Field of the invention:

The present invention relates to a process for the preparation of intermediate compounds used 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 represented by the structural formula

and its pharmaceutically acceptable salts thereof. Background of the invention:

(1 S,3 S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.

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-1-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. 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 bicarbonate 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-ethyl-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 process disclosed in US6395767 B2 has certain disadvantages in that the process involves the usage of trimethylsilyl diazomethane for the etherification of adamantane-1-carboxylic acid, which is a neurological hazard and extremely toxic reagent.

The above disclosed process also involves the usage of lithium aluminum hydride for the reduction of adamantane-1-carboxylic acid methyl ester, which is hygroscopic and highly reactive. Hence it is not suggestible to use it on industrial scale.

Hence there is a need in the art to develop a simple, safe, industrially and commercially viable process for the synthesis of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile to avoid the problems associated with prior-art.

Brief Description of the Invention:

The first aspect of the present invention is to provide an improved process for the preparation of adamantly methanol compound of formula-3, comprising of reducing the adamantane-1-carboxylic acid compound of formula-2 with a suitable reducing agent in a suitable solvent to provide adamantly methanol compound of formula-3.

The second aspect of the present invention is to provide a process for the preparation of benzyloxycarbonyl protected amino hydroxyl adamantine carboxylic acid compound of formula-1, comprising of;

a) Reducing the adamantane-1-carboxylic acid compound of formula-2 with a suitable reducing agent in a suitable solvent to provide adamantly methanol compound of formula-3,

b) oxidizing the compound of formula-3 with a suitable oxidizing agent optionally in presence of a suitable base in a suitable solvent to provide adamantly aldehyde compound of formula-4,

c) treating the compound of formula-4 in-situ with a suitable alkali metal cyanide in presence of sodium bisulfate in a suitable solvent followed by treating with R-(-)-2-phenylglycinol in a suitable solvent to provide phenylglycinol adamantane nitride compound of formula-5,

d) hydrolyzing the canoe compound of formula-5 in presence of a suitable acid in a suitable solvent to provide its corresponding phenylglycinol adamantine carboxylic acid compound of formula-6 or its acid-addition salt,

e) deprotecting the compound of formula-6 or its acid-addition salt by treating it with a suitable deprotecting agent in presence of an acid in a suitable solvent to provide amino adamantine carboxylic acid compound of formula-7 or its acid-addition salt,

f) treating the compound of formula-7 or its acid-addition salt with benzyl chloroform ate in presence of a suitable base in a suitable solvent to provide benzyloxycarbonyl protected amino adamantane carboxylic acid compound of formula-8,

g) hydroxylating the compound of formula-8 by treating it with a suitable hydroxylation agent in presence of a suitable base in a suitable solvent to provide benzyloxycarbonyl protected amino hydroxy adamantane carboxylic acid compound of formula-1.

The third aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-tart-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 C1-C6 alcohol in presence of a suitable catalyst to provide corresponding (S)-alkyl 5-oxopyrrolidine-2-carboxylate compound of general formula-10,

b) treating the compound of general formula-10 with di-tert.butyl bicarbonate in presence of a suitable base in a suitable solvent to provide (S)-l-tert-butyl 2-alkyl 5-oxopyrrolidine-l,2-dicarboxylate compound of general formula-11,

c) admiration of compound of general formula-11 by treating it with a suitable amine source optionally in presence of a suitable base in a suitable solvent to provide (S)-tert-butyl 2-carbamoyl-5-oxopyrrolidine-l-carboxylate compound of formula-12,

d) reducing the compound of formula-12 with a suitable reducing agent in a suitable solvent to provide (2S)-term-butyl 2-carbamoyl-5-hydroxypyrrolidine-l-carboxylate compound of formula-13,

e) dehydrating the compound of formula-13 by treating it with a suitable dehydrating agent in presence or absence of a suitable base in a suitable solvent to provide (S)-term-butyl 2-carbamoyl-2,3 -dihydro-1 H-pyrrole-1 -carboxyl ate compound of formula-14,

f) converting the compound of formula-14 in to (lS,3S,5S)-term-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15 by treating it with a suitable methylene source in presence of a suitable catalyst in a suitable solvent.

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;

a) Esterification of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 by treating it with a suitable C1-C6 alcohol in presence of a suitable catalyst to provide corresponding (S)-alkyl 5-oxopyrrolidine-2-carboxylate compound of general formula-10,

b) treating the compound of general formula-10 with di-tert.butyl bicarbonate in presence of a suitable base in a suitable solvent to provide (S)-l-term-butyl 2-alkyl 5-oxopyrrolidine-l,2-dicarboxylate compound of general formula-11,

c) amidation of compound of general formula-11 by treating it with a suitable amine source optionally in presence of a suitable base in a suitable solvent to provide (S)-term-butyl 2-carbamoyl-5-oxopyrrolidine-l-carboxylate compound of formula-12,

d) reducing the compound of formula-12 with a suitable reducing agent in a suitable solvent to provide (2S)-term-butyl 2-carbamoyl-5-hydroxypyrrolidine-l-carboxylate compound of formula-13,

e) dehydrating the compound of formula-13 with a suitable dehydrating agent in presence or absence of a suitable base in a suitable solvent to provide (S)-term-butyl 2-cyano-2,3-dihydro-lH-pyrrole-1-carboxylate compound of formula-16,

f) converting the compound of formula-16 into (lS,3S,5S)-term-butyl 3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-17 by treating it with a suitable ethylene source in presence of a suitable catalyst in a suitable solvent.

The fifth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-term-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15, comprising of;

a) Admiration of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 by treating it with benzyl amine in presence of a suitable coupling agent optionally in presence of a suitable base in a suitable solvent to provide (S)-N-benzyl-5-oxopyrrolidine-2-carboxamide compound of formula-18,

b) treating the compound of formula-18 with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide (S)-term-butyl 2-(benzylcarbamoyl)-5-oxopyrrolidine-l-carboxylate compound of formula-19,

c) reducing the compound of formula-19 with a suitable reducing agent in a suitable solvent to provide (2S)-term-butyl 2-(benzylcarbamoyl)-5-hydroxypyrrolidine-l-carboxylate compound of formula-20,

d) dehydrating the compound of formula-20 by treating it with a suitable dehydrating agent in presence or absence of a base in a suitable solvent to provide (S)-term-butyl 2-(benzylcarbamoyl)-2,3-dihydro-1 H-pyrrole-1 -carboxylate compound of formula-21,

e) converting the compound of formula-21 into (lS,3S,5S)-tert-butyl 3-(benzylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-22 by treating it with a suitable ethylene source in presence of a suitable catalyst in a suitable solvent,

f) debenzylating the compound of formula-22 by treating it with a suitable debenzylating agent optionally in presence of a suitable acid in a suitable solvent to provide (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15.

The sixth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide acid-addition salt compound of general formula-26, comprising of;

a) Etherification of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 by treating it with a suitable C1-Cg alcohol in presence of a suitable catalyst to provide corresponding (S)-alkyl 5-oxopyrrolidine-2-carboxylate compound of general formula-10,

b) treating the compound of general formula-10 with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide (S)-l-tert-butyl 2-alkyl 5-oxopyrrolidine-l,2-dicarboxylate compound of general formula-11,

c) reducing the compound of general formula-11 with a suitable reducing agent in a suitable solvent to provide (2S)-l-term-butyl 2-alkyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of general formula-23,

d) dehydrating the compound of general formula-23 by treating it with a suitable dehydrating agent in presence of a suitable base in a suitable solvent to provide (S)-l-term-butyl 2-alkyl 2,3-dihydro-l H-pyrrole-1,2-dicarboxylate compound of general formula-24,

e) hydrolyzing the compound of general formula-24 in-situ in presence of a suitable base in a suitable solvent to provide (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2-carboxylic acid compound of formula-25,

f) treating the compound of formula-25 in-situ with methane sulfonyl chloride in presence of a suitable base followed by in-situ treating the obtained compound with a suitable amine source to provide (S)-term-butyl 2-carbamoyl-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-14, g) optionally isolating the compound of formula-14, converting the compound of formula-14 into (lS,3S,5S)-term-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15 by treating it with a suitable ethylene source in presence of a suitable catalyst in a suitable solvent, h) deprotecting the compound of formula-15 by treating it with a suitable deprotecting agent in a suitable solvent to provide (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-26 or its acid-addition salt.

