DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of vildagliptin of following formula (I)

Formula (I)
The present invention also relates to a process for preparation of compound of formula (II)

Formula (II)
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however reference to any prior-art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
“Vildagliptin” [274901-16-5] is an oral anti-hyperglycemic agent (anti-diabetic drug) acting as dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin having an empirical formula of C17H25N3O2 and a molecular weight of 303.40 g/mol. Vildagliptin is the international commonly accepted name for (2S)-1-{2-[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile and has the structure of formula (I)

Formula (I)
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are useful in the treatment of diabetes mellitus. Diabetes mellitus is a relatively common disorder which is characterized by hyperglycemia.
US Patent No. 6,166,063 B2 discloses process for preparation of vildagliptin. The process comprises reaction of l-aminoadamantane-3-ol with 1-chloroacetyl-2-cyanopyrrolidine in presence of potassium carbonate. The reaction is carried out for 6 days yielding vildagliptin as a crude pasty material. Purification is performed by Flash chromatography using methanol and methylene chloride as solvent. The process involves long reaction time, and impracticable purification process.
Vildagliptin exists as (2S) and (2R) enantiomer, (2S) enantiomer is desired for biological activity. Accordingly, it is desirable to synthesize (2S)-vildagliptin with high stereo chemical purity.
J. Med. Chem. 46 (13), pp 2774–2789 (2003) discloses the process for preparation of vildagliptin.
US 7,375,238 B2, WO2008/084383, WO2010/022690, WO2011/012322, WO 2011/101861, WO2011/042765, WO2012/004210 and WO2012/022994 describe processes for preparation of vildagliptin or salt thereof.
The process disclosed in WO2011/012322 involves reaction of pyrrolidine carbonitrile derivative of formula (II) with adamantol of formula (III) in presence of phase transfer catalyst.
However, the main disadvantage of use of phase transfer catalyst in the industrial application is it needs to be separated from the reaction mixture, and its subsequent use or disposal. The complicated nature of the phase transfer catalyst system requires two mass transfer steps and two reaction steps in the organic and aqueous phases. In addition, the equilibrium partitions of the catalysts between two phases also affect the reaction rate. Consequently use of phase transfer catalyst lessens the ease of operation.
In view of the above, it is desirable to have an improved and commercially viable process for preparing highly pure vildagliptin which is suitable for large scale preparation in terms of simplicity of operations and yield & purity of product.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a process for preparation of vildagliptin of formula (I) or salts at industrial scale.

Formula (I)
Another object of the present invention is to provide an improved process for preparation of vildagliptin of formula (I) or its pharmaceutically acceptable salts wherein the reaction of compound of formula (II) and compound of formula (III)

Formula (II) Formula (III)
is carried out in absence of phase transfer catalyst
Another object of the present invention is to provide a process for the preparation of compound of formula (II)
SUMMARY OF THE INVENTION
The main aspect of the present invention provides an improved process for preparation of vildagliptin of formula (I) and its pharmaceutically acceptable salts

Formula (I)
comprising a step of reacting compound of formula (II) with compound of formula (III) in absence of phase transfer catalyst

Formula (II) Formula (III)
wherein LG represents a leaving group.
An another aspect the present invention is to provide a process for preparation of compound of formula (II) comprising a step of reacting compound of formula (V’) with compound of formula (VI)

Formula (II) Formula (V’) Formula (VI)
wherein, LG represents a leaving group such as Cl, Br, I, p-CH3-C6H4-SO2O-, p-NO2-C6H4-SO2O-, C6H5SO2O-, CH3SO2O-, C2H5SO2O- or CF3SO2O- and HX stand for trifluoro acetic acid or p-Toluenesulfonic acid.
DETAILED DESCRIPTION OF THE INVENTION
Following embodiments discloses an improved process for preparation of vildagliptin of formula (I) and compound of formula (II).
In an embodiment the present invention provides a process for preparation of vildagliptin of formula (I) and its pharmaceutically acceptable salts

Formula (I)
wherein, the said process comprises:
reacting a compound of formula (II) with a compound of formula (III)

