compound as a white solid.
1H NMR (400 MHz, DMSO-d6): δ 1 .33 &1.38 (2s, 9H), 1.43 (m, 1 H), 1.51 (m, 2H), 1.63- 1.68 (m, 1 H), 1 .71 (m, 1 H), 1 .89 (m, 1 H), 2.58 (m, 2H), 3.13 (dd, 1 H, J = 10.8 Hz, 2.8 Hz), 3.51 (m, 1 H), 3.87 (dd,1 H, J = 2.8 Hz, 26 Hz); 13C NMR (100 MHz, DMSO-d6): δ 25.58, 28.35, 28.52, 32.34, 32.44, 33.05, 41.34, 42.29, 47.90, 48.96, 52.88, 53.00, 65.73, 66.01 , 79.14, 153.87, 154.28, 174.17, 174.56
Example 38: Preparation of (1 R,2S)-2-(hydroxymethyl)cyclopentanol
Figure imgf000057_0001
Lithium aluminum hydride (7.8 g) and Tetrahydrofuran (200 mL) were charged into a 1000 mL round bottom flask under nitrogen atmosphere and the mixture was cooled to 0°C. The compound obtained in Example 27 (50 g) was dissolved in Tetrahydrofuran (200 mL) and the resulted solution was charged into the reaction mixture at 0°C over a period of 20 minutes. Temperature was raised to 28°C and the reaction mixture was stirred for 2 hours at 28°C. The reaction mixture was quenched with saturated aqueous sodium sulphate (70 mL). The precipitation was filtered and the cake was washed with ethyl acetate (2 X100 mL). The organic layer was concentrated completely under vacuum to yield 20 g of the title product as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 1.26-1.40 (m, 2H), 1.52-1.88 (m, 5H), 3.20 (dd, 1 H, J = 10.6 Hz, 6.4 Hz), 3.34 (dd, 1 H, J = 10.6 Hz, 6.4 Hz), 3.75 (m, 1 H), 4.36 (m, 2H).
Example 39: Preparation of (1 R,2S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopentanol
Figure imgf000058_0001
The compound obtained in Example 38 (2.5 g) and Dichloromethane (50 mL) were charged into a 250 mL round bottom flask and the resulted solution was cooled to 0°C. Imidazole (3.5 g) and tert-Butylchlorodiphenylsilane (5.9 g) were added at 0°C and the resulting mixture was stirred for 2 hours at 28°C. Water (100 mL) was added to the reaction mixture and the resulted solution was extracted with Dichloromethane (2 X 50 mL). The organic layers were combined and dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (20% ethylacetate in hexane) to yield 5.7 g of the title product as colorless oil.
1H NMR (400 MHz, CDCI3) : δ 1.05 (s, 9H), 1.15 (m, 1 H), 1.60 (m, 2H), 1.73 (m, 2H), 1.94 (m, 1 H), 2.02 (m, 1 H), 2.46 (brs, 1 H), 3.54 (t, 1 H, J = 9.6 Hz), 3.78 (dd, 1 H, J = 10.2 Hz, 5.2 Hz), 4.09 (q, 1 H), 7.42 (m, 6H), 7.67 (m, 4H).
Example 40: Preparation of (1 R,2S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopentyl methanesulfonate
Figure imgf000058_0002
The compound obtained in Example 39 (5 g) and Dichloromethane (100 mL) were charged into a 250 mL round bottom flask and mixture was cooled to 0°C. Triethylamine (4.3 mL) was added to the mixture at 0°C over a period of 10 minutes. Methanesulfonylchloride (1.3 mL) was added to the mixture at 0°C over a period of 20 minutes. The mixture was heated to 28°C and stirred for 2 hours. Water (50 mL) was added to the reaction mixture and stirred for 10 minutes. Organic layer was separated and the aqueous layer was extracted with Dichloromethane (2 X100 mL). The organic layers were combined and washed with saturated sodium bicarbonate solution (2 X100 mL) followed by washing with brine solution (2 X 50 mL). The organic layer was dried with anhydrous sodium sulphate (10 gm) and concentrated completely under vacuum to yield 5 g of the title product as brown color solid.
1H NMR (400 MHz, CDCI3): δ 1 .06 (s, 9H), 1.39 (m, 1 H), 1.60-1.80 (m, 2H), 1.86-1.98 (m, 3H), 2.36 (m, 1 H), 2.92 (s, 3H), 3.50 (dd, 1 H, J = 10.2 Hz, 6.8 Hz), 3.69 (dd, 1 H, J = 10.2 Hz, 5.2 Hz), 5.08 (m, 1 H), 7.39 (m, 6H), 7.63 (m, 4H)
Example 41 : Preparation of (1 S,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl) cyclopentanecarbonitrile
Figure imgf000059_0001
The compound obtained in Example 40 (5 g) and Dimethylformamide (50 mL) were charged into a 250 mL round bottom flask. Sodium cyanide (1.13 g) was added at 28°C. The mixture was heated to 60°C and stirred for 16 hours at 60°C. The reaction mixture was cooled to 30°C and water (100 mL) was added. The resulted solution was extracted with ethylacetate (2X100 mL). The ethylacetate layers were combined and washed with water (100 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (10% ethylacetate in hexane) to yield 2.5 g of the title product as colorless oil.
