This application claims priority to the Indian patent application numbers 4203/CHE/2011 filed on Dec 05, 2011 and 521/CHE/2012 dated on Feb 13, 2012 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Saxagliptin intermediate. The present invention also relates to a process for the preparation of Saxagliptin hydrochloride using this intermediate. The present invention is also relates to a novel intermediates of saxagliptin.

BACK GROUND OF THE INVENTION

Saxagliptin is orally active reversible dipeptidyl peptidase-4 (DPP4) inhibitor, which is therapeutic agent for treatment of type-2 diabetes mellitus, obesity or related disease. Saxagliptin is chemically known as (1S, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile and having the below structure.

US patent 6395767 discloses Saxagliptin and it's pharmaceutical^ acceptable salt thereof, wherein Saxagliptin is prepared by condensing the adamentane derivative of SM1 with cyclopropyl derivative of SM2 in presence of coupling agent to get compound of formula IV, reacting compound of formula IV with triethylsilyl triflate to get the compound of formula III, dehydrating the compound of formula III to get compound of formula II, followed by deprotection with trifluroacetic acid to give trifluroacetic acid salt of Saxagliptin.

The entire process is shown in scheme-l.

The US' 767 discloses the process for the preparation of starting material SM1, wherein, esterfication of compound of formula XII in the presence of trimethylsilyl diazomethane to get compound of formula XI, upon reduction of compound of formula XI with lithiumaluminiumhydride produced compound of formula X, oxidation of the compound of the formula X to get aldehyde derivative of formula IX, reaction with R(-)-phenylglycinol in presence of potassium cyanide to get compound of formula VIII, followed by purification by column chromatography to get pure compound of formula VIII.

Hydrolysis of compound of formula VIII in the presence of hydrochloric acid to give compound of formula VII, reduction of compound of formula VII in the presence of palladium hydroxide under hydrogen pressure to get compound of formula VI, upon reaction with ditertiary butyl dicarbonate to get compound of formula V, followed by oxidation in the presence of potassium permanganate to get SM1. Total process of SM1 is schematically shown in scheme-ll.

The US patent 7420079 disclosed the process for the preparation of starting material SM1, wherein, bromination of compound of formula XVII in the presence of N-bromo succinimide to get compound of formula XVI, upon Oxidation of compound of formula XVI with sulfuric acid and Nitric acid to produced the compound of formula Xllla, amination of the compound of the formula Xllla to get compound of formula Xlllb, upon reaction with ditertiary butyl dicarbonate to get compound of formula Xlllc, followed by resolution with 1,2 diphenyl hydroxyl ethylamine to get SM1. Total process of SM1 is schematically shown in scheme-ll.

Scheme-Ill

Though the above process is not feasible in large scale production, it involves column chromatography to get pure product. Thus there is a need for an alternate process for the preparation of SM1. The authors of the present invention are developed simple, cost effective and commercially feasible process for the preparation of intermediate of the Saxagliptin SM1. The present invention involves novel intermediates with desired isomer with improved yield and quality.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide novel process for the preparation of
intermediate of Saxagliptin (SM1) comprising the steps of;

a) esterfying the compound of formula XII to get the compound of formula XI,

b) reducing the compound of formula XI in the presence of metal hydride to get the compound of formula X,

c) oxidizing the compound of formula X in the presence of oxidizing agent to get the compound of formula IX,

d) reacting the compound of formula IX with R-(-)phenyl glycinol and cyanide source to get compound of formula VIII,

e) hydrolyzing the compound of formula VIII to get the compound of formula VII,

f) hydrogenating the compound of formula VII in the presence of a metal catalyst under hydrogen pressure to get the compound of formula VI,

g) reacting the compound of formula VI with propionic anhydride get the compound of formula Via,

h) oxidizing the compound of formula Via in the presence of an oxidizing agent to get the compound of formula Vlb, i) deprotecting the compound of formula Vlb in presence of trifluoroacetic acid to get TFA
salt of SM1, and j) reacting the Trifluoroacetic acid salt of SM1 with ditertiary butyl dicarbonate to get SM1.

Overall synthetic scheme is shown in scheme IV.

Scheme-IV

Another aspect of the present invention is to provide novel process for the preparation of intermediate of Saxagliptin (SM1) comprising the steps of;

a) brominating the compound of formula XVII in the presence brominating agent to get the compound of formula XVI,

b) reacting the compound of formula XVI with chiral base to get compound of formula XV,

c) converting the compound of formula XV to the compound of formula XIV,

d) oxidizing the compound of formula XIV in the presence of an oxidizing agent to get the compound of formula XIII,

e) reacting the compound of formula XIII with aqueous ammonia followed by reaction with ditertiary butyl dicarbonate to get SM 1.

Overall synthetic scheme of the present invention is shown in scheme V.

Yet another aspect of the present inventions is to provide a process for the preparation of Saxagliptin is shown in scheme-VI.

