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  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
  • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
  • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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  • C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
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  • C07C253/00—Preparation of carboxylic acid nitriles
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  • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/24—Oxygen or sulfur atoms
  • C07D207/26—2-Pyrrolidones
  • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
  • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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  • 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
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
  • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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  • C07B2200/07—Optical isomers
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/56—Ring systems containing bridged rings
  • C07C2603/58—Ring systems containing bridged rings containing three rings
  • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
  • C07C2603/74—Adamantanes

Definitions

• the present invention relates to a process for the preparation of (l S,3S,5S)-2- [(2S)-2-amino-2-(3-hydroxyadamantan- 1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3 - carbonitrile represented by the structural formula- 1 ,
• Cyclopropyl fused pyrrolidine based inhibitors of dipeptidyl peptidase-4 and methods for their preparation were first disclosed in US6395767 B2.
• the disclosed process involves the esterification of adamantane-l-carboxylic acid with trimethylsilyl diazomethane followed by the reduction of obtained methyl ester with lithium aluminium hydride to yield adamantyl methanol, which is then oxidized under Swern oxidation conditions to provide adamantyl aldehyde.
• the aldehyde is then treated with potassium cyanide in presence of sodium bisulfite followed by R-(-)-2-phenylglycinol to provide nitrile compound.
• the nitrile compound is then hydrolyzed by heating in cone. HC1 and acetic acid at 80°C for 18 hrs to provide the hydrochloride salt of its corresponding acid.
• N-deprotection of the hydrochloride salt using Pearlman's catalyst (20% Pd(OH) 2 ) provides hydrochloride salt of free amine compound, which is then protected with tert.butyloxy carbonyl group (Boc protection) by treating with di-tert-butyl dicarbonate in presence of potassium carbonate to provide Boc protected amine compound.
• the Boc protected amine is hydroxylated by treating with a solution of potassium permanganate in 2% aq.KOH to provide the corresponding hydroxy compound, which is then condensed with (lS,3S,5S)-2-azabicyclo[3.1.0] hexane-3-carboxamide trifluoroacetic acid salt in presence of 1 -hydroxybenzotriazole, l-ethyI-3-(3-dimethylaminopropyl)carbodiimide) and triethylamine.
• the obtained product is treated with triethylsilyl triflate in presence of diisopropylethyl amine at -78°C to provide O-triethylsilyl protected amide compound, which is treated with imidazole and phosphorous oxychloride in anhydrous pyridine to provide corresponding cyano compound. It is then treated with trifluoroacetic acid and water at 0°C to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile trifluoroacetic acid salt.
• the above disclosed process also involves the usage of lithium aluminium hydride for the reduction of adamantane-l-carboxylic acid methyl ester, which is hygroscopic and highly reactive. Hence it is not suggestible to use it on industrial scale.
• the first aspect of the present invention is to provide an improved process for the preparation of adamantyl methanol compound of formula-3, comprising of reducing the adamantane-l-carboxylic acid compound of formula-2 with a suitable reducing agent in a suitable solvent to provide adamantyl methanol compound of formula-3.
• the second aspect of the present invention is to provide a process for the preparation of benzyloxycarbonyl protected amino hydroxy adamantane carboxylic acid compound of formula-27, comprising of;
• the third aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2- carboxylate compound of formula- 15, comprising of; a) Esterification of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 by treating it with a suitable C 1 -C 6 straight chain or branched chain alcohol in presence of a suitable catalyst to provide corresponding (S)-alkyl 5-oxopyrrolidine-2- carboxylate compound of general formula- 10,
• the fourth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-tert-butyl 3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula- 17, comprising of;
• the fifth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula- 15, comprising of;
• the sixth aspect of the present invention is to provide a process for the preparation of (1 S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-26 or its acid-addition salt, comprising of;
• the seventh aspect of the present invention is to provide an improved process for the preparation of (2S)-l-tert-butyl 2-alkyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of general formula-23, comprising of reducing the (S)-l-tert-butyl 2-alkyl 5- oxopyrrolidine-l,2-dicarboxylate compound of general formula- 11 with a suitable reducing agent in a suitable solvent to provide (2S)-l-tert-butyl 2-alkyl 5- hydroxypyrrolidine-l,2-dicarboxylate compound of general formula-23.
• the eighth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula- 1 , comprising of;
• the ninth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula- 1, comprising of;
• the eleventh aspect of the present invention is to provide a process for the preparation of compound of general formula-30, comprising of;
• the twelfth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;
• the thirteenth aspect of the present invention is to provide a process for the preparation of compound of general formula-40, comprising of;
• the fourteenth aspect of the present invention is to provide a process for the preparation of compound of general formula-43, comprising of;
• the fifteenth aspect of the present invention is to provide a process for the preparation of compound of general formula-42, comprising of;
• the sixteenth aspect of the present invention is to provide a process for the preparation of adamantyl aldehyde compound of formula-4 comprising oxidizing the adamantyl methanol compound of formula-3 with a suitable oxidizing agent optionally in presence of a suitable base or a suitable catalyst in a suitable solvent to provide adamantyl aldehyde compound of formula-4.
