Field of the invention:

The present invention provides novel processes for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound represented by the structural formula-1 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. N-deprotection of the obtained compound using Pearlman's catalyst (20% Pd(OH)2) provides hydrochloride salt of free amine compound, which upon treatment with di-tert-butyl dicarbonate (Boc anhydride) provides 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 triediylamine. 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 pyridine to provide corresponding cyano compound. It is then treated with trifluoroacetic acid in 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 as trifluoroacetic acid salt.

The process disclosed in US63 95767 B2 has certain disadvantages in that the process involves the usage of trimethylsilyl diazomethane for the esterification of adamantane-1-carboxylic acid, which is a neurological hazard and extremely toxic reagent.

The above disclosed process also involves the usage of lithium aluminium 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 and industrially applicable 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 a process for the preparation of (1 S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-, carbonitrile compound of formula-1, comprising of;

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 a suitable base and a suitable catalyst in a suitable solvent to provide adamantyl aldehyde compound of formula-4,

c) treating the compound of formula-4 in-situ with a suitable cyanide source in presence of sodium bisulfite or sodium metabisulfite in a suitable solvent followed by in-situ treating with a-substituted chiral benzylamine in a suitable solvent to provide compound of general formula-5,

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

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

f) treating the compound of formula-7 or its acid-addition salt with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide Boc-protected amine compound of formula-8, g) hydroxylating the compound of formula-8 by treating it with a suitable hydroxylating agent optionally in presence of a suitable base in a suitable solvent followed by optionally treating in-situ with a suitable O-protecting agent to provide compound of general formula-9, h) condensing the compound of formula-9 with (lS,3S,5S)-2- zabicyclo[3.1.0]hexane-3- carboxamide compound of formula-10 or its hydrochloride salt compound of formula-10a in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-11, i) dehydrating the compound of formula-11 by treating it with a suitable dehydrating agent optionally in presence of a suitable base in a suitable solvent to provide compound of general formula-12, j) deprotecting the compound of formula-12 by treating with a suitable deprotecting agent in a suitable solvent to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]- 2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1.

The second aspect of the present invention is to provide a process for the preparation of (1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

a) Condensing the compound of general formula-9 with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride salt compound of formula-13 in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-12,

b) deprotecting the compound of formula-12 by treating it with a suitable deprotecting agent in a suitable solvent to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1.

The third aspect of the present invention is to provide a process for the preparation of (1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

a) Condensing the compound of general formula-9 with (lS,3S,5S)-2-azabicyclo[3.1.0]hexan-3-ylmethanamine hydrochloride salt compound of formula-14 in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-15,

b) treating the compound of formula-15 with trichloroisocyanuric acid (TCICA) in presence or absence of a suitable catalyst or a suitable base in a suitable solvent followed by deprotecting the obtained compound to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1.
The fourth aspect of the present invention is to provide a process for the preparation of compound of general formula-11, comprising of;

a) Condensing the compound of general formula-9 with (lS,3S,5S)-N-benzyl-2-azabicyclo [3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-16 in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-17,

b) debenzylating the compound of formula-17 with a suitable debenzylating agent optionally in presence of a suitable acid in a suitable solvent to provide compound of general formula-11.

The fifth aspect of the present invention is to provide a process for the preparation of (1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

a) Condensing the compound of general formula-18 with (lS,3S,5S)-2-azabicyclo [3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-10a in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-22,

b) reacting the compound of formula-22 with a-substituted chiral benzylamine in a suitable solvent to provide compound of general formula-23,

c) dehydrating the compound of formula-23 by treating it with a suitable dehydrating agent optionally in presence of a suitable base in a suitable solvent to provide compound of general formula-20,

d) reducing the compound of formula-20 with a suitable reducing agent in a suitable solvent to provide compound of general formula-21,

e) deprotecting the compound of formula-21 by treating it with a suitable deprotecting agent in a suitable solvent to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1.

The sixth aspect of the present invention is to provide a process for the preparation of compound of general formula-21, comprising of;

a) Condensing the compound of general formula-18 with (lS,3S,5S)-2-azabicyclo [3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-10 in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-22,

b) reacting the compound of formula-22 with a-substituted chiral benzylamine in a suitable solvent to provide compound of general formula-23,

c) reducing the compound of formula-23 with a suitable reducing agent in a suitable solvent to provide compound of general formula-24,

d) dehydrating the compound of formula-24 by treating it with a suitable dehydrating agent optionally in presence of a suitable base in a suitable solvent to provide compound of general formula-21.

The seventh aspect of the present invention is to provide a process for the preparation of compound of general formula-24, comprising of;

a) Reacting the compound of general formula-18 with a-substituted chiral benzylamine in a suitable solvent to provide compound of general formula-25,

b) reducing the compound of formula-25 with a suitable reducing agent in a suitable solvent to provide compound of general formula-26,

c) condensing the compound of formula-26 with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-10 in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-24.

The eighth aspect of the present invention is to provide a process for the preparation of compound of general formula-23, comprising of;

a) Reacting the compound of general formula-18 with a-substituted chiral benzylamine in a suitable solvent to provide compound of general formula-25,

b) condensing the compound of formula-25 with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-10 in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-23.

The ninth aspect of the present invention is to provide a process for the preparation of adamantyl aldehyde compound of formula-4 comprising, oxidizing the adamantyl methanol compound of formula-3 with a suitable oxidizing agent optionally in presence of a suitable base and a suitable catalyst in a suitable solvent to provide adamantyl aldehyde compound of formula-4.

The tenth aspect of the present invention is to provide a novel process for the preparation of compound of formula-8, comprising of;

a) N-Protection of glycine by treating it with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide N-Boc protected glycine compound of formula-27,

b) reacting the compound of formula-27 with (R)-4-phenyloxazolidin-2-one in a suitable solvent to provide (S)-tert-butyl 2-oxo-2-(2-oxo-4-phenyloxazolidin-3-yl)ethylcarbamate compound of formula-28,

c) reacting the compound of formula-28 with adamantyl bromide compound of formula-29 in presence of a suitable base in a suitable solvent to provide compound of formula-30,

d) hydrolyzing the compound of formula-30 in presence of a suitable base in a suitable solvent to provide compound of formula-8.

The eleventh aspect of the present invention is to provide a novel process for the preparation of compound of formula-8, comprising of;

a) Reacting the adamantyl bromide compound of formula-29 with (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine compound of formula-31 in presence of a suitable base in a suitable solvent to provide compound of formula-32,

b) treating the compound of formula-32 with a suitable acid in a suitable solvent to provide methyl ester compound of formula-3 3,

c) treating the compound of formula-33 with di-tert-butyl dicarbonate in presence of a suitable organic or inorganic base in a suitable solvent selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents or their mixtures to provide compound of formula-42,

d) hydrolyzing compound of formula-42 in presence of a suitable base selected from hydroxides, alkoxides, bicarbonates of alkali metals in a suitable solvent selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, alcohol solvents or mixtures thereof to provide compound of formula-8.

The twelfth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-2-azabicyclo[3.1.0]hexan-3-ylmethanamine hydrochloride compound of formula-14, comprising of;

a) Reducing the (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2-carboxylic acid compound of formula-34 with a suitable reducing agent in a suitable solvent to provide (S)-tert-butyl 2-(hydroxymethyl)-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-35,

b) mesylation of compound of formula-35 with methane sulfonyl chloride in presence of a suitable base in a suitable solvent to provide (S)-tert-butyl 2-((methylsulfonyloxy)methyl)-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-36,

c) azidation of compound of formula-36 by treating with a suitable azide source in a suitable solvent to provide (S)-tert-butyl 2-(azidomethyl)-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-37,

d) reducing the compound of formula-37 with a suitable reducing gent in a suitable solvent to provide (S)-tert-butyl 2-(aminomethyl)-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-38,

e) treating the compound of formula-38 with a suitable methylene source in presence of a suitable catalyst in a suitable solvent to provide (lS,3S,5S)-tert-butyl 3-(aminomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-39,

f) deprotecting the compound of formula-39 with hydrochloric acid in a suitable solvent to provide (lS,3S,5S)-2-azabicyclo[3.1.0]hexan-3-ylmethanamine hydrochloride compound of formula-14.