Yet another aspect of the present invention is to provide novel compounds of formula Via & Vlb.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention relates to an improved process for the preparation of intermediate of Saxagliptin (SM1), which comprising the steps of:

a) esterfying the compound of formula XII to get the compound of formula XI,

b) reducing the compound of formula XI in the presence of metal hydride to get compound of formula X,

c) oxidizing the compound of formula X in the presence of oxidizing agent to get compound of formula IX,

d) reacting the compound of formula IX with R-(-)phenyl glycinol and cyanide source to get compound of formula VIII,

e) hydrolyzing the compound of formula VIII to get the compound of formula VII,

f) hydrogenating the compound of formula VII in the presence of a metal catalyst under hydrogen pressure to get the compound of formula VI,

g) reacting the compound of formula VI with propionic anhydride to get compound of formula Via,

h) oxidizing the compound of formula Via in presence of an oxidizing agent to get comDound of formula Vlb.

i) deprotecting the compound of formula Vlb in presence of trifluoroacetic acid to get TFA salt of SM1, and

j) reacting the Trifluoroacetic acid salt of SM1 with ditertiary butyl dicarbonate to get SM1.

According to present invention adamantane-1-carboxylic acid of formula XII is esterified in alcohol solvent in the presence of an acid, followed by reduction with metal hydride in an ether solvent to get alcohol derivative of formula X. The obtained alcohol compound is oxidized with an oxidizing agent to get aldehyde compound of formula IX as oil. The Aldehyde formula IX is reacted with R-(-) phenylglycinol, followed cyanation reaction with cyanide source in water to get compound of formula VIII. Hydrolysis of cyanide is carried out in presence of an acid to get compound of formula VII. The compound of formula VII is hydrogenating with metal catalyst in an alcohol solvent to get crude product. The crude compound is slurred in ethyl acetate and filtered to get pure compound of formula VI.

The compound of formula VI is reacted with propionic anhydride in the presence of an aqueous inorganic base to get compound of formula Via. The compound of formula Via is oxidized in the presence of an oxidizing agent to get compound of formula XIV. Hydrolyisis of propionyl group is carried out in the presence of trifluoroacetic acid and water to get crude compound as an oil. This oil is treated with ether solvent to get pure trifluoroacetic acid salt of formula XIII. This salt is treated with a base, followed by reaction with di-tertiary butyl dicarbonate to get BOC protected compound as white colour foam. The obtained foam is recrystallised from aqueous alcohol to get pure compound of formula SM1.

Another embodiment, the present invention relates to an improved process for the preparation of intermediate of Saxagliptin (SM1), which comprising the steps of:

a) brominating the compound of formula XVII in the presence brominating agent to get the compound of formula XVI,

b) reacting the compound of formula XVI with chiral base to give compound of formula XV,

c) converting the compound of formula XV to the compound of formula XIV,

d) oxidizing the compound of formula XIV in the presence of an oxidizing agent to get the compound of formula XIII,

e) reacting the compound of formula XIII with aqueous ammonia followed by reacting with ditertiary butyl dicarbonate to get SM 1.

According to present invention adamantine-1-acetic acid of formula XVII is brominated with in brominating agent in the presence of thionyl chloride, followed by resolution with chiral base in a solvent to get compound of formula XV. This compound is treated with an acid to get the compound of formula XIV. The obtained compound is oxidized with an oxidizing agent to get compound of formula XIII. Compound of formula XIII is reacting with aqueous ammonia, followed by reaction with di-tertiary butyl dicarbonate in the presence of a base and solvent to give BOC protected compound as white color foam. The obtained foam is recrystallised from mixture of solvents to get pure compound of formula SM1.

Yet another embodiment, the present inventions is to provide a process for the preparation of Saxagliptin is shown in scheme-VI.

Yet another embodiment of the present invention is to provide novel compounds of formula Via & Vlb.
According to the present invention, solvent used in any step is selected from, aliphatic or aromatic hydrocarbon solvent, chlorinated solvent, dimethyl formamide, dimethylsulfoxide, alkyl ester, alcohol, water, ketone solvent, nitrile or ether.

According to the present invention alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, pentanol or mixture thereof, ether solvent is selected from tetrahydrofuron, 1,4-dioxane, diethyl ether, diisoproyl ether, methyl tertiary butyl ether or mixture thereof, chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform carbon tetrachloride or mixture thereof, ketone solvent selected from acetone, methylethylketone, methylisobutylketone or mixture thereof, ester solvent is etheylacetate, ethyl acetoacetate, methyl acetate isopropyl acetate or mixture thereof, hydrocarbon solvents is selected from hexane, pentane, heptane, cyclo hexane, xylene, toluene or mixture thereof, nitrile solvent is acetonitrile.

According to the present invention the acid is used for esterification is sulfuric acid, hydrochloric
acid or trifluroacetic acid.

According to the present invention, metal hydride employed for ester reduction is selected from lithiumaluminium hydride, sodiumborohydride or vitride. Metal catalyst employed in the hydrogenation is selected from palladium carbon in 5% to 20, platinum oxide or palladium hydroxide.

