WO2013175395A2

WO2013175395A2 - Improved process for preparation of saxagliptin and its salts

Info

Publication number: WO2013175395A2
Application number: PCT/IB2013/054167
Authority: WO
Inventors: Ganesh Varanasi; Prabhakar Macharla; Chandrasekhar Vempati; Rakeshwar Bandichhor; Vilas Hareshwar Dahanukar; Javed Iqbal; Srinivas ORUGANTI; Rajesh Kumar Rapolu; Munaswamy Sekhar Nariyam; Srinivasan Neti
Original assignee: Dr Reddys Laboratories Ltd
Current assignee: Dr Reddys Laboratories Ltd
Priority date: 2012-05-21
Filing date: 2013-05-21
Publication date: 2013-11-28
Anticipated expiration: 2014-11-21
Also published as: WO2013175395A3

Description

IMPROVED PROCESS FOR PREPARATION OF SAXAGLIPTIN AND ITS

SALTS

INTRODUCTION

Aspects of the present application relate to improved processes for preparing saxagliptin or its salt and intermediates thereof.

The drug compound having the adopted name "saxagliptin" has chemical names: (1 S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1 .1³'⁷]dec-1 -yl)acetyl]-2- azabicyclo[3.1 .0]hexane-3-carbonitrile; or (1 S,3S,5S)-2-[(2S)-2-Amino-2-(3- hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1 .0]hexane-3-carbonitrile; and has the structure of formula I.

I

The commercial pharmaceutical product ONGLYZA® tablets contain saxagliptin hydrochloride as the active ingredient. Saxagliptin is a dipeptidyl peptidase-4 inhibitor useful as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. U.S. Patent No. 6,395,767 discloses saxagliptin and its pharmaceutically acceptable salts. Processes for the preparation of saxagliptin and its salts have been disclosed in U.S. Patent Nos. 6,395,767, 7,420,079, 7,741 ,082 and by S. A. Savage et al., "Preparation of Saxagliptin, a Novel DPP-IV Inhibitor," Organic Process Research & Development, Vol. 13, No. 6, pages 1 169-1 176 (2009).

Reported processes for the preparation of saxagliptin involve the condensation of (aS)-a[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo- [3.3.1 .1³,7]decane-1 -acetic acid and (1 S,3S,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamide hydrochloride salt in the presence of N-hydroxybenzotriazole (HOBT) to provide 3-amino carbonyl-(aS)-a-(3-hydroxytricyclo[3.3.1 .1³,7]dec-1 -yl)-3-oxo- (1 S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1 ,1 -dimethylethyl ester, which upon subjected to dehydration using trifluoro acetic anhydride or triethylsilyl triflate to give trifluoro acetate or triethylsilyl oxy compound of formula la. Hydrolysis of compound of formula la using strong base such as sodium hydroxide, potassium hydroxide and lithium hydroxide or using corrosive reagents such as phosphorus oxychloride to give compound of formula lb. Deprotection of compound of formula lb using trifluoroacetic acid or hydrochloric acid followed by treating with base to give saxagliptin of the formula I or its salt.

la lb

wherein R is trifluoroacetyl or triethylsilyl

The above processes suffer from disadvantages including the use of multiple reagents for simple conversions, lengthy workup procedures, long reaction times, low yields, and low product quality. For example, hydrolysis of compound of formula la involves use of multiple reagents (sodium hydroxide, aqueous potassium carbonate), tedious workup procedures (extraction of compound into ethyl acetate layer, washing with buffer solution two times, washing with brine solution, washing with aqueous bicarbonate solution, washing with half saturated brine solution, distillation of organic layer, isolation of compound from heptane), long reaction time (about 8 hours) at lower temperature, low yield (about 73%), low product quality (96.6%).

These disadvantages make the process expensive and industrially unviable.

Thus, there remains a need to provide improved processes for saxagliptin or its salt, which is simple, economic and industrially viable.

SUMMARY

In first aspect, the present application relates to an improved process for the preparation of saxagliptin or its salt, which includes one or more of the following steps: (a) reacting an adamantyl compound of formula II with an azabicyclo compound of formula III in the presence of a coupling agent to provide a compound of formula IV,

wherein P is an amine-protecting group;

(b) converting a compound of formula IV to a compound of formula V in the presence of trifluoroacetic anhydride or an equivalent thereof;

(v;

(c) treating the compound of formula V in the presence of an organic base to obtain compound of formula VI; and

(VI)

(d) deprotecting the compound of formula VI to form saxagliptin or a salt thereof.

In second aspect, the present application relates to a process for the preparation of saxagliptin or its salt, which includes one or more of the following steps: (a) converting a compound of formula IV to a compound of formula V in the presence of trifluoroacetic anhydride or an equivalent thereof;

(v;

wherein P is amine protecting group.

(b) treating the compound of formula V in the presence of an organic base to obtain compound of formula VI; and

(VI)

(c) deprotecting the compound of formula VI to form saxagliptin or a salt thereof.

In third aspect, the present application relates to an improved process for preparation of 2-azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula III or its acid addition salt, which include one or more of the following:

a) protecting the L-pyroglutamic acid ester of formula VII with an amino- protecting group to provide an N-protected L-pyroglutamic acid ester of formula VIII:

wherein P is an amine-protecting group and R is C C₆ alkyl;

b) reducing the compound of formula VII I in the presence of reducing reagent to provide an alcohol compound of formula IX;

HO^ _^COOR IX

wherein P and R is defined above

c) dehydrating compound of formula IX in the presence of dehydrating agent to provide 2, 3-dihydro pyrrole compound of formula X;

X

wherein P and R is defined above

d) converting compound of formula X to carboxamide com ound of formula XI

a. ^{X XI} wherein P and R is defined above

e) cyclopropanation of compound of formula XI to provide azabicyclo compound of formula XII.

XII

wherein P is an amine-protecting group

f) deprotecting the compound of formula XII to provide 2-zabicyclo [3.1 .0] hexane-3-carboxamide compound of formula II or its acid addition salt.

g) optionally converting the 2-azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula III or its acid addition salt obtained in step (f) in to another acid addition salt of compound of the formula III.

In fourth aspect, the present application relates to process for the preparation of adamantyl compound of formula II, which includes one or more of the following steps: a) treating 1 -adamatanaol with 3-ethoxy-3-oxopropanoic acid to provide acid compound of formula XIII,

XIII

b) converting acid compound of formula XIII to amide compound of formula XIV,

XIV

c) converting amide compound of formula XIV to amino acid compound of formula XV,

XV

d) esterification of compound of formula XV to provide ester compound of formula XVI,

XVI e) treating the compound of formula XVI with suitable resolution reagent to provide compound of formula XVII,

XVII f) protecting the compound of formula XVII with an amino- protecting group to provide an N-protected compound of formula XVIII,

XVIII g) hydroxylation of compound of formula XVIII to provide hydroxyl compound of formula XIX; and

XIX

h) hydrolysis of compound of formula XIX to provide adamantyl compound of formula II.

DETAILED DESCRIPTION

In first aspect, the present application relates to an improved process for preparation of saxagliptin or its salt, which includes one or more of the following steps:

(a) reacting the adamantyl compound of formula II with an azabicyclo compound of formula III in the presence of a coupling agent to provide an amide compound of formula IV,

wherein P is an amine-protecting group;

(v;

(VI)

Step (a) of first aspect involves the reacting compound of formula II with the compound of formula III, in the presence of a coupling agent, to provide the compound of formula IV.

The compound of formula II I may be used either in its free base form or as its acid addition salt. Suitable acid addition salts include, but not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid, nitric acid; organic acids such as formic acid, acetic acid, propanoic acid, tartaric acid, oxalic acid, maleic acid, mandellic acid, malonic acid, methane sulphonic acid, p-toluene sulphonic acid or trifluoroacetic acid or any other suitable acid.