1H NMR (400 MHz, CDCI3) : δ 1 .07(s, 9H), 1.40-1.52 (m, 1 H), 1.65-1 .80 (m, 2H), 1.87 (m,1 H), 1.95-2.10 (m, 2H), 2.31 (m, 1 H), 3.10 (m, 1 H), 3.80 (d, 2H, J = 7.2 Hz), 7.42 (m, 6H), 7.70 (m, 4H).
Example 42: Preparation of ((1 S,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopentyl) methanamine
Figure imgf000060_0001
The compound obtained in Example 41 (2.5 g) and Ethanol (25 mL) were charged into a 100 mL round bottom single neck flask. Raney Nickel (1 g) was charged in the mixture under nitrogen atmosphere. Using a balloon hydrogen gas is applied and the reaction mixture is maintained for 16 hours at 27°C. Under nitrogen atmosphere the reaction mixture was filtered through a celite bed and the celite bed was washed with ethanol (25 mL). The filtrate was concentrated completely under reduced pressure to get 2.2 g of the title product as yellowish syrup.
1H NMR (400 MHz, DMSO-d6): δ 1.02 (s, 9H), 1 .23-1.36 (m, 1 H), 1.40-1.51 (m, 2H), 1.53-1.72 (m, 3H), 1.91 (m, 1 H), 2.18 (m, 1 H), 2.41 (dd, 1 H, J = 12.2 Hz, 8.4 Hz), 2.62 (dd, 1 H, J = 9.2 Hz, 6 Hz), 3.50 (dd, 1 H, J = 10.4 Hz, 6.8 Hz), 3.65 (dd, 1 H, J = 10 Hz, 6.4 Hz), 7.44 (m, 6H), 7.60 (m, 4H).
Example 43: Preparation of ((1 R,2S)-2-(aminomethyl)cyclopentyl)methanol
Figure imgf000060_0002
The compound obtained in Example 42 (2.2 g) and Methanolic hydrochloride (20 mL) was charged into a 100 mL round bottom flask and the resulted mixture was stirred for 2 hours at 28°C. The reaction mixture was evaporated to dryness under reduced pressure. Diethyl ether (25 mL) was added to the obtained crude and the resulted mixture was concentrated under reduced pressure to yield 650 mg of the title product as yellowish syrup.
1H NMR (400 MHz, DMSO-d6): δ 1.26-1.49 (m, 3H), 1.51 -1.74 (m, 3H), 2.15 (m, 2H), 2.72 (m, 1 H), 2.98 (m, 1 H), 3.39 (m, 2H), 7.90 (brs, 3H).
Example 44: Preparation of tert-butyl (((1 S,2R)-2-(hydroxymethyl)cyclopentyl)methyl) carbamate
Figure imgf000061_0001
The compound obtained in Example 43 (600 mg) and Methanol (6 mL) were charged into a 50 mL round bottom flask. Triethylamine (0.9 mL) was added the mixture at 0°C. Boc anhydride (1.2 mL) was added at 0°C and the resulted mixture was stirred for 1 hour at 28°C. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added to the crude and the obtained solution was extracted with Dichloromethane (2X 50 mL). The combined organic layer was dried over anhydrous sodium sulfate (2 g) and concentrated under reduced pressure. The crude was purified by column chromatography (10% ethylacetate in hexane) to yield 400 mg of the title compound as white solid.
1H NMR (400 MHz, CDCI3): δ 1.23-1.42 (m, 2H), 1.44 (s, 9H), 1.48-1.71 (m, 2H), 1.73- 2.02 (m, 2H), 2.10-2.24 (m, 2H), 3.14 (d, 1 H, J = 7.2 Hz), 3.60 (m, 2H).
Example 45: Preparation of tert-butyl (((1 S,2R)-2-formylcyclopentyl)methyl)carbamate c
Figure imgf000061_0002
The compound obtained in Example 44 (200 mg) and Dichloromethane (4 mL) were charged into a 25 mL round bottom flask and the mixture was cooled to 0°C. Dess-Martin Periodinane (DMP, 740 mg) was added and the reaction mixture was stirred at 28°C for 2 hours. Dichloromethane was evaporated under Nitrogen atmosphere. To the residue diethyl ether (15 mL) and hexane (25 mL) were charged and the resulted mixture was stirred for 10 minutes. The precipitation was filtered and the filtrate was concentrated under reduced pressure to yield 150 mg of the title product as brownish oil. The obtained crude material was taken up for next reaction without any further purification.
Example 46: Preparation of tert-butyl (((1 S,2R)-2-(dimethoxymethyl)cyclopentyl)methyl) carbamate Boc
Figure imgf000062_0001
The compound obtained in Example 45 (700 mg) and Methanol (7 mL) were charged into a 100 mL round bottom flask. Trimethylorthoformate (3.6 mL) and p-Toluene sulfonic acid (10 mg) were added at 30°C and the resulting mixture was stirred for 16 hours at 30°C. Potassium carbonate (50 mg) was added to the reaction mixture and the resulted mixture was concentrated under vacuum at 30°C. Water (25 mL) was added to the residue and the solution was extracted with dichloromethane (2X25 mL). The organic layer was dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum to yield 700 mg of the title product as colorless liquid. The obtained crude compound was taken up for the next reaction without any further purification.