The thirteenth aspect of the present invention is to provide a process for the preparation of (lS,3S,5S)-N-benzyl-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-16, comprising of;

a) Reacting the (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2-carboxylic acid compound of formula-34 with benzylamine in presence of a suitable coupling agent in optionally in presence of a suitable base in a suitable solvent to provide (S)-tert-butyl 2-(benzylcarbamoyl)-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-40,

b) treating the compound of formula-40 with a suitable methylene source in presence of a suitable catalyst in a suitable solvent to provide (lS,3S,5S)-tert-butyl 3-(benzylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-41,

c) deprotecting the compound of formula-41 with hydrochloric acid in a suitable solvent to provide (1 S,3 S,5S)-N-benzyl-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride compound of formula-16.

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 and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulphoxide, dioxane, acetonitrile 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.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide; alkali meta hydrides such as sodium hydride, potassium hydride, lithium hydride; alkali meta amides such as sodium amide, potassium amide, lithium amide and the like, ammonia; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide, n-butyl lithium; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and/or their mixtures thereof.

The first aspect of the present invention provides a process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

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 a suitable base and a suitable catalyst in a suitable solvent to provide adamantyl aldehyde compound of formula-4,

c) treating the compound of formula-4 in-situ with a suitable cyanide source in presence of sodium bisulfite or sodium metabisulfite in a suitable solvent followed by in-situ treating with a-substituted chiral benzylamine of the structural formula

wherein, "R" represents -CH3 or -CH2OH in a suitable solvent to provide compound of general formula-5, d) hydrolyzing the compound of formula-5 in presence of a suitable acid in a suitable solvent to

provide compound of general formula-6 or its acid addition salt, ' e) treating the compound of formula-6 or its acid addition salt with a suitable deprotecting agent optionally in presence of an acid in a suitable solvent to provide compound of formula-7or its acid addition salt,

f) treating the compound of formula-7 or its acid addition salt with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide Boc-protected amine compound of formula-8,

g) hydroxylating the compound of formula-8 by treating it with a suitable hydroxylating agent optionally in presence of a suitable base in a suitable solvent followed by optionally treating in-situ with a suitable O-protecting agent to provide compound of general formula-9,

h) condensing the compound of general formula-9 with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-10 or its hydrochloride salt compound of formula-10a in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-11,

i) dehydrating the compound of formula-11 by treating it with a suitable dehydrating agent optionally in presence of a suitable base in a suitable solvent to provide compound of general formula-12,

j) deprotecting the compound of general formula-12 by treating with a suitable deprotecting agent in a suitable solvent followed by optionally treating with a suitable base to provide (1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1.

Wherein, in step-a) the suitable reducing agent is sodium borohydride optionally in combination with BF3.etherate; and the suitable solvent is selected from ether solvents, ester solvents, alcoholic solvents, hydrocarbon solvents, polar solvents or mixtures thereof, preferably ether solvents;

in step-b) the suitable oxidizing agent is selected from oxalyl chloride/dimethyl sulfoxide, sodium hypochlorite or trichloroisocyanuric acid (TCICA) optionally in presence of catalytic amount of TEMPO ((2,2,6,6-tetramethyl-piperidin-l-yl)oxyl), pyridinium chlorochromate, oxone and the like; the suitable base is selected from organic or inorganic bases; and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, polar-aprotic solvents or mixtures thereof; preferably chloro solvents;

in step-c),the suitable cyanide source is selected from acetone cyanohydrin, alkali metal cyanides such as sodium cyanide, potassium cyanide and the like; the suitable solvent is selected from polar solvents, alcoholic solvents, chloro solvents, ester solvents or mixtures thereof;

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

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; the suitable acid is acetic acid; and the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, polar solvents or mixtures thereof; preferably alcoholic solvents;

in step-f) the suitable base is selected from organic bases, hydroxides, carbonates and bicarbonates of alkali metals; preferably alkali metal carbonates; the suitable solvent is selected from chloro solvents, nitrile solvents, ether solvents, ester solvents, polar solvents or mixtures thereof; preferably water;

in step-g) the suitable hydroxylating agent is selected from potassium permanganate, H2SO4/HNO3; preferably potassium permanganate; the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides and organic bases; preferably alkali metal hydroxides; the suitable solvent is selected from chloro solvents, nitrile solvents, ether solvents, polar solvents or mixtures thereof; preferably water;

In step-h) the suitable coupling agent is selected from N,N'-dicyclohexyl carbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1), alkyl, aryl or aralkyl chloroformates such as methyl chloroformate, ethyl chloroformate, phenyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride 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'-tetrarnethyl uronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), 4-dimethylaminopyridine (DMAP); the suitable base is selected from organic and inorganic bases; the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents, nitrile solvents or mixtures thereof; preferably a mixture of ethyl acetate and acetonitrile;

In step-i) the suitable dehydrating agent is selected from acetic anhydride, trifluoro acetic anhydride (TFAA), trifluoroacetic acid, phthalic anhydride, phosphorous pentoxide, phosphoric acid, phosphoryl chloride in presence or absence of imidazole, phosphoric acid, polyphosphoric acid, sulfuric acid, dicyclohexyl carbodiimide, cyanuric chloride; and the suitable base wherever necessary is selected from organic bases like triethylamine, diisopropyl amine, diisopropyl ethylamine, pyridine, 4-dimethylamino pyridine (DMAP), 2,6-lutidine and the like; the suitable solvent is selected from ether solvents, ester solvents, hydrocarbon solvents, chloro solvents, nitrile solvents, ketone solvents, polar aprotic solvents, alcoholic solvents or mixtures thereof;

In step-j) the suitable deprotecting agent is selected from but not limited to tri(Ci-Ce)alkylsilyl halides, acetyl chloride in combination with alcohol, acids such as hydrochloric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid and the like, bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates and hydrogenating agents such as Pd, Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Raney-Ni, triethylsilane and the like; the suitable solvent is selected form ether solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar-aprotic solvents, polar solvents or mixtures thereof.

The O-protecting group 'P' of the present invention is selected from 3,4-dihydro-2H-pyran (DHP), tetrahydropyranyl (THP), acetyl, benzyl, benzoyl, trifluoroacetyl, pivaloyl, tri(Ci-C6 alkyl)silyl (eg.,trimethylsilyl, triethylsilyl, tert.butyldimethylsilyl and the like), triphenylmethyl (trityl) group, tert.butoxycarbonyl (Boc) and the like and it can be removed by treating the corresponding O-protected compound with a suitable acid or a suitable base or by hydrogenolysis depending on the nature of the protecting group employed.

A preferred embodiment of the present invention provides a process for the preparation of (1 S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

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 with oxalyl chloride/dimethyl sulfoxide in presence of triethylamine in dichloromethane to provide adamantyl aldehyde compound of formula-4,

c) treating the compound of formula-4 in-situ with sodium cyanide/acetone cyanohydrin in presence of sodium bisulfite/sodium meta bisulfite in water followed by in-situ treating with R-(-)-2-phenyl glycinol in methanol to provide compound of formula-5a,

d) hydrolyzing the compound of formula-5a in presence of cone, hydrochloric acid in acetic acid to provide hydrochloride salt compound of formula-6a,

e) treating the compound of formula-6a 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 di-tert.butyl dicarbonate in presence of sodium carbonate in water to provide boc-protected amine compound of formula-8,

g) hydroxylating the compound of formula-8 by treating with potassium permanganate in presence of potassium hydroxide in water provides compound of formula-9a,

h) condensing the compound of formula-9a with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-10a in presence of N,N'-dicyclohexylcarbodiimide (DCC)/l-hydroxybenzotriazole (HOBt) and diisopropylethyl amine in a mixture of ethyl acetate and acetonitrile to provide compound of formula-1 la, i) dehydrating the compound of formula-lla by treating it with trifluoroacetic anhydride in presence of 2,6-lutidine in ethyl acetate to provide compound of formula-12a,

j) deprotecting the compound of formula-12a by treating with acetyl chloride in methanol provides (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo
[3.1.0]hexane-3-carbonitrile hydrochloride salt compound of formula-la, which on further in-situ treatment with potassium carbonate provides (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1.