• the seventeenth aspect of the present invention is to provide a novel process for the preparation of compound of formula-28, comprising of;
• the eighteenth aspect of the present invention is to provide a novel process for the preparation of compound of formula-28, comprising of; a) Reacting the adamantyl bromide compound of formula-48 with (R)-2-isopropyl-3,6- dimethoxy-2,5-dihydropyrazine compound of formula-50 in presence of a suitable base in a suitable solvent to provide compound of formula-51 ,
• the nineteenth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-2-azabicyclo[3.1.0]hexan-3-ylmethanamine hydrochloride compound of fonnula-33, comprising of;
• the twentieth aspect of the present invention is to provide a process for the preparation of (1 S,3S,5S)-N-benzyl-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-35, comprising of;
• suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethylether, diethylether, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulphoxide, dioxane and the like; “nitrile solvents” such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; “chloro solvents” such as dichloromethane, dichlor
• suitable base refers to "alkali metal carbonates” such as sodium carbonate, potassium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; alkali meta amides such as sodium amide, potassium amide, lithium amide and the like, ammonia; and organic bases like dimethyl amine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4- dimethylaminopyridine (DMAP), N-
• 'Cbz' represents benzyloxycarbonyl group
• 'Boc' represents tert-butyloxycarbonyl group
• 'Bn' represents benzyl group
• 'R' represents C 1 -C 6 straight chain or branched chain alkyl group
• "Ri" represents -CH 3 or -CH 2 OH.
• the first aspect of the present invention provides an improved process for the preparation of adamantyl methanol comp of formula-3
• the suitable reducing agent is preferably sodium borohydride optionally in combination with BF 3 .etherate; and the suitable solvent is selected from ether solvents, ester solvents, alcoholic solvents, hydrocarbon solvents, polar solvents and/or their mixtures thereof; preferably ether solvents.
• a preferred embodiment of the present invention provides an improved process for the preparation of adamantyl methanol compound of formula-3 comprising of reducing the adamantane-l-carboxylic acid compound of formula-2 with sodium borohydride-BF 3 .etherate in tetrahydroiuran provides adamantyl methanol compound of formula-3.
• the second aspect of the present invention provides an improved process for the preparation of benzyloxycarbonyl protected amino hydroxy adamantane carboxylic acid compound of formula-27, comprising of;
• the suitable reducing agent is sodium borohydride optionally in combination with BF 3 .etherate; and the suitable solvent is selected from ether solvents, ester solvents, alcoholic solvents, hydrocarbon solvents, polar solvents and/or their mixtures thereof, preferably ether solvents;
• the suitable oxidizing agent is selected from oxalyl chloride/dimethyl sulfoxide, sodium hypochlorite or trichloroisocyanuric acid (TCICA) in presence of catalytic amount of TEMPO ((2,2,6,6-Tetramethyl-piperidin-l-yl)oxyl), pyridinium chlorochromate, oxone;
• the suitable base is selected from organic bases, preferably triethylamine;
• the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, polar-aprotic solvents and/or their mixtures thereof; preferably chloro solvents;
• the suitable solvent is selected from alcoholic solvents, chloro solvents, ester solvents, polar solvents and/or their mixtures thereof;
• the suitable acid is selected from cone. HC1, sulfuric acid; preferably cone. HC1; and the suitable solvent is selected from acetic acid and alcoholic solvents; preferably acetic acid;
• the suitable deprotecting agent is selected from Pd, Pd/C, Raney Ni, palladium acetate, platinum oxide, platinum black, Rh/C, Ru, Ir and the like in combination with hydrogen; preferably Pd/C; and the suitable acid is acetic acid; and the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, polar solvents and/or their mixtures thereof; preferably alcoholic solvents;
• the suitable base is selected from alkali metal carbonates and alkali metal bicarbonates
• the suitable solvent is selected from ether solvents, ester solvents, polar solvents and/or their mixtures thereof;
• the suitable hydroxylating agent is selected from potassium permanganate, H 2 S0 4 /HN0 3 ; preferably potassium permanganate;
• the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides and organic bases;
• the suitable solvent is selected from chloro solvents, nitrile solvents, ether solvents, polar solvents and/or their mixtures thereof.