Example 47: Preparation o aS)-octahydrocyclopenta[c]pyrrole-1 -carbonitrile
Figure imgf000062_0002
The compound obtained in Example 46 (600 mg), 1 N HCI (102 mL) and KCN (570 mg) were charged into a 250 mL round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 30°C. 30% KOH solution (5 mL) was added to the reaction mixture and extracted with ethyl acetate (2X25 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (20% ethylacetate in hexane) to yield 180 mg of the title compound as brown liquid.
1H NMR (400 MHz, CDCI3): δ 1.29-1.42 (m, 2H), 1.44-1.51 (m, 1 H), 1 .61 -1.70 (m, 1 H), 1.83-1.97 (m, 2H), 2.68 (m, 1 H), 2.78 (dd, 1 H, J = 9.8 Hz, 2 Hz), 3.24 (dd, 1 H, J = 10 Hz, 7.6 Hz), 3.68 (d,1 H, J = 2 Hz). Example 48: Preparation of (1 S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxylic acid.
Figure imgf000063_0001
The compound obtained in Example 47 (80 mg) and concentrated HCI (1 mL) were charged into a 25 mL round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 100°C. The reaction mixture was concentrated under vacuum and crude was triturated with diethyl ether (10 mL). The obtained crude was dissolved in methanol (5 mL), triethylamine (0.15 mL) and Boc20 (124 mg) at 30°C. The resulting mixture was stirred for 30 min at 30°C and the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2X25 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum to yield 90 mg of the title compound as a white solid.
1H NMR (400 MHz, DMSO-d6): δ 1 .33 &1.38 (2s, 9H), 1.43 (m, 1 H), 1.51 (m, 2H), 1.63- 1.68 (m, 1 H), 1 .71 (m, 1 H), 1 .89 (m, 1 H), 2.58 (m, 2H), 3.13 (dd, 1 H, J = 10.8 Hz, 2.8 Hz), 3.51 (m, 1 H), 3.87 (dd,1 H, J = 2.8 Hz, 26 Hz); 13C NMR (100 MHz, DMSO-d6): δ 25.58, 28.35, 28.52, 32.34, 32.44, 33.05, 41.34, 42.29, 47.90, 48.96, 52.88, 53.00, 65.73, 66.01 , 79.14, 153.87, 154.28, 174.17, 174.56.
Example 49: Preparation o aS)-octahydrocyclopenta[c]pyrrole-1 -carbonitrile
Figure imgf000063_0002
The compound obtained in Example 45 (500 mg), 1 N HCI (100 mL) and KCN (520 mg) were charged into a 250 mL round bottom flask at 30°C and the resulting mixture was agitated for 16 hours at 30°C. 30% KOH solution (5 mL) was added to the reaction mixture and extracted with ethyl acetate (2X25 mL). The organic layer was dried with anhydrous sodium sulphate (1 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (20% ethylacetate in hexane) to yield 150 mg of the title compound as brown liquid.
Example 50: Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1 -(cyclopropyl amino)-1 -2- dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1 -carboxamide (Telaprevir)
Figure imgf000064_0001
Ethylacetate (20 mL) and acetic acid (2 mL) were charged into a 100 mL round bottomed flask and the mixture was cooled to 0°C. (1 S,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)-octa hydrocyclopenta[c]pyrrole-1 - carboxamide (2 g) and N-acetamido-TEMPO (63 mg) and potassium permanganate (1 g) were added at 10°C and the reaction mixture was stirred for 6 hours at 10°C. Water (20 mL) was added to the reaction mixture and the resulted solution was agitated for 10 minutes. Layers were separated and the organic layer was washed with 10% aqueous hydrochloric acid solution, and 5% aqueous sodium sulphate solution followed by 10% aqueous sodium chloride solution. Organic layer was concentrated under vacuum completely and fresh ethyl acetate (10 mL) was added to the residue and the resulted solution was stirred for 30 minutes at 28°C. The precipitation was filtered and the wet cake was washed with ethyl acetate (5 mL) and the solid was dried under vacuum at 43°C to yield 0.52 gm of telaprevir.
Purity: 94.02% (by HPLC); XRD pattern: similar to figure 1.
Example 51 : Purification of Telaprevir
Telaprevir (35 gm) and dichloromethane (105 mL) were charged into a 500 mL round bottomed flask and stirred to get clear solution and the solution was filtered. Dichloromethane was distilled out completely under vacuum and fresh dichloromethane (35 mL) was added to the residue. Ethylacetate (350 mL) was added to the mass and the resulted mixture was stirred for 30 minutes at 28°C. The precipitation was filtered and the wet cake was washed with ethylacetate (35 mL). The wet material was charged into another 500 mL round bottomed flask, dichloromethane (90 mL) was added and stirred to get clear solution. Ethylacetate (300 mL) was added to the clear solution and the resulting mixture was stirred for 30 minutes at 28°C. The precipitation was filtered and the wet cake was washed with ethylacetate (35 mL). The wet material was dried under vacuum at 40°C to yield 28.2 gm of telaprevir.
Purity: 99.72% (by HPLC), XRD pattern: similar to figure 1.