The hydrochloride salt compound of formula-la obtained in step-j) of the first aspect of the present invention can be optionally isolated as a solid from a suitable solvent.

The (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-10a utilized in the above step-h) can be synthesized as follows;

Esterification of (S)-5-oxopyrrolidine-2-carboxylic acid with ethanol in presence of sulfuric acid to provide (S)-ethyl 5-oxopyrrolidine-2-carboxylate, N-protecting the ethyl ester compound with di-tert.butyl dicarbonate in presence of N,N-dimethylaminopyridine to provide (S)-l-tert-butyl 2-ethyl 5-oxopyrrolidine-l,2-dicarboxylate (formula-43), reducing the N-Boc protected compound with lithium triethylborohydride or L-selectride to provide (2S)-l-tert-butyl 2-ethyl 5-hydroxypyrrolidine-l,2-dicarboxylate (formula-44) followed by in-situ treated with trifluoroacetic anhydride in presence of N,N-dimethylaminopyridine to provide (S)-l-tert-butyl 2-ethyl 2,3-dihydro-lH-pyrrole-l,2-dicarboxylate (formula-45), hydrolyzing the ester compound in-situ in presence of lithium hydroxide followed by amination of the obtained acid by treating it in-situ with methane sulfonyl chloride followed by ammonia to provide (S)-tert-butyl 2-carbamoyl-2,3-dihydro-lH-pyrrole-l-carboxylate (formula-46). Converting the resulting compound into (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (formula-47) by treating it with diiodomethane in presence of diethyl zinc to provide followed by N-deprotection of the obtained compound with hydrochloric acid to provide (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride compound of formula-10a.

In a further embodiment of the present invention (S)-l-tert-butyl 2-ethyl 2,3-dihydro-lH-pyrrole-l,2-dicarboxylate (formula-45) can be directly amidated with formamide in presence of sodium methoxide solution to provide compound of formula-46.

The second aspect of the present invention provides a process for the preparation of (1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

a) Condensing the compound of general formula-9 with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride salt compound of formula-13 in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-12,

b) deprotecting the compound of formula-12 by treating it with a suitable deprotecting agent in a suitable solvent to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1.

Wherein, in step-a) the suitable coupling agent, suitable base and the suitable solvent are same as defined for step-h) of the first aspect of the present invention;

In step-b) the suitable deprotecting agent and the suitable solvent are same as defined for step-j) of the first aspect of the present invention.

The (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride salt compound of formula-13 utilized in step-a) of the second aspect of the present invention can be synthesized by dehydrating the (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-10a obtained by the process as described above with a suitable dehydrating agent in presence of a suitable base in a suitable solvent, followed by converting the (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile free base into its hydrochloride salt.

Wherein, the suitable dehydrating agent, the suitable base and the suitable solvent are same as described for step-i) of the first aspect of the present invention.

The third aspect of the present invention provides a process for the preparation of (1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

a) Condensing the compound of general formula-9 with (lS,3S,5S)-2-azabicyclo[3.1.0]hexan-3-ylmethanamine hydrochloride salt compound of formula-14 in presence of a .suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-15,

b) treating the compound of general formula-15 with trichloroisocyanuric acid (TCICA) in presence or absence of a suitable catalyst or a suitable base in a suitable solvent followed by optionally deprotecting the obtained compound to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile compound of formula-1.

Wherein, the suitable coupling agent, the suitable base and the suitable solvent used in step-a) are same as described for step-h) of the first aspect of the present invention;

In step-b) the suitable catalyst is selected from (2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO), 4-hydroxy-TEMPO, 4-acetamido-TEMPO and the like; the suitable base is selected from organic bases and ammonia; and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, polar-aprotic solvents or mixtures thereof;

The fourth aspect of the present invention provides a process for the preparation of compound of general formula-11, comprising of;

a) Condensing the compound of general formula-9 with (lS,3S,5S)-N-benzyl-2-azabicyclo [3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-16 in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-17,

b) debenzylating the compound of formula-17 with a suitable debenzylating agent optionally in presence of a suitable acid in a suitable solvent to provide compound of general formula-11.

Wherein, the suitable coupling agent, the suitable base and the suitable solvent used in step-a) are same as described for step-h) of the first aspect of the present invention;

In step-b) the suitable debenzylating agent is selected from Pd, Pd/C, palladium acetate, Pd(OH)2, platinum oxide, platinum black, Raney Ni, Rh/C, Ru, Ir, conc.HCl and the like optionally in combination with hydrogen; the suitable acid is acetic acid; and the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents or mixtures thereof.

The compound of general formula-11 obtained in the fourth aspect of the present invention can be further converted to (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1 according to the process disclosed in the first aspect of the present invention.

The fifth aspect of the present invention provides a process for the preparation of (1 S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

a) Condensing the compound of general formula-18 with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-10a in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-22,

b) reacting the compound of formula-22 with a-substituted chiral benzylamine as mentioned in step-c) of the first aspect in a suitable solvent to provide compound of general formula-23,

c) dehydrating the compound of formula-23 by treating it with a suitable dehydrating agent optionally in presence of a suitable base in a suitable solvent to provide compound of general formula-20„

d) reducing the compound of formula-20 with a suitable reducing agent in a suitable solvent to provide compound of general formula-21,

e) deprotecting the compound of formula-21 by treating it with a suitable deprotecting agent in a suitable solvent to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1.

Wherein, in step-a) the suitable coupling agent, the suitable base and the suitable solvent are same as defined for step-h) of the first aspect of the present invention;

In step-b) the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents or mixtures thereof;

In step-c) the suitable dehydrating agent, the suitable base and the suitable solvent are same as defined for step-i) of the first aspect of the present invention;

In step-d) the suitable reducing agent is selected from sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, lithium borohydride, Pd/C, Pt/C, Pt02, Raney Ni, sodium bis(2-methoxyethoxy)aluminum hydride (vitride), diisobutylaluminium hydride (DIBAL or DIBAL-H) and the like; the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, alcoholic solvents, polar solvents or mixtures thereof;

In step-e) the suitable deprotecting agent and the suitable solvent are same as defined for step-j) of the first aspect of the present invention.

The compound of general formula-18 utilized in the condensation step-a) of the fifth aspect of the present invention can be synthesized by treating the corresponding hydroxy compound with a suitable protecting agent, wherein the hydroxy compound can be synthesized by any of the processes known in the art.

The sixth aspect of the present invention provides a process for the preparation of compound of general formula-21, comprising of;

a) Condensing the compound of general formula-18 with (lS,3S,5S)-2-azabicyclo[3.1.0] hexane-3-carboxamide hydrochloride salt compound of formula-10a in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-22,

b) reacting the compound of formula-22 with a-substituted chiral benzylamine as mentioned in step-c) of the first aspect in a suitable solvent to provide compound of general formula-*23,

c) reducing the compound of formula-23 with a suitable reducing agent in a suitable solvent to provide compound of general formula-24,

d) dehydrating the compound of formula-24 by treating it with a suitable dehydrating agent optionally in presence of a suitable base in a suitable solvent to provide compound of general formula-21.