According to the present invention, oxidation of alcohol to aldehyde is carried out using oxalyl chloride /DMSO, sodium hypohalite/TEMPO (2, 2, 6, 6-Tetramethyl-1-piperidinyloxy) or any known oxidation reagent. Oxidation of compound of formula Via to get hydroxyl compound of formula Vlb is carried out with mixture of sulfuric acid and nitric acid. The same oxidation also performs with potassium permanganate.

According to the present invention brominating agent is selected from bromine or N-bromo succinimide. The chiral base used in the present invention for resolution is selected from (S)-(+)-2-phenylglycine or Norephedrine.

According to the presence invention cyanide source is selected from sodium cyanide or potassium cyanide.

According to the present invention, acid is selected from organic or inorganic acid. Organic acid is such as acetic acid and inorganic acid is such as hydrochloric acid.

According to the present invention the reaction conditions can be carried out at -70 °C to 130°C, depending on the reaction.

According to the present invention, base is selected from organic or inorganic, inorganic base is such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and organic base is such as triethylamine, diisopropyl ethyl amine.

ADVANTAGES OF THE PRESENT INVENTION

a) the present invention avoid the column chromatography purification,

b) this process provides pure compounds in all the stages, so that pure saxagliptin is obtained from this process. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Example 1: Preparation of compound of formula XI

Adamantane -1-carboxylic acid of the formula XII (100 g) was dissolved in methanol (750.0 mL) at room temperature, stirred for 10 minutes, sulfuric acid (20 mL) was added slowly for 30 minutes at 25-30°C. After completion of addition, the reaction mass was stirred for 10-15 minutes, raised the temperature to reflux and maintained for 5-7 hours. The reaction mass was distilled up to 300-350mL. To the resultant mass water (300mL) was added, extracted with dichloromethane (2 X 100mL) and concentrated at 35-40°C under reduced pressure. Glassy brown colored solid obtained.

Weight of Product: 90-100 g HPLC purity: - 95-97 %.

Example -2:- Preparation of compound of formula X

Lithium aluminium hydride (30 g) in tetrahydrofuran (1000 mL) was cooled to 0 - 5 C under nitrogen atmosphere and stirred for 30-45 minutes. To this mixture, compound of formula XI (100 g) in tetrahydrofuran (500 mL) was added 10-15°C. After completion of addition, cooling was removed and stirring was continued at 25-30°C for 3-4 hours. After completion of the reaction, cooled to 0-5°C, quenched with water (50 mL) and 15% NaOH (50 mL). The precipitated solid was stirred at 25-30°C for 30 minutes, filtered the solids under vacuum and washed the wet cake with ethyl acetate. The filtrate was combined and concentrated under reduced pressure at 65-70 °C to get white solid. The resultant white solid was slurred in n-heptane (500 mL) at 25-30°C for 1-1.5 hours, filtered under vacuum and dried at 45-50 °C till constant weight was obtained. Weight of Product = 80-82 gm HPLC purity: - 90-95%

Example -3:- Preparation of compound of formula IX

Dichloromethane (1550 mL) and DMSO (117.66 g) were taken under nitrogen atmosphere, cooled to -70 to -75°C, and oxalyl chloride (107 g) was added at -65°C. After completion of addition reaction mixture was stirred at -70 to -75°C for 45 - 60 minute. To this solution, compound of formula X was added at -65°C (100 g dissolved in 775 mL dichloromethane), stirred the reaction mixture at -70 to -75°C for 60-90 minutes. Triethylamine (417 mL) was added at -65°C, reaction mixture was maintained at -65°C for 2-3 hours. The reaction mass was warmed to 25-30°C, quenched with 20% aqueous potassium dihydrogen phosphate (300 mL), water was added (800 mL) and stirred for 30-45 minutes. The separated organic layer washed with 10% aqueous potassium dihydrogen phosphate (2 x 1000mL) followed by washing with water (1000mL) , concentrated under reduced pressure at 40-45°C to get viscous oil of compound of formula IX.

Weight of Product = 92-95 gm HPLC purity: - 93-95% Alternative process for the preparation of compound of formula IX

P
DCM, TEMPO, KBr
NaOCl, water, NaHCO3 OHC
OH
X IX

The compound of formula X (100 g) was dissolved in dichloromethane (900mL) at 25-30°C, solution was cooled to -7 to -5°C, TEMPO solution (1.0 g dissolved in 100 mL of dichloromethane) and potassium bromide solution (7.12 g dissolved in 100 mL water) were added to the reaction mixture. The reaction mixture was vigorously stirred and maintained. Then Sodium hypochlorite solution (By adding Sodium bicarbonate (1000 mL) to NaOCl (560 mL) to adjust pH 9.5 to 9.7) was added at pH 9.5 to the reaction mixture at -5°C, and maintained for 2 hours. The aqueous layer was separated and extracted with dichloromethane (500mL). Both organic layers were combined and washed with aqueous HCI (100mL) containing potassium iodide (7.16 g), and washed with aqueous sodium thiosulfate (100 mL), water (100 mL), subsequently the organic layer was concentrated at 45-60°C to get the desired product. Weight of Product = 75-80 gm HPLC purity: - 93-95%

Example -4:- Preparation of compound of formula Vlll.