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.

Detailed description of the invention:

The term "suitable solvent" used in the present invention 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, dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulphoxide and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like; "polar solvents" such as water; and/or their mixtures thereof.

The term "suitable base" used in the present invention 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 meth oxide, potassium tert.butoxide and the like; and organic bases like diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, N-methyl morpholine (NMM), lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and/or their mixtures thereof.

As used herein the present invention 'Cbz' represents benzyloxycarbonyl group, 'Boc' represents tert-butyloxycarbonyl group, 'Bn' represents benzyl group, 'R' represents Q-C6 straight chain or branched chain alkyl group.

The first aspect of the present invention provides an improved process for the preparation of adamantvl methanol comoound of formula-3 comprising of reducing the adamantane-1-carboxylic acid compound of formula-2 with a suitable reducing agent in a suitable solvent provides adamantyl methanol compound of formula-3.

Wherein, the suitable reducing agent is preferably sodium borohydride-BF3.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-1-carboxylic acid compound of formula-2 with sodium borohydride-BF3.etherate in

tetrahydrofuran 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-1, comprising of;

a) Reducing the adamantane-1-carboxylic acid compound of formula-2 with a suitable reducing agent in a suitable solvent to provide adamantyl methanol compound of formula-3,

b) oxidizing the compound of formula-3 with a suitable oxidizing agent optionally in presence of suitable base in a suitable solvent to provide adamantyl aldehyde compound of formula-4,

c) treating the compound of formula-4 in-situ with a suitable alkali metal cyanide in presence of sodium bisulfite in a suitable solvent followed by treating with R-(-)-2-phenylglycinol in a suitable solvent to provide phenylglycinol adamantane nitrile compound of formula-5,

d) hydrolyzing the compound of formula-5 in presence of a suitable acid in a suitable solvent to provide phenylglycinol adamantane carboxylic acid compound of formula-6 or its acid-addition salt,

e) deprotecting the compound of formula-6 or its acid-addition salt by treating it with a suitable deprotecting agent in presence of an acid in a suitable solvent to provide amino adamantine carboxylic acid compound of formula-7 or its acid-addition salt,

Formula-7 f) treating the compound of formula-7 or its acid-addition salt with benzyl chloroformate in presence of a suitable base in a suitable solvent to provide benzyloxycarbonyl protected amino adamantane carboxylic acid compound of formula-8,

g) hydroxylating the compound of formula-8 with a suitable hydroxylating agent in presence of a suitable base in a suitable solvent to provide benzyloxycarbonyl protected amino hydroxy adamantane carboxylic acid compound of formula-1.

Wherein, in step-a) the suitable reducing agent is sodium borohydride-BF3.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;

in step-b) the suitable oxidizing agent is selected from oxalyl chloride/dimethyl sulfoxide; sodium hypochlorite, trichloroisocyanuric acid in presence of catalytic amount of TEMPO ((2,2,6,6-tetramethyl-piperidin-l-yl)oxyl), pyridinium chlorochromate; and the suitable base is selected from organic bases, preferably triethylamine; and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, polar-aprotic solvents and/or their mixtures thereof; preferably chloro solvents; in step-c) the suitable solvent is selected from alcoholic solvents, chloro solvents, ester solvents, polar solvents and/or their mixtures thereof; In place of sodium bisulfite, sodium meta bisulfite is also used.

in step-d) the suitable acid is selected from conc.HCl, sulfuric acid; preferably cone. HC1; and the suitable solvent is selected from acetic acid and alcoholic solvents; preferably acetic acid;

in step-e) 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, chloral solvents, hydrocarbon solvents, polar solvents and/or their mixtures thereof; preferably alcoholic solvents;

in step-f) the suitable base is selected from alkali metal carbonates and alkali metal bicarbonates; and the suitable solvent is selected from ether solvents, ester solvents, polar solvents and/or their mixtures thereof;

in step-g) the suitable hydroxylation agent is preferably potassium permanganate; and the suitable base is selected from alkali metal hydroxides, alkali metal lakesides and organic bases; and the suitable solvent is selected from chloral solvents, nitride solvents, ether solvents, polar solvents and/or their mixtures thereof.

The third aspect of the present invention provides a process for the preparation of (lS,3S,5S)-term-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15, comprising of; a) Etherification of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9
by treating it with a suitable C1-C6 alcohol in presence of a suitable catalyst to provide corresponding (S)-alkyl 5-oxopyrrolidine-2-carboxylate compound of general formula-10,

wherein, 'R' represents Q-C6 straight chain or branched chain alkyl; b) treating the compound of general formula-10 with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide (S)-l-tert-butyl 2-alkyl 5-oxopyrrolidine-l,2-dicarboxylate compound of general formula-11,

c) amidation of compound of general formula-11 by treating it with a suitable amine source optionally in presence of a suitable base in a suitable solvent to provide (S)-term-butyl 2- carbamoyl-5-oxopyrrolidine-l-carboxylate compound of formula-12,

d) reducing the compound of formula-12 with a suitable reducing agent in a suitable solvent to provide (2S)-tert-butyl 2-carbamoyl-5-hydroxypyrrolidine-l-carboxylate compound of formula-13,
e) dehydrating the compound of formula-13 by treating it with a suitable dehydrating agent in presence or absence of a suitable base in a suitable solvent to provide (S)-term-butyl 2-carbamoyl-2,3 -dihydro-1 H-pyrrole-1 -carboxylate compound of formula-14,

f) converting the compound of formula-14 into (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15 by treating it with a suitable methylene source in presence of a suitable catalyst in a suitable solvent.

Wherein, in step-a) the suitable catalyst is selected from thionyl chloride, hydrochloric acid, cone, sulfuric acid, trifluoro acetic acid, methane sulfonic acid and the like;

In step-b) 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; and the suitable solvent is selected from nitrile solvents, ketone solvents, chloro solvents, ether solvents, polar solvents and/or their mixtures thereof;

In step-c) 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 selected from inorganic bases; and the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents, polar solvents and/or their mixtures thereof;

In step-d) 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, and lithium aluminium hydride and the like; and the suitable solvent is selected form ether solvents, alcoholic solvents, ester solvents, nitrile solvents and/or their mixtures thereof;

In step-e) the suitable dehydrating agent is selected from acetic anhydride, trifluoro acetic anhydride (TFAA), trifluoroacetic acid, phosphorous pentoxide, phosphoryl chloride, phosphoric acid, sulfuric acid, dicyclohexyl carbodiimide; the suitable base 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;

In step-f) the suitable methylene source is diiodomethane, chloro iodomethane and 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;

a) Esterification of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 by treating it with a suitable C1-C6 alcohol in presence of a suitable catalyst to provide corresponding (S)-alkyl 5-oxopyrrolidine-2-carboxylate compound of general formula-10,

b) treating the compound of general formula-10 with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide (S)-l-term-butyl 2-alkyl 5-oxopyrrolidine-l,2-dicarboxylate compound of general formula-11,

c) amidation of compound of general formula-11 by treating it with a suitable amine source optionally in presence of a suitable base in a suitable solvent to provide (S)-tert-butyl 2-carbamoyl-5-oxopyrrolidine-l-carboxylate compound of formula-12,

d) reducing the compound of formula-12 with a suitable reducing agent in a suitable solvent to provide (2S)-term-butyl 2-carbamoyl-5-hydroxypyrrolidine-l-carboxylate compound of formula-13,

e) dehydrating the compound of formula-13 with a suitable dehydrating agent in presence or absence of a suitable base in a suitable solvent to provide (S)-term-butyl 2-cyano-2,3-dihydro-lH-pyrrole-1-carboxylate compound of formula-16,

f) converting the compound of formula-16 into (lS,3S,5S)-term-butyl 3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-17 by treating it with a suitable methylene source in presence of a suitable catalyst in a suitable solvent.