Suitable coupling agents that may be used in step (a) include, propylphosphonic anhydride (T3P), 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT), 4- (4,6-Dimethoxy-1 ,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), N- hydroxybenzotriazole (HOBT), 4,5-dicyanoimidazole, dicyclohexylcarbodiimide (DCC), dicyclopentylcarbodiimide, diisopropylcarbodiimide, 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC HCI), 1 ,1 '- carbonyldiimidazole, cyclohexylisopropylcarbodiimide (CIC), bis[[4-(2,2-dimethyl-1 ,3- dioxolyl)]methyl] carbodiimide, N,N'-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-CI), an acid chloride, ethyl chloroformate, and the like or the any two or more reagents combination thereof or any other suitable reagents known in the art.

Suitable bases that may be used in step (a) include, organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N- diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, and the like.

Step (a) may be optionally carried out in the presence of a suitable catalyst, such as, for example, triethylamine, pyridine, diisopropylethylamine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,4-diazabicyclo[2.2.2]octane (DABCO), 1 - methylmorpholine, 1 -methylpiperidine, 1 ,5-diazabicyclo[4.3.0]non-5-ene, N,N- dimethylpiparazine, Ν,Ν-dimethylaniline, 4-(dimethylamino)-pyridine (DMAP), hexamethylenetetramine (HMTA), tetramethylethylenediamine (TMEDA), collidine, 2,3,5,6-tetramethylpyridine (TEMP), and the like.

Suitable solvents that may be used in step (a) include alcohols, ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.

Suitable temperature that may be used in step (a) may be less than about 100^<€, less than about 70^<€, less than about 40 °C, less than about 30^<€, less than about 10^<€, less than about 0 °C, less than about -10°C, less than about -20 °C, or any other suitable temperature.

The reaction mixture obtained from step (a) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (a) may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (b) or it may be isolated as a solid. The isolation of the step (a) product may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, and the like. Stirring or other alternate methods, such as for example, shaking, agitation, and the like, that mix the contents may also be employed for isolation. Steps (b) to (d) of the first aspect and steps (a) to (c) of the second aspect are same. Hence all the reaction conditions, solvents, reagents, etc. used/defined in steps (b) to (d) are applicable for steps (a) to (c) of the second aspect respectively.

Step (b) involves the converting a compound of formula IV to a compound of formula V in the presence of trifluoroacetic anhydride or an equivalent thereof.

Optionally compound of formula IV may be converted to a compound of VI using suitable reagents include propylphosphonic anhydride (T3P), diethyl chlorophosphate, phosphorus pentoxide, titanium tetrachloride, thionyl chloride, triphenylphosphine, diphosgene, (methoxycarbonylsulfamoyl) triethylammonium hydroxide, ethyl iodide, acetic anhydride, formic acid, organotin oxides, pivaloyl chloride, aluminium chloride, palladium chloride, dichlorophosphate and the like.

Suitable solvents that may be used in step (b) include alcohols, ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane or mixtures of thereof.

Suitable temperature that may be used in step (b) may be less than about 130^<€, less than about 100°C, less than about 70^<€, less than about 40^<€, less than about 20^<€, less than about 10°C, less than about -10 °C, less than about -20 °C, or any other suitable temperature.

The reaction mixture obtained in step (b) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (b) may be isolated directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, the obtained crude product may be directly used for step (c) or it may be isolated as a solid. The isolation of the product of step (b) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Step (c) involves the treating the compound of formula V in the presence of an organic base to obtain compound of formula VI. Suitable bases that are used in step (c) include, methyl amine, ethyl amine, diethyl amine, triethyl amine, tributyl amine, diisopropyl ethyl amine, N-methyl pyrrolidine, N-methyl morpholine, 4-(N,N-dimethylamino) pyridine, morpholine and the like or any other suitable organic bases known in the art.

Suitable solvents that may be used in step (c) include alcohols, ketones, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane or mixtures thereof.

Suitable temperature that may be used in step (c) may be less than about 130^<€, less than about 100°C, less than about 70^<€, less than about 40^<€, less than about 20^<€, less than about 10°C, less than about -10 °C, less than about -20°C, or any other suitable temperature.

The reaction mixture obtained in step (c) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (c) may be isolated directly from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, the obtained crude product may be directly used for step (d) or it may be isolated as a solid. The isolation of the product of step (c) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation

Step (d) involves deprotecting the compound of formula VI to form saxagliptin or a salt thereof.

Suitable deprotection techniques that may be used in step (d) include, catalytic hydrogenation using hydrogen gas in the presence of a metal, including Raney nickel, palladium on carbon, and the like; or hydrolysis using an acid or base; or with any other suitable deprotection techniques known in the art.

Optionally, catalytic hydrogenation may be carried out in the presence of one or more suitable reagents. Suitable reagents that may be used include, but are not limited to, acids, bases, resins, and any mixtures thereof, either alone or as their solutions in water, organic solvents or their mixtures. Suitable acids that may be used in step (d) include, organic acids, including acetic acid, formic acid, propionic acid, butyric acid, isobutyric acid, fumaric acid, oxalic acid, tartaric acid, citric acid, and the like; and inorganic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p- toluenesulfonic acid, and the like. Suitable bases that may be used in step (d) include, inorganic bases, including ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like; and organic bases, such as triethylamine, pyridine, N-methylmorpholine, diisopropylamine, diisopropylethylamine, and the like. Suitable resins that may be used in step (d) include, ion exchange resins, such as: resins bound to metal ions, including lithium, sodium, potassium, and the like; and resins bound to acids, including phosphoric, sulfonic, methanesulfonic, p-toluenesulfonic, and the like.

Suitable solvents that may be used in step (d) include water, alcohols, ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane or mixtures thereof.

Suitable temperature that may be used for the reaction in step (d) may be less than about 130^<€, less than about 100°C, less than about 70°C, less than about 40 ^<€, less than about 20^<€, less than about 10^<€, less than about -I CO, less than about -20 °C, or any other suitable temperature.

The reaction mixture obtained in step (d) may optionally be processed to remove any insoluble solids or particles by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids. The product so obtained may be isolated as a solid directly from the reaction mixture after the reaction is complete in step (d), or after conventional work up; by techniques such as filtration, quenching with a suitable reagent, extraction, and the like. The said isolation may include removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation. .

The resulting compound may be in the form of a crystalline compound, a solvate, an amorphous compound, or a mixture thereof. The solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150^<€, less than about 120°C, less than about 100°C, less than about 60 °C, less than about 40 °C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere, such as nitrogen, argon, neon, or helium. The drying may be carried out for desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.

Optionally suitable salt of saxagliptin may be prepared by adding suitable compound (which form salt with the saxagliptin) to the solution containing saxagliptin base or by adding the suitable compound (which form salt with saxagliptin) to the reaction mixture obtained from the step (d).

Suitable salts that may be prepared from saxagliptin include, but are not limited to, water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine (Ν,Ν'- dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate, hexylresorcinate, hydrabamine (Ν,Ν'- bis(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, 1 -hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, iodide, isothionate (2-hydroxyethanesulfonate), lactate, lactobionate, laurate, lauryl sulfate, lithium, magnesium, malate, maleate, mandelate, meglumine (1 -deoxy-1 - (methylamino)-D-glucitol), mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate (4,4'-methylenebis-3-hydroxy-2-naphthoate, or embonate), pantothenate, phosphate, picrate, polygalacturonate, potassium, propionate, p- toluenesulfonate, salicylate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate (8-chloro-3,7-dihydro-1 ,3- dimethyl-1 H-purine-2,6-dione), triethiodide, tromethamine (2-amino-2- (hydroxymethyl)-1 ,3-propanediol), valerate, zinc salts, and 2-fluoroethyl quaternary ammonium trifluoroacetates. Optionally the product obtained from step (d), which comprises saxagliptin of the formula I or its salt may be further purified by recrystallization, slurrying in a suitable solvent, acid-base treatment, column chromatography, treating with adsorbent materials such as, but not limited to, silica gel, aluminium oxide, synthetic resin, and the like; or any other suitable techniques.