Vlll

The compound of formula IX (100 g) was dissolved in methanol (500 mL), water (1500 mL) was added under nitrogen atmosphere at room temperature and stirred for 15-20 minutes. Sodium bisulfite (69.66 g) was added at same temperature and maintained for 30-45 minutes. R (-) Phenyl glycinol (125.3 g) was added and maintained for 30-45 minutes. Sodium cyanide (45g) was added at room temperature, and maintained for 30-45 minutes. The reaction temperature was raised up to 80-85°C, and maintained for 15-18 hours. The reaction was cooled to 25-30°C and extracted with ethyl acetate (3 X 1000mL). The ethyl acetate layer was combined and distilled out completely at 55 - 60°C to obtain a viscous mass. Isopropanol was added to the viscous mass (600 mL) to get a clear solution; aqueous hydrochloride (600 mL) was added to precipitate the product stirred at 25-30°C for 1-1.5 hours. The product was filtered and washed with isopropanol (100 mL and dried at 55-60°C till constant weight was obtained. Weight of Product = 105-110gm HPLC purity: - 85-87 %.

Example -5:- Preparation of compound of formula VII.

The compound of formula Vlll (100 g) and acetic acid (500 mL) were added to aqueous hydrochloric acid (2000 mL) at room temperature under nitrogen atmosphere and stirred for 10-15 minutes. The temperature of the reaction mass was raised to 80-85°C and maintained for 24 hours to get off-white solid. The mixture was cooled to 25-30°C, precipitated solids were filtered and suck dried for 1-2 hours. Product was dried at 55 -60 °C for 3-4 hours. Weight of Product = 75-80 gm HPLC purity: - 95-98 %.

Example -6:- Preparation of compound of formula VI.

Methanol (1000 mL) was taken in to autoclave, compound of formula VII (100 g), 20% palladium on carbon (20 g) and acetic acid (200 mL) were added. Hydrogenolysis was carried out at hydrogen pressure of 60-70 psi. for 18-20 hours. After completion of reaction catalyst was filtered and washed with methanol (100 mL). The filtrate was distilled under vacuum at 55-60°C and obtained white solid was co-distilled with ethyl acetate (2X500 mL). The white solid product was slurred in ethylacetate, filtered at 25-30°C and dried under vacuum till constant weight was obtained. Weight of Product = 60-65 gm Example -7:- Preparation of compound of formula Via.

The compound of formula VI (100 g) was suspended in and water (1000 mL) at room temperature and rose to 50-55 °C. To this mixture, sodium hydroxide (81.63 g) was added to get a clear solution and maintained for 15 minures. Propionic anhydride (159 mL) was added slowly at 50- 55°C to get the precipitation. The reaction mass was stirred for 2-3 hrs at same temperature.

After completion of reaction heating was stopped and reaction was allowed to cool at 25-30 °C.

The separated product was filtered and washed with water (200 mL) and dried under vacuum till
constant weight was obtained.

Weight of Product = 100-105 gm
HPLC purity: - 95-97 %.
1HNMR5inDMSO-d6
0.98 (t, 3H), 1.23-1.83 (m, 12.0 H), 2.08 (s, 3 H), 2.11-2.25 (m, 2 H), 3.95 (d, 1 H), 7.69 (d, 1H)

Example -8:- Preparation of compound of formula Vlb.

The compound of formula Via (100 g) was dissolved in sulphuric acid (200 mL) at room temperature under nitrogen atmosphere, cooled to 0-5°C. The nitrating (nitric acid 60 mL to sulphuric acid 600 mL at 0-5°C) mixture was added at the same temperature. After completion of addition, cooling was removed and reaction mixture was maintained at 25-30°C for 3-4 hours. The reaction mixture was poured into ice cold water (1000 mL) at 5 °C pH of the reaction was adjusted to 10-11 using sodium hydroxide solution (880 mL) and washed with ethyl acetate (500 ml). The aqueous layer was acidified to pH 2-3 using aqueous hydrochloride (140 mL) and extracted with ethyl acetate (3X1000 mL). The organic layer was distilled off to obtain foamy solid.