Wherein, the solvents, bases, catalysts, reagents used in 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 (lS,3S,5S)-term-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15, comprising of;

a) Admiration of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 by treating with benzyl amine in presence of a suitable coupling agent optionally in presence of a suitable base in a suitable solvent to provide (S)-N-benzyl-5-oxopyrrolidine-2-carboxamide compound of formula-18,

b) treating the compound of formula-18 with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide (S)-tert-butyl 2-(benzylcarbamoyl)-5-oxopyrrolidine-l-carboxylate compound of formula-19,

c) reducing the compound of formula-19 with a suitable reducing agent in a suitable solvent to provide (2S)-tert-butyl 2-(benzylcarbamoyl)-5-hydroxypyrrolidine-l-carboxylate compound of formula-20,

d) dehydrating the compound of formula-20 by treating it with a suitable dehydrating agent in presence or absence of a suitable base in a suitable solvent to provide (S)-tert-butyl 2-(benzylcarbamoyl)-2,3-dihydro-1 H-pyrrole-1 -carboxylate compound of formula-21,

e) converting the compound of formula-21 into (lS,3S,5S)-tert-butyl 3-(benzylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-22 by treating it with a suitable methylene source in presence of a suitable catalyst in a suitable solvent,

f) debenzylating the compound of formula-22 by treating with a suitable debenzylating agent optionally in presence of a suitable acid in a suitable solvent to provide (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0] hexane-2-carboxylate compound of formula-15.

Wherein, in step-a) the suitable coupling agent is selected from N,N'- dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide, 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 and the like optionally in combination with l-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), 4-dimethylaminopyridine (DMAP); the suitable base can be selected from organic or inorganic bases; the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents and/or their mixtures thereof;

In step-b) the suitable base and the suitable solvent are same as defined for step-b) of the third aspect of the present invention;

In step-c) the suitable reducing agent and the suitable solvents are same as defined for step-d) of the third aspect of the present invention;

In 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;

In step-e) the suitable ethylene source, the suitable catalyst and the suitable solvent are same as defined for step-f) of the third aspect of the present invention;

In step-f) the suitable debenzylating 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, cone. HC1; 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 acid-addition salt compound of general formula-26, comprising of;

a) Esterification of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 by treating it with a suitable C1-C6 alcohol in presence of a suitable catalyst to provide corresponding (S)-alkyl 5-oxopyrrolidine-2-carboxylate compound of general formula-10,

b) treating the compound of general formula-10 with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide (S)-l-tert-butyl 2-alkyl 5-oxopyrrolidine-l,2-dicarboxylate compound of general formula-11,

c) reducing the compound of general formula-11 with a suitable reducing agent in a suitable solvent provides (2S)-l-tert-butyl 2-alkyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of general formula-23,

wherein, 'R' is as defined above; d) dehydration of compound of general formula-23 by treating it with a suitable dehydrating agent in presence of a suitable base in a suitable solvent to provide (S)-l-tert-butyl 2-alkyl 2,3-dihydro-lH-pyrrole-l,2-dicarboxylate compound of general formula-24,

e) hydrolyzing the compound of general formula-24 in-situ in presence of a suitable base in a suitable solvent provides (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2-carboxylic acid compound of formula-25,

f) treating the compound of formula-25 in-situ with methane sulfonyl chloride in presence of a suitable base followed by in-situ treating the obtained compound with a suitable amine source provides (S)-tert-butyl 2-carbamoyl-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-14,

g) optionally isolating the compound of formula-14, converting it into (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15 by treating it with a suitable methylene source in presence of a suitable catalyst in a suitable solvent,

h) deprotecting the compound of formula-15 by treating it with a suitable deprotecting agent in a suitable solvent provides (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-26 or its acid-addition salt.

Wherein, in step-a) the suitable catalyst is same as defined in step-a) of third aspect of the present invention;

In step-b) the suitable base and suitable solvent are same as defined in step-b) of third aspect of the present invention;

In step-c) the suitable reducing agent and the suitable solvents are same as defined for step-d) of the third aspect of the present invention;

In 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;

In step-e) 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;

In step-f) 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;

In 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;

In step-h) 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 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-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.

Wherein, the suitable reducing agent is selected form sodium borohydride, L-selectride, diisobutyl aluminium hydride; and 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-ethyl 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-lib with sodium borohydride in methanol to provide (2S)-1-tert-butyl 2-ethyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of formula-23b.

The compound of formula-1 obtained above can be further converted into (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile by coupling it with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-26 or its acid-addition salt in presence of a suitable coupling agent followed by dehydration using a suitable dehydrating agent and subsequently deprotection using suitable deprotecting agent provides (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile. The suitable coupling agent and the suitable dehydrating agent are same as defined in any of the above aspects and the suitable deprotecting agent is selected from cone. HC1, Pd, Pd/C, Raney Ni, optionally in combination with hydrogen and optionally in presence of a suitable acid agents. The compound (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile obtained in the present invention is in the form of monohydrate.

The compounds obtained as per the present invention are the useful intermediates for the preparation of DPP-IV inhibitor i.e., (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile and its pharmaceutically acceptable salts thereof.

The (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo .1.0]hexane-3-carbonitrile and its hydrochloride salt obtained by the present invention are treated with ethylene glycol, 1,3-propane diol optionally in presence of water they were ended with corresponding ethylene glycol solvate or 1,3-propane diol solvate forms.

The (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- abicyclo[3.1.0]hexane-3-carbonitrile and its hydrochloride salt of the present invention were analyzed by HPLC under the following conditions:

Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector and integrator; Column: Symmetry CI8, 150x4.6 mm, 3.5 um or equivalent; Flow rate: 1.2 mL/min; Wavelength: 215 nm; Column temperature: 45°C; Auto sampler temperature: 5°C; Injection volume: 5 uL; Run time: 43 min; Diluent: 0.1% H3PO4 and acetonitrile in the ration of (9:1 v/v); Elution: gradient; Buffer: Weigh accurately 1.36 gm of potassium dihydrogen orthophosphate and 6.0 gm of 1-octane sulfonic acid sodium salt anhydrous into 1000 ml of milli-Q-water and adjusted the pH to 2.5 with diluted ortho phosphoric acid (85%). Filtered the solution through 0.22 urn Nylon membrane filter paper and sonicated to degas it.

The particle size distribution of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and its hydrochloride salt of the present invention is measured using Malvern Mastersizer 2000 instrument.

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. Scheme-I:

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:

Example-1: Preparation of adamanryl methanol (Formula-3)

Tetrahydrofuran (2000 ml) and sodium borohydride (63 gm) were charged in to a clean and dry RBF at 25-3 0°C under nitrogen atmosphere. The reaction mixture was cooled to 0-5°C and a solution of adamantane-1-carboxylic acid (250 gm) in tetrahydrofuran (1000 ml) was slowly added. Stirred the reaction mixture for 1 hr at 0-5°C and BF3.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. After completion of the reaction, the reaction mixture was cooled to 0-5°C and water was slowly added at the same temperature. Conc.HCl followed by dichloromethane were slowly added to the reaction mixture. Heated the reaction mixture to 25-35°C and stirred for 45 min at the same temperature. Both the organic and aqueous layers were separated, dichloromethane was added to the aqueous layer and stirred for 30 min. Separated the organic and aqueous layers and a solution of sodium bicarbonate in water was added to the total organic layer. Stirred the reaction mixture for 30 min at 25-35°C and separated the organic and aqueous layers. Dried the organic layer over sodium sulfate and distilled off completely.

The obtained solid was filtered, washed with dichloromethane and then dried to get the title compound as a solid. Yield: 210 gm.

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 to get the title compound as a pure solid. Yield: 193 gm.

