PROCESS FOR PREPARATION OF SAXAGLIPTIN INTERMEDIATES

INTRODUCTION

Aspects of the present application relate to process for preparation of intermediates of saxagliptin.

The drug compound having the adopted name saxagliptin, has a chemical name (1S,3S,5S)-2-[(2S)-2-Amino-2-(3hydroxytricyclo[3.3.1.13J]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, and is represented by structure of formula I.

Saxagliptin is a dipeptidyl peptidase-4 inhibitor indicated 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. The azabicyclo intermediates of formula II:

wherein P is an amine-protecting group and R is C1-C6 alkyl; are useful intermediates for the preparation of saxagliptin of formula I and its pharmaceutically acceptable salts. Process for the preparation of azabicyclo intermediate of formula II and process for its preparation have been disclosed in U.S. Patent No. 6,395,767 and U.S. Patent application publication No. 2010/0274025. The above processes suffer from major disadvantages, including use of highly expensive reagents, large amounts of catalysts, longer reaction time, low yield, and low quality.

SUMMARY

The present application provides a process for the preparation of azabicyclo intermediate of formula II, useful for the preparation of saxagliptin.

In an aspect, the present application relates to a process, which includes one or more of the following steps:

(a) protecting an L-pyroglutamic acid ester of formula III with a suitable amine-protecting group to provide an N-protected L-pyroglutamic acid ester of formula IV:

wherein P is an amine-protecting group and R is C1-C6 alkyl;

(b) reducing the keto group of a compound of formula IV with a suitable reducing reagent to provide an alcohol compound of formula V;

(c) dehydrating an alcohol compound of formula V to provide an alkene compound of formula VI; and

(d) cyclopropanation of an alkene compound of formula VI with suitable reagents to provide an azabicyclo intermediate of formula II.

ii DETAILED DESCRIPTION

In an aspect, the present application relates to a process, which includes one or more of the following steps:

(a) protecting an L-pyroglutamic acid ester of formula III with a suitable amine-protecting group to provide N-protected L-pyroglutamic acid ester of formula IV:

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

(b) reducing the keto group of a compound of formula IV with a suitable reducing reagent to provide an alcohol compound of formula V;

(c) dehydrating an alcohol compound of formula V to provide an alkenecompound of formula VI; and

(d) cyclopropanation of alkene compound of formula VI with suitable reagents to provide an azabicyclo intermediate of formula II.

II Step (a) involves protecting L- pyroglutamic acid ester of formula III with a suitable amine-protecting group to provide an N-protected L- pyroglutamic acid ester of formula IV. Suitable protecting group may be, for example, lower alkanoyl having 2 to 4 carbon atoms; 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 -C12)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, but not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; nitriles, such as acetonitrile or propionitrile; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; aromatic hydrocarbons, such as toluene; or any mixtures of two or more thereof.

Step (b) involves reducing keto group of the formula IV with suitable reducing reagent to provide alcohol compound of formula V. Suitable reduction techniques that may be used in step (b) include, for example, catalytic hydrogenation; reduction by a an alkali metal hydride, such as lithium aluminum hydride, 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, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; alcohols, such as 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, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or Ci-C6 alcohols; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; aromatic hydrocarbons, such as toluene; or any mixtures of two or more thereof. Suitable temperatures that may be used for the reaction of (b) may be less than about 50°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -70°C, less than about -80°C, 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 alcohol compound of formula V to provide alkene compound of formula VI. 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°C, 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 step (d) 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 cyclopropanation of alkene compound of formula VI with suitable reagents to provide azabicyclo intermediate of formula II. Suitable reagents that may be used in step (d) include, but are not limited to diiodomethane, chloroiodomethane, Simmons-Smith reagent, or any other suitable reagent known in the art. Suitable catalysts that may be used in step (d) include, but are not limited to diethyl zinc, zinc-copper, or any other suitable reagent known in the art. Suitable solvents that may be used in step (d) include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide; sulfoxides, such as dimethylsulfoxide; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; aromatic hydrocarbons, such as toluene; or any mixtures of two or more thereof. Suitable temperatures that may be used for the reaction of (d) may be less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures.

The reaction mixture obtained in step (d) 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 (d) may be isolated directly from the reaction mixture itself after the reaction is complete in step (d), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. The isolation in step (d) 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.
In another aspect, the present application relates to a process comprising dehydrating an alcohol compound of formula V to provide an alkene compound of formula VI:

wherein P is an amine-protecting group and R is C1-C6 alkyl and using an inert heat transfer medium like silicon oil without any added reagent.

In one embodiment, the process further comprises providing the alcohol compounds of formula V by reducing the keto group of the compounds of formula IV with a suitable reducing reagent.