Suitable solvents that may be used for purification of saxagliptin of formula I or its salt include, alcohols, ketones, esters, ethers, unsubstituted or substituted aliphatic or alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, water; and any mixtures of two or more thereof.

The product thus obtained may be recovered as solid using conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art. The resulting compound may be in the form of a crystalline compound, a solvate, an amorphous compound, or a mixture thereof. The solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150^, less than about 120°C, less than about 100^<€, less than about 60 °C, less than about 40 °C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere, such as nitrogen, argon, neon, or helium. The drying may be carried out for desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.

Optionally the steps (a) to (d) of first aspect and/or the steps (a) to (c) of second aspect may be carried out in-situ, i.e. without isolating the intermediates formed in one or more stages.

Saxagliptin or its salt, preferably hydrochloride salt of Saxagliptin of the formula (I) obtained according to the process of the present invention may be substantially free of one or more of its corresponding impurities e.g., amide impurity of formula (XX), cyclic amidine impurity of formula (XXI), BOC protected saxagliptin of formula (XXII) (when BOC is used as amine protecting group) and Deshydroxy Saxagliptin of the formula (XXIII). For example each impurity in Saxagliptin or its salt obtained according to the process of the present invention may be present in an amount of less than about 5% or less than about 3% or less than about 2% or less than about 1 % or less than about 0.5% or less than about 0.3% or less than about

xx XXI XXIII A high performance liquid chromatography (HPLC) method for the analysis of the amide impurity of formula (XX), cyclic amidine impurity of formula (XXI), BOC protected saxagliptin of formula (XXII) and Deshydroxy Saxagliptin of the formula (XXIII) utilizes a C 18 or equivalent column and additional parameters are described below.

Column : Agilent Poroshell 120 SB C18, 100 x 4.6 mm,

2.7 micron

Flow : 0.90ml_ /min

Column Oven Temperature : 40 *C

Wave length : 215 nm

Injection volume : 10 μΙ_

Run Time : 67 min

Diluent : Mixture of Mobile phase A: Mobile phase B in the ratio 7:3

Elution : Gradient

Gradient program:

In third aspect, the present application relates to an improved process for preparation of 2-azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula III or its acid addition salt, which includes one or more of the following steps: (a) protecting the L-pyroglutamic acid ester of formula VII with an amino- protecting group to provide an N-protected L-pyroglutamic acid ester of formula VIII:

VII VIII

wherein P is an amine-protecting group and R is CrC₆ alkyl;

(b) reducing the compound of formula VIII in the presence of reducing reagent to provide an alcohol compound

IX

wherein P and R is defined above

(c) dehydrating compound of formula IX in the presence of dehydrating agent to provide 2, 3-dihydro pyrrole compound of formula X;

X

wherein P and R is defined above

(d) converting compound of formula X to carboxamide compound of formula XI

X XI

wherein P and R is defined above

(e) cyclopropanation of compound of formula XI to provide azabicycio compound of formula XII.

XI]

wherein P is an amine-protecting group

(f) deprotecting the compound of formula XI I to provide 2-zabicyclo [3.1 .0] hexane-3-carboxamide compound of formula I I or its acid addition salt.

(g) Optionally converting the 2-azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula I II or its acid addition salt obtained in step (f) in to another acid addition salt of compound of the formula I II.

Step (a) involves protecting the L-pyroglutamic acid ester of formula VI I with an amino- protecting group to provide an N-protected L-pyroglutamic acid ester of formula VI I I.

Suitable protecting groups that may be used in step (a) include, trityl having phenyl groups that may be substituted with groups including, for example, monomethoxy, dimethoxy, or 4,4'-dimethoxy; trifluoroacetyl; 9H-fluoren-9- ylmethoxycarbonyl (FMOC); alkyloxycarbonyl such as t-butyloxycarbonyl; or any other suitable protecting group. Suitable protecting groups may be derived from halo carbonates such as (C₆ -Ci₂)aryl; lower alkyl carbonates such N-benzyloxycarbonyl; biphenyl alkyl halo carbonates; tertiary alkyl halo carbonates such as tertiary-butyl halo carbonates; tertiary butyl chlorocarbonate; di(lower)alkyl dicarbonates {e.g., di(t- butyl)-dicarbonate); or phthalates.

Suitable solvents that may be used in step (a) include ethers, nitriles, halogenated hydrocarbons, aromatic hydrocarbons, water or mixtures thereof.

Step (b) involves reducing the compound of formula VII I in the presence of reducing reagent to provide an alcohol compound of formula IX.

Suitable reduction techniques that may be used in step (b) include, for example, catalytic hydrogenation; reduction by a an alkali metal hydride, such as sodium borohydride, lithium aluminum hydride, sodium trimethoxy borohydride, Lithium borohydride, acetoxyborohydride, cyanoborohydride, sodium dihydro-bis-(2- methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, 9- borabicyclo(3.3.1 )nonane (9-BBN), or the like; sodium dithionite in alkaline medium; a combination thereof; or any other suitable reducing agent known in the art.

Suitable solvents that may be used in step (b) include ethers, alcohols, halogenated hydrocarbons, aromatic hydrocarbons or any mixtures of two or more thereof.

Suitable temperatures that may be used for the reaction of (b) may be less than about 150^<€, less than about 130°C, less than about 1 10°C, less than about 80 °C, less than about 60 ^<€, less than about 30^<€, less than about 0°C, less than about -20 °C, less than about -40 °C, less than about -60^<€, less than about -80^<€, or any other suitable temperatures.

The reaction mixture obtained in step (b) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids. The product of step (b) may be isolated directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally the obtained crude product may be directly used for the step (c) or may be isolate as solid. The isolation in step (b) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Step (c) involves dehydrating compound of formula IX in the presence of dehydrating agent to provide 2, 3-dihydro pyrrole compound of formula X.

Suitable solvents that may be used in step (c) include ethers, halogenated hydrocarbons, aromatic hydrocarbons or mixtures thereof.

Suitable dehydrating reagents that may be used in step (c) include, trifluoroacetic anhydride, methanesulfonyl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, 2,6-lutidine, N,N-diisopropylethylamine, 4- dimethylaminopyridine, triethylamine, hexamethylphosphoramide, or resins like Tulsion T-66, Sepabeads SP207, ADS 551 , SL-668, PVC resinBI O, hydrophobic silicon dioxide and MMJ-106MQ or the like; or any other suitable reagent known in the art. Optionally, step (c) may be carried out without using a solvent or a reagent; using an inert heat transfer medium like silicon oil with or without any added reagent; or any other conditions known in the art. Suitable temperatures that may be used for the reaction of (c) may be less than about 250 °C, less than about 200 °C, less than about 150°C, less than about -130 °C, less than about 120°C, less than about 100^<€, less than about 90°C, less than about 80 °C, or any other suitable temperatures.

The reaction mixture obtained in step (c) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids. The product of step (c) may be isolated directly from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally the obtained crude product may be directly used for the next step or may be isolate as solid. The isolation in step (c) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Step (d) involves converting compound of formula X to carboxamide compound of formula XI.

Suitable reagents that may be used in step (d) include formamide, hydrazine hydrate, ammonia or any other suitable ammonia source known in the art.

Suitable solvents that be used in step (d) include, water, alcohols, ethers, halogenated hydrocarbons, aromatic hydrocarbons or mixtures thereof.

Suitable temperature that may be used for the reaction of (d) may be less than about 120^<€, less than about 100°C, less than about 80°C, less than about 60 ^<€, less than about 50 °C, less than about 40^<€, less than about 30^<€, less than about 20 °C, or any other suitable temperature.

Step (e) involves cyclopropanation of compound of formula XI to provide azabicyclo compound of formula XII.

Suitable reagents that may be used in step (e) include diiodomethane, chloroiodomethane, Simmons-Smith reagent, or any other suitable reagent known in the art. Suitable catalysts that may be used in step (e) include diethyl zinc, zinc- copper, or any other suitable reagent known in the art.