Example-3: Preparation of adamantyl aldehyde (Formula-4) Dichloromethane (1500 ml) and oxalyl chloride (280 ml) were charged in to a clean and dry RBF under nitrogen atmosphere at 25-30°C. Cooled the reaction mixture to -78°C, dimethyl sulfoxide (270 ml) was slowly added and stirred for 21/2 hrs at the same temperature. A solution of adamantyl methanol (150 gm) in dichloromethane (1500 ml) was slowly added to the reaction mixture at -78°C and stirred for 2xh hrs at the same temperature. Slowly added triethylamine (1000 ml) to the reaction mixture at -78°C and stirred for W2 hrs at the same temperature. After completion of the reaction, the temperature of the reaction mixture was raised to 25-35°C and stirred for 30 min at the same temperature. Water was added to the reaction mixture at 25-35°C and stirred for 45 min at the same temperature. Both the organic and aqueous layers were separated, dichloromethane was added to the aqueous layer at 25-35°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and a solution of sodium chloride in water was added to the organic layer. Stirred the reaction mixture at 25-35°C for 45 min and the organic and aqueous layers were separated. Distilled off the organic layer under reduced pressure to get the title compound as a residue.

Example-4: Preparation of phenylglycinol adamantane nitrile (Formula-5) Water (3000 ml) and sodium bisulfite (150 gm) were added to the residue obtained in above example-3 in a clean and dry RBF at 25-35°C and stirred for 2 hrs at the same temperature. Sodium cyanide (49 gm) was added to the reaction mixture at 25-35°C and stirred for 30 min at the same temperature. A solution of R-(-)-2-phenylglycinol (140 gm) in methanol (900 ml) was added to the reaction mixture at 25-35°C. Heated the reaction mixture to 80-85°C and stirred for 15 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-35°C. Ethyl acetate was added to the reaction mixture at 25-35°C and stirred for 45 min at the same temperature. Both the organic and aqueous layers were separated, ethyl acetate was added to the aqueous layer at 25-35°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and a solution of sodium chloride in water was added to the organic layer at 25-35°C and stirred for 30 min at the same temperature. Separated the organic and aqueous layers, dried the organic layer over sodium sulfate and distilled off the solvent under reduced pressure. The obtained residue was cooled to 25-3 5°C and methanol (225 ml) was added. Water (2000 ml) and conc.HCl (600 ml) was charged in to another RBF and slowly added the above obtained methanolic solution at 25-35°C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with water and then suck dried to get the title compound. Yield: 207 gm.

Example-5: Purification of phenylglycinol adamantane nitrile (Formula-5) Phenylglycinol adamantane nitrile compound of formula-5 (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. Yield: 192 gm.

Example-6: Preparation of phenylglycinol adamantane carboxylic acid hydrochloride salt (Formula-6a) Phenylglycinol adamantane nitrile compound of formula-5 (150 gm), acetic acid (450 ml) and conc.HCl (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 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 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. Yield: 130 gm.

Example-7: Preparation of amino adamantane carboxylic acid hydrochloride salt (Formula-7a) Phenylglycinol adamantane carboxylic acid hydrochloride salt compound of formula-6a (50 gm), methanol (500 ml), acetic acid (500 ml) and 5% Pd/C (50 gm) were charged into a clean and dry autoclave vessel and 4-5 kg pressure of hydrogen gas was applied to the reaction mixture. The resulting mixture was heated to 40-45°C and stirred for 12 hrs under 5 kg hydrogen pressure at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-35°C and filtered through hyflow bed. Washed the Pd/C with methanol and decomposed using dilute hydrochloric acid. The filtrate was distilled off under reduced pressure. Added methyl tert.butyl ether (250 ml) to the obtained gummy solid at 25-35°C and stirred for 1V2 hrs at the same temperature. The obtained solid was filtered, washed with methyl tert.butyl ether and then dried to get the title compound. Yield: 28.0 gm.

Example-8: Preparation of benzyloxycarbonyl protected amino adamantane carboxylic acid (Formula-8) Sodium bicarbonate (20 gm) and tetrahydrofuran (50 ml) were added to a solution of amino adamantane carboxylic acid hydrochloride salt compound of formula-7a (10 gm) in water (100 ml) at 25-30°C. Benzyl chloroformate (12.5 gm) was slowly added to the resulting reaction mixture at 25-30°C and stirred for 12 hrs at the same temperature. After completion of the reaction, ethyl acetate was added to the reaction mixture at 0-5°C and the pH of the resulting mixture was adjusted to 3 by adding 2N HC1 solution at 0-5°C. Both the organic and aqueous layers were separated and the product was extracted from the aqueous layer using ethyl acetate. The total organic layer was washed with saturated sodium chloride solution and the organic layer was concentrated under reduced pressure to get the pure title compound. Yield: 15.8 gm.

Example-9: Preparation of benzyloxycarbonyl protected amino hydroxy adamantane carboxylic acid (Formula-1) 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. After completion of the reaction, cooled the reaction mixture to 0-5°C and methyl tert.butyl ether was slowly added. The pH of the reaction mixture was adjusted to 3 by adding 2N HC1 solution. Both the organic and aqueous layers were separated and the aqueous layer was extracted with methyl tert.butyl ether. The total organic layer was washed with sodium chloride solution and the organic layer was concentrated under reduced pressure to get the title compound. The obtained compound is further purified by column chromatography on silica gel to get the title compound. Yield: 6.5 gm.

Example-10: Preparation of phenylglycinol adamantane nitrile compound of formula-5 Water (3000 ml) and sodium meta bisulfite (150 gm) were added to the residue obtained in above example-3 in a clean and dry RBF at 25-35°C and stirred for 2 hrs at the same temperature. Sodium cyanide (48 gm) was added to the reaction mixture at 25-3 5°C and stirred for 30 min at the same temperature. A solution of R-(-)-2-phenylglycinol (140 gm) in methanol (900 ml) was added to the reaction mixture at 25-35°C. Heated the reaction mixture to 80-85°C and stirred for 15 hrs at the same temperature. After the completion of the reaction, the reaction mixture was cooled to 25-35°C. Ethyl acetate (3000 ml) was added to the reaction mixture at 25-35°C and stirred for 45 min at the same temperature. Both the organic and aqueous layers were separated, ethyl acetate (1500 ml) was added to the aqueous layer at 25-35°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and a solution of sodium chloride (150 gm) in water (1500 ml) was added to the organic layer at 25-35°C and stirred for 30 min at the same temperature. Separated the organic and aqueous layers, dried the organic layer over sodium sulfate and distilled at below 55°C under reduced pressure. The obtained residue was cooled to 25-3 5°C and methanol (225 ml) was added. Water (2000 ml) and conc.HCl (600 ml) was charged in to another RBF and slowly added the above obtained methanolic solution at 25-3 5°C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with water and then suck dried to get the title compound. Yield: 206 gm.

Example-11: Preparation of benzyloxycarbonyl protected amino adamantane carboxylic acid (Formula-8) 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-12: Preparation of (S)-ethyl 5-oxopyrrolidine-2-carboxylate (Formula-lOb) 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. After completion of the reaction, distilled off the solvent from the reaction mixture under reduced pressure and then cooled to 25-30°C. Dichloromethane followed by water were added to the reaction mixture and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with 10% sodium bicarbonate solution followed by 10% sodium chloride solution and dried over sodium sulfate. The resulting organic layer containing (S)-ethyl 5-oxopyrrolidine-2-carboxylate was utilized in the next step without isolating the title compound.

Example-13: Preparation of (S)-methyl 5-oxopyrrolidine-2-carboxylate (Formula-lOa) The title compound is prepared by the process described in example-12, using methanol instead of ethanol for the esterification step.

Example-14: Preparation of (S)-l-tert-buryl 2-ethyl 5-oxopyrrolidine-l,2-dicarboxylate (Formula-lib) 4-dimethylaminopyridine (4.8 gm) followed by di-tert-butyl dicarbonate (236.5 gm) were slowly added to the organic layer containing (S)-ethyl 5-oxopyrrolidine-2-carboxylate obtained in example-12 at 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, the reaction mixture was quenched with water. Both the organic and aqueous layers were separated. Organic layer was washed with 2% HC1 solution followed by with 10% sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely from the organic layer. 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. Yield: 160.0 gm; M.P: 40-45°C.

Example-15: Preparation of (S)-l-tert-butyl 2-methyl 5-oxopyrrolidine-l,2-dicarboxyIate (Formula-lla) The title compound is prepared by the process described in example-14, using (S)-methyl 5-oxopyrrolidine-2-carboxylate (Formula-10a) instead of (S)-ethyl 5-oxopyrrolidine-2-carboxylate (Formula-10b) as a starting material.