In one embodiment, the process further comprises cyclopropanation of the alkene compound of formula VI with suitable reagents to provide the azabicyclo intermediates of formula II:

In one embodiment, the process further comprises protecting an L-pyroglutamic acid ester of formula III with a suitable amine-protecting group to provide N-protected L-pyroglutamic acid ester of formula IV:

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 "Cx-Cy", where x and y are the lower and upper limits, respectively. For example, a group designated as "C1-C6° 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 the substituents, such as alkoxy substitutions or the like.

An "alcohol" is an organic compound containing a carbon bound to a hydroxyl group. "C1-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, or 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 tolgene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.

"Amine-protecting group" refers to a radical 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, C1-C6 aliphatic acid chlorides or anhydrides, C6-C14arylcarboxylic 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 pages 385-397 of T. W. Green, P. G. M. Wuts, "Protective Groups in Organic Synthesis, Second Edition", Wiley-lnterscience, New York, 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, or the like.

An "ether" is an organic compound containing an oxygen atom -O- bonded to two other 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, or 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, or 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, or 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, or 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 application 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 obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.

EXAMPLES
EXAMPLE 1: Preparation of (2S)-1-tert-butyl 2-ethyl-5-oxopyrrolidine-1,2-dicarboxylate. A solution of di-tert-butyl dicarbonate (14.5 g) in toluene (50 mL) is added to L-pyroglutamic acid ethyl ester (10 g), 4-dimethyl amino pyridine (0.38 g) and toluene (50 mL) at 2°C and the reaction mixture is stirred at 24°C for 31/2 hours. Half saturated sodium bicarbonate solution (100 mL) is added to the reaction mixture at 3°C over 40 minutes. The aqueous and organic layers are separated and the organic layer is evaporated below 50°C under reduced pressure. The obtained compound is further purified using column chromatography to afford title compound. Yield: 7.0g.

EXAMPLE 2: 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) is slowly added to L-pyroglutamic acid ethyl ester (110 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 (1100 mL) is added to the reaction mixture at 2°C. The aqueous and organic layers are separated and organic layer is evaporated below 50°C under reduced pressure. The obtained compound is further purified using column chromatography to afford title compound. Yield: 112.2g.

EXAMPLE 3: Preparation of (2S)-1-tert-butyl 2-ethyl-5-hydroxypyrrolidine-1,2-dicarboxylate. (2S)-1-tert-Butyl 2-ethyl-5-oxopyrrolidine-1,2-dicarboxylate (5.0 g) and dry tetrahydrofuran (135 ml_) is charged into a round bottom flask at 27°C and cooled to -73°C. DIBAL-H (20% in toluene, 40 mL) is added to the reaction mixture at -72°C under nitrogen atmosphere and reaction mixture is stirred at -75°C for 2 hours. A 10% potassium acetate solution (100 mL) is slowly added to the reaction mixture at -73°C and the resultant reaction mixture is transferred to another round bottom flask containing ammonium chloride (10 g) and water (100 mL) at -28°C. Toluene (100 mL) is charged into reaction mixture and stirred for 2 hours 15 minutes. Filtered the reaction mixture and washed with toluene (100 mL). The aqueous and organic layers are separated, aqueous layer is extracted with toluene (50 mL), and organic layer is washed with 10% ammonium chloride solution (100 mL). The resultant organic layer is dried with sodium sulfate (10 g) and is evaporated of solvent completely at below 44°C under reduced pressure to afford title compound. Yield: 4.2g.

EXAMPLE 4: Preparation of (2S)-1-tert-butyl 2-ethyl-5-hydroxypyrrolidine-1,2-dicarboxylate. (2S)-1-tert-Butyl 2-ethyl-5-oxopyrrolidine-1,2-dicarboxylate (200.0 g) and dry tetrahydrofuran (5400 mL) is charged into a round bottom flask at 27°C and cooled to -78°C. DIBAL-H (25% in toluene, 1300 mL) is added to the reaction mixture at -79°C under nitrogen atmosphere and reaction mixture is stirred at -78°C for 3 hours. A 20% potassium acetate solution (2000 mL) is slowly added to the reaction mixture at -79°C and the resultant reaction mixture is transferred to another round bottom flask containing ammonium chloride (400 g) and water (2000 mL) at -28°C. Diethyl ether (5200 mL) is charged into reaction mixture and stirred for 3 hours. Filtered the reaction mixture and washed with diethyl ether (2000 mL). The aqueous and organic layers are separated, aqueous layer is extracted with diethyl ether (2000 mL). Filtered the organic layer and washed with diethyl ether (2000 mL). Filtrate is washed with 20% ammonium chloride solution (2000 mL). The resultant organic layer is dried with sodium sulfate (600 g) and is evaporated of solvent completely at below 35°C under reduced pressure to afford title compound. Yield: 190.0g.