Formula (II) Formula (III)
The above reaction may be carried out in absence of phase transfer catalyst, and in presence of a suitable base and solvent.
In another embodiment the present invention provides a process for preparation of vildagliptin comprising following steps:
converting 1-adamantylamine hydrochloride of formula (IV) to (1r,3s,5R,7S)-3-nitroadamentane-1-amine of formula (IVa)

Formula (IV) Formula (IVa)
reacting, compound of formula (IVa) with a base in presence of an alcohol and suitable solvent to obtain the compound of formula (III) and

Formula (III)
condensing a compound of formula (III) with compound of formula (II)

Formula (II)
in the presence of suitable base and solvent to obtain the compound of formula (I)
Another embodiment of the present invention provides a process for preparation of compound of formula (II).
The compound of formula (II) can be prepared by reacting compound of formula (V’) and compound of formula (VI)

Formula (V’) Formula (VI)
wherein HX stand for trifluoro acetic acid or p-Toluenesulfonic acid.
Another embodiment of the present invention provides a process for the preparation of compound of formula (II) wherein the LG is tosyl group [represented as formula (II’)]; the process comprises following steps:
i) reacting, (S)-pyrrolidine-2-carboxamide of formula (IX) in the presence of a base and suitable solvent with Di-tert-butyl dicarbonate to obtain the compound of formula (VIII)

Formula (IX) Formula (VIII)
ii) dehydrating a compound of formula (VIII) by suitable dehydrating agent in presence of a base and solvent to obtain compound of formula (VII)

Formula (VII)
iii) deprotecting compound of formula (VII) by suitable deprotecting agent to obtain the compound of formula (VI)

Formula (VI)
wherein HX stand for trifluoro acetic acid or p-Toluenesulfonic acid.
iv) condensing a compound of formula (VI) with the compound of formula (V)

Formula (V)
using suitable reagents and solvent to obtain the compound of formula (II’)

Formula (II’)
In general, solvents or suitable solvents as used herein and after comprising aromatic hydrocarbons such as but not limited to toluene and xylene; aliphatic hydrocarbons such as but not limited to heptanes and hexane; alcohols such as but not limited to methanol, ethanol, propanol, butanol; ethers such as but not limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether; cyclic ethers such as but not limited to tetrahydrofuran, and 1 ,4-dioxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran and the like; nitriles such as but not limited to acetonitrile, and propionitrile; dialkylformamides, dialkylacetamides; dialkylsulfoxides; halogenated hydrocarbons such as dichloromethane, and dichloroethane; ketones such as acetone or mixtures thereof.

In general, the base used herein and after is either organic or inorganic base. The inorganic base used in process is selected from the group comprising of alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide, and lithium hydroxide.

The organic base used in process is selected from the group comprising of alkyl amines such as but not limited to di-isopropyl ethyl amine, di-isopropyl amine, and triethyl amine; pyridine; or lutidines.

In general, reagents like Ethyl chloroformate or isobutyl chloroformate, pivaloyl chloride and n-propanephosphonic acid anhydride may be used.

In general, dehydrating agents are trifluoro acetic anhydride and triethyl amine, phosphorous oxychloride, thionyl chloride, sodium borohydride and P2O5.

In general, the acid as used in the process comprising organic and inorganic acid wherein, organic acid used is selected from the group comprising of acetic acid, trifluoro acetic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, malic acid, glutamic acid, lactic acid, citric acid, salicylic acid, methane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, malonic acid, mandelic acid, succinic acid or mixtures thereof.

The inorganic acid used is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, preferably the acid used is nitric acid and sulfuric acid.

In general embodiment of the present invention the process for preparation of vildagliptin of formula (I) may be illustrated as scheme 1.