Example-16: Preparation of (S)-tert-butyl 2-carbamoyl-5-oxopyrrolidine-l-carboxylate (FormuIa-12) (S)-l-tert-butyl 2-ethyl 5-oxopyrrolidine-l,2-dicarboxylate compound of formula-lib (10 gm) and formamide (5 gm) were charged into a clean and dry RBF at 25-30°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C, sodium methoxide solution (20 ml) was added and stirred for 2'/2 hrs at the same temperature. After completion of the reaction, water was slowly added to the reaction mixture at 0-5°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with n-butanol. The combined organic layer is dried over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 3.5 gm.

Example-17: Preparation of (2S)-tert-butyl 2-carbamoyl-5-hydroxypyrrolidine-l-carboxylate (Formula-13) Sodium borohydride (1.25 gm) was slowly added to a solution of (S)-tert-butyl 2-carbamoyl-5-oxopyrrolidine-l-carboxylate compound of formula-12 (5 gm) in methanol (25 ml) at -10 to -15°C and stirred for 60 min at the same temperature. After completion of the reaction, 1% sodium bicarbonate solution followed by dichloromethane was slowly added to the reaction mixture at -10 to -15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. 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. Dried the organic layer over sodium sulfate and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 3.5 gm.

Example-18: Preparation of (S)-tert-butyl 2-carbamoyI-2,3-dihydro-lH-pyrroIe-l-carboxylate (Formula-14) Diisopropylethyl amine (9.8 gm) was slowly added to (2S)-tert-butyl 2-carbamoyl-5-hydroxypyrrolidine-1-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. After completion of the reaction, 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. Stirred the reaction mixture for 10 minutes. Separated the both aqueous and organic layers and washed the organic layer with aqueous HC1 solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 2.4 gm.

Example-19: Preparation of (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (Formula-15) Diiodomethane (15.1 ml) and 20% diethyl zinc solution (58 ml) were slowly added to a solution of (S)-tert-butyl 2-carbamoyl-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-14 (10 gm) in toluene (200 ml) and 1,2-dimethoxy ethane (13.8 ml) at -10-0°C under N2 atmosphere and stirred for 15 min at the same temperature. Heated the reaction mixture to 40-45 °C and stirred for 3 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C and 10% sodium bicarbonate solution was added. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the reaction mixture and washed with toluene. Both the organic and aqueous layers were separated from the filtrate. Extracted the aqueous layer with ethyl acetate and the combined organic layer was washed with 10% sodium chloride solution and put aside. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with pet ether. To the obtained residue, pet ether (50 ml) was added at 25-30°. Cooled the reaction mixture to 0-5°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with pet ether and dried to get the title compound. Yield: 6.5 gm.

Example-20: Preparation of (S)-tert-butyL2-cyano-2,3-dihydro-lH-pyrrole-l-carboxylate (Formula-16) Diisopropylethyl amine (11 gm) was slowly added to a solution of (2S)-tert-butyl 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. Add water to the reaction mixture and followed by ethyl acetate. Stirred the reaction mixture for 10 minutes. Separated the both aqueous and organic layers and washed the organic layer with aqueous HC1 solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 3.3 gm.

Example-21: Preparation of (lS,3S,5S)-tert-butyl 3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylate (Formula-17) Diiodomethane (8.3 ml) and 20% diethyl zinc solution (31.5 ml) were slowly added to a solution of (S)-tert-butyl 2-cyano-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-16 (5 gm) in toluene (100 ml) and 1,2-dimethoxy ethane (7.5 ml) at -10°C to 0°C under N2 atmosphere and stirred the reaction mixture for 15 min at the same temperature. Raised the temperature of the reaction mixture to 40-45°C and stirred for 3 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C and 10% sodium bicarbonate solution was added. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the reaction mixture and washed with toluene. Both the organic and aqueous layers were separated from the filtrate. Extracted the aqueous layer with ethyl acetate and the combined the organic layer. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with pet ether. To the obtained residue, pet ether (25 ml) was added and cooled the reaction mixture to 0-5°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with pet ether and dried to get the title compound. Yield: 3.6 gm.

Example-22: Preparation of (S)-N-benzyl-5-oxopyrrolidine-2-carboxamide (Formula-18) (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 (10 gm) and ethyl acetate (50 ml) were charged into a clean and dry RBF at 25-30°C and stirred for 20 min at the same temperature. Slowly heated the reaction mixture to 40-45°C, benzylamine (8.6 gm) was added and stirred for 90 min at the same temperature. Slowly heated the reaction mixture to 50-55°C, thionyl chloride (12 gm) was added and stirred for 5 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture at 25-3 0°C and stirred for 10 min at the same temperature. Further cooled the reaction mixture to 10-15°C and dichloromethane was added. Basified the reaction mixture using 10% sodium bicarbonate solution at 10-15°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. The combined organic layer was washed with water and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound as a solid. Yield: 6.0 gm.

Example-23: Preparation of (S)-tert-butyl 2-(benzylcarbamoyl)-5-oxopyrrolidine-l-carboxylate (Formula-19) 4-Dimethylaminopyridine (0.13 gm) followed by di-tert-butyl dicarbonate (7.0 gm) were slowly added to a solution of (S)-N-benzyl-5-oxopyrrolidine-2-carboxamide compound of formula-18 (5 gm) in dichloromethane (50 ml) at 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction quenched the reaction mixture with water. Both the organic and aqueous layers were separated, and the organic layer was washed with 2% HC1 solution at 5-10°C and followed by washed with 10% sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely from the organic layer to get the title compound. Yield: 5.1 gm.

Example-24: Preparation of (2S)-tert-butyl 2-(benzylcarbamoyl)-5-hydroxypyrrolidine-l-carboxylate (Formula-20) Sodium borohydride (0.9 gm) was slowly added to a solution of (S)-tert-butyl 2-(benzylcarbamoyl)-5-oxopyrrolidine-l-carboxylate compound of formula-19 (5 gm) in methanol (25 ml) at -10 to -15°C and stirred for 60 min at the same temperature. After completion of the reaction, 1% sodium bicarbonate solution followed by dichloromethane were slowly added to the reaction mixture at -10 to -15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. 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. Dried the organic layer over sodium sulfate and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 3.4 gm.

ExampIe-25: Preparation of (S)-tert-butyl 2-(benzyIcarbamoyl)-2,3-dihydro-lH-pyrrole-l-carboxylate (Formula-21) Diisopropylethyl amine (10 gm) was slowly added to a solution of (2S)-tert-butyl 2-(benzylcarbamoyl)-5-hydroxypyrrolidine-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. Add water to the reaction mixture and followed by ethyl acetate. Stirred the reaction mixture for 10 minutes. Separated the both aqueous and organic layers and washed the organic layer with aqueous HC1 solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 3.2 gm.

Example-26: Preparation of (lS,3S,5S)-tert-butyl 3-(benzylcarbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate(Formula-22) Diiodomethane (5.3 ml) and 20% diethyl zinc solution (20 ml) were slowly added to a solution of (S)-tert-butyl 2-(benzylcarbamoyl)-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-21 (5 gm) in toluene (100 ml) and 1,2-dimethoxy ethane (5 ml) at -10°C to 0°C under N2 atmosphere and stirred for 15 min at the same temperature. Heated the reaction mixture to 40-45 °C and stirred for 3 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C and 10% sodium bicarbonate solution was added. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the reaction mixture and washed with toluene. Both the organic and aqueous layers were separated from the filtrate. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with pet ether to get the title compound. Yield: 3.6 gm.

Example-27: Preparation of (lS,3S,5S)-tert-butyl 3-carbamoyI-2-azabicyclo[3.1.0]hexane-2-carboxylate (Formula-15) (lS,3S,5S)-tert-butyl 3-(benzylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-22 (5 gm), methanol (35 ml), acetic acid (35 ml) were charged into a clean and dry RBF at 25-30° and stirred for 15 min at the same temperature. Carbon (2 gm) was added to the reaction mixture at 25-30°C and stirred for 90 min at the same temperature. Filtered the reaction mixture through high-low bed and washed with a mixture of methanol and acetic acid. A solution of 5% Pd/C (2 gm) in methanol (5 ml) was added to the filtrate under nitrogen atmosphere in an autoclave vessel at 25-30°C. 4-5 kg/Cm2 of hydrogen gas pressure was applied to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 12 hrs at the same temperature. After completion of the reaction, the reaction mixture was filtered through high-low bed at 25-35°C and washed with methanol. Distilled off the solvent from the filtrate under reduced pressure and co-distilled with methyl tert. butyl ether to get the title compound. Yield: 3.2 gm.