The seventh aspect of the present invention provides a process for the preparation of compound of general formula-24, comprising of;

a) Reacting the compound of general formula-18 with a-substituted chiral benzylamine as mentioned in step-c) of the first aspect in a suitable solvent to provide compound of general formula-25,

b) reducing the compound of formula-25 with a suitable reducing agent in a suitable solvent to provide compound of general formula-26,

c) condensing the compound of general formula-26 with (1 S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-10a in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-24.

Wherein, the suitable coupling agent, the suitable base and the suitable solvent used in step-a) and step-c) respectively of the sixth and seventh aspects are same as defined for step-h) of the first aspect of the present invention;

The suitable solvent used in step-b) & step-a) respectively of the sixth and seventh aspects is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents or mixtures thereof;

The suitable reducing agent and the suitable solvent used in step-c) & step-b) respectively of the sixth and seventh aspects are same as defined for step-d) of the fifth aspect of the present invention;

The suitable dehydrating agent, the suitable base and the suitable solvent used in step-d) of the sixth aspect are same as defined for step-i) of the first aspect of the present invention.

The eighth aspect of the present invention provides a process for the preparation of compound of general formula-23, comprising of;

a) Reacting the compound of general formula-18 with a-substituted chiral benzylamine as mentioned in step-c) of the first aspect in a suitable solvent to provide compound of general formula-25,

b) condensing the compound of formula-25 with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-10a in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide compound of general formula-23.

Wherein, in step-a) the suitable solvent is selected form alcoholic solvents, chloro solvents, ether solvents, ester solvents, hydrocarbon solvents or mixtures thereof;

In step-b) the suitable coupling agent, the suitable base and the suitable solvent are same as defined for step-h) of the first aspect of the present invention.

The ninth aspect of the present invention provides a process for the preparation of adamantyl aldehyde compound of formula-4 comprising, oxidizing the adamantyl methanol compound of formula-3 with a suitable oxidizing agent optionally in presence of a suitable base and a suitable catalyst in a suitable solvent to provide adamantyl aldehyde compound of formula-4.

Wherein, the suitable oxidizing agent is selected from sodium hypochlorite, trichloroisocyanuric acid (TCICA), bis(acetoxy)iodo benzene (BAIB), pyridinium chlorochromate, chromium trioxide, N-chlorosuccinimide (NCS), oxone and the like; the suitable catalyst wherever necessary is selected from (2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO), 4-hydroxy-TEMPO, 4-acetamido TEMPO and the like; the suitable base wherever necessary is selected from organic and inorganic bases, preferable alkali metal bicarbonates; and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, polar-aprotic solvents or mixtures thereof;

A preferred embodiment of the present invention provides a process for the preparation of adamantyl aldehyde compound of formula-4 comprising, oxidizing the adamantyl methanol compound of formula-3 with sodium hypochlorite in presence of sodium bicarbonate, (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and a catalytic amount of potassium bromide in dichloromethane to provide adamantyl aldehyde compound of formula-4.

The tenth aspect of the present invention provides a novel process for the preparation of compound of formula-8, comprising of;

a) N-Protection of glycine by treating it with di-tert.butyl dicarbonate in presence of a suitable base in a suitable solvent to provide N-Boc protected glycine compound of formula-27,

b) reacting the compound of formula-27 with (R)-4-phenyloxazolidin-2-one in a suitable solvent to provide (S)-tert-butyl 2-oxo-2-(2-oxo-4-phenyloxazolidin-3-yl)ethylcarbamate compound of formula-28,

c) reacting the compound of formula-28 with adamantyl bromide compound of formula-29 in presence of a suitable base in a suitable solvent to provide compound of formula-3 0,

d) hydrolyzing the compound of formula-30 in presence of a suitable base in a suitable solvent to provide compound of formula-8.

Wherein, in step-a) the suitable base and the suitable solvent are same as defined for step-f) of the first aspect of the present invention;

In step-b) the suitable solvent is selected form hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents, ketone solvents or mixtures thereof;

In step-c) the suitable base is selected from organic bases and organosilicon bases; and the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents or mixtures thereof;

In step-d) the suitable base is selected from hydroxides, alkoxides and carbonates of alkali metals; and the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents or mixtures thereof.

The eleventh aspect of the present invention provides a novel process for the preparation of compound of formula-8, comprising of;

a) Reacting the adamantyl bromide compound of formula-29 with (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine compound of formula-31 in presence of a suitable base in a suitable solvent to provide compound of formula-32,

b) treating the compound of formula-32 with a suitable acid in a suitable solvent to provide methyl ester compound of formula-33,

c) treating the compound of formula-33 with di-tert-butyl dicarbonate in presence of a suitable base in a suitable solvent provides Boc protected compound of formula-42,

d) hydrolyzing the compound of formula-42 in presence of a suitable base in a suitable solvent to provide carboxylic acid compound of formula-8.

Wherein, in step-a) the suitable base is selected from organic bases and organosilicon bases; and the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents or mixtures thereof;

In step-b) the suitable acid is hydrochloric acid; and the suitable solvent is selected from ester solvents, ether solvents, chloro solvents, polar-aprotic solvents or mixtures thereof;

In step-c) the suitable base is selected from organic and inorganic bases and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents or mixtures thereof;

In step-d) the suitable base is selected from hydroxides, alkoxides, bicarbonates of alkali metals and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents or mixtures thereof;

The (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine compound of formula-31 utilized in step-a) of the eleventh aspect of the present invention is commercially available or it can be synthesized by the methods known in the art for example Org. Process Res. Dev., 2005, 9(2), 185-187, Tetrahedron: Asymmetry 1998, 9, 321-327.

The compounds of formulae-7 & 8 obtained in the eleventh and tenth aspects respectively can be converted to (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1 as per the process disclosed in the first aspect of the present invention.

The twelfth aspect of the present invention provides a process for the preparation of (lS,3S,5S)-2-azabicyclo[3.1.0]hexan-3-ylmethanamine hydrochloride compound of formula-14, comprising of;

a) Reducing the (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2-carboxylic acid compound of formula-34 with a suitable reducing agent in a suitable solvent to provide (S)-tert-butyl 2-(hydroxymethyl)-2,3-dihydro-lH-pyrrole-l-carboxylate of formula-35,

b) mesylation of compound of formula-35 with methane sulfonyl chloride in presence of a suitable base in a suitable solvent to provide (S)-tert-butyl 2-((methylsulfonyloxy)methyl)-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-36,

c) azidation of compound of formula-36 by treating with a suitable azide source in a suitable solvent to provide (S)-tert-butyl 2-(azidomethyl)-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-37,

d) reducing the compound of formula-37 with a suitable reducing gent in a suitable solvent to provide (S)-tert-butyl 2-(aminomethyl)-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-38,

e) treating the compound of formula-38 with a suitable methylene source in presence of a suitable catalyst in a suitable solvent to provide (lS,3S,5S)-tert-butyl 3-(aminomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-39,

f) deprotecting the compound of formula-39 with hydrochloric acid in a suitable solvent to provide (lS,3S,5S)-2-azabicyclo[3.1.0]hexan-3-ylmethanamine hydrochloride compound of formula-14.

Wherein, in step-a) the suitable reducing agent is selected from sodium borohydride-BF3.etherate, sodium cyanoborohydride, lithium aluminium hydride, lithium borohydride, borane-dimethyl sulfide, sodium bis(2-methoxyethoxy)aluminum hydride (vitride), diisobutyl aluminium hydride (DIBAL) and the like; the suitable solvent is selected from alcoholic solvents, ether solvents, chloro solvents, hydrocarbon solvents, ester solvents, polar solvents or mixtures thereof.

