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  • 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
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  • 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
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  • 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
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  • C07C223/00—Compounds containing amino and —CHO groups bound to the same carbon skeleton
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/30—Compounds having groups
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  • 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
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  • 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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  • 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
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  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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  • 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
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  • 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
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  • 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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