• the third aspect of the present invention provides a process for the preparation of (1 S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15, comprising of;
• 'R' represents C 1 -C 6 straight chain or branched chain alkyl
• the suitable catalyst is selected from thionyl chloride, hydrochloric acid, cone, sulfuric acid, trifluoro acetic acid, methane sulfonic acid and the like;
• the suitable base is selected from organic bases like 4- dimethylaminopyridine (DMAP), triethylamine, diisopropylethyl amine and inorganic bases like alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates;
• the suitable solvent is selected from nitrile solvents, ketone solvents, chloro solvents, ether solvents, polar solvents and/or their mixtures thereof;
• the suitable amine source is selected from ammonia, formamide, ammonia gas, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartrate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate and alkyl or aryl amines; the suitable base can be
• the suitable reducing agent is selected from L-selectride, sodium borohydride, potassium borohydride, vitride, diisobutyl aluminium hydride, tetralkylammonium borohydride, calcium borohydride, zinc borohydride, sodium cyanoborohydride, lithium aluminium hydride and the like;
• the suitable solvent is selected form ether solvents, alcoholic solvents, ester solvents, nitrile solvents and/or their mixtures thereof;
• the suitable dehydrating agent is selected from acetic anhydride, trifluoro acetic anhydride (TFAA), trifluoroacetic acid, phthalic anhydride, phosphorous pentoxide, phosphoric acid, phosphoryl chloride in presence or absence of imidazole, phosphoric acid, polyphosphoric acid, sulfuric acid, dicyclohexyl carbodiimide; and the suitable base wherever necessary is selected from organic bases like triethylamine, diisopropyl amine, diisopropyl ethylamine, 4-dimethylamino pyridine (DMAP) and the like; and the suitable solvent is selected from ether solvents, ester solvents, hydrocarbon solvents and/or their mixtures thereof;
• the suitable methylene source is selected from dihalomethanes such as diiodomethane, chloro iodomethane; the suitable catalyst is diethyl zinc; and the suitable solvent is selected from hydrocarbon solvents, ether solvents, chloro solvents and/or their mixtures thereof.
• the fourth aspect of the present invention provides a process for the preparation of (lS,3S,5S)-tert-butyl 3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula- 17, comprising of;
• step-a) to step-f) of the fourth aspect are same as defined in step-a) to step-f) respectively of the third aspect of the present invention.
• the fifth aspect of the present invention provides a process for the preparation of (1 S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula- 15, comprising of;
• the suitable coupling agent is selected from ⁇ , ⁇ '- dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '-diisopropylcarbodiimide (DIC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i- BuCOCOCl), benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like optionally
• step-b) the suitable base and the suitable solvent are same as defined for step-b) of the third aspect of the present invention.
• step-c) the suitable reducing agent and the suitable solvent are same as defined for step-d) of the third aspect of the present invention.
• step-d) the suitable dehydrating agent, the suitable base and the suitable solvent are same as defined for step-e) of the third aspect of the present invention.
• step-e) the suitable methylene source, the suitable catalyst and the suitable solvent are same as defined for step-f) of the third aspect of the present invention.
• the suitable debenzylating agent is selected from cone. HC1, Pd, Pd/C, Raney Ni, palladium acetate, platinum oxide, platinum black, Rh/C, Ru, Ir and the like optionally in combination with hydrogen; the suitable acid is acetic acid; and the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents and/or their mixtures thereof.
• the sixth aspect of the present invention provides a process for the preparation of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-26 or its acid-addition salts, comprising of;
• step-a) the suitable catalyst is same as defined in step-a) of the third aspect of the present invention.
• step-b) the suitable base and suitable solvent are same as defined in step-b) of third aspect of the present invention.
• step-c) the suitable reducing agent and the suitable solvent are same as defined for step-d) of the third aspect of the present invention.
• step-d) the suitable dehydrating agent, the suitable base and the suitable solvent are same as defined for step-e) of the third aspect of the present invention.
• the suitable base is selected from alkali metal hydroxides; and the suitable solvent is selected from polar solvents, alcoholic solvents, ether solvents, hydrocarbon solvents and/or their mixtures thereof;
• the suitable base is selected from organic bases like diisopropyl amine, diisopropylethylamine, triethylamine and inorganic bases like hydroxides, alkoxides, carbonates and bicarbonates of alkali metals; and the suitable amine source is same as defined in step-c) of third aspect of the present invention;
• step-g) the suitable methylene source and suitable catalyst and suitable solvent are same as defined in step-f) of third aspect of the present invention.
• the suitable deprotecting agent can be selected from hydrochloric acid, acetyl chloride, methane sulfonic acid, trifluoroacetic acid; and the suitable solvent, is selected from ether solvents, ester solvents, hydrocarbon solvents, chloro solvents, alcoholic solvents and/or their mixtures thereof;
• the preferred embodiment of the present invention provides a process for the preparation of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-26a, comprising of;
• a suitable hydrochloric acid source such as cone.
• HC1, ethyl acetate-HCl, isopropyl acetate-HCl, methanolic HC1, ethanolic HC1, isopropanolic HC1 or acetyl chloride in presence of alcohol in a suitable solvent provides (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-26 or its hydrochloride salt.
• the seventh aspect of the present invention provides an improved process for the preparation of (2S)- l-tert-butyl 2-alkyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of general formula-23, comprising of reducing the (S)-l-tert-butyl 2-alkyl 5- oxopyrrolidine-l,2-dicarboxylate compound of general formula- 1 1 with a suitable reducing agent in a suitable solvent to provide (2S)-l-tert-butyl 2-alkyl 5- hydroxypyrrolidine-l,2-dicarboxylate compound of general formula-23.
• the suitable reducing agent is selected form sodium borohydride optionally in combination with BF 3 .etherate, L-selectride, diisobutyl aluminium hydride; preferably sodium borohydride;
• the suitable solvent is selected from hydrocarbon solvents, chloro solvents, alcoholic solvents, ether solvents, ester solvents, polar solvents and/or their mixtures thereof; preferably hydrocarbon solvents.