Weight of Product = 60-65 gm HPLC purity: - 85-90 %. 1HNMR5inDMSO-d6

1.11 (t, 3H), 1.38-1.63 (m, 12.0 H), 2.10 (s, 2 H), 2.15-2.30 (m, 2 H), 4.06 (d, 1 H) and 7.85 (d, 1H)
The compound of formula V (100 g) was dissolved in a mixture of trifluoroacetic acid (1000 mL) and water (2000 mL) at room temperature heated to 75-80°C and maintained for 24 hours. After completion of reaction, the reaction mixture concentrated under reduced pressure at 60-65°C to get a gummy mass, swapped the obtained gummy mass with methanol (2X 500 mL) and MTBE (2 X 500mL). Viscous mass was slurred in MTBE (600 mL) and stirred at 25-30° C for 1 hour to get a solid. The obtained solid filtered under nitrogen to get off white solid. Weight of Product = 90-95 gm

Example -10:- Preparation of compound of formula SM1.

The compound of formula XIII (100 g) was taken into a mixture o f tetrahydrofuran (700 mL) and
water (300 mL) at 25-30° C. Sodium hydroxide (35.39 g) was added to the reaction mixture and
stirred for 30 minutes to get clear solution. Di- tertiary butyl pyrrocarbonate (193.14g) was added
at 25-30° and maintained for 3-4 hours. After completion of reaction, tetrahydrofuram was distilled
under reduced pressure at 60 - 65°C to get gummy mass. Water (1000 mL) was added to the resultant gummy mass and washed with ethyl acetate (1500 mL X 2). Aqueous layer was cooled to 0-5° C and acidified with a solution of sulfuric acid: water (1:1) (90 ml) to pH 3-4, and extracted with ethyl acetate (1500 mL X 2). The organic layer was treated with activated charcoal (10 g) at 25-30°C for 1 hr. The reaction mixture was filtered through celite bed and filtrate was distilled under reduced pressure to obtain a white colored foaming solid (100g).

Purification:-

Foaming solid (100 g) was dissolved in ethanol (500 mL) at 70-75°C and stirred for 10-15 minutes. The reaction mass was decolorized by charcoal (10.0 g), and then filtered, water (500 mL) was added to the filtrate and heated to 75-80 °C, and maintained for 15-30 minutes. The reaction mass was cooled to 25-30°C, the separated solids and white solid was filtered, dried at 65-70°C.

Weight of Product = 58-60 gm
HPLC purity: - 90-95 %.

Example 11: Preparation of compound of formula XVI

Adamantine-1-acetic acid of formula XVII (100 g) and thionyl chloride was taken at room temperature followed by addition of dimethylformamide (0.1 mL), stirred the reaction mixture for 2 hours at room temperature. N-bromosuccinamide (110.0g) was added to the reaction mixture in lot wise, heated to 60-65 °C and maintained the temperature for 3 hours. After completion of reaction, heptane (300mL) was added, excess thionyl chloride was distilled off at 78-80 °C and reaction mixture was cooled to 5-10 °C. Water (200ml), heptane (150mL) were added, separated the organic layer, additional (100ml) water was added to the heptane layer and distilled off heptane to remove traces of thionyl chloride. Tetrahydrofuran (400mL) was added to aqueous layer and reaction mixture was stirred vigorously at room temperature for 16-18 hours. After completion of reaction tetrahydrofuran was distilled off to get white solid, water was added, stirred for one hour, filtered the solid and washed with water, dried at 60 °C for 4-5 hours. Weight of solid: 100g HPLC purity: 97%.

Example 12: Preparation of compound of formula XV.

Compound of formula XVI (100g) was dissolved in ethyl acetate (1500mL) and (S)-(+)-2-phenylglycine amide (54.5g) was added to the clear solution. The reaction mixture was heated to 70-75 °C, maintained for 1 hour and gradually cooled to room temperature to form precipitation at 40-45 °C. The obtained solid was filtered, washed with ethyl acetate and dried at 55 °C. The solids were recrystallized from methanol and ethyl acetate mixture to get a pure diasteromeric salt of formula XV. Weight of Product: 52 g HPLC purity: 96%

Example 13: Preparation of compound of formula XIV.

Compound of formula XV (52 g) was taken in to mixture of water (520mL) and ethyl acetate (260mL), cooled to 10-15 °C. Concentrated hydrochloride was added till the pH attained to 2.0, separated the aqueous layer and compound was extracted in ethyl acetate, the combined ethyl acetate was distilled off under reduced pressure to get a white solid and dried at 50-55 °C. Weight of Product: 32 gm HPLC purity:
98%

Example 14: Preparation of compound of formula XIII.

Aqueous nitric acid solution (13mL) was added slowly to pre-cooled sulphuric acid (108mL) at 2-4 °C. To this mixture compound of formula XIV was added in lot wise within 30-40 minutes at same temperature, gradually raised to 55-60 °C and maintained for 1 to 2 hours, gradually cooled to 5-10 °C, reaction mixture was quenched with cold water (320mL), compound was extracted in ethylacetate and distilled off ethyl acetate. The obtained solid was dried at 50-55 °C. Weight of Product: 32 g HPLC purity: 85%

Example 15: Preparation of compound of formula SM1.