Example-28: Preparation of (2S)-l-tert-butyl 2-ethyl 5-hydroxypyrrolidine-l,2-dicarboxylate (Formula-23b) Sodium borohydride (22 gm) was slowly added to a solution of (S)-l-tert-butyl 2-ethyl 5-oxopyrrolidine-l,2-dicarboxylate compound of formula-lib (100 gm) in methanol (500 ml) at -10 to -15°C and stirred for 60 min at the same temperature. After completion of the reaction, 1% sodium bicarbonate solution followed by dichloromethane were slowly added to the reaction mixture at -10 to -15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. 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. Dried the organic layer over sodium sulfate and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 93.0 gm.

Example-29: Preparation of (S)-l-tert-butyl 2-ethyl 2,3-dihydro-lH-pyrrole-l,2-dicarboxylate (Formula-24b) Diisopropylethyl 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-28 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. Add water to the reaction mixture and followed by ethyl acetate. Stirred the reaction mixture for 10 minutes. Separated the both aqueous and organic layers and washed the organic layer with aqueous HC1 solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.

Example-30: Preparation of (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2- carboxylic acid (Formula-25) Aq.lithium hydroxide solution (79.2 gms of LiOH in 400 ml of water) was slowly added to (S)-l-tert-butyl 2-ethyl 2,3-dihydro-lH-pyrrole-l,2-dicarboxylate compound of formula-24b obtained in example-29 and tetrahydrofuran (1000 ml) at 0-5°C 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 followed by methyl tert.butyl ether were added to the reaction mixture at 25-30°C and stirred for 20 min at the same temperature. Both the organic layer and the aqueous layers were separated and the aqueous layer was washed with methyl tert.butyl ether. Toluene 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 the resulting organic layer containing (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2-carboxylic acid was utilized in the next step without isolating the title compound.

Example-31: Preparation of (S)-tert-butyl 2-carbamoyl-2,3-dihydro-lH-pyrrole-l-carboxylate (Formula-14) Diisopropylethyl amine (150 gm) was slowly added to the organic layer obtained in example-30 at -15°C to -20°C under nitrogen atmosphere. Methane sulfonyl chloride (66.7 gm) was slowly added to the reaction mixture at 15°C to -20°C and stirred for 3 hrs at the same temperature. Slowly passed ammonia gas into the reaction mixture for 2-3 hrs at -15°C to -20°C. Expel the reaction mixture using N2 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. Yield: 50.0 gm; M.R: 100-104°C; SOR: (-) 128.93° (C= 1% in methanol at 25°C and 589 nm).

Example-32: Preparation of (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0Jhexane-2-carboxylate (Formula-15) Diisopropylethyl 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-28 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. Cooled the reaction mixture to 0-5°C, aq.lithium hydroxide solution was slowly added and stirred for 30 min at the same temperature. Raised the temperature of the reaction mixture to 25-3 0°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 25-3 0°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. Diisopropylethyl amine (150 gm) followed by methane sulfonyl chloride (66.7 gm) were slowly added to the organic layer at -15°C to -20°C under nitrogen atmosphere and stirred for 3 hrs at the same temperature. Slowly passed ammonia gas into the reaction mixture for 2-3 hrs at -15°C to -20°C. Expel the reaction mixture using N2 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. To the obtained compound toluene (1000 ml) and 1,2-dimethoxy ethane (69 ml) were added and cooled the reaction mixture to -10-0°C. Diiodomethane (75.5 ml) and 20% diethyl zinc solution (290 ml) were slowly added to the reaction mixture at -10-0°C under N2 atmosphere and stirred for 15 min at the same temperature. Heated the reaction mixture to 40-45°C and stirred for 3 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C and 10% sodium bicarbonate solution was added. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the reaction mixture and washed with toluene. Both the organic and aqueous layers were separated from the filtrate. Extracted the aqueous layer with ethyl acetate and the combined organic layer was washed with 10% sodium chloride solution and put aside. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with pet ether. To the obtained residue, pet ether (50 ml) was added at 25-30°. Cooled the reaction mixture to 0-5°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with pet ether and dried to get the title compound. Yield: 35 gm.

Example-33: Preparation of (lS,3S,5S)-2-azabicydo[3.1.0]hexane-3-carboxamide hydrochloride salt (Formula-26a) Ethyl acetate-HCl (75 ml) was slowly added to a solution of (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15 (5 gm) in tetrahydrofuran (20 ml) at 25-30°C and stirred for 6 hrs at the same temperature. Filtered the solid under nitrogen atmosphere, washed with ethyl acetate and suck dried to get the title compound. Yield: 4.9 gm.

ExampIe-34: Preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitriIe Ethyl acetate-HCl (75 ml) was slowly added to a solution of (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15 (5 gm) in tetrahydrofuran (20 ml) at 25-30°C and stirred for 6 hrs at the same temperature. Filtered the solid under nitrogen atmosphere, washed with ethyl acetate and suck dried for 40 min. The obtained solid was kept aside. Hydroxybenzotriazole (3 gm) was added to a solution of adamantyl intermediate compound of formula-1 (7.5 gm) in acetonitrile (22 ml) and ethyl acetate (10 ml) in another RBF at 0-5°C and stirred for 10 min at the same temperature. N,N'-Dicyclohexylcarbodiimide (5.5 gm) was added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. To the obtained reaction mixture, the above obtained solid followed by diisopropylethyl amine (12 gm) were slowly added at 0-5°C and stirred for 5 hrs at the same temperature. Filtered the reaction mixture and washed with chilled ethyl acetate. Water (50 ml) and dichloromethane (50 ml) were added to the filtrate at 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 20% hydrochloric acid solution followed by 10% sodium bicarbonate solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure. To the obtained compound ethyl acetate (80 ml) and 2,6-lutidine (7.2 gm) were
added and cooled the reaction mixture to 0-5°C. 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. Quenched the reaction mixture with water at below 10°C and slowly raised the temperature of the reaction mixture to 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 were added to the organic layer 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. Added methanol (35 ml) to the obtained compound and charged in an autoclave vessel. Acetic acid (35 ml) was added to the reaction mixture. A solution of 5% Pd/C (2 gm) in methanol (5 ml) was added to the reaction mixture under nitrogen atmosphere at 25-30°C. 4-5 kg/Cm2 of hydrogen gas pressure was applied to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 12 hrs at the same temperature. After completion of the reaction, the reaction mixture was filtered through hyflow bed at 25-35°C and washed with methanol. Distilled off the solvent from the filtrate under reduced pressure to get the title compound. Yield: 3.0 gm.

Example-35: Purification of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyI]-2-azabicyclo[3.1.0]hexane-3-carbonitrile Methanol (15 ml) was added to (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (10 gm) at 25-30°C and stirred for 20 min at the same temperature. Carbon (1 gm) was added to the reaction mixture at 25-3 0°C and stirred for 60 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (17 ml) was added to the filtrate at 0-5°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed with chilled water and dried under vacuum to get pure title compound. Yield: 6.0 gm; Purity by HPLC: 99.97%; Deshydroxy impurity: Not detected; Cyclic amidine impurity: 0.01%.

Particle size distribution: D(0.1) is 3.99 urn; D(0.5) is 16.45 um; D(0.9) is 42.02 um, D(4,3) is 20.54 um. Example-36: Preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride salt (1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile (10 gm) and methanol (30 ml) were charged into a clean and dry RBF at 25-30°C and stirred for 15 min at the same temperature. Carbon (1.0 gm) was added to the reaction mixture at 25-30° and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Cooled the filtrate to 0-5°C, isopropyl alcohol-HCl (6.5 ml) and isopropyl alcohol (43.5 ml) were added at 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 4.9 gm; Purity by HPLC: 99.98% Particle size distribution: D(0.1) is 1.30 um; D(0.5) is 8.98 um; D(0.9) is 48.67 um, D(4,3) is 18.05 um.