Example 52: Purification of Telaprevir
Telaprevir (24 gm) and dichloromethane (72 mL) were charged into a 500 mL round bottomed flask and stirred to get clear solution and the solution was filtered. Dichloromethane was distilled out completely under vacuum and fresh dichloromethane (24 mL) was added to the residue. Ethylacetate (240 mL) was added to the solution and the resulted mixture was stirred for 30 minutes at 28°C. The precipitation was filtered and the wet cake was washed with ethylacetate (24 mL). The wet material was charged into another 500 mL round bottomed flask dichloromethane (72 mL) was added and stirred to get clear solution. Dichloromethane was distilled out completely under vacuum and fresh dichloromethane (24 mL) was added to the residue. Ethylacetate (240 mL) was added to the clear solution and the resulting mixture was stirred for 30 minutes at 28°C. The precipitation was filtered and the wet cake was washed with ethylacetate (24 mL). The wet material was dried under vacuum at 45°C to yield 22.2 gm of telaprevir. Purity: 99.90% (by HPLC); XRD pattern: similar to figure 1.
Example 53: Preparation of (1 R,2R)-methyl-2-((methylsulfonyl)oxy)cyclopentene carboxylate
Figure imgf000065_0001
(1 R,2R)-methyl-2-hydroxycyclopentanecarboxylate (50 g) and Dichloromethane (1000 mL) were charged into a 3L round bottom flask and the mixture was cooled to 0°C. Triethylamine (96.8 mL) was added to the mixture at 0°C over a period of 10 minutes. Methanesulfonylchloride (29.5 mL) was added to the mixture at 0°C over a period of 10 minutes. The mixture was heated to 30°C and stirred for 2 hours. Water (500 mL) was added to the reaction mixture and stirred for 10 minutes. Organic layer was separated and the aqueous layer was extracted with Dichloromethane (500 mL). The organic layers were combined and washed with saturated sodium bicarbonate solution (3 x 1 L) and brine solution (1 L). The organic layer was dried with anhydrous sodium sulphate (15 gm) and concentrated completely under vacuum. The resulted residue was purified by column chromatography to yield 69.3 g of the title product as yellow syrup.
1H NMR (400 MHz, CDCI3): δ 1.73-1.85 (m, 3H), 1.94-2.01 (m, 2H), 2.10-2.18 (m, 2H), 3.01 (s, 3H), 3.05 (m, 1 H), 3.72 (s, 3H), 5.27 (m, 1 H).
Example 54: Preparation of (1 R,2R)-2-(1 ,3-dioxolan-2-yl)cyclopentyl methanesulfonate
Figure imgf000066_0001
The compound obtained in Example 53 (30 g) was charged into a 1000 mL round bottom flask and Toluene (300 mL) was added under nitrogen atmosphere. The mixture was cooled to -78°C and Diisobuylaluminum hydride (DIBAL-H, 1 M in Toluene, 202.5 mL) was added over a period of 30 minutes at -78°C and the reaction mixture was stirred for 2 hours at -78°C. The reaction mixture was quenched with methanol (5 mL) at -78°C and saturated ammonium chloride solution (250 mL) was slowly added to the resulted solution at -78°C. The resulted solution was slowly heated to 30°C and filtered through a celite bed and the bed was washed with Toluene (2 x 100 mL). Organic layer was dried with anhydrous sodium sulphate (10 gm) and charged into a 1000 mL round bottom flask. Ethylene glycol (60 mL) and p-Toluene sulfonic acid (3.4 gm) were added at 30°C and the resulting mixture was stirred for 16 hours at 30°C. Water (300 mL) and was added to the reaction mixture and the organic layer was separated. The organic layer was washed with saturated sodium bicarbonate solution (2 x 250 mL) and brine solution (200 mL). The organic layer was dried with anhydrous sodium sulphate (10 gm) and concentrated completely under vacuum and the residue was purified by column chromatography to yield 14 gm of the title product as yellow syrup.
Example 55: Preparation of (1 S,2R)-2-(1 ,3-dioxolan-2-yl)cyclopentanecarbonitrile
Figure imgf000067_0001
The compound obtained in Example 54 (24 gm) and Dimethylformamide (144 ml_) and Sodium cyanide (19.9 gm) were charged into a 500 ml_ round bottom flask. The mixture was heated to 65°C and stirred for 16 hours. The reaction mixture was cooled to 30°C and water (250 ml_) was added. The resulted solution was extracted with ethylacetate (2 x 250 ml_). The ethylacetate layers were combined and washed with water (2 x 250 ml_) and brine solution (2 x 150 ml_). The organic layer was dried with anhydrous sodium sulphate (10 gm) and concentrated completely under vacuum and the residue was purified by column chromatography to yield 13 gm of the title product as yellow syrup.
Example 56: Preparation of tert-butyl (((1 S,2R)-2-(1 ,3-dioxolan-2- yl)cyclopentyl)methyl)carbamate
Figure imgf000067_0002
The compound obtained in Example 55 (13 g) and Methanol (260 ml_) were charged into a 1 L steel vessel. Raney Nickel (3 g) was charged in the mixture under nitrogen atmosphere. The reaction mixture was stirred for 16 hours at 27°C under hydrogen pressure (80 psi) using parr hydrogenator. Under nitrogen atmosphere the reaction mixture was filtered through a celite bed and the celite bed was washed with methanol (200 ml_). The filtrate was taken into a 1000 ml_ round bottom flask, triethylamine (21 .6 ml_) and boc anhydride (16.9 ml_) were added and the resulting mixture was stirred for 2 hours at 28°C. The reaction mass was concentrated completely under reduced pressure and the crude was diluted with water and the solution was extracted with ethylacetate (2 x 250 ml_). The organic layer was washed with 5% citric acid solution to remove excess boc anhydride and washed with brine solution. The organic layer was dried over sodium sulphate (10 g) and concentrated under reduced pressure to get 15.0 g of the title product as pale yellow syrup.