EXAMPLE 5: Preparation of (2S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-
pyrrole-1,2-dicarboxylate. (2S)-1-tert-Butyl 2-ethyl-5-hydroxypyrrolidine-1,2-
dicarboxylate (10 g) and silicon oil (50 mL) are charged into a round bottom flask at 27°C and stirred at 168°C for 2 hours. Methanol (100 mL) is charged into reaction mixture at 28°C and stirred for 30 minutes. Methanol layer is separated from the reaction mixture and silicon oil layer is extracted with methanol (100 mL). The resultant methanol layer is evaporated of completely below 65°C under reduced pressure to afford title compound. Yield: 7.5g.

EXAMPLE 6: Preparation of (2S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate. (2S)-1-tert-Butyl 2-ethyl-5-hydroxypyrrolidine-1,2-dicarboxylate (30 g) is charged into a round bottom flask at 26°C and stirred at 111 °C for 6 hours to afford title compound. Yield: 25.0g.

EXAMPLE 7: Preparation of (2S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate. (2S)-1-tert-Butyl 2-ethyl-5-hydroxypyrrolidine-1,2-dicarboxylate (50 g) is charged into a round bottom flask at 26°C and stirred at 164°C for 1 hour to afford title compound. Yield: 42.0g.

EXAMPLE 8: Preparation of (2S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate. (2S)-1-tert-Butyl 2-ethyl-5-hydroxypyrrolidine-1,2-dicarboxylate (55 g) is charged into a round bottom flask at 27°C and stirred at 164°C for 40 minutes to afford title compound. Yield: 46.8g.

EXAMPLE 9: Preparation of (2S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate. (2S)-1-tert-Butyl 2-ethyl-5-hydroxypyrrolidine-1,2-dicarboxylate (50 g) is charged into a round bottom flask at 28°C and stirred at 164°C for 30 minutes to afford title compound. Yield: 42.4g.

EXAMPLE 10: Preparation of (1S, 3S, 5S)-2-tert-butyl 3-ethyl 2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate. Dichloromethane (84 mL) charged into round bottom flask and cooled to -30°C. Dimethoxy ethane (8.4 g) is charged into dichloromethane at -30°C and stirred for 15 minutes. Diethyl zinc (18.5% in toluene, 93.6 mL) is added to the reaction mixture at -30°C and stirred for 10 minutes.

Diiodomethane (40.8 g) is added to the reaction mixture at-30°C and stirred for 45 minutes. The resultant reaction mixture is added to mixture of (2S)-1-tert-Butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (8.4 g) and dichloromethane (42 mL) at -29°C and stirred at 22°C for 16 hours. An 8% sodium bicarbonate solution is added to the reaction mass at 5-15°C and stirred for 2 hours. Reaction mass is filtered and washed with dichloromethane (84 mL). Organic layer is separated from the filtrate and washed with 10% sodium chloride solution. The resultant organic layer is dried with sodium sulfate (70 g) and is evaporated of solvent completely at below 39°C under reduced pressure to afford title compound. Yield: 11.0g.

EXAMPLE 11: Preparation of (1S, 3S, 5S)-2-tert-butyl 3-ethyl 2-azabicyclo [3.1.0]hexane-2,3-dicarboxylate. Dichloromethane (100 mL) charged into round bottom flask and cooled to -30°C. Dimethoxy ethane (8.4 g) is charged into dichloromethane at -30°C and stirred for 15 minutes. Diethyl zinc (18.5% in toluene, 50.6 mL) is added to the reaction mixture at -30°C and stirred for 10 minutes. Diiodomethane (40.8 g) is added to the reaction mixture at -29°C and stirred for 50 minutes. The resultant reaction mixture is added to mixture of (2S)-1-tert-Butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (8.4 g) and dichloromethane (50 mL) at -29°C and stirred at 22°C for 15 hours 35 minutes. An 8% sodium bicarbonate solution is added to the reaction mass at 5-15°C and stirred for 2 hours. Reaction mass is filtered and washed with dichloromethane (100 mL). Organic layer is separated from the filtrate and washed with 10% sodium chloride solution. The resultant organic layer is dried with sodium sulfate (30 g) and is evaporated of solvent completely at below 39°C under reduced pressure to afford title compound. Yield: 14.5g.

CLAIMS:

1. A process for the preparation of azabicyclo intermediate of formula II, useful for the preparation of saxagliptin, which includes one or more of the following steps:

(a) protecting an L-pyroglutamic acid ester of formula III with a suitable amine-protecting group to provide an N-protected L-pyroglutamic acid ester of formula IV:

wherein P is an amine-protecting group and R is C1-C6 alkyl;

(b) reducing the keto group of a compound of formula IV with a suitable reducing reagent to provide an alcohol compound of formula V;

(c) dehydrating an alcohol compound of formula V to provide an alkene compound of formula VI; and

(d) cyclopropanation of an alkene compound of formula VI with suitable reagents to provide an azabicyclo intermediate of formula II.

2. The process of claim 1, wherein suitable protecting group used in step (a) is N-tert-utoxycarbonyl.

3. The process of claim 1, wherein suitable reducing agent used in step (b) is Diisobutyl aluminium hydride.