Compound of formula XIII (32 g) was taken in aqueous ammonia at room temperature and heated to 60-65°C for 15 hours. After completion of reaction water was distilled out to get residue, swapped with ethanol (2X16 mL) to obtain a yellow residue. Tetrahydrofuran (224mL) and water (96mL) was added at room temperature, followed by sodium hydroxide (13.28g), stirred the mixture for 30 minutes to get a clear solution and to this solution di-tertiary butyl pyrocarbonate (72.39g) was added at room temperature. After completion of reaction, tetrahydrofuran was distilled out under reduced pressure at 60-65 °C. Water (160ml) was added, washed with ethylacetate (2X160mL), aqueous layer was further cooled to 0-5 °C, acidified with concentrated hydrochloride to reach the pH 3-4, compound was extracted with ethylacetate (3X160mL) and ethyl acetate layer was treated with charcoal and distilled out ethylacetate under reduced pressure to obtain foamy solid. This solid was dissolved in ethyl acetate (64mL) at 65-70°C and heptane was added to the clear solution at same temperature, stirred for one hour, the mixture was cooled to room temperature and stirred for one hour to precipitate. The obtained solid was filtered, washed with heptane and dried at 55 °C.

Weight of Product: 25 g HPLC purity: 98%.

Process for synthesis of Saxagliptin:

Example 16:- Preparation of compound of formula SM2.

Boc protected SM2 (100.0 g) was treated with methanesulfonic acid (55.22gm) in isopropanol (500mL) at 55-65 °C, and maintained at 60-65 °C for 3-4 hours, reaction mixture was cooled to 10-15 °C, followed by filtration and washed with isopropanal (100mL) and n-heptane (200mL) and dried under vacuum oven at 45 -50 °C for 4.0 hours to get a constant weight. Weight of Product: 90g HPLC purity: 90 to 95%

Exarrmle 17:- Prena ration of compound of formula IV

Compound of formula SM1 (100.0g) in Tetrahydrofuron (500mL) was cooled to -5 to -10 °C under nitrogen atmosphere, and methane sulphonyl chloride (38.88g) was added at the same temperature, and stirred for 10-15 minutes Triethylamine (124.4g) was added to the reaction mass at -5 to -10 °C, and maintained for 1.0 hour and reaction completion (mix anhydride formation) was formed by HPLC. The compound of formula SM2 (89.0g) and HOBT (2.08g) was added to reaction mixture, and stirred for 10-15 minutes. The reaction temperature was raised to 25-30 °C and reaction was stirred for 4 hours. After completion of reaction, cooled the reaction mass to 0 - 5 °C, ethyl acetate (1.0 Litre) and water (250mL) were added. After 10-15 minutes, aqueous hydrochloride (100mL concentrated hydrochloride diluted in 250mL of water) was added, and was stirred for 10-15 minutes. The reaction mass allowed to settle layers were separated and extracted aqueous layer with ethyl acetate (500mL). The combined organic layer was washed with 10% sodium bicarbonate solution (50.0g in 500mL water). Organic layer was distilled out under vacuum at 40 - 45 °C to get foam solid. The foam solid was further swapped with cyclohexane (200mL). Cyclohexane (700 mL) was charged to the foamy solid and stirred at 25-30 C for 1.0 hour. The obtained product was filtered and washed with cyclohexane (100mL). Weight of Product: 130g HPLC purity: 93 to 96%

Example 18:- Preparation of compound BOC protected Saxagliptin.

The compound of formula IV (100g) was dissolved in ethylacetate (1500mL) at 25-30 °C and stirred for 10-15 minutes. Pyridine (72.8g) was charged at the same temperature and cooled to -10 to -15 °C. Trifluoroacetic anhydride (120.96g) was added at -5 to -10 °C, and stirred for 1.0 hour. After completion of reaction, water (10.0 vol.) and TMEDA (0.6 vol.) was added at 0 to - 5 °C and raised to 15-20 °C, and stirred for 15 -20 minutes. The layer was separated and aqueous layer was extracted with ethyl acetate (500mL). To the combined organic layer, water (500mL) was added, cooled to 0 to 5 °C, aqueous hydrochloric acid (100mL) was added and stirred for 15 minutes. The ethyl acetate layer was separated, and washed with aqueous sodium bicarbonate (50g in 500mL water).

Methanol (150mL, 1.5 vol) and 25% aqueous potassium carbonates (240g in 720mL water) were added to ethyl acetate layer, and heated to 40-45°C, for 6-8 hrs.

After completion of reaction, reaction mass was and the layers were separated and aqueous layer was further extracted with ethyl acetate (500mL). Ethyl acetate layers were combined and water (1000mL) was added, and pH of reaction mixture was adjusted to 6-8 using aqueous hydrochloric acid. The layers were separated and ethyl acetate was distilled of under vacuum at 40-45 °C to get foam solid. The obtained solid was further swapped with cyclohexane (200mL). Cyclohexane (700mL) was added to the resultant solid and stirred at 25-30 °C for 1.0 hour. Product was filtered and washed with cyclohexane (100mL).