Example 57: Preparation o aS)-octahydrocyclopenta[c]pyrrole-1 -carbonitrile
Figure imgf000068_0001
The compound obtained in Example 56 (14 gm), 2N HCI (3L) and KCN (13.4 gm) were charged into a 5L round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 30°C. 30% KOH solution (1.1 L) was added to the reaction mixture and extracted with dichloromethane (2 x 500 ml_). The organic layer was dried with anhydrous sodium sulphate (10 gm) and concentrated completely under vacuum to give 4 gm of the title compound as colorless syrup.
1H NMR (400 MHz, CDCI3): δ 1.29-1.42 (m, 2H), 1.44-1.51 (m, 1 H), 1 .61 -1.70 (m, 1 H), 1.83-1.97 (m, 2H), 2.68 (m, 1 H), 2.78 (dd, 1 H, J = 9.8 Hz, 2 Hz), 3.24 (dd, 1 H, J = 10 Hz, 7.6 Hz), 3.68 (d,1 H, J = 2 Hz).
Example 58: Preparation of (1 S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxylic acid
Figure imgf000068_0002
The compound obtained in Example 57 (4 g) and concentrated HCI (28 ml_) were charged into a 250 ml_ round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 100°C. The reaction mixture was concentrated under vacuum and the obtained crude was triturated with ether and decanted the ether layer and dried under vacuum to give 4 g of crude title product. To the above crude (4 g), methanol (40 mL), triethylamine (8.17 mL) and di-tert- butyl dicarbonate (B0C2O, 7.05 mL) were charged at 0°C. The resulting mixture was stirred for 2 hours at 30°C. The reaction mixture was concentrated under vacuum and diluted with saturated NaHC03 solution (100 mL) and extracted with ethyl acetate (200 mL). The aqueous solution was acidified using saturated citric acid to pH ~5 and the aqueous solution was extracted with ethyl acetate (200 mL). Organic layer was dried with anhydrous sodium sulphate (5 gm) and concentrated completely. The obtained crude compound was triturated with hexane for 2 hours and the white solid was filtered and dried under vacuum to give 4.48 gm of the title compound as a white solid.
1H NMR (400 MHz, DMSO-d6): δ 1 .33 &1.38 (2s, 9H), 1.43 (m, 1 H), 1.51 (m, 2H), 1.63- 1.68 (m, 1 H), 1 .71 (m, 1 H), 1 .89 (m, 1 H), 2.58 (m, 2H), 3.13 (dd, 1 H, J = 10.8 Hz, 2.8 Hz), 3.51 (m, 1 H), 3.87 (dd,1 H, J = 2.8 Hz, 26 Hz); 13C NMR (100 MHz, DMSO-d6): δ 25.58, 28.35, 28.52, 32.34, 32.44, 33.05, 41.34, 42.29, 47.90, 48.96, 52.88, 53.00, 65.73, 66.01 , 79.14, 153.87, 154.28, 174.17, 174.56.
Chemical purity: 98%, chiral purity: 99.8% by HPLC.
Example 59: Preparation of (1 R,2S)-2-(hydroxymethyl)cyclopentanol
Figure imgf000069_0001
Lithium aluminum hydride (33 g) and Tetrahydrofuran (1.7L) were charged into a 3L round bottom flask under nitrogen atmosphere and the mixture was cooled to 0°C. The compound obtained in Example 27 (85 g) was dissolved in Tetrahydrofuran (700 mL) and the resulted solution was added to the reaction mixture at 0°C over a period of 20 minutes. Temperature was raised to 28°C and the reaction mixture was stirred for 5 hours at 28°C. The reaction mixture was cooled to 0°C and quenched with saturated aqueous sodium sulphate (250 mL). The precipitation was filtered and the cake was washed with ethyl acetate (1000 mL). The organic layer dried over sodium sulphate (10 g) and concentrated completely under vacuum to yield 70 g of the title product as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 1.26-1.40 (m, 2H), 1.52-1.88 (m, 5H), 3.20 (dd, 1 H, J = 10.6 Hz, 6.4 Hz), 3.34 (dd, 1 H, J = 10.6 Hz, 6.4 Hz), 3.75 (m, 1 H), 4.36 (m, 2H).
Example 60: Preparation of (1 R,2S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopentanol
Figure imgf000070_0001
The compound obtained in Example 59 (70 g) and Dichloromethane (1.4L) were charged into a 3L round bottom flask and the resulted solution was cooled to 0°C. Imidazole (98 g) and tert-Butylchlorodiphenylsilane (165 g) were added at 0°C and the resulting mixture was stirred for 2 hours at 28°C. Water (1000 mL) was added to the reaction mixture and the resulted solution was extracted with Dichloromethane (2 x 250 mL). The organic layers were combined and washed with brine solution and dried over anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (15% ethylacetate in hexane) to yield 160 g of the title product as colorless oil.
1H NMR (400 MHz, CDCI3) : δ 1.05 (s, 9H), 1.15 (m, 1 H), 1.60 (m, 2H), 1.73 (m, 2H), 1.94 (m, 1 H), 2.02 (m, 1 H), 2.46 (brs, 1 H), 3.54 (t, 1 H, J = 9.6 Hz), 3.78 (dd, 1 H, J = 10.2 Hz, 5.2 Hz), 4.09 (q, 1 H), 7.42 (m, 6H), 7.67 (m, 4H).