We Claim:

1. A process for the preparation of adamantyl methanol compound of formula-3 comprising of reducing the adamantane-1-carboxylic acid compound of formula-2 with sodium borohydride optionally in combination with BF3.etherate in a suitable solvent selected from ether solvents, ester solvents, alcoholic solvents, hydrocarbon solvents, polar solvents or their mixtures thereof to provide adamantyl methanol compound of formula-3.

2. A process for the preparation of benzyloxycarbonyl protected amino hydroxy adamantane carboxylic acid compound of formula-1, comprising of;

a) Reducing the adamantane-1-carboxylic acid compound of formula-2 with a suitable reducing agent such as sodium borohydride optionally in combination with BF3.etherate, in a suitable solvent selected from ether solvents, ester solvents, alcoholic solvents, hydrocarbon solvents, polar solvents or their mixtures thereof to provide adamantyl methanol compound of formula-3,

b) oxidizing the compound of formula-3 with a suitable oxidizing agent selected from oxalyl chloride/dimethyl sulfoxide; sodium hypochlorite, trichloroisocyanuric acid in presence of catalytic amount of TEMPO ((2,2,6,6-Tetramethyl-piperidin-l-yl)oxyl), pyridinium chlorochromate optionally in presence of a suitable organic or inorganic base in a suitable solvent selected from chloro solvents, hydrocarbon solvents, ester solvents, polar-aprotic solvents or their mixtures thereof to provide adamantyl aldehyde compound of formula-4,

c) treating the compound of formula-4 in-situ with a suitable alkali metal cyanide such as sodium cyanide or potassium cyanide in a suitable solvent selected from alcoholic solvents, chloro solvents, ester solvents, polar solvents or their mixtures thereof in presence of sodium bisulfite followed by treating with R-(-)-2-phenylglycinol in a suitable solvent to provide phenylglycinol adamantane nitrile compound of formula-5,

d) hydrolyzing the compound of formula-5 in presence of a suitable acid selected from conc.HCl, sulfuric acid in a suitable solvent selected from acetic acid and alcoholic solvents to provide phenylglycinol adamantane carboxylic acid compound of formula-6 or its acid-addition salt,

Formula-6 e) deprotecting the compound of formula-6 or its acid-addition salt by treating it with a suitable deprotecting agent selected from Pd, Pd/C, Raney Ni optionally in combination with hydrogen, conc.HCl optionally in presence of an acid such as acetic acid in a suitable solvent selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, polar solvents or their mixtures thereof to provide amino adamantane carboxylic acid compound of formula-7 or its acid-addition salt,

f) treating the compound of formula-7 or its acid-addition salt with benzyl chloroformate in presence of a suitable base selected from alkali metal carbonates and alkali metal bicarbonates in a suitable solvent selected from ether solvents, ester solvents, polar solvents or their mixtures thereof to provide benzyloxycarbonyl protected amino adamantane carboxylic acid compound of formula-8,

g) hydroxylating the compound of formula-8 with potassium permanganate in presence of a suitable base selected from alkali metal hydroxides, alkali metal alkoxides and organic bases in a suitable solvent selected from chloro solvents, nitrile solvents, ether solvents, polar solvents or their mixtures thereof to provide benzyloxycarbonyl protected amino hydroxy adamantane carboxylic acid compound of formula-1.

3. A process for the preparation of benzyloxycarbonyl protected amino hydroxy adamantane carboxylic acid compound of formula-1, comprising of;

a) Reducing the adamantane-1-carboxylic acid compound of formula-2 with sodium borohydride-BF3.etherate in tetrahydrofuran to provide adamantyl methanol compound of formula-3,

b) oxidizing the compound of formula-3 by treating it with oxalyl chloride and dimethylsulfoxide in presence of triethyl amine in dichloromethane to provide adamantyl aldehyde of formula-4,

c) treating the compound of formula-4 in-situ with sodium cyanide in presence of sodium bisulfite in water followed by treating it with R-(-)-2-phenylglycinol in methanol to provide phenylglycinol adamantane nitrile compound of formula-5,

d) hydrolyzing the compound of formula-5 in presence of cone. HC1 in acetic acid to provide phenylglycinol adamantane carboxylic acid hydrochloride salt compound of formula-6a,

e) deprotecting the compound of formula-6a by treating it with Pd/C in presence of acetic acid in methanol to provide amino adamantane carboxylic acid hydrochloride salt compound of formula-7a,

f) treating the compound of formula-7a with benzyl chloroformate in presence of sodium bicarbonate in a mixture of water and tetrahydrofuran to provide benzyloxycarbonyl protected amino adamantane carboxylic acid compound of formula-8, g) hydroxylating the compound of formula-8 by treating it with potassium permanganate in presence of potassium hydroxide in water to provide benzyloxycarbonyl protected amino hydroxy adamantane carboxylic acid compound of formula-1.

4. A process for the preparation of benzyloxycarbonyl protected amino hydroxy adamantane
carboxylic acid compound of formula-1, comprising of;

a) Reacting the amino adamantane carboxylic acid compound of formula-7 or its acid-addition salt with benzyl chloroformate in presence of a suitable base selected from alkali metal carbonates, alkali metal bicarbonates, organic bases in a suitable solvent selected from ether solvents, ester solvents, polar solvents or their mixtures thereof to provide benzyloxycarbonyl protected amino adamantane carboxylic acid compound of formula-8,

b) hydroxylating the compound of formula-8 with potassium permanganate in presence of a suitable base selected from alkali metal hydroxides, alkali metal alkoxides and organic bases in a suitable solvent selected from chloro solvents, nitrile solvents, ether solvents, polar solvents or their mixtures thereof to provide benzyloxycarbonyl protected amino hydroxy adamantane carboxylic acid compound of formula-1.

5. 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 C1-C6 straight chain or branched chain alcohol in presence of a suitable catalyst selected from thionyl chloride, hydrochloric acid, conc.sulfuric acid, trifluoroacetic acid, methane sulfonic acid to provide (S)-alkyl 5-oxopyrrolidine-2-carboxylate compound of general formula-10,
wherein, 'R' represents C1-C6 straight chain or branched chain alkyl;

b) treating the compound of general formula-10 with di-tert.butyl dicarbonate in presence of a suitable organic or inorganic base in a suitable solvent selected from nitrile solvents, chloro solvents, ether solvents, polar solvents or their mixtures thereof to provide (S)-l-tert-butyl 2-alkyl 5-oxopyrrolidine-l,2-dicarboxylate compound of general formula-11,

wherein, 'R' is as defined above; c) amidation of compound of general formula-11 by treating it with a suitable amine source selected from ammonia, formamide, ammonia gas, ammonium formate, ammonium phosphate, ammonium acetate, ammonium chloride, ammonium carbonate, ammonium hydroxide optionally in presence of a suitable inorganic base in a suitable solvent selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents or their mixtures thereof to provide (S)-tert-butyl 2-carbamoyl-5-oxopyrrolidine-l-carboxylate compound of formula-12,

d) reducing the compound of formula-12 with a suitable reducing agent selected from lithium tri-sec-butyl(hydrido)borate(l-) (L-selectride), sodium borohydride, vitride, diisobutyl aluminium hydride, tetralkylammonium borohydride, sodium cyanoborohydride, lithium aluminium hydride in a suitable solvent selected form ether solvents, alcoholic solvents, ester solvents, nitrile solvents or their mixtures thereof to provide (2S)-tert-butyl 2-carbamoyl-5-hydroxypyrrolidine-l-carboxylate compound of formula-13,

e) dehydrating the compound of formula-13 by treating it with a suitable dehydrating agent selected from acetic anhydride, trifluoroacetic anhydride, trifluoroacetic acid, phosphorous pentoxide, phosphoryl chloride, phosphoric acid, sulfuric acid, dicyclohexyl carbodiimide in presence or absence of a suitable base in a suitable solvent selected from ether solvents, ester solvents or their mixtures thereof to provide (S)-tert-butyl 2-carbamoyl-2,3 -dihydro-1 H-pyrrole-1 -carboxylate compound of formula-14,

f) converting the compound of formula-14 in-situ into (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15 by treating it with a suitable methylene source such as diiodomethane, chloro iodomethane in presence of diethyl zinc in a suitable solvent selected from hydrocarbon solvents, ether solvents, chloro solvents or their mixtures thereof.