Suitable solvents that may be used in step (e) include, ethers, formamide, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide, dimethylsulphoxide, halogenated hydrocarbons, aromatic hydrocarbons or mixtures thereof.

Suitable temperature that may be used for the reaction of (e) may be less than about 120^<€, less than about 100°C, less than about 80°C, less than about 60 ^<€, less than about 50 °C, less than about 40^<€, less than about 30^<€, less than about 20 °C, or any other suitable temperature.

The reaction mixture obtained in step (e) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids. The product of step (e) may be isolated directly from the reaction mixture itself after the reaction is complete in step (e), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. The isolation in step (e) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Step (f) involves deprotecting the compound of formula XII to provide 2- zabicyclo [3.1 .0] hexane-3-carboxamide compound of formula III or its acid addition salt.

Step (f) may be carried out using any suitable deprotection technique, including, for example, catalytic hydrogenation using hydrogen gas in the presence of a metal, including Raney nickel, palladium on carbon, and the like; or hydrolysis using an acid or base; or any other suitable deprotection agents known in the art. Suitable reagents that may be used for deprotection include, acids, bases, resins, or mixtures thereof, either alone or as their solutions in water, organic solvents or their mixtures. Suitable acids that may be used in step (f) include but are not limited to: organic acids, including acetic acid, formic acid, propionic acid, butyric acid, isobutyric acid, fumaric acid, oxalic acid, tartaric acid, citric acid, and the like; and inorganic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulphonic acid, and the like. Suitable bases that may be used in step (f) include but are not limited to: inorganic bases, including ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like; and organic bases, such as triethylamine, pyridine, N-methylmorpholine, diisopropylamine, diisopropylethylamine, and the like. Suitable resins that may be used in step (f) include, but are not limited to, ion exchange resins, such as: resins bound to metal ions, including lithium, sodium, potassium, and the like; and resins bound to acids, including phosphoric, sulphonic, methanesulphonic, p- toluenesulphonic, and the like.

Suitable solvents that may be used in step (f) include water, alcohols, ketones, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles, or mixtures thereof.

Step (f) may be carried out at suitable temperature may be less than about 150^<€, less than about 100°C, less than about 60^<€, less than about 40 ^<€ or any other suitable temperature.

Optionally, step (f) may be carried out at atmospheric pressure or under pressure. Suitable pressures that may be used are less than about 10 kg/cm², less than about 5 kg/cm², less than about 3 kg/cm², less than about 1 kg/cm², or any other suitable pressures.

Ste (g) involves optionally converting the 2-azabicyclo[3.1 .0]hexane-3- carboxamide compound of formula III or its acid addition salt obtained in step (f) in to another acid addition salt of compound of the formula III.

Suitable acids that may be used for the preparation of acid addition salt of 2- azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula II I include but not limited to acetic acid, trifluoro acetic acid, formic acid, propionic acid, butyric acid, isobutyric acid, fumaric acid, oxalic acid, tartaric acid, citric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulphonic acid, and the like.

Optionally the product obtained in Step (e), step (f) or step (g) may be further purified by using purification techniques known in the art, for example using column chromatography or various types of isolation methods including recrystallization, slurry in solvent, crystallization by adding an anti-solvent to a solution and the like or any other suitable purification techniques known in the art. Suitable solvents that may be used for the purification of the compound obtained in Step (e), step (f) or step (g) include, but not limited to water; alcohols, ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.

In fourth aspect, the present application relates to process for the preparation of adamantyl compound of formula II, which includes one or more of the following steps:

a) treating 1 -adamatanaol with 3-ethoxy-3-oxopropanoic acid to provide acid compound of formula XIII,

XIII

b) converting acid compound of formula XIII to amide compound of formula XIV,

XIV

XV

XIX

Step (a) involves treating 1 -adamatanaol with 3-ethoxy-3-oxopropanoic acid to provide acid compound of formula XIII,

Suitable reagents that may be used in step (a) include, Lewis acids such as boron trifluoride diethyl etherate, boron trifluoride tert-butyl methyl etherate, boron trifluoride methyl etherate, aluminum isopropoxide or the like or any other suitable reagent.

Suitable solvents that may be used in step (a) include halogenated hydrocarbons solvents, ethers, aromatic hydrocarbon solvents or the mixtures thereof.

Step (b) involves converting acid compound of formula XIII to amide compound of formula XIV

Suitable methods that are used for the step (b) include use of suitable coupling agent such as for example DCC, HOBt, EDC HCI and the like or by converting acid compound to acid chloride using suitable reagents such as for example thionyl chloride and the like and then reaction with amine to provide amide or any other suitable methods known in the art.

Suitable solvents that may be used in step (b) include halogenated hydrocarbon solvents, ethers, aromatic hydrocarbon solvents or the mixtures thereof.

Step (c) involves the converting amide compound of formula XIV to amino acid compound of formula XV.

Suitable reagents that are used in step (c) include sodium hypohalite such as for example sodium hypochlorite, sodium hypobromite, sodium hypoiodite or the like or any other suitable reagent known in the art.

Suitable bases that are used in step (c) include alkali and alkaline earth metal hydroxides such as for example sodium hydroxide, potassium hydroxide, lithium hydroxide and the like or any other suitable base.

Suitable solvents that may be used in step (c) include halogenated hydrocarbon solvents, ethers, aromatic hydrocarbon solvents or the mixtures thereof.

Step (d) involves esterification of compound of formula XV to provide ester compound of formula XVI.

Suitable reagents that may be used in step (d) include thionyl chloride, sulfuric acid, dry hydrochloric acid or the like.

Step (e) involves treating the compound of formula XVI with suitable resolution reagent to provide compound of formula XVII.

Suitable resolution reagents that are used in step (e) include, di-benzoyl-L- tartaric acid, di-p-toluoyl-L-tartaric acid, di-pivaloyl-L-tartaric acid and the like or any suitable resolution reagent known in the art.

Suitable solvents that may be used in step (e) include halogenated hydrocarbon solvents, ethers, alcohols, ketones, aromatic hydrocarbon solvents or the mixtures thereof.

Step (f) involves protecting the compound of formula XVII with an amino- protecting group to provide an N-protected compound of formula XVIII,

Suitable protecting groups that may be used in step (f) include, trityl having phenyl groups that may be substituted with groups including, for example, monomethoxy, dimethoxy, or 4,4'-dimethoxy; trifluoroacetyl; 9H-fluoren-9- ylmethoxycarbonyl (FMOC); alkyloxycarbonyl such as t-butyloxycarbonyl; or any other suitable protecting group. Suitable protecting groups may be derived from halo carbonates such as (C₆ -Ci₂)aryl; lower alkyl carbonates such N-benzyloxycarbonyl; biphenyl alkyl halo carbonates; tertiary alkyl halo carbonates such as tertiary-butyl halo carbonates; tertiary butyl chlorocarbonate; di(lower)alkyl dicarbonates {e.g., di(t- butyl)-dicarbonate); or phthalates.

Suitable solvents that may be used in step (f) include, but not limited to: ethers, nitriles, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, water or any mixtures of two or more thereof.

Step (g) involves hydroxylation of compound of formula XVI II to provide hydroxyl compound of formula XIX; and

Suitable reagents that are used for the step (g) include, KMn0₄ and KOH, hydrogen peroxide, sodium hypohalite in the presence of metal catalysts such as for example RuCI₃ and the like or any other suitable reagents known in the art.

Suitable solvents that may be used in step (g) include esters, ketones, ethers, halogenated hydrocarbon solvents, water or mixture thereof.

Step (h) involves the hydrolysis of compound of formula XIX to provide adamantyl compound of formula II.

Suitable reagents that may be used in step (h) include acids such as hydrochloric acid, sulfuric acid and the like or the bases such as alkali and alkaline earth metal hydroxides such as for example sodium hydroxide, potassium hydroxide, lithium hydroxide and the like or any other suitable base.