Scheme 1

EXAMPLES
Example-1: Synthesis of tert-butyl (S)-2-carbamoylpyrrolidine-1-carboxylate (Formula - VIII)
In 5 liter three necked round bottomed flask equipped with mechanical stirrer, thermometer and an addition funnel, L-Prolinamide (250 gm) in methylene chloride (1250 ml), Potassium carbonate (166.5 gm) and Di-tert-butyl di carboxylate (525.8 gm) were added at 0-5oC. Reaction was stirred for 2 hr at 0-5oC. After completion of reaction (reaction monitored by TLC). Water (1250 ml) was added at 0-5oC and stirred for 30 minutes. Organic layer was separated; methylene chloride was distilled out atmospherically and solid was stripped out with n-Heptane (250 ml). n-Heptane (3L) was added and heated up to 70-80oC. Cooled gradually up to 25-35oC and maintained for 30 minutes. Solid was filtered and washed with n-Heptane (500 ml) to obtain off-white to light brown colored solid [yield: 402 gm]

Example-2: Synthesis of tert-butyl (S)-2-cyanopyrrolidine-1-carboxylate (Formula - VII)
In 5 liter three necked round bottomed flask equipped with mechanical stirrer, thermometer and an addition funnel, tert-butyl (S)-2-carbamoylpyrrolidine-1-carboxylate (400 gm) in methylene chloride (2400 ml), Triethylamine (976 ml) and Trifluoroacetic anhydride (398 ml) were added at -5 to 5oC. Reaction was then stirred for 2 hr at 0-5oC. After completion of reaction (reaction monitored by TLC). Water (4000 ml) was added at 0-10oC and stirred for 30 minutes. Organic layer was separated and washed with 5% aq.Hydrochloric acid followed by 5% Sodium bicarbonate solution. Methylene chloride was distilled out to obtain brown colored oily mass.

Example-3: Synthesis of (S)-pyrrolidine-2-carbonitrile trifluoro acetate (Formula - VI)
In 5 liter three necked round bottomed flask equipped with mechanical stirrer, thermometer and an addition funnel, crude tert-butyl (S)-2-cyanopyrrolidine-1-carboxylate (25 gm) as obtained in example 2 in methylene chloride (250 ml), Trifluoro acetic acid (101.67 gm) was added drop wise at 0-5oC and stirred at 0-5 oC for 3 hours. After completion of reaction (reaction monitored by TLC), solvent was distilled out under vacuum and stripped out with ethyl acetate (50 ml). Diethyl ether (325 ml) was added at room temperature. Cooled gradually up to 0-5oC and maintained for 30 minutes. Solid was filtered and washed with Diethyl ether (25 ml) to get light yellow colored solid [yield: 11.3 gm].

Example-4: Synthesis of (S)-2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl 4-methylbenzenesulfonate (Formula - II’)
In 5 liter three necked round bottomed flask equipped with mechanical stirrer, thermometer and an addition funnel, 2-(tosyloxy)-actic acid (100 gm) in Tetrahydrofuran (300 ml), isobutyl chloroformate (71.18 gm) and N-Methyl morpholine (52.7 gm) were added at -5 to 5oC and stirred for 10-15 minutes. To this solution (S)-pyrrolidine-2-carbonitrile 4-methylbenzene sulfonate (139.6 gm) in Tetrahydrofuran (800 ml) and N-Methyl morpholine (166.5 gm) (separately prepared) was added at -5 to 5oC in one hour. Reaction was then stirred for 4 hours at -5 to 5oC. After completion of reaction (reaction monitored by TLC), Water (1000 ml) was added at 0-5oC and stirred for 15 minutes. Organic layer was separated out and washed with 5% aq. Hydrochloric acid and 5% Sodium bicarbonate solution followed by brine solution (1000 ml). Organic layer was dried over anhydrous sodium sulphate and distilled out under vacuum at 50-55oC. To this residue, Methyl tert-butyl ether (500 ml) was added and heated at 50-55oC for 30 minutes. Cooled gradually up to 25-35oC and maintained for 1 hr. Solid was filtered and washed with Methyl tert-butyl ether (100 ml. off white to light brown colored solid [yield: 82 gm].