Example 61 : Preparation of (1 R,2S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopentyl methanesulfonate
Figure imgf000070_0002
The compound obtained in Example 60 (160 g) and Dichloromethane (3.2L) were charged into a 5L round bottom flask and mixture was cooled to 0°C. Triethylamine (125 mL) and Methanesulfonylchloride (38 mL) were added to the mixture at 0°C. The mixture was heated to 28°C and stirred for 2 hours. Water (2L) was added to the reaction mixture and stirred for 10 minutes. Organic layer was separated and the aqueous layer was extracted with Dichloromethane (3 x 500 mL). The organic layers were combined and washed with saturated sodium bicarbonate solution (2 x 1 L) followed by washing with brine solution (2 x 1 L). The organic layer was dried with anhydrous sodium sulphate (20 gm) and concentrated completely under vacuum to yield 195 g of the title product as white solid.
1H NMR (400 MHz, CDCI3): δ 1 .06 (s, 9H), 1.39 (m, 1 H), 1.60-1.80 (m, 2H), 1.86-1.98 (m, 3H), 2.36 (m, 1 H), 2.92 (s, 3H), 3.50 (dd, 1 H, J = 10.2 Hz, 6.8 Hz), 3.69 (dd, 1 H, J = 10.2 Hz, 5.2 Hz), 5.08 (m, 1 H), 7.39 (m, 6H), 7.63 (m, 4H)
Example 62: Preparation of (1 S,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl) cyclopentanecarbonitrile
Figure imgf000071_0001
The compound obtained in Example 61 (160 g), Dimethylformamide (960 ml_) and Sodium cyanide (72 g) were charged into a 3L round bottom flask. The mixture was heated to 65°C and stirred for 48 hours at 65°C. The reaction mixture was cooled to 30°C and water (1.5L) was added. The resulted solution was extracted with ethylacetate (3 x 500 ml_). The organic layer was dried with anhydrous sodium sulphate (20 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (7% ethylacetate in hexane) to yield 70 g of the title product as colorless oil.
1H NMR (400 MHz, CDCI3) : δ 1 .07(s, 9H), 1.40-1.52 (m, 1 H), 1.65-1 .80 (m, 2H), 1.87 (m,1 H), 1.95-2.10 (m, 2H), 2.31 (m, 1 H), 3.10 (m, 1 H), 3.80 (d, 2H, J = 7.2 Hz), 7.42 (m, 6H), 7.70 (m, 4H).
Example 63: Preparation of ((1 S,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopentyl) methanamine
Figure imgf000071_0002
The compound obtained in Example 62 (70 g), Methanol (700 mL) and Raney Nickel (1 g) were charged into a 2L steel vessel under nitrogen atmosphere, the reaction mixture was stirred for 16 hours at 27°C under hydrogen pressure (80 psi) using parr hydrogenator. The reaction mixture was filtered through a celite bed and the celite bed was washed with Methanol (500 mL). The filtrate was concentrated completely under reduced pressure to get 65 g of the title product as yellowish syrup. 1H NMR (400 MHz, DMSO-d6): δ 1.02 (s, 9H), 1 .23-1.36 (m, 1 H), 1.40-1.51 (m, 2H), 1.53-1.72 (m, 3H), 1.91 (m, 1 H), 2.18 (m, 1 H), 2.41 (dd, 1 H, J = 12.2 Hz, 8.4 Hz), 2.62 (dd, 1 H, J = 9.2 Hz, 6 Hz), 3.50 (dd, 1 H, J = 10.4 Hz, 6.8 Hz), 3.65 (dd, 1 H, J = 10 Hz, 6.4 Hz), 7.44 (m, 6H), 7.60 (m, 4H).
Example 64: Preparation of tert-butyl (((1 S,2R)-2-(hydroxymethyl)cyclopentyl)methyl) carbamate
Figure imgf000072_0001
The compound obtained in Example 63 (65g) and Methanol (650 mL) were charged into a 2L round bottom flask. HCI gas was passed in to reaction mixture for 4 hours at 0°C. The reaction mixture was basified using Triethylamine (47 mL). Boc anhydride (45 mL) was added at 0°C and the resulted mixture was stirred for 2 hours at 28°C. The reaction mixture was concentrated under reduced pressure. Water (500 mL) was added to the crude and the obtained solution was extracted with Dichloromethane (2 x 500 mL). The combined organic layer was dried over anhydrous sodium sulfate (10 g) and concentrated under reduced pressure. The crude was purified by column chromatography (7% ethylacetate in hexane) to yield 20 mg of the title compound as white solid. Purity: 72.7% by HPLC.
1H NMR (400 MHz, CDCI3): δ 1.23-1.42 (m, 2H), 1.44 (s, 9H), 1.48-1.71 (m, 2H), 1.73- 2.02 (m, 2H), 2.10-2.24 (m, 2H), 3.14 (d, 1 H, J = 7.2 Hz), 3.60 (m, 2H).