Suitable solvents that are used in step (h) include, water, alcohols, ethers, halogenated hydrocarbon solvents, aliphatic hydrocarbon solvents or mixtures thereof.

Optionally the product obtained in steps (a) to step (h) may be further purified by using purification techniques known in the art, for example using column chromatography or various types of isolation methods including recrystallization, slurry in solvent, crystallization by adding an anti-solvent to a solution and the like or any other suitable purification techniques known in the art.

Suitable solvents that may be used for the purification of the compound obtained in steps (a) to step (h) include water; alcohols, ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or mixtures thereof. DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated "C_x-C_y", where x and y are the lower and upper limits, respectively. For example, a group designated as "CrC₆" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of any substituents, such as alkoxy substitutions or the like.

An "alcohol" is an organic compound containing a carbon bound to a hydroxyl group. "Ci-C₆ alcohols" include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, and the like.

An "aliphatic hydrocarbon" is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called "aromatic." Examples of C₅-C₈ aliphatic or aromatic hydrocarbons include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3- dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3- trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, and the like.

"Amine-protecting group" refers to a radical that, when attached to a nitrogen atom in a target molecule, is capable of surviving subsequent chemical reactions applied to the target molecule, i.e., hydrogenation, reaction with acylating agents, alkylation, etc. The amine-protecting group can later be removed. Amine-protecting groups include, but are not limited to, fluorenylmethoxycarbonyl (FMOC), tert- butoxycarbonyl (t-BOC), benzyloxycarbonyl (Z), those of the acyl type {e.g., formyl, benzoyl, trifluoroacetyl, p-tosyl, aryl- and alkylphosphoryl, phenyl- and benzylsulfonyl, o-nitrophenylsulfenyl, o-nitrophenoxyacetyl), and of the urethane type {e.g. tosyloxyalkyloxy-, cyclopentyloxy-, cyclohexyloxy-, 1 ,1 -dimethylpropyloxy, 2-(p- biphenyl)-2-propyloxy- and benzylthiocarbonyl). Amine-protecting groups are made using a reactive agent capable of transferring an amine-protecting group to a nitrogen atom in the target molecule. Examples of an amine-protecting agent include, but are not limited to, CrC₆ aliphatic acid chlorides or anhydrides, C₆-Ci₄ arylcarboxylic acid chlorides or anhydrides, t-butyl chloroformate, di-tert-butyl dicarbonate, butoxycarbonyloxyimino-2-phenylacetonitrile, t-butoxycarbonyl azide, t- butyl fluoroformate, fluorenylmethoxy carbonyl chloride, fluorenylmethoxycarbonyl azide, fluorenylmethoxycarbonyl benzotriazol-1 -yl, (9- fluorenylmethoxycarbonyl)succinimidyl carbonate, fluorenylmethoxycarbonyl pentafluorophexoxide, trichloroacetyl chloride, methyl-, ethyl-, trichloromethyl- chloroformate, and other amine protecting agents known in the art. Examples of such known amine-protecting agents are found in T. W. Green, P. G. M. Wuts, "Protective Groups in Organic Synthesis, Second Edition," Wiley-lnterscience, New York, pages 385-397, 1991 .

An "ester" is an organic compound containing a carboxyl group -(C=0)-0- bonded to two other carbon atoms. "C₃-C₆ esters" include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and the like.

An "ether" is an organic compound containing an oxygen atom -O- bonded to two carbon atoms. "C₂-C₆ ethers" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like.

A "halogenated hydrocarbon" is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 , 1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, and the like.

A "ketone" is an organic compound containing a carbonyl group -(C=0)- bonded to two other carbon atoms. "C₃-C₆ ketones" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, and the like.

A "nitrile" is an organic compound containing a cyano -(C≡N) bonded to another carbon atom. "C₂-C₆ nitriles" include, but are not limited to, acetonitrile, propionitrile, butanenitrile, and the like.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to encompass all such changes and modifications that are within the scope of this disclosure.

EXAMPLES

EXAMPLE 1 : Preparation of carbamic acid, N-[(1S)-2-[(1S,3S,5S)-3- cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.1³'⁷]dec-1-yl)-2- oxoethyl]-, 1 ,1-dimethylethyl ester. 2-Azabicyclo[3.1 .0]hexane-3-carboxamide, (1 S,3S,5S)-, methanesulfonate (120 g), (aS)-a [[(1 , 1 -Dimethylethoxy) carbonyl] amino]-3-hydroxytricyclo [3.3.1 .1^{3, 7}] decane-1 -acetic acid (175 g), 1 -Ethyl-3-(3- dimethylaminopropyl)carbodiimide. HCI (126 g), Hydroxybenzotriazole (61 .8 g), toluene (600 mL) and acetonitrile (240 mL) are placed into a round bottom flask. Diisopropylethylamine (189 mL) was slowly added to the reaction mass and thus obtained reaction mixture was stirred at 30 °C for 5 hours. Potassium bicarbonate solution (prepared by dissolving 60 g of potassium bicarbonate in 600 mL of water) and toluene (600 mL) was added to the reaction mixture at 30 °C and stirred for 30 minutes. The aqueous and organic layers are separated, aqueous layer extracted with toluene (2x600 mL) and total organic layer was washed with 0.5 N HCI solution (600 mL). Total organic layer is concentrated up to reaction mass volume reaches to 10 volumes at below 55 °C under reduced pressure. Toluene (1200 mL) and ethylnicotinate (240 mL) was added to the reaction mixture at 29 °C and stirred for 15 minutes. Trifluoroacetic anhydride (153 mL) was slowly added to the reaction mixture at 12 °C over 75 minutes. Water (1050 mL) was added to the reaction mixture at 15 °C and stirred for 15 minutes. Triethylamine (315 mL) was added to the reaction mixture at 20 °C and stirred for 20 minutes. The aqueous and organic layers are separated, organic layer was washed with 2N HCI solution (500 mL). Total organic layer solvent was evaporated at below 55 °C under reduced pressure. Resultant crude was chased with methanol (2x600 mL) at below 50 °C under reduced pressure. Charged methanol (670 mL), heated to 50 °C and stirred at 50 °C for 10 minutes. Triethylamine (91 .5 mL) was added to the crude compound at 28 °C and stirred at 28 °C for 2 hours 20 minutes. Water (2235 mL) was added slowly to the reaction mass at 28 °C and stirred at 28 °C for 40 minutes. Separated solid was filtered, washed with water (450 mL). Charged wet compound, methanol (640 mL) into round bottom flask and stirred for 20 minutes. Water (1600 mL) was slowly added to the reaction mixture at 28 °C and stirred at same temperature for 40 minutes. Separated solid was filtered, washed with water (320 mL) and dried at 68 °C under reduced pressure for 6 hours to afford 144.0 g of title compound.