6. 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) Amidation of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 by treating with benzyl amine in presence of a suitable coupling agent selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide, 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 and the like optionally in combination with 1-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), 4-dimethylaminopyridine (DMAP); optionally in presence of a suitable organic or inorganic base in a suitable solvent selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents or their mixtures thereof to provide (S)-N-benzyl-5-oxopyrrolidine-2-carboxamide compound of formula-18,

b) treating the compound of formula-18 with di-tert.butyl dicarbonate in presence of a suitable organic or inorganic base in a suitable solvent selected from nitrile solvents, chloro solvents, ether solvents, polar solvents or their mixtures thereof to provide (S)-tert-butyl 2-(benzylcarbamoyl)-5-oxopyrrolidine-l-carboxylate compound of formula-19,

c) reducing the compound of formula-19 with a suitable reducing agent selected from L-selectride, sodium borohydride, vitride, diisobutyl aluminium hydride, tetralkylammomum borohydride, sodium cyanoborohydride, lithium aluminium hydride in a suitable solvent selected form ether solvents, alcoholic solvents, ester solvents, nitrile solvents or their mixtures thereof to provide (2S)-tert-butyl 2-(benzylcarbamoyl)-5-hydroxypyrrolidine-1-carboxylate compound of formula-20,

d) dehydrating the compound of formula-20 by treating it with a suitable dehydrating agent selected from acetic anhydride, trifluoro acetic anhydride, trifluoro acetic acid, phosphorous pentoxide, phosphoryl chloride, phosphoric acid, sulfuric acid, dicyclohexyl carbodiimide in presence of a suitable organic or inorganic base in a suitable solvent selected from ether solvents, ester solvents, hydrocarbon solvents or their mixtures thereof to provide (S)-tert-butyl 2-(benzylcarbamoyl)-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-21,

Formula-21 e) converting the compound of formula-21 into (lS,3S,5S)-tert-butyl 3-(benzylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-22 by treating it with a suitable methylene source such as diiodomethane, chloro iodomethane in presence of diethyl zinc in a suitable solvent selected from hydrocarbon solvents, ether solvents, chloro solvents or their mixtures thereof,

f) debenzylating the compound of formula-22 by treating with a suitable debenzylating agent selected from Pd, Pd/C, Raney Ni optionally in combination with hydrogen, conc.HCl optionally in presence of an acid such as acetic acid in a suitable solvent selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents or their mixtures thereof to provide (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0] hexane-2-carboxylate compound of formula-15.

7. A process for the preparation of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-26 or it's acid addition salt, comprising of;

a) Esterification of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 by treating it with a suitable Q-C6 alcohol in presence of a suitable catalyst such as thionyl chloride, hydrochloric acid, cone, sulfuric acid to provide corresponding (S)-alkyl 5-oxopyrrolidine-2-carboxylate compound of general formula-10,

b) treating the compound of general formula-10 with di-tert.butyl dicarbonate in presence of a suitable organic or inorganic base in a suitable solvent selected from nitrile solvents, chloro solvents, ether solvents, polar solvents or their mixtures thereof to provide (S)-l-tert-butyl 2-alkyl 5-oxopyrrolidine-l,2-dicarboxylate compound of general formula-11,

c) reducing the compound of general formula-11 with a suitable reducing agent selected from L-selectride, sodium borohydride, potassium borohydride, vitride, tetralkylammonium borohydride, sodium cyanoborohydride, lithium aluminium hydride in a suitable solvent selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, polar solvents or their mixtures thereof to provide (2S)-l-tert-butyl 2-alkyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of general formula-23,

wherein, 'R' represents Ci-Cg straight chain or branched chain alkyl; d) dehydrating the compound of general formula-23 by treating it with a suitable dehydrating agent selected from acetic anhydride, trifluoro acetic anhydride (TFAA),

trifluoro acetic acid, phosphorous pentoxide, phosphoryl chloride, phosphoric acid, sulfuric acid, dicyclohexyl carbodiimide in presence of a suitable organic or inorganic base in a suitable solvent selected from ether solvents, ester solvents, nitrile solvents or their mixtures thereof to provide (S)-l-tert-butyl 2-alkyl 2,3-dihydro-lH-pyrrole-l,2-dicarboxylate compound of general formula-24,

wherein, R is as denned above; e) hydrolyzing the compound of general formula-24 in-situ in presence of a suitable base preferably alkali metal hydroxide in a suitable solvent selected from polar solvents, alcoholic solvents, ether solvents, hydrocarbon solvents or their mixtures thereof to provide (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2-carboxylic acid compound of formula-25,

f) treating the compound of formula-25 in-situ with methane sulfonyl chloride in presence of a suitable organic or inorganic base followed by in-situ treating the obtained compound with a suitable amine source selected from ammonia, formamide, ammonia gas, ammonium formate, ammonium phosphate, ammonium acetate, ammonium chloride, ammonium carbonate, ammonium hydroxide to provide (S)-tert-butyl 2-carbamoyl-2,3 -dihydro-1 H-pyrrole-1 -carboxylate compound of formula-14,

g) converting the compound of formula-14 in-situ into (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15 by treating it with a suitable methylene source such as diiodomethane, chloro iodomethane in presence of diethyl zinc in a suitable solvent selected from hydrocarbon solvents, ether solvents, chloro solvents or their mixtures thereof,

h) deprotecting the compound of formula-15 by treating it with a suitable deprotecting agent selected from hydrochloric acid, acetyl chloride, methane sulfonic acid, trifluoroacetic acid in a suitable solvent selected from ether solvents, ester solvents, hydrocarbon solvents, chloro solvents, alcoholic solvents or their mixtures thereof to provide (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-26 or its acid-addition salt.

8. A 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 sodium borohydride in a suitable solvent selected from alcoholic solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents or their mixtures thereof to provide (2S)-1-tert-butyl 2-alkyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of general formula-23.

9. Compounds having the structural formulae

10. A process for the preparation of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-26 or it's acid addition salt, comprising of;

a) Esterification of (S)-5-oxopyrrolidine-2-carboxylic acid compound of formula-9 by treating it ethanol in presence of thionyl chloride to provide (S)-ethyl 5-oxopyrrolidine-2-carboxylate compound of formula-10b,

b) treating the compound of formula-10b with di-tert.butyl dicarbonate in presence of 4-dimethylamino pyridine in dichloromethane to provide (S)-l-tert-butyl 2-ethyl 5-oxopyrrolidine-l,2-dicarboxylate compound of formula-1 lb,

c) reducing the compound of formula-1 lb with sodium borohydride in methanol to provide (2S)-l-tert-butyl 2-alkyl 5-hydroxypyrrolidine-l,2-dicarboxylate compound of formula-23b,

d) dehydrating the compound of formula-23b by treating it with trifluoro acetic anhydride (TFAA) in presence of isopropyl ethyl amine in tetrahydrofuran to provide (S)-l-tert-butyl 2-ethyl 2,3-dihydro-lH-pyrrole-l,2-dicarboxylate compound of formula-24b,

e) hydrolyzing the compound of formula-24b in-situ in presence of aqueous lithium hydroxide in tetrahydrofuran to provide (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2-carboxylic acid compound of formula-25,

f) treating the compound of formula-25 in-situ with methane sulfonyl chloride in presence of diisopropylethylamine followed by in-situ treating the obtained compound with ammonia to provide (S)-tert-butyl 2-carbamoyl-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-14,

g) converting the compound of formula-14 in-situ into (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-15 by treating it with diazomethane in presence of diethyl zinc in a mixture of toluene and 1,2-dimethoxy ethane,

h) deprotecting the compound of formula-15 by treating it ethyl acetate-HCl in tetrahydrofuran to provide (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-26a.