In step-b) the suitable base is selected from organic and inorganic bases; the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents or mixtures thereof;

In step-c) the suitable azide source is selected from sodium azide, diphenylphosphoryl azide (DPPA), bis(p-nitrophenyl)phosphorazidate, tosyl azide, trifluoromethanesulfonyl azide, azidotrimethylsilane, hydrogen azide (HN3) and the like; the suitable solvent is selected from ether solvents, polar-aprotic solvents, chloro solvents, hydrocarbon solvents, ester solvents or mixtures thereof.

In step-d) the suitable reducing agent is selected from NaBEL*, UAIH4, H2/Lindlar catalyst, Z11/NH4CI, dichloroindium hydride, Fe/AICk, Fe/BiCl3, triphenyl phosphine (Staudinger reaction), hydroiodic acid; the suitable solvent is selected from alcoholic solvents, ether solvents, chloro solvents, hydrocarbon solvents, ester solvents or mixtures thereof.

In step-e) the suitable methylene source is selected from diiodomethane, chloro iodomethane and the suitable catalyst is diethyl zinc; the suitable solvent is selected from hydrocarbon solvents, ether solvents, chloro solvents, ester solvents or mixtures thereof.

In step-f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents or mixtures thereof.

The thirteenth aspect of the present invention provides a process for the preparation of (lS,3S,5S)-N-benzyl-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt compound of formula-16, comprising of;

a) Reacting the (S)-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrrole-2-carboxylic acid compound of formula-34 with benzylamine in presence of a suitable coupling agent optionally in presence of a suitable base in a solvent to provide (S)-tert-butyl 2-(benzylcarbamoyl)-2,3-dihydro-1 H-pyrrole-1 -carboxylate compound of formula-40,

b) treating the compound of formula-40 with a suitable methylene source in presence of a suitable catalyst in a suitable solvent to provide (lS,3S,5S)-tert-butyl 3-(benzylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-41,

c) deprotecting the compound of formula-41 with hydrochloric acid in a suitable solvent to provide (1 S,3 S,5S)-N-benzyl-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride compound of formula-16.

Wherein, in step-a) the suitable coupling agent, the suitable base and the solvent are same as defined in step-h) of first aspect of the present invention;

In step-b) the suitable methylene source, the suitable catalyst and the suitable solvent are same as described for step-e) of the twelfth aspect of the present invention;

In step-c) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, ketone solvents, polar solvents or mixtures thereof.

The (1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo
[3.1.0]hexane-3-carbonitrile obtained in the present invention is in the form of monohydrate.

The (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo
[3.1.0]hexane-3-carbonitrile compound of formula-1 and its hydrochloride salt compound of formula-la obtained by the present invention when treated with ethylene glycol or 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 following impurities are identified by the present inventors in (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.

(IS, 3S, 5S)-2-((2S)-2-Amino-2-(3-hydroxyadamantan-l-yl) acetyl)-2-azabicyclo [3.1.0] hexane-3carbaxamide hydrochloride (Amide impurity), (IS, 3S, 5S)-2-((2R)-2-Amino-2-(3-hydroxyadamantan-l-yl)acetyl)-2-azabicyclo [3.1.0] hexane-3carbonitrile (RSSS impurity), (IS, 3S, 5S)-2-[(2S)-2-amino-2-(adamantan-l-yl)-acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile (Deshydroxy impurity), (1 aS,4S,6aR,7aS)-4-(( 1 R,3R,5R,7S)-3-Hydroxyadamantan-1 -yl)-6-iminohexahydro-1 H-cyclopropa[4,5]pyrrolo[ 1,2-a]-pyrazin-3( 1 aH)-one (Cyclic amidine impurity), (IS, 3S, 5S)-2-((2S)-2-amino-2-(4-oxo-adamantan-l-yl)acetyl)-2-azabicyclo[3.1.0] hexane-3-carbonitrile (keto impurity), Ter-butyl (S)-2-((lS,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-1 -(3-hydroxyadamantan-1 -yl)2-oxoethylcarbomate (boc protected impurity).

The(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 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 urn 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 ratio 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 um Nylon membrane filter paper and sonicated to degas it; Mobile phase-A: Buffer; Mobile phase-B: Buffer: Acetonitrile (40:60 v/v).

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:

Scheme-Ill:

Scheme-V:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples: Example-1: Preparation of adamantyl 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 the completion of the reaction, the reaction mixture was cooled to 0-5°C and water (2000 ml) was slowly added at the same temperature. Conc.HCl (150 ml) followed by dichloromethane (2000 ml) 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 (1000 ml) was added to the aqueous layer and stirred for 30 min. Separated the organic and aqueous layers and a solution of sodium bicarbonate (100 gm) in water (1000 ml) was added to the total organic layer. 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 at 50-55°C. Filtered the precipitated solid, washed with dichloromethane and dried to get title compound. 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 25-3 5°C and the resulting reaction mixture was stirred for 2 hrs at the same temperature. The obtained solid was filtered, washed with pet ether and then dried at 50-55°C to get the title compound as a pure solid. 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 2lA 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 2!/2 hrs at the same temperature. Slowly added triethylamine (1000 ml) to the reaction mixture at -78°C and stirred for VA hrs at the same temperature. After the 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 (1500 ml) was added to the reaction mixture at 25-3 5°C and stirred for 45 min at the same temperature. Both the organic and aqueous layers were separated, dichloromethane (750 ml) was added to the aqueous layer at 25-3 5°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and a solution of sodium chloride (75 gm) in water (1500 ml) 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 at below 50-55 °C to get the title compound as a residue. Example-4: Preparation of adamantyl aldehyde (Formula-4)

Sodium bicarbonate (151.7 gm) was added to a solution of adamantyl methanol compound of formula-3 (100 gm) in dichloromethane (800 ml) at 25-30°C and stirred for 15 min at the same temperature. Potassium bromide (14.4 gm) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to -10°C to -5°C, a solution of 0.2 gm of (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) in dichloromethane (20 ml) was added to the reaction mixture and stirred for 15 min at the same temperature. Slowly added sodium hypochlorite (408 ml) to the reaction mixture at -10°C to -5°C and stirred for 30 min at the same temperature. After completion of the reaction, 10% sodium thiosulfate solution and water were added to the reaction mixture at below 10°C and stirred for 15 min at the same temperature. 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 30% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 97.0 gm. Example-5: Preparation of phenylglycinol adamantane nitrile (Formula-5a)

Water (3000 ml) and sodium metabisulfite (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 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 25-3 5°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 25-35°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: 206 gm. Example-6: Purification of phenylglycinol adamantane nitrile (Formula-5a)

Phenylglycinol adamantane nitrile compound of formula-5a (205 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-7: Preparation of phenylglycinol adamantane carboxylic acid (Formula-6a)

Phenylglycinol adamantane nitrile compound of formula-5a (150 gm), acetic acid (450 ml) and cone. HC1 (750 ml) were charged in to a clean and dry RBF at 25-35°C. The reaction mixture was heated to 80-85°C and stirred for 12 hrs at the same temperature. After the completion of the reaction, the reaction mixture was completely distilled off at 80-85°C. Cooled the reaction mixture to 0-5°C and water (750 ml) was added and stirred for 2 hrs at the same temperature. The obtained solid was filtered, washed with water and then dried to get the title compound as hydrochloride salt. Yield: 130 gm. Example-8: Preparation of amino adamantane carboxylic acid hydrochloride (Formula-7a)

Phenylglycinol adamantane carboxylic acid compound of formula-6a (50 gm), methanol (500 ml), acetic acid (500 ml) and 5% Pd/C (50 gm) were charged in to a clean and dry autoclave vessel and 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 the 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 at 50-55°C. Added methyl tert.butyl ether (250 ml) to the obtained gummy solid at 25-35°C and stirred for P/2 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-9: Preparation of boc-protected amine compound of formula-8

Amino adamantane carboxylic acid hydrochloride salt compound of formula-7a (100 gm) was added to a mixture of water (1000 ml) and sodium carbonate (108 gm) at 25-30°C. Di-tert.butyl dicarbonate (134 gm) was slowly added to the reaction mixture at 25-3 0°C and stirred for 22 hrs at the same temperature. After completion of the reaction, ethyl acetate was added to the reaction mixture at 25-30°C and cooled the reaction mixture to 0-5°C. Adjusted the pH of the reaction mixture to 3.5 using aqueous hydrochloric acid solution at 0-5°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Distilled off the solvent completely from the combined organic layer under reduced pressure and co-distilled with pet ether. 300 ml of pet ether was added to the obtained solid at 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with pet ether and dried to get the title compound. Yield: 90.0 gm; SOR: (+) 20.1°(C=1% in methanol).