EXAMPLE 2: Preparation of carbamic acid, N-[(1S)-2-[(1S,3S,5S)-3- cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.1^3,7]dec-1-yl)-2- oxoethyl]-, 1 ,1-dimethylethyl ester. 2-Azabicyclo[3.1 .0]hexane-3-carboxamide, (1 S,3S,5S)-, methanesulfonate (400 g), (aS)-a [[(1 , 1 -Dimethylethoxy) carbonyl] amino]-3-hydroxytricyclo [3.3.1 .1^{3, 7}] decane-1 -acetic acid (590 g), 1 -Ethyl-3-(3- dimethylaminopropyl)carbodiimide. HCI (420 g), Hydroxybenzotriazole (206 g), toluene (2 L) and acetonitrile (800 mL) are placed into a reactor. Diisopropylethylamine (630 mL) was slowly added to the reaction mass and thus obtained reaction mixture was stirred at 30 °C for 5 hours. Potassium bicarbonate solution (prepared by dissolving 200 g of potassium bicarbonate in 2 L of water) and toluene (2 L) was added to the reaction mixture at 30 °C and stirred for 20 minutes. The aqueous and organic layers are separated, aqueous layer extracted with toluene (2x2 L) and total organic layer was washed with 0.5 N HCI solution (2 L). Total organic layer is concentrated up to reaction mass volume reaches to 10 volumes at below 55 °C under reduced pressure. Toluene (4 L) and ethylnicotinate (780 mL) was added to the reaction mixture at 29 °C and stirred for 10 minutes. Trifluoroacetic anhydride (510 mL) was slowly added to the reaction mixture at 12 °C over 70 minutes. Water (3.51 L) was added to the reaction mixture at 15 °C and stirred for 10 minutes. Triethylamine (1 .05 L) was added to the reaction mixture at 20 °C and stirred for 25 minutes. The aqueous and organic layers are separated, organic layer was washed with 2N HCI solution (3.51 L). Total organic layer solvent was evaporated at below 55 °C under reduced pressure. Resultant crude was chased with methanol (2x2 L) at below 50 °C under reduced pressure. Charged methanol (2.24 L) and triethylamine (310 mL) was added to the crude compound at 28 °C and stirred at 28 °C for 2 hours 30 minutes. Water (7.45 L) was added slowly to the reaction mass at 28 °C and stirred at 28 °C for 40 minutes. Separated solid was filtered, washed with water (750 mL) and dried at 50 °C under reduced pressure for 4 hours to afford 260.4 g of title compound with 99.49% of chemical purity by HPLC.

EXAMPLE 3: Preparation of Saxagliptin hydrochloride. Carbamic acid, N- [(1 S)-2-[(1 S,3S,5S)-3-cyano-2-azabicyclo[3.1 .0] hex-2-yl]-1 -(3-hydroxytricyclo [3.3.1 .1^3J]dec-1 -yl)-2-oxoethyl]-, 1 ,1 -dimethylethyl ester (175 g) and methyl ethyl ketone (1050 mL) charged into flask and stirred at 26 °C for 30 minutes. Acidic carbon (8.8 g) in methyl ethyl ketone (52.5 mL) was added to the reaction mixture and stirred for 30 minutes. The resulted reaction mixture was filtered, washed with methyl ethyl ketone (44 mL). Water (35 mL) was added to the filtrate at 26° C and stirred for 20 minutes. Aqueous HCI (1 10 mL) was added to the reaction mass at 26 °C and stirred at 26 °C for 20 minutes and at 45 °C for 6 hours. The resultant reaction mass was cooled to 27 °C and stirred for 40 minutes. Separated solid was filtered, wet material press dried with nitrogen pressure, washed with methyl ethyl ketone (525 mL) and dried at 28 °C (relative humidity of 60±20%) for 6 hours to afford 142 g of title compound. Purity by HPLC: 99.86%, Amide: 0.02%, deshydroxy Saxagliptin: 0.04%, cyclic amidine: Not detected and Boc protected saxagliptin: Not Detected.

EXAMPLE 4: Preparation of Saxagliptin hydrochloride. Carbamic acid, N- [(1 S)-2-[(1 S,3S,5S)-3-cyano-2-azabicyclo[3.1 .0] hex-2-yl]-1 -(3-hydroxytricyclo [3.3.1 .1^3J]dec-1 -yl)-2-oxoethyl]-, 1 ,1 -dimethylethyl ester (250 g) and methyl ethyl ketone (1500 mL) charged into flask and stirred at 26 °C for 30 minutes. The resulted clear solution was passed through Millipore filter paper at 26 °C. Aqueous HCI (130 mL) was added to the filtrate at 26 °C and stirred at same temperature for 4 hours. Separated solid was filtered, washed with methyl ethyl ketone (500 mL) and dried at 40 °C under reduced pressure for 5 hours 30 minutes to afford 196 g of title compound.

Purity by HPLC: 99.85%, Amide: 0.05%, deshydroxy Saxagliptin: 0.05%, cyclic amidine: Not detected and Boc protected saxagliptin: Not Detected.

EXAMPLE 5: Preparation of Saxagliptin hydrochloride. Carbamic acid, N-[(1 S)-2-[(1 S,3S,5S)-3-cyano-2-azabicyclo[3.1 .0] hex-2-yl]-1 -(3-hydroxytricyclo [3.3.1 .1³'⁷]dec-1 -yl)-2-oxoethyl]-, 1 ,1 -dimethylethyl ester (175 g) and methyl ethyl ketone (1400 mL) charged into flask and stirred at 26 °C for 15 minutes. Acidic carbon (8.8 g) was added to the reaction mixture and stirred for 30 minutes. The resulted reaction mixture was filtered, washed with methyl ethyl ketone (2x 350 mL). Water (35 mL) and aqueous HCI (1 10 mL) was added to the filtrate at 26 °C and stirred at 45 °C for 6 hours. Cooled to 25 °C and stirred for 20 minutes. Separated solid was filtered, washed with methyl ethyl ketone (525 mL) and dried at atmospheric pressure for 16 hours to afford 142 g of title compound.

Purity by HPLC: 99.86%, Amide: 0.02%, deshydroxy Saxagliptin: 0.05%, cyclic amidine: Not detected and Boc protected saxagliptin: Not Detected.

EXAMPLE 6: Preparation of (2S)-1-tert-butyl 2-ethyl-5-oxopyrrolidine-1 ,2- dicarboxylate. A solution of di-tert-butyl dicarbonate (160.3 g) in toluene (550 mL) was slowly added to L-pyroglutamic acid ethyl ester (1 10 g), 4-dimethyl amino pyridine (4.26 g), and toluene (550 mL) at 3°C and the reaction mixture is stirred at 24 ^<C for 3¹/₂ hours. Half saturated sodium bicarbonate solution (1 100 mL) is added to the reaction mixture at 2°C. The aqueous and organic layers were separated and organic layer was evaporated below 50 °C under reduced pressure. The obtained compound is further purified using column chromatography to afford title compound. Yield: 1 12.2g. EXAMPLE 7: Preparation of (2S)-1-tert-butyl 2-ethyl 2, 3-dihydro-1 H- pyrrole-1 ,2-dicarboxylate. (2S)-1 -tert-Butyl 2-ethyl-5-oxopyrrolidine-1 , 2- dicarboxylate (50.0 g), methanol (500 mL) and toluene (500 mL) are charged into a round bottom flask at 26 °C. Sodium borohydride (22 g) was added portion wise to the reaction mixture at -35 °C under nitrogen atmosphere. The resultant reaction mixture temperature slowly raised to -20 °C and stirred at -20 °C for 3 hours. 10% aqueous ammonium chloride solution (500 mL) was slowly added to the reaction mixture at -40 °C. Product was extracted with toluene (2x500 mL) and organic layer is washed with brine solution (500 mL). The resultant organic layer is dried with sodium sulfate and solvent was evaporated completely at below 50 °C under reduced pressure. To the crude compound toluene (500 mL) and Tulsion T-66 resin (5 g) was added, the resulted reaction mixture was heated to 120 °C and stirred at same temperature for 12 hours. Reaction mixture was cooled to 26°C, passed through the celite bed and washed with toluene (100 mL). The resultant reaction mass solvent was evaporated at below 60°C to afford title compound.

Yield: 44g.

EXAMPLE 8: Preparation of (S)-tert-butyl 2-carbamoyl-2,3-dihydro-1 H- pyrrole-1 -carboxylate. ((2S)-1 -tert-butyl 2-ethyl 2, 3-dihydro-1 H-pyrrole-1 ,2- dicarboxylate (44 g) and methanol (264 mL) charged into a round bottom flask at 26 °C and stirred for 15 minutes. Formamide (93 mL) was slowly added to the reaction mixture at 26 C. Sodium methoxide (19.7 g) in methanol (176 mL) solution was slowly added to the reaction mass at 26 °C and the resultant reaction mixture was stirred at 26 °C for 8 hours. 10% ammonium acetate solution (26.5 g in 264 mL methanol) was added to the reaction mixture at 26 °C and thus obtained reaction mixture solvent was evaporated at below 50 °C. Water (500 mL) and toluene (150 mL) was added to the reaction mixture at 26 °C. Layers were separated and organic layer was extracted with water (4x250 mL). Product was extracted with ethyl acetate (4x500 mL) from combined aqueous layers. The resultant organic layer is dried with sodium sulfate and solvent was evaporated completely at below 50 °C under reduced pressure to afford title compound.