Example 65: Preparation of tert-butyl (((1 S,2R)-2-formylcyclopentyl)methyl)carbamate
Figure imgf000073_0001
The compound obtained in Example 64 (20 g) and Dichloromethane (400 ml_) were charged into a 2L round bottom flask and the mixture was cooled to 0°C. Dess- Martin Periodinane (DMP, 74 g) was added and the reaction mixture was stirred at 28°C for 2 hours. Dichloromethane was evaporated under Nitrogen atmosphere. To the residue diethyl ether (450 ml_) and hexane (1 L) were charged and the resulted mixture was stirred for 10 minutes. The resulting solution was filtered through a celite and the filtrate was concentrated under reduced pressure to yield 18 mg of the title product as pale yellow syrup. The obtained crude material was taken up for next reaction without any further purification.
Example 66: Preparation of tert-butyl (((1 S,2R)-2-(dimethoxymethyl)cyclopentyl)methyl) carbamate
Boc
Figure imgf000073_0002
The compound obtained in Example 65 (18 g), Trimethylorthoformate (93 ml_), p- Toluene sulfonic acid (180 mg) and Methanol (180 ml_) were charged at 30°C and the resulting mixture was stirred for 16 hours at 30°C. Potassium carbonate (10 g) was added to the reaction mixture to adjust pH 9.5 and the resulted mixture was concentrated under vacuum at 30°C. Water (500 ml_) was added to the residue and the solution was extracted with dichloromethane (2 x 250 ml_). The organic layer was dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum to yield 18 g of the title product as yellow liquid. The obtained crude compound was taken up for the next reaction without any further purification.
Example 67: Preparation of (1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1 -carbonitrile
Figure imgf000074_0001
The compound obtained in Example 66 (18 g), 1 N HCI (3L) and KCN (17 g) were charged into a 5L round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 30°C. pH was adjusted to 14 with 30% KOH solution (700 ml_) and extracted with dichloromethane (2 x 500 ml_). The organic layer was dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum. The crude was purified by column chromatography (20% ethylacetate in hexane) to yield 5 g of the title compound as yellow liquid.
1H NMR (400 MHz, CDCI3): δ 1.29-1.42 (m, 2H), 1.44-1.51 (m, 1 H), 1 .61 -1.70 (m, 1 H), 1.83-1.97 (m, 2H), 2.68 (m, 1 H), 2.78 (dd, 1 H, J = 9.8 Hz, 2 Hz), 3.24 (dd, 1 H, J = 10 Hz, 7.6 Hz), 3.68 (d,1 H, J = 2 Hz).
Example 68: Preparation of (1 S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta [c]pyrrole-1 -carboxylic acid.
Figure imgf000074_0002
The compound obtained in Example 67 (5 g) and concentrated HCI (25 ml_) were charged into a 250 ml_ round bottom flask at 30°C and the resulting mixture was stirred for 16 hours at 100°C. The reaction mixture was concentrated under vacuum and crude was triturated with diethyl ether (10 ml_). The obtained crude was dissolved in methanol (50 ml_), triethylamine (10.2 ml_) and B0C2O (9.79 ml_) at 0°C. The resulting mixture was stirred for 2 hours at 30°C. The reaction mixture was concentrated under vacuum and diluted with saturated sodium bicarbonate solution (100 ml_) and extracted with ethyl acetate (250 ml_). The aqueous layer was acidified using saturated citric acid (pH 4.5) and extracted with ethyl acetate (250 ml_). The organic layer was dried with anhydrous sodium sulphate (5 gm) and concentrated completely under vacuum to yield 5 g of the title compound as a white solid. Chemical purity: 99.31%, chiral purity: 99.79% by HPLC.
1H NMR (400 MHz, DMSO-d6): δ 1.33 &1.38 (2s, 9H), 1.43 (m, 1H), 1.51 (m, 2H), 1.63- 1.68 (m, 1H), 1.71 (m, 1H), 1.89 (m, 1H), 2.58 (m, 2H), 3.13 (dd, 1H, J = 10.8 Hz, 2.8 Hz), 3.51 (m, 1H), 3.87 (dd,1H, J = 2.8 Hz, 26 Hz); 13C NMR (100 MHz, DMSO-d6): δ 25.58, 28.35, 28.52, 32.34, 32.44, 33.05, 41.34, 42.29, 47.90, 48.96, 52.88, 53.00, 65.73, 66.01, 79.14, 153.87, 154.28, 174.17, 174.56.

Claims

1. A process for preparation of (1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1 - carboxylic acid of formula (Vllb), comprising:
(a) reducing a compound of formula XX with a suitable reducing agent to form a compound of formula XIX
Figure imgf000076_0001
xx XIX
wherein X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl; R is hydrogen or Ci-C alkyl or C5-C12 aralkyl,
(b) protecting the aldehyde functionality of the compound of formula XIX to form a compound of formula XVIII.