Example-10: Preparation of compound of formula-9a

A mixture of water (2500 ml) and potassium hydroxide (26.7 gm) was stirred for 20 min at 25-30°C. Compound of formula-8 (100 gm) was added to the reaction mixture at 25-30°C.
Potassium permanganate (102 gm) was added to the reaction mixture at 0-5°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25-3 0°C and stirred for 20 hrs at the same temperature. After completion of the reaction, 25% sodium thiosulfate solution was slowly added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. Filtered the reaction mixture and washed with water. Adjusted the pH of the filtrate to 3.0 using aqueous hydrochloric acid at 0-5°C and stirred for 30 min at the same temperature. Methyl isobutyl ketone was added to the reaction mixture at 0-5°C and stirred for 45 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water followed by methyl isobutyl ketone. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with ethyl acetate. 150 ml of ethyl acetate was added to the obtained solid, heated the reaction mixture to 60-65°C and stirred for 60 min at the same temperature. Reduced the temperature of the reaction mixture to 25-3 0°C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 56.0 gm. Example-11: Purification of compound of formula-9a

Compound of formula-9a (50 gm) was added to ethyl acetate (80 ml) at 25-30°C and stirred for 20 min at the same temperature. Heated the reaction mixture to 70-75°C and stirred for 60 min at the same temperature. Slowly cooled the reaction mixture to 0-5°C and stirred for 4 hrs at the same temperature. Filtered the precipitated solid, washed with chilled ethyl acetate and dried to get the pure title compound. Yield: 40.0 gm.

Example-12: Preparation of (2S)-l-tert-butyl 2-ethyl 5-hydroxypyrrolidine-l,2-dicarboxylate (Formula-44)

Sodium borohydride (22 gm) was slowly added to a pre-cooled solution of (S)-l-tert-butyl 2-ethyl 5-oxopyrrolidine-l,2-dicarboxylate compound of formula-43 (100 gm) in methanol (500 ml) at -10°C to -15°C and stirred for 60 min at the same temperature. After completion of the reaction, 1% sodium bicarbonate solution and dichloromethane were added to the reaction mixture at -10°C 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 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-13: Preparation of (S)-l-tert-butyl 2-ethyl 2,3-dihydro-lH-pyrroIe-l,2-dicarboxylate (Formula-45)

Dichloromethane (1000 ml) was added to (2S)-l-tert-butyl 2-ethyl 5-hydroxypyrrolidine-1,2-dicarboxylate compound of formula-44 obtained in example-12 at 25-30°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to -65°C to -70°C, diisopropylethyl amine (250 gm) was slowly added and stirred for 20 min at the same temperature. Slowly added trifluoroacetic anhydride (122 gm) to the reaction mixture at -65°C to -70°C and stirred for 30 min at the same temperature. Slowly raised the temperature of the reaction mixture to 20-25°C and stirred for 3 hrs at the same temperature. After completion of the reaction, water was slowly added to the reaction mixture at 25-30°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water. 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: 100.0 gm.

Example-14: Preparation of (S)-tert-butyl 2-carbamoyl-2,3-dihydro-lH-pyrrole-l-carboxylate (Formula-46)

Formamide (50 gm) was added to (S)-l-tert-butyl 2-ethyl 2,3-dihydro-lH-pyrrole-l,2-dicarboxylate compound of formula-45 obtained in example-13 at 25-30°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C, sodium methoxide solution (200 ml) was added and stirred for 4 hrs at the same temperature. After completion of the reaction, water and cyclohexane were added to the reaction mixture at 0-5 °C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°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 dichloromethane. Dried the organic layer over sodium sulfate and washed with dichloromethane. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with cyclohexane. Cyclohexane (300 ml) was added to the obtained residue 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: 48.0 gm; Specific optical rotation: (-)137.5°.

Example-15: Preparation of (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (Formula-47)

Diiodomethane (15.1 ml) and 20% diethyl zinc solution (58 ml) were slowly added to a mixture of (S)-tert-butyl 2-carbamoyl-2,3-dihydro-lH-pyrrole-l-carboxylate compound of formula-46 (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 and extracted the aqueous layer with ethyl acetate. Distilled off the solvent completely from the combined 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-16: Preparation of (S)-tert-butyl 2-carbamoyl-2,3-dihydro-lH-pyrrole-l-carboxylate (Formula-46) Formamide (50 gm) was added to (S)-l-tert-butyl 2-ethyl 2,3-dihydro-lH-pyrrole-l,2-dicarboxylate compound of formula-45 obtained in example-13 at 25-30°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C, sodium methoxide solution (200 ml) was added and stirred for 4 hrs at the same temperature. After completion of the reaction, water and cyclohexane were added to the reaction mixture at 0-5 °C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25-3 0°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 dichloromethane. Dried the organic layer over sodium sulfate and washed with dichloromethane. Distilled off the solvent completely from the organic layer under reduced pressure. Diiodomethane (72 ml) and 20% diethyl zinc solution (278.5 ml) were slowly added to the obtained compound. Toluene (950 ml) and 1,2-dimethoxy ethane (66.25 ml) were 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 25-3 0°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 and extracted the aqueous layer with ethyl acetate. Distilled off the solvent completely from the combined organic layer under reduced pressure and co-distilled with pet ether. To the obtained residue, pet ether (240 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: 31.0 gm.

Example-17: Preparation of (lS,3S,5S)-2-azabicyclo[3.1.0)hexane-3-carboxamide hydrochloride salt (Formula-lOa)

Hydrochloric acid (25 ml, 2.5M solution in ethyl acetate) was added to a solution of (lS,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-47 (5 gm) in tetrahydrofuran (20 ml) at 25-30°C and stirred for 18 hrs at the same temperature. After completion of the reaction, methyl tertbutyl ether was added to the reaction mixture at 25-30°C and stirred for 30 min at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and dried to get the title compound. Yield: 3.6 gm. Example-18: Preparation of compound of formula-lla

Ethyl acetate-HCl (1500 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-47 (100 gm) in tetrahydrofuran (400 ml) at 25-3 0°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 and 1-hydroxybenzotriazole (60 gm) was added to a solution of adamantyl compound of formula-9a (135 gm) in acetonitrile (425 ml) and ethyl acetate (200 ml) in another RBF at 0-5°C and stirred for 10 min at the same temperature. N,N'-Dicyclohexylcarbodiimide (109.5 gm) was added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. To the obtained reaction mixture, the above obtained solid followed by diisopropylethyl amine (237 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 (1000 ml) and dichloromethane (1000 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. Toluene (300 ml) was added to the obtained residue at 35-40°C and stirred for 30 min at the same temperature. Reduced the temperature of the reaction mixture to 25-3 0°C and filtered. The filtrate was slowly added to n-heptane (900 ml) at 25-3 0°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 170.0 gm; Example-19: Preparation of compound of formula-12a

Trifluoroacetic acetic anhydride (121.5 gm) was slowly added to a mixture of amide compound of formula-lla (100 gm), ethyl acetate (1000 ml) and 2,6-lutidine (99 gm) at 0-5°C and stirred for 60 min at the same temperature. Another 25 gm of 2,6-lutidine and 24 gm of trifluoroacetic anhydride were slowly added to the reaction mixture at 0-5 °C and stirred for 60 min at the same temperature. Quenched the reaction mixture with water at below 10°C and slowly raised the temperature of the reaction mixture 25-3 0°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and water was added to the organic layer. Cooled the reaction mixture to 5-10°C and the pH of the reaction mixture was slowly adjusted to 2.5 using hydrochloric acid. Both the organic and aqueous layers were separated. Potassium carbonate solution followed by methanol (300 ml) were added to the reaction mixture at 10-15°C and stirred for 10 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 10% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Methanol (150 ml) was added to the obtained solid at 25-3 0°C and stirred for 10 min at the same temperature. Isopropyl alcohol (150 ml) was added to the reaction mixture at 25-30°C and stirred for 30 min at the same temperature. Carbon (10 gm) was added to the reaction mixture at 25-30°C and stirred for 60 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol followed by isopropyl alcohol. Water (1000 ml) was slowly added to the filtrate at 25-3 0°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 60.0 gm; Purity by HPLC: 97.8%.