Purification: - After cyclohexane purification, the wet product was dissolved in isopropanol (240mL) at 55 - 60 °C, and water (800mL) was added to get clear solution. The reaction mass was cooled to 25 -30 °C and stirred for 3.0hours. Further, reaction mixture was cooled to 0 -5 °C and maintained for 1 hour. The separated product was filtered, washed with water (100mL) and dried under vacuum at 45 -50 °C for 4-5 hr till constant weight was obtained. Weight of Product: 65 g HPLC purity: 93 to 96%

Example 19:- Preparation of Saxagliptin trifluoroacetate salt.

Boc protected Saxaglipitn TFA salt of saxagliptin

Water (300mL) and trifluoroacetic acid (82.57g) were added to boc protected Saxagliptin (100g) in isopropanol (300mL) at room temperature to get clear solution and observed, heated to 60 - 65 °C for 6-8 hours. After completion of reaction, trifluoroacetic acid, water and isopropanol were distilled off under reduced pressure to get gummy mass. The gummy mass was taken in ethylacetate (1000mL), and reaction mass was heated at 75 - 80 °C to get a suspension, and maintained for 30 minutes. The reaction mass was cooled to 20 -25 °C and maintained for 1hour. The product was filtered and washed with ethyl acetate (100mL).

Purification: - The Saxagliptin trifluoroacetae salt obtained from the above batch was further purified by crystallization at 90-95°C from a mixture of butanol (400mL): Ethyl acetate (400mL) and wet cake washed with Ethyl acetate (100mL). Weight of Product: 90 g HPLC purity: 97-99% TFAsaltofsaxagliptinSaxaglipitn base Saxagliptin trifluoroacetate salt (100g) was dissolved in water (300 mL) at 25 -30 °C and stirred fori5 minutes. Ethyl acetate (300mL) was added and stirred for 15 minutes. Aqueous and organic layers were separated. To the aqueous layer, dichloromethane (20.0 V) was charged and cooled to 0-5 °C To the heterogeneous mixture, potassium carbonate solution (38.5g in 200mL water) was added at 0-5 °C and stirred for 10-15 minutes. The pH of the reaction mass was 9.0 to 9.5. The reaction temp was raised to 10-15 °C. Aqueous and organic layers were separated. Further aqueous layer was extracted with dichloromethane (4 X 500mL). The combined dichloromethane layer was treated with 10 % charcoal and distilled under vacuum till ~5.0 vol of dichloromethane remains inside.

To the enriched dichloromethane layer, ethyl acetate (400mL) and water (4.0mL) was added subsequently. Repeated ethyl acetate: Water swapping. Finally, reaction mass was concentrate up to 3.0V solvent inside, and added 2.0V ethyl acetate and 4.0mL water. The reaction mass stirred slurry at 25-30°C for 1hour, cooled to 0-5°C and stirred for 1 hour. Precipitated solid was filtered and washed with 5% wet ethyl acetate (100mL) Purification:

Crude Saxagliptin base was recrystallized from ethanol: tertiary butyl methyl ether (2:8 Vol.) and washed with TBME (2.0V) Weight of Product: 60 g HPLC purity: 99.85 to 99.90% Example 21:- Preparation of Saxagliptin hydrochloride Saxagliptin base monohydrate (60.0 gm) was dissolved in dichloromethane (1000 mL). To a clear solution aqueous hydrochloric acid (22.75mL, 1.2 eq in 45mL water) was added at 0- 5 °C. The reaction mixture was stirred for 30 minutes at same temperature and raised to 20-25 °C, maintained for 2 hours. After completion the reaction distilled off dichloromethane. To this residue, ethanol (240mL) and water (10mL) were added and heated to 50-55 °C to get clear solution. To this clear solution tertiary butyl methyl ether was added and maintained same temperature for 30 minutes, slowly cooled to 15-20°C for one hour and maintained another one hour, filtered the product washed with tertiary butyl methyl ether and dried under vacuum below 35-40 °C for 3 hours. Weight of Product: 55 g HPLC purity: 99.85 to 99. 90 %

Example 22:- Process for the preparation of Saxagliptin hydrochloride dihydrate.

The BOC protected Saxagliptin (1.0 gm) was taken in dichloromethane (13mL) and water (2mL). To this solution cone, hydrochloride (0.65mL) was added at 25-30 °C. The reaction mixture was stirred was stirred at 35-40 °C for 4.0 hours. After completion of reaction dichloromethane was distilled off under vacuum at 35-40 °C, after completion of dichloromethane, reaction mixture was swapped with toluene (10mLX2) at 50-55 °C. The obtained residue was further triturated with diethyl ether (10mL). The suspension was further stirred for one hour; product was filtered and dried under vacuum at 35-40 °C for 2 hours. Dry weight: 0.6g HPLC purity: 97%

Example 23:- Process for the preparation of Saxagliptin hydrochloride dihydrate.