Figure imgf000076_0002
XIX XVIII
wherein R1 and R2 are C1-C5 alkyl or both form a cyclic ring,
(c) cyanating the compound of formula XVIII with a suitable cyanating agent to form compound of formula XVII
Figure imgf000076_0003
XVIII XVII
(d) reducing the compound of formula XVII in the presence of a suitable catalyst to obtain compound of formula XVI,
Figure imgf000076_0004
XVII XVI (e) treating the compound of formula XVI with an acid and an alkali metal cyanide to form compound of formula XV, and
Figure imgf000077_0001
(f) hydrolyzing the compound of formula XV to form compound of formula Vllb or its acid addition salt
Figure imgf000077_0002
XV Vllb
2. A process for preparation of a compound of formula Vllb, comprising:
(a) reducing the compound of formula XX with a suitable reducing agent to form a compound of formula VIII
Figure imgf000077_0003
XX VITT
wherein X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl; R is hydrogen or C C4 alkyl or C5-C12 aralkyl,
(b) protecting the primary hydroxyl group of compound of formula VIII to get compound of formula IX,
Figure imgf000077_0004
VTTT IX
wherein P is a protecting group,
(c) cyanating the compound of formula IX with a suitable cyanating agent to form compound of formula X
Figure imgf000078_0001
ix x
(d) reducing the compound of formula X in the presence of a suitable catalyst to obtain compound of formula XI,
Figure imgf000078_0002
X XI
(e) optionally, deprotecting the compound of formula XI to form compound of formula XII,
Figure imgf000078_0003
XI XII
(f) oxidizing the compound of formula XII to form compound of formula XIII,
Figure imgf000078_0004
(g) optionally, protecting the aldehyde of the compound of formula XIII to form compound of formula XVI.
Figure imgf000078_0005
XIII xvi
R1 and R2 are C1 -C5 alkyl or both form a cyclic ring,
(h) treating the compound of formula XIII or the compound of formula XVI with an alkali metal cyanide to form a compound of formula XV, and
Figure imgf000079_0001
XVI XV
(i) hydrolyzing the compound of formula XV to form compound of formula Vllb or its acid addition salt
Figure imgf000079_0002
XV Vllb
3. The process according to claim 1 or claim 2 further comprises:
(a) reacting the compound of formula Vllb or protected form of formula Vllb with a compound of formula Via or its salt in the presence of a suitable coupling reagent to form compound of formula Va or its salt,
Fo
Figure imgf000079_0003
rmula Vllb Formula Via
Formula Va
wherein P is an amine protecting group;
(b) deprotecting the compound of formula Va or its salt using an acid pound of formula Ilia or a salt thereof.
Figure imgf000079_0004
Formula Va Formula Ilia
(c) reacting a compound of formula Ilia or a salt thereof with a compound of formula IVa or a salt thereof in the presence of a suitable coupling reagent to form a compound of formula Ma,
Figure imgf000080_0001
(d) oxidizing the compound of Formula lla using a suitable oxidizing reagent to form telaprevir.
Figure imgf000080_0002
4. The process according to claim 3, wherein the oxidizing reagent of step (c) is selected from the group comprising 1 ,1 -dihydro-1 ,1 ,1 -triacetoxy-1 ,2-benzoiodooxol- 3(1 H)-one, chromic acid in acetone, sodium hypochlorite in the presence of (2,2,6,6- tetramethyl-piperidin-1 -yl)oxyl, sodium hypochlorite in the presence of (4-Acetamido- 2,2,6,6-tetramethyl-piperidin-1 -yl)oxyl, potassium permanganate in the presence of (4- Acetamido-2,2,6,6-tetramethyl-piperidin-1 -yl)oxyl.
5. The process according to claim 3, wherein the oxidizing reagent is sodium hypochlorite in the presence of (4-Acetamido-2,2,6,6-tetramethyl-piperidin-1 -yl)oxyl.
6. Compounds of formula XVII. Formula VIII and formula XIX and isomers thereof
Figure imgf000080_0003
XVII XVIII XIX
wherein X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl; R1 and R2 are C1 -C5 alkyl or together with the atoms to which they are attached may form a cyclic ring.
7. The compound of formula XVIII according to claim 6 selected from the group consisting of:
Figure imgf000081_0001
8. The compound of formula XVII according to claim 6 selected from the group consisting of:
Figure imgf000081_0002
9. The compound of formula XIX according to claim 6 is:
Figure imgf000081_0003
10. Compounds of formula IX to formula XVI and isomers thereof
Figure imgf000081_0004
IX X XI XIII XVI
wherein X is hydrogen or a leaving group such as mesyl, tosyl, acetyl or trifluoroacetyl; R1 and R2 are C1 -C5 alkyl or together with the atoms to which they are attached may form a cyclic ring, P is hydrogen or a protecting group.
11. The compound of formula IX according to claim 10 is selected from the group consisting of:
Figure imgf000081_0005
12. The compound of formula X according to claim 10 is selected from the group consisting of:
Figure imgf000082_0001
13. The compound of formula XI according to claim 10 is selected from the group consisting of:
Figure imgf000082_0002
14. The compound of formula XIII according to claim 10 is selected from the group consisting of:
c
Figure imgf000082_0003
15. The compound of formula XVI according to claim 10 is selected from the group consisting of:
Figure imgf000082_0004
16. Use of the compounds according to claim 6 or claim 15 in the preparation of compound of formula Vllb or protected form of compound of formula Vllb or pharmaceutically acceptable salts thereof.
17. Compound of formula 1Mb
Figure imgf000082_0005
lib
18. The compound of formula lllb according to claim 17 is (1 S,3aR,6aS)-N-((3S)-1 - (cyclopropyl amino)-2-hydroxy-1 -oxohexan-3-yl)carbamoyl)octahydrocyclopenta- [c]pyrrole-1 -carboxamide hemisulphate.
19. Use of the compound of formula lllb in preparation of telaprevir.
PCT/IB2013/058808 2012-09-24 2013-09-24 Process for preparation of intermediates of telaprevir Ceased WO2014045263A2 (en)

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