Example-5: Synthesis of (S)-1-(((1r,3R,5R,7S)-3-hydroxyadamantan-1-yl)glycyl)pyrrolidine-2-carbonitrile (Formula - I)
In 5 liter three necked round bottomed flask equipped with mechanical stirrer, thermometer and an addition funnel, 1-Amino admantane-3-ol (71.6 gm) in Acetone (2110 ml), Potassium carbonate (65.1 gm) and Potassium iodide (14.3 gm) were added at 30-35oC. To this reaction mass, added a solution of (S)-2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl 4-methylbenzenesulfonate (132 gm) in Acetone (530 ml) in three lots and reaction was then stirred for 5 hr at 30-35oC. After completion of reaction (reaction monitored by TLC), distilled out Acetone under vacuum. Water (1320 ml) and methylene chloride (1320ml) were added and pH adjusted to 5-5.5 by using 20% aq. Potassium Hydrogen Sulfate solution. Stirred for 15 minutes and layers separated out. Aq. Layer washed with methylene chloride (1320 ml). pH of aq. Layer was adjusted 9-9.5 by using 20% aq. Potassium carbonate solution and extracted with methylene chloride (3 x 1320 ml). Distilled out methylene chloride and stripped out with Isopropyl acetate (265 ml). To this was added Isopropyl acetate (400 ml) and stirred for 30 minutes at 50-55oC. Cooled gradually up to 10-15oC and maintained for 60 minutes. Solid was filtered and washed with Isopropyl acetate (70 ml) to get white to off white colored solid [yield: 75.6 gm]. ,CLAIMS:1. A process for preparation of vildagliptin of formula (I) or its pharmaceutically acceptable salts

Formula (I)
comprising:
reacting a compound of formula (II) with a compound of formula (III)

Formula (II) Formula (III)
in absence of phase transfer catalyst, wherein LG represents a leaving group.

2. The process as claimed in claim 1, wherein the reaction is carried out in presence of base selected from the group consisting of alkali metal carbonates.

3. The process as claimed in claim 1, wherein the reaction is carried out in presence of solvent selected from group comprising of aromatic hydrocarbon, aliphatic hydrocarbon; nitrile; formamide, acetamide, sulfoxide, halogenated hydrocarbon or mixtures thereof.

4. The process as claimed in claim 1, wherein, LG is selected from Cl, Br, I, p-CH3-C6H4-SO2O-, p-NO2-C6H4-SO2O-, C6H5SO2O-, CH3SO2O-, C2H5SO2O- or CF3SO2O-.

5. A process for preparation of compound of formula (II)

Formula (II)
comprising:
reacting compound of formula (V’) with compound of formula (VI)

Formula (V’) Formula (VI)
wherein HX represents trifluoro acetic acid or p-Toluenesulfonic acid, LG represents a leaving group.

6. The process as claimed in claim 5, which comprises

Formula (II’)
i) reacting, (S)-pyrrolidine-2-carboxamide of formula (IX) with Di-tert-butyl dicarbonate in presence of a base and a suitable solvent to obtain the compound of formula (VIII)

Formula (IX) Formula (VIII)
ii) dehydrating the compound of formula (VIII) in presence of a base and solvent to obtain compound of formula (VII)

Formula (VII)
iii) deprotecting compound of formula (VII) to obtain the compound of formula (VI)

Formula (VI)
wherein HX represents trifluoro acetic acid or p-Toluenesulfonic acid.
iv) condensing compound of formula (VI) with compound of formula (V)

Formula (V)
to obtain the compound of formula (II’).

Formula (II’)

7. The process as claimed in claim 6, wherein suitable base is selected from the group comprising of alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide and solvent is selected from the group comprising halogenated hydrocarbons such as dichloromethane and dichloroethane; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as heptanes and hexane.

8. The process as claimed in claim 6, wherein suitable dehydrating agent is selected from the group comprising phosphorous oxychloride, thionyl chloride, trifluoro acetic anhydride and phosphorus pentoxide.

9. The process as claimed in claim 6, wherein suitable deprotecting agent comprises acetic acid, trifluoro acetic acid and p-toluene sulfonic acid; inorganic acid is selected from the group comprises hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.

10. The process as claimed in claim 6, wherein suitable condensing reagent comprises pivaloyl chloride, n-propanephosphonic acid anhydride and isobutyl chloroformate.