• a preferred embodiment of the present invention provides an improved process for the preparation of (2S)-l-tert-butyl 2-ehtyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of formula-23b, comprising of reducing the (S)-l-tert-butyl 2-ethyl 5- oxopyrrolidine-l,2-dicarboxylate compound of formula-l ib with sodium borohydride in methanol to provide (2S)-l-tert-butyl 2-ethyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of formula-23b.
• the compound of formula-27 obtained above can be further converted into
• the suitable coupling agent, dehydrating agent are same as defined in any of the above aspects and the suitable deprotecting agent is same as the debenzylating agents as defined above.
• the compounds obtained as per the present invention are the useful intermediates for the preparation of DPP-IV inhibitor i.e., (l S,3S,5S)-2-[(2S)-2-amino-2-(3- hydroxyadamantan- 1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and its pharmaceutically acceptable salts thereof.
• the eighth aspect of the present invention provides a process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile compound of formula-1, comprising of;
• step-a) to step-g) the suitable reagents, the suitable bases and the suitable solvents are same as defined for step-a) to step-g) of the second aspect of the present invention;
• step-h) the suitable coupling agent, the suitable base and the suitable solvent are same as defined for step-a) of the fifth aspect of the present invention.
• step-i) the suitable dehydrating agent and the suitable solvent are same as defined for step-e) of the third aspect of the present invention.
• the suitable deprotecting agent is selected from but not limited to acids such as hydrochloric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid and the like, bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates and hydrogenating agents such as Pd, Pd/C, Pd(OH) 2 /C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Raney-Ni, triethylsilane, TMSCl and the like; the suitable solvent is selected form ether solvents, hydrocarbon solvents, chloro solvents, polar- aprotic solvents, and/or their mixtures thereof.
• acids such as hydrochloric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid and the like
• bases such as alkali metal hydroxides, alkali
• the O-protecting group 'P' of the present invention can be selected from but not limited to tert.butoxycarbonyl (Boc), 3,4-dihydro-2H-pyran (DHP), tetrahydropyranyl (THP), acetyl, benzyl, benzoyl, trifluoroacetyl, pivaloyl, tri ⁇ -Ce alkyl)silyl (eg.,trimethylsilyl, triethylsilyl, tert.butyldimethylsilyl and the like), triphenylmethyl (trityl) groups and the like and it can be removed by treating the corresponding O- protected compound with a suitable acid or a suitable base or by hydrogenolysis depending on the nature of the protecting group employed.
• Boc tert.butoxycarbonyl
• DHP 3,4-dihydro-2H-pyran
• THP tetrahydropyranyl
• acetyl benzyl, be
• the preferred embodiment of the present invention provides a process for the preparation of ( 1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan- 1 -yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula- 1, comprising of;
• the ninth aspect of the present invention provides a process for the preparation of (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile compound of formula- 1, comprising of;
• step-a) deprotecting the compound of general formula-31 by treating it with a suitable deprotecting agent in a suitable solvent to provide (l S,3S,5S)-2-[(2S)-2-amino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula- 1.
• the suitable coupling agent, suitable base and the suitable solvent are same as defined for step-a) of the fifth aspect of the present invention;
• step-b) the suitable deprotecting agent and the suitable solvent are same as defined for step-j) of the eighth aspect of the present invention.
• the (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride salt compound of formula-32 utilized in the above condensation step-a) of the ninth aspect can be synthesized by dehydrating the (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamide compound of formula-26 obtained by the process as described above with a suitable dehydrating agent in presence of a suitable base in a suitable solvent, followed by converting the (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile free base into its hydrochloride salt.
• the suitable dehydrating agent, the suitable base and the suitable solvent are same as described for step-i) of the eighth aspect of the present invention.
• the tenth aspect of the present invention provides a process for the preparation of
• step-a) the suitable coupling agent, the suitable base and the suitable solvent used in step-a) are same as described for step-a) of the fifth aspect of the present invention.
• the suitable catalyst is selected from (2,2,6,6-tetramethylpiperidin-l- yl)oxyl (TEMPO), 4-hydroxy-TEMPO, 4-acetamido-TEMPO;
• the suitable base is selected from organic bases and ammonia;
• the suitable solvent is selected from chloro solvents, hydrocarbon solvents, polar-aprotic solvents and/or their mixtures thereof;
• the eleventh aspect of the present invention provides a process for the preparation of compound of general formula-30, comprising of;
• 'P' is hydrogen or O-protecting group as defined above;
• step-a) the suitable coupling agent, the suitable base and the suitable solvent used in step-a) are same as described for step-a) of the fifth aspect of the present invention.
• step-b) the suitable debenzylating agent and the suitable solvent are same as defined for step-f) of the fifth aspect of the present invention.
• the compound of general formula-30 obtained in the eleventh aspect of the present invention can be further converted to (lS,3S,5S)-2-[(2S)-2-amino-2-(3- hydroxyadamantan- 1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula- 1 according to the process disclosed in the eighth aspect of the present invention.
• the twelfth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- ; azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula- 1, comprising of;
• step-a) the suitable coupling agent, the suitable base and the suitable solvent are same as defined for step-h) of the eighth aspect of the present invention.