The boc protected Saxagliptin (1.0 gm) was taken in dichloromethane (13mL) and water (2mL). To this solution 5% ethyl acetate hydrochloride (15mL) was added at 25-30 °C. The reaction mixture was stirred was stirred at 35-40 °C for 7.0 hours. After completion of reaction dichloromethane and ethyl acetate was distilled under vacuum at 35-40 °C. To this residue diethyl ether (10mL) was added and stirred for one hour, product was filtered and dried under vacuum at 35-40 °C for 2 hours. Dry weight: 0.6g HPLC purity: 97%

Example 24:- Process for the preparation of Saxagliptin hydrochloride dihydrate.

The Saxagliptin base (2.0 gm) was dissolved in dichloromethane (50mL) and reaction mass was cooled to 0-5 °C. To this solution 1N aqueous hydrochloric acid was added at 0-5 °C. The reaction mixture was stirred was stirred at 0-5 °C for 1.5 hours. After completion of reaction dichloromethane was distilled under vacuum to get the residue, this residue was swapped with toluene (50mL) and dried on rotary evaporator under vacuum. This residue was triturated with diethyl ether (30mL); product was filtered under reduced pressure and dried at 35-40 °C under reduced pressure for 2 hours. Dry weight: 1.9gm
Example 25:- Process for the preparation of Saxagliptin hydrochloride dihydrate.

The Saxagliptin base (2.0 gm) was dissolved in dichloromethane (50mL) and reaction mass was cooled to 0-5 °C. To this solution 1N aqueous hydrochloric acid was added at 0-5 °C. The reaction mixture was stirred was stirred at 0-5 °C for 1.5 hours. After completion of reaction dichloromethane was distilled under vacuum to get the residue, this residue was swapped with dichloromethane (2X 25mL) under vacuum till the solid was obtained. Weight of solid: 2.1 gm

Example 26:- Process for the preparation of Saxagliptin hydrochloride dihydrate.

The Saxagliptin base (2.0 gm) was dissolved in dichloromethane (50mL) and reaction mass was cooled to 0-5 °C. To this solution 1N aqueous hydrochloric acid was added at 0-5 °C. The reaction mixture was stirred was stirred at 0-5 °C for 1.5 hours. After completion of reaction dichloromethane was distilled under vacuum to get the residue, this residue was swapped with dichloromethane (2X 25mL) under vacuum till the solid was obtained, further swapped with toluene (50mL) under reduce pressure. Weight of solid: 1.6 gm

We claim:

1. An improved process for the preparation of intermediate of Saxagliptin (SM1), which comprising the steps of: a) esterfying the compound of formula XII to get the compound of formula XI,

b) reducing the compound of formula XI in the presence of metal hydride to get compound of formula X,

c) oxidizing the compound of formula X in the presence of oxidizing agent to get compound of formula IX,

d) reacting the compound of formula IX with R-(-)phenyl glycinol and cyanide source to get compound of formula VIII,

e) hydrolyzing the compound of formula VIII to get the compound of formula VII,
f) hydrogenating the compound of formula VII in the presence of a metal catalyst under hydrogen pressure to get the compound of formula VI,

g) reacting the compound of formula VI with propionic anhydride to get compound of formula Via,

h) oxidizing the compound of formula Via in presence of an oxidizing agent to get compound of formula Vlb,

i) deprotecting the compound of formula Vlb in presence of trifluoroacetic acid to get TFA saltofSMI, and

j) reacting the Trifluoroacetic acid salt of SM1 with ditertiary butyl dicarbonate to get SM1.

2. An improved process for the preparation of intermediate of Saxagliptin (SM1), which comprising the steps of:

a) brominating the compound of formula XVII in the presence brominating agent to get the compound of formula XVI,

b) reacting the compound of formula XVI with chiral base to give compound of formula XV,

c) converting the compound of formula XV to compound of formula XIV,

d) oxidizing the compound of formula XIV in the presence of an oxidizing agent to get the compound of formula XIII,

e) reacting the compound of formula XIII with aqueous ammonia followed by reacting with ditertiary butyl dicarbonate to get SM 1.

3. The process according to claim 1, wherein the metal hydride is selected from Lithiumaluminium hydride, sodium borohydride or vitride.

4. The process according to claim 1 & 2, wherein the oxidizing agent is selected from dimethyl sulfoxide, TEMPO (2, 2, 6, 6-Tetramethyl-1-piperidinyloxy), potassium permanganate or sulfuric acid and nitric acid.

5. The process according to claim 1, wherein the metal catalyst is selected from Palladium carbon, palladium hydroxide or Platinum oxide.

6. The process according to claim 1, wherein the cyanide source is selected from potassium cyanide or sodium cyanide.

7. The process according to claim 2, wherein the brominating agent is selected from bromine or N-bromo succinimide.

8. The process according to claim 2, wherein the chiral base is selected from (S)-(+)-2-phenylglycine or Norephedrine.

9. The process according to claim 1 & 2, intermediate SM1 is used in the preparation of the saxagliptin hydrochloride.

10. Compound of formula Via & Vlb