ExampIe-20: Preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (Formula-1)

Acetyl chloride (57 gm) was slowly added to a solution of compound of formula-12a (100 gm) in methanol (400 ml) at 0-5°C and stirred for 10 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 10-15°C. Water (1000 ml) was slowly added to the reaction mixture at 10-15°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25-3 0°C, dichloromethane (300 ml) was added and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and dichloromethane (500 ml) was added to the aqueous layer. Slowly adjusted the pH of the reaction mixture to 10.0 using potassium carbonate solution at 10-15°C and stirred for 30 min at the same temperature. Sodium chloride was added to the reaction mixture at 10-15°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Distilled off the solvent completely from the organic layer under reduced pressure at below 40°C. Ethyl acetate (400 ml) was added to the obtained solid at 25-30°C, heated the reaction mixture to 35-40°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 25-30°C, water (100 ml) was added and stirred for 20 min at the same temperature. Cooled the reaction mixture to 0-5° and stirred for 3 hrs at the same temperature. Filtered the solid, washed with a mixture of chilled ethyl acetate and water and dried to get the title compound. Yield: 60.0 gm.

Example-21: Purification of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile(Formula-l)

Methanol (150 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 (100 gm) at 25-30°C and stirred for 20 min at the same temperature. Carbon (10 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 (170 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: 60.0 gm; Water content: 5.3% w/w;

Purity by HPLC: 99.97%; Deshydroxy impurity: Not detected; RSSS impurity: Not detected; Cyclic amidine impurity: 0.01%; Keto impurity: 0.05%; Amide impurity: 0.07%; Boc proteccted impurity: Not detected.

Particle size distribution: D(0.1) is 3.99 urn; D(0.5) is 16.45 urn; D(0.9) is 42.02 urn, D(4,3) is 20.54 urn.

Example-22: Preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl] -2-azabicyclo [3.1.0] hexane-3-carbonitrile (Formula-1)

Acetyl chloride (57 gm) was slowly added to a solution of compound of formula-12a (100 gm) in methanol (400 ml) at 0-5°C and stirred for 10 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 10-15°C. Water (1000 ml) was slowly added to the reaction mixture at 10-15°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C, dichloromethane (300 ml) was added and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and dichloromethane (500 ml) was added to the aqueous layer. Slowly adjusted the pH of the reaction mixture to 10.0 using potassium carbonate solution at 10-15°C and stirred for 30 min at the same temperature. Sodium chloride was added to the reaction mixture at 10-15°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Distilled off the solvent completely from the organic layer under reduced pressure at below 40°C. Ethyl acetate (200 ml) was added to the obtained compound at 25-30°C and stirred for 30 min at the same temperature. Distilled off the solvent completely under reduced pressure. To the obtained compound, isopropyl alcohol (100 ml) and water (250 ml) were added at 25-30°C and stirred for 15 min at the same temperature. Heated the reaction mixture to 40-45 °C and stirred for 30 min at the same temperature. Carbon (10 gm) was added to the reaction mixture at 40-45 °C and stirred for 45 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with a mixture of isopropyl alcohol and water. Cooled the filtrate to 25-30°C and stirred for 60 min at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred for 4 hrs at the same temperature. Filtered the precipitated solid, washed with chilled water and dried to get the pure title compound. Yield: 35.0 gm.

Particle size distribution: D(0.1) is 14.49 um; D(0.5) is 36.91 um; D(0.9) is 73.53 urn, D(4,3) is 40.76 um; Specific surface area: 0.509 m7g.

Example-23: 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 (Formula-la)

(1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile compound of formula-1 (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.

Example-24: 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 (Formula-la)

Acetyl chloride (57 gm) was slowly added to a pre-cooled solution of compound of formula-12a in isopropyl alcohol (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. Heated the reaction mixture to 60-65°C and stirred for 4 hrs at the same temperature. Water (100 ml) was added to the reaction mixture at 60-65°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 25-3 0°C and stirred for 6 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound.

Yield: 75.0gm. Water content: 9.3% w/w.

Particle size distribution: D(0.1) is 3.15 um; D(0.5) is 11.02 urn; D(0.9) is 32.27 urn, D(4,3) is 15.35 um; Specific surface area: 1.01 m2/g.

Example-25: Preparation of (lS,3S,5S)-2-[(2S)-2-ainino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride (Formula-la)

Acetyl chloride (60 gm) was slowly added to a solution of compound of formula-12a (100 gm) in methanol (400 ml) at 0-5°C and stirred for 10 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid to get the title compound. Yield: 70 grams; 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.

Example-26: Purification of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride (Formula-la)

(1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile hydrochloride (100 gm) was added to a mixture of methanol (200 ml) and water (100 ml) at 25-30°C and stirred for 20 min at the same temperature. Filtered the reaction mixture, isopropyl alcohol (1500 ml) was slowly added to the filtrate at 25-30°C and stirred for 5 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the pure title compound.

Yield: 90.0 gm; Purity by HPLC: 99.98%; Water content: 9.4% w/w. Example-27: Preparation of compound of formula-33

n-Butyl lithium (5.2 ml) was slowly added to a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine compound of formula-31 (1.3 gm) in tetrahydrofuran (10 ml) at -75°C to -80°C and stirred for 1 hr at the same temperature. A solution of adamantyl bromide (1.0 gm) in tetrahydrofuran (5 ml) was slowly added to the reaction mixture at -75°C to -80°C. Raised the temperature of the reaction mixture to 0-5 °C and stirred for 6 hrs at the same temperature. 2N hydrochloric acid (10 ml) was added to the reaction mixture at 0-5°C and stirred for 2 hrs at the same temperature. The reaction mixture was slowly added to chilled saturated sodium bicarbonate solution. Dichloromethane was added to the obtained reaction mixture and both the organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic layer was washed with water. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 0.7 gm. Example-28: Preparation of compound of formula-42

Slowly added di-tert.butyl dicarbonate (0.52 gm) to a solution of compound of formula-33 (0.5 gm), 4-dimethylaminopyridine (0.15 gm) in dichloromethane (10 ml) at 25-30°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and washed with IN hydrochloric acid. 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 to get the title compound. Yield: 0.7 gm. Example-29: Preparation of compound of formula-8

Lithium hydroxide hydrate (0.1 gm) was added to a solution of compound of formula-42 (0.5 gm) in methanol (3 ml) and water (2 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 7 hrs at the same temperature. Water (10 ml) and methyl tert.butyl ether (5 ml) were added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated, dichloromethane (15 ml) was added to the aqueous layer at 0-5°C. Adjusted the pH of the reaction mixture to 3.0 using phosphoric acid. 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 to get title compound. Yield: 0.3 gm. Example-30: Preparation of compound of formula-17a

Ethyl acetate-HCl (75 ml) was slowly added to a solution of (lR,3R,5R)-tert-butyl 3-(benzylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate compound of formula-41 (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 and hydroxybenzotriazole (2 gm) was added to a solution of adamantyl intermediate compound of formula-9a (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 (3.7 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 (8 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. Toluene (15 ml) was added to the obtained residue at 35-40°C and stirred for 30 min at the same temperature. Reduced the temperature of the reaction mixture to 25-30°C and filtered. The filtrate was slowly added to n-heptane (45 ml) at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 6.0 gm. Example-31: Preparation of compound of formula-lla

Compound of formula-17a (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 hyflow 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 hyflow bed at 25-3 5°C and washed with methanol. Distilled off the solvent from the filtrate under reduced pressure at 50-55°C and co-distilled with methyl tert.butyl ether. 25 ml of methyl tert.butyl ether was added to the obtained solid at 25-35°C and stirred for 3 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: 2.8 gm.