Yield: 69g.

EXAMPLE 9: Preparation of (1S, 3S, 5S)-tert-butyl 3-carbamoyl-2- azabicyclo[3.1.0]hexane-2-carboxylate. Dimethoxy ethane (20 mL) was added to the reaction mixture containing (S)-tert-butyl 2-carbamoyl-2,3-dihydro-1 H-pyrrole-1 - carboxylate (20 g) & dichloromethane (200 mL) at -30 °C. To the resultant reaction mixture diiodomethane (30 mL) followed by diethyl zinc 20% solution in toluene (1 16.4 mL) was slowly added at -30 °C. After stirring the reaction mixture at 26 °C for 5 hours, 10% Sodium bicarbonate solution (200 mL) was added at 0 °C. The resultant reaction mass was passed through celite bed and washed with dichloromethane (400 mL). Organic layer from filtrate was separated, aqueous layer was extracted with dichloromethane (200 mL). Combined organic layer was washed with 5% sodium bicarbonate solution (200 mL) followed by brine solution (200 mL) and finally dried with sodium sulfate. The resultant organic layer solvent was evaporated completely at below 40°C under reduced pressure, n-heptane (200 mL) was added to the crude compound at 26 °C and thus obtained mixture was stirred at 26 °C for 30 minutes. Separated solid was filtered, washed with n-heptane (40 mL). Wet compound and n-butyl acetate (40 mL) was charged into flask, heated to 120°C and stirred at 120 °C for 5 minutes. To the resultant mixture n-heptane (80 mL) was added at 25 °C and stirred at 25 °C for 30 minutes. Separated solid was collected by filtration, washed with n-heptane (40 mL) to afford title compound.

Yield: 1 1 .3g.

EXAMPLE 10: Preparation of methane sulfonic acid salt of (1S, 3S, 5S)-2- azabicyclo[3.1.0]hexane-3-carboxamide. (1 S, 3S, 5S)-tert-butyl 3-carbamoyl-2- azabicyclo[3.1 .0]hexane-2-carboxylate (5 g) and isopropyl alcohol (30 mL) charged into round bottom flask. Methanesulfonic acid (1 .86 mL) was added to the reaction mixture at 60†8C and stirred at 60 °C for 4 hours. The resultant reaction mixture was cooled to 26 °C and stirred at 26 °C for 1 hour. Separated solid was collected by filtration, washed with isopropyl alcohol (5 mL) to afford title compound.

Yield: 4.4; Purity by HPLC: 99.14%.

EXAMPLE 11 : Preparation of 2-(adamantan-1-yl)-3-ethoxy-3- oxopropanoic acid. Boron trifluoride diethyl etherate (419.5 g) was slowly added to the reaction mixture containing 1 -Adamantanol (150 g), dichloromethane (3.0 L) and 3-ethoxy-3-oxopropanoic acid (130 g) at 3°C under nitrogen atmosphere and the resultant reaction mixture was stirred at 28 °C for 24 hours. Reaction mixture was poured into the ice cold water (1500 mL) and stirred for 15 minutes. Aqueous and organic layers were separated, aqueous layer extracted with dichloromethane (1200 mL) and the combined organic layer was washed with water (900 mL), brine solution (900 mL) & dried with sodium sulphate. The resultant organic layer solvent was distilled off completely at below 55 °C under reduced pressure. The obtained crude compound was purified using column chromatography (mixture of n-hexane and ethyl acetate) to afford title compound.

Yield: 150 g

EXAMPLE 12: Preparation of ethyl 2-(adamantan-1-yl)-3-amino-3- oxopropanoate. 2-(adamantan-1 -yl)-3-ethoxy-3-oxopropanoic acid (150 g) and toluene (1 .5 L) were charged into flask and stirred for 10 minutes. Thionyl chloride (368.5 g) was added to the reaction mixture at 28 °C and stirred at 90 °C for 2 hours. The resultant reaction mixture solvent and thionyl chloride was distilled off completely at below 95°C under reduced pressure. Dichloromethane (1 .5 L) was added to the crude compound and ammonia gas was purged at 3 ^ for 1 hour. Separated solid was filtered, washed with dichloromethane (450 mL). Filtrate solvent was distilled off completely at below 50 °C under reduced pressure. To the obtained compound n-hexane (300 mL) was added and stirred for 20 minutes. Separated solid was filtered, washed with n-hexane (150 mL) and dried at 40°C for 3 hours to afford title compound.

Yield: 101 g

EXAMPLE 13: Preparation of 2-(adamantan-1-yl)-2-aminoacetic acid.

Ethyl 2-(adamantan-1 -yl)-3-amino-3-oxopropanoate (100 g), 1 ,4-dioxane (1.0 L) and water (1.0 L) were charged into flask and stirred for 15 minutes. Sodium hydroxide (45.2 g) was added to the reaction mixture at 10 °C. Mixture of 4% sodium hypochlorite solution (1 12.15g) and aqueous sodium hydroxide solution (30 g in 100 mL water) (prepared by stirring sodium hydroxide solution and sodium hypochlorite solution at 3°C for 20 minutes) solution was added to the reaction mixture at 10°C and stirred at 100°C for 90 minutes. The resultant reaction mixture was cooled to 28 C, washed with ethyl acetate (1 .0L) and aqueous layer pH was adjusted to 4.0 with 18% aqueous hydrochloride solution. Reaction mixture was stirred at 28°C for 17 hours, separated solid was filtered, washed with water (200 mL) and dried at 60 °C for 8 hours to afford title compound.

Yield: 50.6g

EXAMPLE 14: Preparation of methyl 2-(adamantan-1-yl)-2-aminoacetate.

Thionyl chloride (568.3 g) was added to the reaction mixture containing 2- (adamantan-1 -yl)-2-aminoacetic acid (50 g) & methanol (2.5 L) at 3^ and the resultant reaction mixture was stirred at 75 °C for 24 hours. Reaction mass was concentrated at below 75^ under reduced pressure and water (1 .5 L) was added to the crude compound. Reaction mass was washed with ethyl acetate (3x200 ml.) and aqueous layer pH was adjusted to 7.5 using saturated bicarbonate solution. Aqueous layer was extracted with dichloromethane (3x300 ml.) and combined organic layer was washed with water (300 ml_), brine solution (300 ml.) & dried with sodium sulfate. Organic layer solvent was completely distilled off at below 55 °C under reduced pressure to afford title compound.

Yield: 32g

EXAMPLE 15: Preparation of methyl (S)-2-(adamantan-1 -yl)-2- aminoacetate. Methyl 2-(adamantan-1 -yl)-2-aminoacetate (30 g) and methanol (450 ml.) were charged in to flask and heated to 70 °C. Di-p-toluoyl-L-tartaric acid solution (51 .9 g in 450 ml. of methanol) was slowly added to the reaction mass at 70 °C. Isopropyl acetate (450 ml.) was added at 70 °C and stirred at 70 °C for 1 hour. The resultant reaction mixture was cooled to 28 °C and stirred at 28 °C for 20 minutes. Separated solid was filtered, washed with isopropyl acetate (60 ml.) and dried at 40 °C for 1 hour. The resultant dry compound and methanol (4.125 L) was charged into flask, heated to 70°C and stirred at 70 °C for 30 minutes. Reaction mass was cooled to 28 °C and stirred at 28 °C for 13 hours. Separated solid was filtered, washed with isopropyl acetate and dried at 28 °C for 1 hour. The obtained dry compound was charged into aqueous bicarbonate solution (15.15 g of sodium bicarbonate in 220 ml. of water) and stirred for 10 minutes. Dichloromethane (440 ml.) was added and stirred for 4 hours. Aqueous and organic layers were separated, aqueous layer was extracted with dichloromethane (440 ml.) and combined organic layer was washed with water (440 ml_), brine solution (440 ml.) and dried with sodium sulphate. Organic layer solvent was completely distilled off at below 50 °C under reduced pressure to afford title compound.