• the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents and/or their mixtures thereof;
• step-c) the suitable dehydrating agent, the suitable base and the suitable solvent are same as defined for step-i) of the eighth aspect of the present invention.
• the suitable reducing agent is selected from sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, lithium borohydride, Pd/C, Pt/C, PtO 2 , Raney Ni, sodium bis(2-methoxyethoxy)aluminum hydride (vitride), diisobutylaluminium hydride (DIBAL or DIBAL-H or DIBAH) and the like; and the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, alcoholic solvents and/or their mixtures thereof;
• step-e) the suitable deprotecting agent and the suitable solvent are same as defined for step-j) of the eighth aspect of the present invention.
• the compound of general formula-37 utilized in the condensation step-a) of the twelfth aspect can be synthesized by treating the corresponding hydroxy compound with a suitable protecting agent.
• the thirteenth aspect of the present invention is to provide a process for the preparation of compound of general formula-40, comprising of;
• the fourteenth aspect of the present invention provides a process for the preparation of compound of general formula-43, comprising of;
• step-a) and step-c) respectively of the thirteenth and fourteenth aspects are same as defined for step-a) of the fifth aspect of the present invention.
• the suitable solvent used in step-b) & step-a) respectively of the thirteenth and fourteenth aspects is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents and/or their mixtures thereof;
• step-c) & step-b) respectively of the thirteenth and fourteenth aspects are same as defined for step-d) of the twelfth aspect of the present invention.
• the suitable dehydrating agent, the suitable base and the suitable solvent used in step-d) of the thirteenth aspect are same as defined for step-e) of the third aspect of the present invention.
• the fifteenth aspect of the present invention provides a process for the preparation of compound of general formula-42, comprising of;
• the suitable solvent is selected form alcoholic solvents, chloro solvents, ether solvents, ester solvents, hydrocarbon solvents and/or their mixtures thereof;
• step-b) the suitable coupling agent, the suitable base and the suitable solvent are same as defined for step-a) of the fifth aspect of the present invention.
• the sixteenth aspect of the present invention is to provide a process for the preparation of adamantyl aldehyde compound of formula-4 comprising oxidizing the adamantyl methanol compound of formula-3 with a suitable oxidizing agent optionally in presence of a suitable base, or a suitable catalyst in a suitable solvent to provide adamantyl aldehyde compound of formula-4.
• the suitable oxidizing agent is selected from trichloroisocyanuric acid
• TCICA bis(acetoxy)iodo benzene
• BAIB bis(acetoxy)iodo benzene
• NCS N-chlorosuccinimide
• oxone pyridinium chlorochromate
• chromium trioxide chromium trioxide and the like
• the suitable catalyst wherever necessary is selected from (2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO), 4-hydroxy-TEMPO, 4-acetamido TEMPO and the like
• the suitable base wherever necessary is selected from organic bases
• the suitable solvent is selected from chloro solvents, hydrocarbon solvents, polar-aprotic solvents and/or their mixtures thereof;
• the seventeenth aspect of the present invention provides a novel process for the preparation of compound of formula-28, comprising of;
• step-a) the suitable base and the suitable solvent are same as defined for step-b) of the third aspect of the present invention.
• the suitable solvent is selected form hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents and/or their mixtures thereof;
• the suitable base is selected from organic bases and organosilicon bases; and the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents and/or their mixtures thereof;
• the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar- aprotic solvents and/or their mixtures thereof;
• the eighteenth aspect of the present invention provides a novel process for the preparation of compound of formula-28, comprising of;
• step-a) hydrolyzing compound of formula-63 in presence of a suitable base in a suitable solvent to provide compound of formula-28.
• the suitable base is selected from organic bases and organosilicon bases; and the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents and/or their mixtures thereof;
• the suitable acid is hydrochloric acid
• the suitable solvent is selected from ester solvents, ether solvents, chloro solvents, polar-aprotic solvents and/or their mixtures thereof;
• the suitable base is selected from organic and inorganic bases and, the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents and/or their mixtures thereof;
• the suitable base is selected from hydroxides, alkoxides, bicarbonates of alkali metals and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, alcohol solvents and/or their mixtures thereof;
• the (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine compound of formula- 50 utilized in step-a) of the eighteenth aspect of the present invention is commercially available or it can be synthesized by the methods known in the art for example Org. Process Res. Dev., 2005, 9(2), 185-187, Tetrahedron: Asymmetry 1998, 9, 321-327.
• the compounds of formulae-28 & 7 obtained in the seventeenth and eighteenth aspects respectively can be converted to (lS,3S,5S.)-2-[(2S)-2-amino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo [3.1.0]hexane-3-carbonitrile compound of formula- 1 as per the process disclosed in the eighth aspect of the present invention.
• the nineteenth aspect of the present invention provides a process for the preparation of (lS,3S,5S)-2-azabicyclo[3.1.0]hexan-3-ylmethanamine hydrochloride compound of formula-33, comprising of;
• the suitable reducing agent is selected from sodium borohydride-BF 3 .etherate, sodium cyanoborohydride, lithium aluminium hydride, lithium borohydride, borane-dimethyl sulfide, sodium bis(2-methoxyethoxy)aluminum hydride (vitride), diisobutyl aluminium hydride (DIBAL); and the suitable solvent is selected from alcoholic solvents, ether solvents, chloro solvents, hydrocarbon solvents, ester solvents and/or their mixtures thereof;
• the suitable base is selected from organic bases and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents and/or their mixtures thereof;
• the suitable azide source is selected from sodium azide, bis(p- nitrophenyl) phosphorazidate, azidotrimethylsilane, hydrogen azide (HN 3 ) and the like; and the suitable solvent is selected from ether solvents, chloro solvents, hydrocarbon solvents and/or their mixtures thereof;
• the suitable reducing agent is selected from sodium borohydride, lithium aluminium hydride, H2/Lindlar catalyst, Zn/NH 4 CI, dichloroindium hydride, Fe/AlCl 3 , Fe/BiCl 3 , triphenyl phosphine (Staudinger reaction), hydroiodic acid; and the suitable solvent is selected from alcoholic solvents, ether solvents, chloro solvents, hydrocarbon solvents, ester solvents and/or their mixtures thereof;
• the suitable methylene source is selected from dihalomethanes such as diiodomethane, chloroiodomethane and the suitable catalyst is diethyl zinc;
• the suitable solvent is selected from hydrocarbon solvents, ether solvents, chloro solvents and/or their mixtures thereof;
• the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents and/or their mixtures thereof.
• the twentieth aspect of the present invention provides a process for the preparation of (1 S,3S,5S)-N-benzyl-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-35, comprising of;
• step-a) the suitable coupling agent, the suitable base and the suitable solvent are same as defined for step-a) of the fifth aspect of the present invention.
• step-b) the suitable methylene source, the suitable catalyst and the suitable solvent are same as described for step-f) of the third aspect of the present invention.
• the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents and/or their mixtures thereof.
• the (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo [3.1.0]hexane-3-carbonitrile compound or its hydrochloride salt produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
• Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
• the present invention is schematically represented as follows.
• Example-1 Preparation of adamantyl methanol (FormuIa-3)
• Tetrahydrofuran (2000 ml) and sodium borohydride (63 gm) were charged in to a clean and dry RBF at 25-30°C under nitrogen atmosphere.
• the reaction mixture was cooled to 0-5°C and a solution of adamantane-l-carboxylic acid (250 gm) in tetrahydrofuran (1000 ml) was slowly added.
• Stirred the reaction mixture for 1 hr at 0- 5°C and BF 3 .etherate (280 ml) was slowly added to it at the same temperature. Heated the reaction mixture to 25-35°C and stirred for 7 hrs at the same temperature.
• reaction mixture was cooled to 0-5°C and water (2000 ml) was slowly added at the same temperature.
• Conc.HCl 150 ml
• dichloromethane 2000 ml
• Both the organic and aqueous layers were separated, dichloromethane (1000 ml) was added to the aqueous layer and stirred for 30 min. Separated the organic and aqueous layers and a solution of sodium bicarbonate (100 gm) in water (1000 ml) was added to the total organic layer.
• Example-2 Purification of adamantyl methanol
• Pet ether (250 ml) and adamantyl methanol obtained in above example-1 were charged in to a clean and dry RBF at 25-35°C and the resulting reaction mixture was stirred for 2 hrs at the same temperature. The obtained solid was filtered, washed with pet ether and then dried at 50-55°C to get the title compound as a pure solid.
• Example-5 Purification of phenylglycinol adamantane nitrile compound of formula-5a
• Phenylglycinol adamantane nitrile compound of formula-5a (207 gm) and cyclohexane (750 ml) were charged in to a clean and dry RBF at 25-35°C and stirred for 3 hrs at the same temperature. The obtained compound was filtered, washed with cyclohexane and then dried to get the title compound as a pure solid.
• Example-6 Preparation of phenylglycinol adamantane carboxylic acid compound of formula-6a
• Phenylglycinol adamantane nitrile compound of formula-5a 150 gm
• acetic acid 450 ml
• cone. HC1 (750 ml) were charged in to a clean and dry RBF at 25-35°C.
• the reaction mixture was heated to 80-85°C and stirred for 12 hrs at the same temperature. After the completion of the reaction, the reaction mixture was completely distilled off at 80-85°C. Cooled the reaction mixture to 0-5°C and water (750 ml) was added and stirred for 2 hrs at the same temperature. The obtained solid was filtered, washed with water and then dried to get the title compound as hydrochloride salt. Yield: 130 gm.
• Potassium hydroxide (4.0 gm) was added to a solution of benzyloxycarbonyl protected amino adamantane carboxylic acid compound of formula-8 (10 gm) in water (100 ml) at 25-30°C.
• the reaction mixture was cooled to 0-5°C and solid potassium permanganate (9.5 gm) was added at the same temperature. Heated the reaction mixture to 25-30°C and stirred at the same temperature up to the completion of the reaction. Cooled the reaction mixture to 0-5°C and methyl tert.butyl ether (50 ml) was slowly added.
• the pH of the reaction mixture was adjusted to 3 by adding 2N HC1 solution.
• Amino adamantane carboxylic acid compound of formula-7 (10 gm) and water (150 ml) were charged into a clean and dry RBF at 25-30°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 15-20°C and sodium bicarbonate (10 gm) was slowly added for 3 hrs. Slowly added benzyl chloroformate (19.5 gm, 50% solution in toluene) to the reaction mixture at 15-20°C and stirred for 24 hrs at 20-25°C. After completion of the reaction, filtered the reaction mixture and both the organic and aqueous layers were separated from the filtrate. Washed the aqueous layer with cyclohexane, cooled to 0-5°C.
• Dichloromethane was added to the aqueous layer at 0-5°C. Adjusted the pH of the reaction mixture to below 1.5 using 5% aq.HCl at 0-5°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated, extracted the aqueous layer with dichloromethane and distilled off the solvent completely from the organic layer to get the title compound.
• Example-11 Preparation of (S)-ethyl 5-oxopyrrolidine-2-carboxylate (Formula-10b) Thionyl chloride (67.9 ml) was slowly added to a pre-cooled solution of (S)-5- oxopyrrolidine-2-carboxylic acid compound of formula-9 (100 gm) in ethanol (200 ml) at 0-5 °C and stirred for 3 hrs at the same temperature. Distilled the reaction mixture at below 40°C under reduced pressure and then cooled to 25-30°C. Dichloromethane (1000 ml) followed by water (200 ml) were added to the reaction mixture and stirred for 15 min at the same temperature.
• Example-12 Preparation of (S)-methyl 5-oxopyrrolidine-2-carboxylate (Formula- 10a) The title compound is prepared by the process described in example-1 1, using methanol instead of ethanol for the esterification step.
• Pet ether 100 ml was added to the obtained solid and heated the reaction mixture to 35- 40°C and stirred for 20 min at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure, pet ether (300 ml) was added to the obtained compound and stirred for 10 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with pet ether and then dried to get the title compound.
• the title compound is prepared by the process described in example-13, using (S)-methyl 5-oxopyrrolidine-2-carboxylate (Formula- 10a) instead of (S)-ethyl 5- oxopyrrolidine-2-carboxylate (Formula- 10b) as a starting material.
• Diisopropylethyl amine (9.8 gm) was slowly added to (2S)-tert-butyl 2- carbamoyl-5-hydroxypyrrolidine-l-carboxylate compound of formula-13 (3.5 gm) in tetrahydrofuran (45 ml) at -65°C to -75°C and stirred for 20 min at the same temperature.
• Trifluoroacetic anhydride (4.7 gm) was slowly added to the reaction mixture at -65°C to - 75°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 20-25°C and stirred for 3 hrs at the same temperature. Add water to the reaction mixture and followed by ethyl acetate.
• 2-carbamoyl-5-hydroxypyrrolidine-l-carboxylate compound of formula- 13 (5 gm) in tetrahydrofuran (65 ml) at -65°C to -75°C and stirred for 20 min at the same temperature.
• Trifluoroacetic anhydride (10 gm) was slowly added to the reaction mixture at -65°C to - 75°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 20-25°C and stirred for 3 hrs at the same temperature.
• Diisopropylethyl amine (10 gm) was slowly added to a solution of (2S)-tert-butyl 2-(benzylcarbamoyl)-5-hydroxypyiTolidine-l-carboxylate compound of formula-20 (5 gm) in tetrahydrofuran (60 ml) at -65°C to -75°C and stirred for 20 min at the same temperature.
• Trifluoroacetic anhydride (4.9 gm) was slowly added to the reaction mixture at -65°C to -75°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 20-25°C and stirred for 3 hrs at the same temperature.
• Diisopropylethyl amine 250 gm was slowly added to a solution of (2S)-1 -tert- butyl 2-ethyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of formula-23b obtained in example-27 in tetrahydrofuran (1000 ml) at -65°C to -75°C and stirred for 20 min at the same temperature.
• Trifluoroacetic anhydride 122 gm was slowly added to the reaction mixture at -65°C to -75°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 20-25°C and stirred for 3 hrs at the same temperature.
• Diisopropylethyl amine 150 gm was slowly added to the organic layer obtained in example-29 at -15°C to -20°C under nitrogen atmosphere.
• Methanesulfonyl chloride (66.7 gm) was added to the reaction mixture at -15°C to -20°C and stirred for 3 hrs at the same temperature.
• Expel the reaction mixture using N 2 gas to the reaction mixture for 2-3 hrs at 0-5°C.
• Sodium bicarbonate solution was slowly added to the reaction mixture at 0-5°C and stirred for 45 min at the same temperature.
• Both the organic and aqueous layers were separated and extracted the aqueous layer with toluene. Both the organic layers were combined and distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with cyclohexane. Toluene (50 ml) was added to the obtained compound and stirred for 60 min. at 25-30°C. Cyclohexane (300 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with cyclohexane and dried to get the title compound.
• Diisopropyl ethyl amine 250 gm was slowly added to a solution of (2S)-l-tert- butyl 2-ethyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of formula-23b obtained in example-27 in tetrahydrofuran (1000 ml) at -65°C to -75°C and stirred for 20 min at the same temperature.
• Trifluoroacetic anhydride 122 gm was slowly added to the reaction mixture at -65°C to -75°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 20-25°C and stirred for 3 hrs at the same temperature.
• aq.lithium hydroxide solution (79.2 gm of LiOH in 400 ml of water) was slowly added and stirred for 30 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Water (500 ml) followed by methyl tert.butyl ether (800 ml) were added to the reaction mixture at 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was washed with methyl tert.butyl ether.
• Toluene 1000 ml was added to the aqueous layer at 25-30°C and cooled the reaction mixture to 0-5°C. Adjusted the pH of the aqueous layer to 3.5 using orthophosphoric acid at 0-5°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with toluene. The combined organic layers were washed with 10% sodium chloride solution and dried over sodium sulfate.
• Trifluoroacetic anhydride (9.0 gm) was slowly added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature.
• Another 2.0 gm of 2,6-lutidine and 1.8 gm of trifluoroacetic anhydride were slowly added to the reaction mixture at 0-5 °C and stirred for 60 min at the same temperature.
• Example-35 Purification of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula- 1
• Lithium hydroxide hydrate (0.17 gm) was added to a solution of compound of formula-52 (0.5 gm) in methanol (3 ml) and water (2 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 7 hrs at the same temperature. Water (10 ml) and methyl tert.butyl ether (5 ml) were added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated, dichloromethane (15 ml) was added to the aqueous layer at 0-5°C. Adjusted the pH of the reaction mixture to 3.0 using phosphoric acid.
• Lithium hydroxide hydrate (0.1 gm) was added to a solution of compound of formula-63 (0.5 gm) in methanol (3 ml) and water (2 ml) at 0-5°C. Raised the temperature of. the reaction mixture to 25-30°C and stirred for 7 firs at the same temperature. Water (10 ml) and methyl tert.butyl ether (5 ml) were added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated, dichloromethane (15 ml) was added to the aqueous layer at 0-5°C. Adjusted the pH of the reaction mixture to 3.0 using phosphoric acid. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with 10% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get title compound.
• Hydrochloride salt compound of formula-7 (100 gm) was added to a mixture of water (1000 ml) and sodium carbonate (108 gm) at 25-30°C.
• Di-tert.butyl dicarbonate (134 gm) was slowly added to the reaction mixture at 25-30°C and stirred for 22 hrs at the same temperature.
• ethyl acetate was added to the reaction mixture at 25-30°C and cooled the reaction mixture to 0-5°C. Adjusted the pH of the reaction mixture to 3.5 using aqueous hydrochloric acid solution at 0-5°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate.
• Methyl isobutyl ketone was added to the reaction mixture at 0-5°C and stirred for 45 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water followed by methyl isobutyl ketone. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with ethyl acetate. 150 ml of ethyl acetate was added to the obtained solid, heated the reaction mixture to 60-65°C and stirred for 60 min at the same temperature. Reduced the temperature of the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 56.0 gm.
• Example-42 Purification of compound of formu!a-29a
• the obtained solid was kept aside and hydroxybenzotriazole (60 gm) was added to a solution of adamantyl compound of formula-29a (135 gm) in acetonitrile (425 ml) and ethyl acetate (200 ml) in another RBF at 0-5°C and stirred for 10 min at the same temperature.
• N,N'-Dicyclohexylcarbodiimide (109.5 gm) was added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature.
• diisopropylethyl amine (237 gm) were slowly added at 0-5°C and stirred for 5 hrs at the same temperature.
• Trifluoroacetic acetic anhydride (121.5 gm) was slowly added to a mixture of amide compound of formula-30a (100 gm), ethyl acetate (1000 ml) and 2,6-lutidine (99 gm) at 0-5°C and stirred for 60 min at the same temperature.
• Another 25 gm of 2,6- lutidine and 24 gm of trifluoroacetic anhydride were slowly added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. Quenched the reaction mixture with water at below 10°C and slowly raised the temperature of the reaction mixture 25- 30°C and stirred for 30 min at the same temperature.
• Both the organic and aqueous layers were separated and water was added to the organic layer. Cooled the reaction mixture to 5-10°C and the pH of the reaction mixture was slowly adjusted to 2.5 using hydrochloric acid. Both the organic and aqueous layers were separated. Potassium carbonate solution followed by methanol (300 ml) were added to the reaction mixture at 10-15°C and stirred for 10 min at the same temperature. Raised the temperature of the reaction mixture to 25- 30°C and stirred for 3 hrs at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 10% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure.
• Acetyl chloride (57 gm) was slowly added to a solution of compound of formula- 31a (100 gm) in methanol (400 ml) at 0-5 °C and stirred for 10 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 10-15°C. Water (1000 ml) was slowly added to the reaction mixture at 10-15°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C, dichloromethane (300 ml) was added and stirred for 20 min at the same temperature.
• Acetyl chloride 60 gm was slowly added to a solution of compound of formula- 31a (100 gm) in methanol (400 ml) at 0-5°C and stirred for 10 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid to get the title compound. Yield: 70 grams; Purity by HPLC: 99.98%;
• D(0.1) is 1.30 ⁇ ; D(0.5) is 8.98 ⁇ ; D(0.9) is 48.67 ⁇ , D(4,3) is 18.05 ⁇ .

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