We Claim:

1) A process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

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 with oxalyl chloride/dimethyl sulfoxide in presence of triethylamine in dichloromethane to provide adamantyl aldehyde compound of formula-4,

c) treating the compound of formula-4 in-situ with sodium cyanide/acetone cyanohydrin in presence of sodium bisulfite/sodium meta bisulfite in water followed by treating with R-(-)-2-phenyl glycinol in methanol to provide compound of formula-5a,

d) hydrolyzing the compound of formula-5a in presence of cone, hydrochloric acid in acetic acid to provide compound of formula-6a or its hydrochloride salt,

e) treating the compound of formula-6a or its hydrochloride salt with Pd/C in presence of acetic acid in methanol to provide compound of formula-7a or its hydrochloride salt,

f) treating the compound of formula-7a or its hydrochloride salt with di-tert.butyl dicarbonate in presence of sodium carbonate in water to provide Boc-protected amine 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 compound of formula-9a,

h) condensing the compound of formula-9a with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane:3-carboxamide hydrochloride salt compound of formula-10a in presence of N,N'-dicyclohexylcarbodiimide (DCC)/l-hydroxybenzotriazole (HOBt) and diisopropylethyl amine in a mixture of ethyl acetate and acetonitrile to provide compound of formula-1 la,

i) dehydrating the compound of formula-11a by treating with trifluoroacetic anhydride in presence of 2,6-lutidine in ethyl acetate to provide compound of formula-12a,

j) deprotecting the compound of formula-12a by treating it with acetyl chloride in methanol followed by treating with potassium carbonate to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile compound of formula-1.

2) A process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride compound of formula-la, comprising of;

a) Condensing the compound of formula-9a with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-10,

or its hydrochloride salt compound of formula-10a in presence of N,N'-dicyclohexyl carbodiimide (DCC) optionally in combination with l-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), l-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxy succinamide (HOSu) or 4-dimethylaminopyridine (DMAP) in presence of a suitable organic or inorganic base in a suitable solvent selected from ester solvents, nitrile solvents, polar-aprotic solvents, alcoholic solvents, ether solvents, chloro solvents or their mixtures to provide compound of formula-1 la,

b) dehydrating the compound of formula-11 a by treating it with a suitable dehydrating agent selected from acetic anhydride, trifluoroacetic anhydride (TFAA), phosphorous pentoxide, phosphoryl chloride, phosphoric acid, sulfuric acid, dicyclohexyl carbodiimide optionally in presence of a suitable organic or inorganic base in a suitable solvent selected from ether solvents, ester solvents, chloro solvents, hydrocarbon solvents or their mixtures to provide nitrile compound of formula-12a,

c) deprotecting the compound of formula-12a by treating it with acetyl chloride in a suitable alcohol solvent to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride compound of formula-la.)

3) A process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

a) Condensing the compound of formula-9a with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamide compound of formula-10 or its hydrochloride salt compound of formula-10a in presence of N,N'-dicyclohexylcarbodiimide (DCC) optionally in combination with l-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol-l -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), 4-dimethylaminopyridine (DMAP) and in presence of a suitable organic or inorganic base in a suitable solvent selected from ester solvents, nitrile solvents, polar-aprotic solvents, alcoholic solvents, ether solvents, chloro solvents or their mixtures to provide compound of formula-1 la,

b) dehydrating the compound of formula-1 la by treating it with a suitable dehydrating agent selected from acetic anhydride, trifluoroacetic anhydride (TFAA), phosphorous pentoxide, phosphoryl chloride, phosphoric acid, sulfuric acid, dicyclohexyl carbodiimide optionally in presence of a suitable organic or inorganic base in a suitable solvent selected from ether solvents, ester solvents, chloro solvents, hydrocarbon solvents or their mixtures to provide compound of formula-12a,

c) deprotecting the compound of formula-12a by treating it with acetyl chloride in a suitable alcohol solvent followed by in-situ treating with alkali metal carbonate to provide (1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile compound of formula-1.

4) A process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of;

a) Condensing the compound of formula-9a with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride compound of formula-10a in presence of N,N'-dicyclohexyl carbodiimide (DCC) in combination with 1-hydroxybenzotriazole (HOBt) and diisopropylethyl amine in a mixture of ethyl acetate and acetonitrile to provide compound of formula-11 a,

b) dehydrating the compound of formula-1 la by treating it with trifluoroacetic anhydride in presence of 2,6-lutidine in ethyl acetate to provide nitrile compound of formula-12a,

c) deprotecting the compound of formula-12a by treating it with acetyl chloride in methanol followed by in-situ treating with potassium carbonate to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3 -hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1.

5) A process for preparing the compound of formula-11 a, comprising of condensing the compound of formula-9a with (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide compound of formula-10 or its hydrochloride salt compound of formula-10a in presence of N,N'-dicyclohexyl carbodiimide (DCC) in combination with 1-hydroxybenzotriazole (HOBt) in presence of a base in a suitable solvent selected from ether solvents, ester solvents, nitrile solvents, chloro solvents, hydrocarbon solvents or mixtures thereof to provide compound of formula-11a.

6) A process for preparing (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1, comprising of deprotecting the compound of formula-12a by treating it with acetyl chloride in a suitable alcoholic solvent followed by treating with a suitable base selected from alkali metal carbonates and alkali metal bicarbonates to provide (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3 -carbonitrile compound of formula-1.

7) A process for the preparation of compound of formula-8, comprising of;

a) Reacting the (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine compound of formula-31 with adamantyl bromide in presence of a suitable base selected from organic bases and organosilicon bases in a suitable solvent selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents or mixtures thereof to provide adamantyl pyrazine compound of formula-32,

b) treating the compound of formula-32 with a suitable acid to provide methyl ester compound of formula-3 3,

c) treating the compound of formula-3 3 with di-tert-butyl dicarbonate in presence of a suitable organic or inorganic base in a suitable solvent selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents or their mixtures to provide compound of formula-42,

d) hydrolyzing compound of formula-42 in presence of a suitable base selected from hydroxides, alkoxides, bicarbonates of alkali metals in a suitable solvent selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, alcohol solvents or mixtures thereof to provide compound of formula-8.

8) A process for the purification of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile compound of formula-1 comprising of purifying the compound of formula-1 from a mixture of water and C1-C5 alcoholic solvent.

9) A process for the purification of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride salt compound of formula-la, comprising of;

a) Dissolving the compound of formula-1 a in a mixture of methanol and water,

b) adding isopropyl alcohol to the reaction mixture,

c) filtering the precipitated solid to get pure (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy adamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride salt compound of formula-la.

10) (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane- 3-carbonitrile compound of formula-1 or its hydrochloride salt compound of formula-la having keto impurity in an amount of less than 0.5% by HPLC, preferably less than 0.1% by HPLC.

11) Compound having the structural formula