Yield: 7.5g

EXAMPLE 16: Preparation of methyl (S)-2-(adamantan-1-yl)-2-((tert- butoxycarbonyl)amino)acetate. Sodium bicarbonate (1 1 .3 g) and water (250 ml.) were charged in to flask and stirred for 15 minutes. Solution of methyl (S)-2- (adamantan-1 -yl)-2-aminoacetate (5 g) in tetrahydrofuran (500 ml.) was slowly added to the reaction mass at 28 °C and stirred for 5 minutes. Di-tert-butyl dicarbonate (9.8 g) was slowly added to the reaction mass at 28 °C and stirred at 28 °C for 18 hours. Aqueous and organic layer were separated, aqueous layer was extracted with ethyl acetate (3x135 mL) and combined organic layer washed with water (2x250 mL), brine solution (250 mL) & dried with sodium sulphate. Organic layer solvent was distilled off completely at below 50 °C under reduced pressure and the obtained crude compound was purified using column chromatography to afford title compound.

Yield: 4.7 g

EXAMPLE 17: Preparation of methyl (2S)-2-((tert-butoxycarbonyl)amino)- 2-(3-hydroxyadamantan-1 -yl)acetate. Methyl (S)-2-(adamantan-1 -yl)-2-((tert- butoxycarbonyl)amino)acetate (4 g) and ethyl acetate (160 mL) charged in to flask. Ruthenium chloride trihydrate (0.48 g) followed by 13% sodium hypochlorite (5.5 g) was charged in to the reaction mass at 28 °C and stirred at 28 °C for 24 hours. Aqueous and organic layers were separated, aqueous layer extracted with ethyl acetate (200 mL), combined organic layer washed with water (400 mL), brine solution and dried with sodium sulphate. Organic layer solvent was distilled off completely at below 50 °C under reduced pressure and the resultant crude compound was purified using column chromatography to afford title compound. Yield: 2.3g

EXAMPLE 18: Preparation of (2S)-2-((tert-butoxycarbonyl)amino)-2-(3- hydroxyadamantan-1 -yl)acetic acid. Solution of methyl (2S)-2-((tert- butoxycarbonyl)amino)-2-(3-hydroxyadamantan-1 -yl)acetate (2 g) in methanol (100 mL) was added to the reaction mixture containing water (40 mL) and sodium hydroxide (1 .4g) at 15 ^ and the resultant mixture was stirred at 27°C for 8 hours. Reaction mass was concentrated at below 45 °C under reduced pressure. Water (50 mL) and ethyl acetate (100 mL) was added to the reaction mass at 28 °C and stirred for 10 minutes. Aqueous layer and organic layers were separated, aqueous layer pH was adjusted 3.2 with 1 N hydrochloric acid at 12°C. The resultant aqueous layer was extracted with ethyl acetate (2x100 mL), combined organic layer washed with water (160 mL), brine solution (160 mL) and dried with sodium sulphate. Organic layer solvent was distilled off completely at below 45 °C under reduced pressure and n- hexane (100 mL) was added to the obtained crude compound. Reaction mass was heated to 72 °C, stirred at 72 °C for 1 hour and stirred at 28 ^<€ for 1 hour. Separated solid was filtered, washed with n-hexane (26 mL) and dried at 45 °C for 3 hours to afford title compound.

Yield: 1 .3g

Claims

Claims:

1 . An improved process for the preparation of saxagliptin or its salt, which comprises:

(a) converting a compound of formula IV to a compound of formula V in the presence of trifluoroacetic anhydride or an equivalent thereof;

(V)

wherein P is an amine protecting group.

(b) treating the compound of formula V in the presence of an organic base to obtain a compound of formula VI; and

(VI)

2. The process according to claim 1 , wherein the organic base is selected from methyl amine, ethyl amine, diethyl amine, triethyl amine, tributyl amine, diisopropyl ethyl amine, N-methyl pyrrolidine, N-methyl morpholine, 4-(N,N- dimethylamino) pyridine, morpholine or mixtures thereof.

3. The process according to claim 2, wherein the organic base is selected from ethyl amine, diethyl amine, triethyl amine, tributyl amine, diisopropyl ethyl amine or mixtures thereof.

4. The process according to claim 3, wherein the organic base is selected from triethyl amine, tributyl amine, diisopropyl ethyl amine or mixtures thereof.

5. The process according to claims 4, wherein the organic base is triethyl amine or tributyl amine.

6. The process according to claim 1 , wherein the solvent for converting a compound of formula V to a compound of formula VI is an alcohol solvent.

7. The process according to claim 6, wherein the alcohol is selected from methanol, ethanol, isopropyl alcohol, n- butanol, 2-butanol or t-butyl alcohol.

8. The process according to claims 6-7, wherein the alcohol is methanol or isopropyl alcohol.

9. The process according to claim 1 , wherein the deprotecting the compound of formula VI comprises catalytic hydrogenation, or treating with acids or bases.

10. The process according to claim 1 , wherein the solvent for the deprotection is selected from water, alcohols, ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles polar aprotic solvents or mixtures thereof.

1 1 . The process according to claim 10, wherein solvent is selected from water, alcohols, ketones, esters, halogenated hydrocarbons or mixtures thereof.

12. The process according to claims 10-1 1 , wherein the solvent is selected from water, methanol, ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane or mixtures thereof.

13. The process according to claims 10-12, wherein the solvent is water, methyl ethyl ketone or mixtures thereof.

14. The process according to claim 1 , wherein compound of formula IV is prepared by a process comprising treating adamantyl compound of formula II with an azabicyclo compound of formula III in the presence of a coupling agent to provide a compound of formula IV,

wherein P is an amine-protecting group;

15. The process according to claim 14, wherein the coupling agent is selected from propylphosphonic anhydride (T3P), 4-(4,6-Dimethoxy-1 ,3,5-triazin-2-yl)-4- methylmorpholinium chloride (DMTMM), N-hydroxybenzotriazole (HOBT), 4,5- dicyanoimidazole, dicyclohexylcarbodiimide (DCC), dicyclopentyl carbodiimide, diisopropylcarbodiimide, 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC HCI) or combinations thereof.

16. The process according to claim 15, wherein the coupling agent is propylphosphonic anhydride (T3P).

17. The process according to claim 15, wherein the coupling agent is 1 -ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC HCI) and N- hydroxybenzotriazole (HOBT).

18. The process according to claim 14, wherein compound of formula II is prepared by a process which includes one or more of the following steps:

a) treating 1 -adamatanaol with 3-ethoxy-3-oxopropanoic acid to provide acid compound of formula XIII

XIII

b) converting acid compound of formula XIII to amide compound of formula XIV,

XIV

XV

XVII

f) protecting the compound of formula XVII with an amino- protecting group to provide an N-protected compound of formula XVIII,

XIX

19. The process according to claim 14, wherein compound of formula III is prepared by a process which includes one or more of the following steps:

wherein P is an amine-protecting group and R is CrC₆ alkyl;

b) reducing the compound of formula VI II in the presence of reducing reagent to provide an alcohol compound of formula IX,

IX

wherein P and R is defined above

X wherein P and R is defined above

d) converting compound of formula X to carboxamide compound of formula XI

X XI

wherein P and R is defined above

e) cyclopropanation of compound of formula XI to provide azabicycio compound of formula XI I.

XD

wherein P is an amine-protecting group

f) deprotecting the compound of formula XI I to provide 2-zabicyclo [3.1 .0] hexane-3-carboxamide compound of formula I I or its acid addition salt.

g) optionally converting the 2-azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula II I or its acid addition salt obtained in step (f) in to another acid addition salt of compound of the formula I II.

20. Saxagliptin or its salt substantially free of one or more of the following compounds: