DESC:Detailed description of the invention:
The present invention relates to a process for the preparation of Alogliptin compound of formula I. The present invention also relates to process for preparation of compounds of formula II with high purity from compound of formula I, wherein compound of formula II is used as intermediate for the preparation of Alogliptin.

6-Chlorouracil (I) is alkylated with 2- (bromomethyl)benzonitrile in the presence of NaHCO3 and in a NMP to produce intermediate compound of formula II, which comprises mainly Di-alkylated impurity (A). Further compound of formula II was purified with Toluene and N,N-Dimethyl formamide at 100 to 110 0C.

Pure intermediate-II further reacts with Methyl iodide & in presence of sodium hydride to give Intermediate of formula-III. Alternatively methylation reaction can be performed by using Potassium carbonate and methyl iodide.

In another embodiment, present invention provides method of preparation of Alogliptin benzoate polymorph A comprising
Compound of formula III react with 3(R)- aminopiperidine dihydrochloride in acetonitrile in the presence of Potassium carbonate to provide Alogliptin free base (IV) which is then converted in to hydrochloride salt. Hydrochloride salt is neutralized with aqueous NH3 to give free base (IV) which is then converted to Alogliptin benzoate by reaction of Benzoic acid in the presence of Ethanol & N,N-Dimethyl formamide.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustration of the process of this invention. However, it is not intended in any way to limit the scope of the present invention.

Example-1 Preparation of 2-[(6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl) methyl] benzonitrile (II)
To a solution of 6-chlorouracil (100 g) in N-methyl pyrollidinone (300 ml), was added sodium bicarbonate (63.1g) and 1-bromomethyl ortho benzonitrile (133.8 g) at 25-350C. Reaction mass was heated at 45°C and stirred for 8 hrs. Toluene (300ml) was charged to the reaction mass and stirred for 30 min. Reaction mass was cooled and poured in to water (900 ml) and stirred for 30 min. The precipitate was collected by filtration, washed with water followed by addition of toluene and dried to obtained crude (II). Yield- 150g

Purification of 2-[(6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]benzo nitrile (II)
Solution of Crude-II (100 g) in Toluene (600 ml) was heated at 105°C. The solution was slowly charged with N,N-Dimethyl formamide (300 ml) and stirred for 0.5 hr. Reaction mass was cooled at 10°C and stirred for 1 hr. Solid was filtered, washed with toluene & dried. Yield – 63g.

Example-2 Preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (III)
To a cold (0°C) solution of benzylated 6-chlorouracil (II) (100 g) in DMF (800 mL), was added NaH (60%, 16.05 g) in portions, followed by adding LiBr (19.9 g). The temperature of reaction mixture was increased to 28°C and iodomethane (65.12g) was added slowly, the reaction mass was stirred at this temperature for 1 hr. After completion, reaction mass poured in to water (2.4 L) and again stirred for 1 hr. Solid was filtered, washed with water (200ml × 2) and dried. Yield=104 g.

Example-3 Preparation of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (III)
To a solution of benzylated 6-chlorouracil (II) (100gm) in N,N-Dimethyl formamide (500 ml) was added Potassium carbonate (70.14g) followed by Methyl iodide (65.12g) at 250C. Heated reaction mass to 52°C and stirred for 3 hrs. Reaction mass was cooled to 250C, poured into water (2.5 L) and stirred for 1 hr. Solid was filtered, washed with water (400 ml) and dried. Yield=100g.

Example-4 Preparation Alogliptin benzoate (I)
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2-H-pyrimidin-1-ylmethyl)-benzonitrile (100 g), (R)-3-amino-piperidine dihydrochloride (69.1g) and Potassium carbonate (200.2g) were stirred with Acetonitrile (500mL) at 83°C for 8 h. The reaction was cooled, filtered through Celite, washed with Acetonitrile (200ml). To the filtrate, added HCl slowly in dioxane till pH~2 and stirred for 2-3 hr. Solid was filtered & washed with Acetonitrile (100ml). Crude HCl salt was isolated and washed with water. To a solution of Crude HCl salt with water (500 ml) added Liquor Ammonia (315ml) till pH~10. Product was extracted with MDC (3 x 300ml), washed with water (300 ml) to the organic layer & evaporated organic layer. To a hot (72°C) solution of residue in ethanol (200ml) was added activated charcoal (5g) stirred, filtered & washed with hot ethanol (200ml). To the filtrate, added solution of benzoic acid (48.7) in Ethanol: DMF (50 ml: 50 ml) in one lot and heated at 70-75°C for 2 hr. Reaction mass was cooled to 25 to 30°C and stirred for 2-3 hr. Solid was filtered, washed with Ethanol and dried. Yield=130 g.

Example-5 Preparation Alogliptin benzoate (I)
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2-H-pyrimidin-1-ylmethyl)-benzonitrile (100 g), (R)-3-amino-piperidine dihydrochloride (69.1g) and Potassium carbonate (200.2g) were stirred with Acetonitrile (500 mL) at 82°C for 6 h. The reaction was cooled; activated charcoal (5.0g) was added and stirred. Reaction mass filtered through Celite, washed with Acetonitrile (200ml). To the filtrate, added Benzoic acid (48.6 g) and heated for 0.5 hr. Reaction mass was cooled, solid was filtered & washed with Acetonitrile (200ml). Crude benzoate salt was stirred with water (81 mL), Isopropyl alcohol (819 mL) and heated to 820C. Cooled reaction mass to 50°C, seeded with Alogliptin benzoate (0.5g) and stirred. Solid was filtered, washed with mixture of Isopropyl alcohol: Water and dried.

Dated this 25th day of February 2014.
,CLAIMS:We claim,
1. A process for purification of 2-[(6-chloro-2,4-dioxo-3,4-dihydro pyrimidin-1(2H)-yl)methyl] benzonitrile (II) comprising the steps of

(II)

crystallizing compound of formula-II from solvent system comprising of Toluene and N, N-Dimethyl formamide.
2. A process for the preparation of highly pure Alogliptin benzoate of formula-I comprising the steps of:
a) reacting a compound comprising the formula

with a compound comprising the formula

in presence of Sodium bicarbonate that form a reaction product comprising the formula-II

(II)
b) purification of compound of formula-II from solvent systems comprising of Toluene and N, N-Dimethyl formamide.
c) reacting a compound comprising the formula-II

with a Methyl iodide in presence of sodium hydride or Potassium carbonate that form a reaction product comprising the formula-III

III
d) reacting a compound comprising the formula-III

with compound comprising the formula

in presence of Potassium carbonate that form a reaction product comprising the formula-I
e) crystallization of compound of formula-I from solvent systems comprising of Ethanol, N, N-Dimethyl formamide and acetonotrile
3. A process as claimed in claim 2 wherein Alogliptin benzoate is in crystalline form A.

Dated this 25th day of February 2014.