DESC:The present invention relates to an improved process for the preparation of Linagliptin. More particularly, the present invention relates to an efficient process for the preparation of Linagliptin of formula (I) in higher yields and purity.

The present invention relates an improved process for the preparation of Linagliptin of formula (I) comprising the steps of:

reacting 8-Bromo-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione of Formula–II

with R-amino Piperidine dihydrochloride of formula (III) or an acid addition salt thereof such as R-amino Piperidine dihydrochloride

in presence of a suitable base in an inert organic solvent and inert atmosphere at a temperature ranging from 50°C to 75°C and maintained for a time period of about 90-120 Hrs to obtain Linagliptin of formula (I),

with purity greater than 98% and wherein regioisomer impurity (Formula-IV) is controlled below 0.25%.

The organic solvent used in the reaction is selected from a group consisting of methylisobutylketone (MIBK), Acetone, Dimethyl sulfoxide (DMSO), Dimethylformamide (DMF) and the mixtures thereof. The suitable base used in the reaction is selected from the group consisting of potassium carbonate, Sodium Bicrabonate, Sodium Carbonate, Sodium hydroxide, Triethyl amine and mixtures thereof.

Isolation and Purification of Linagliptin can be carried out using conventional methods.

In an embodiment there is provided a process for preparation of compound of formula II comprising the steps of:

Reacting 8-Bromo-7-but-2-ynyl-3-methyl-3,7-dihydro-purine-2,6-dione, compound of formula V with 2-(Chloromethyl)-4-methylquinazoline in presence of base such as potassium carbonate and solvent such as Dimethyl sulfoxide (DMSO).

The reaction scheme for the preparation of Linagliptin by the process of the present invention is as follow:

EXAMPLES

The following examples are used to illustrate the invention but are not intended to limit the invention in any way.

Example 1: Process for the preparation of Formula III:

8-Bromo-7-but-2-ynyl-3-methyl-3,7-dihydro-purine-2,6-dione (Formula V, 100 gm) Dimethyl Sulfoxide (500 ml), Potassium Carbonate (69.8 gm) and 2-(Chloromethyl)-4-methylquinazoline (77.8 gm) were charged into RBF equipped with mechanical stirrer. The reaction mass was heated to 80-85 0C and Maintained the reaction mass for 4-5 hours. The reaction mass was cooled to 15-20 0C and Water (1500 ml) was added. The Solid was collected by filtration and washed with water (200 ml) and methanol (200 ml). The wet Cake was charged into RBF and Methanol (500 ml) was added into it and the reaction mass was heated to reflux temperature and maintained it for 1-2 hrs. The reaction mass was cooled to 25-30 0C and Solid was collected by filtration and washed with methanol (200 ml). The Solid was dried in oven under vacuum at 50 to 55 0C to get of title compound of Formula II. (Purity = 99.00%)

Example 2: Process for the preparation of Formula I:

1-[(4-methyl-quinazoline-2yl) methyl]-3methyl-7-(2-butyn-1-yl)-8-bromoxanthine (Formula–II, 50 gm) and MIBK (500 ml), potassium carbonate (122 gm) and R-amino Piperidine dihydrochloride (Formula-III, 28.63 gm) were charged into RBF under nitrogen atmosphere at room temperature. The reaction mass is heated to 50-75 0C and maintained for 90-120 hours. Reaction mixture was cooled to 40-45 deg C, filtered and washed with MIBK (100 ml). The filtrate was treated with 20% Acetic acid solution (750 ml) and stirred for 30 minutes at room temperature. The layers were separated. The aqueous layer is basified in presence of MDC (500 ml) by treating with 24% sodium hydroxide solution (500 ml). The mixture was stirred for 30-60 minutes. Aqueous layer was again extracted with MDC (250 ml). Combined organic layers washed with brine solution. Charcoal treatment was carried out for MDC layer; MDC layer dried over sodium sulphate and solvent evaporated under reduced pressure to get wet cake. Wet cake poured in mixture of acetonitrile (100 ml) and MTBE (100 ml). The reaction mixture was stirred for 1-2 hours at Room temperature. Reaction mass filtered and washed with Acetonitrile (25 ml) and MTBE (25 ml), and dried under vacuum to get pure Linagliptin (Formula-I, 40 gm) with greater than 99.50% purity by HPLC and Regioisomer (Formula-IV) is controlled below 0.15% which is as per ICH limit.

Example 3: Process for the preparation of Formula I:

1-[(4-methyl-quinazoline-2yl) methyl]-3methyl-7-(2-butyn-1-yl)-8-bromoxanthine (Formula–II, 10 gm) and MIBK (100 ml), potassium carbonate (24.4 gm) and R-amino Piperidine dihydrochloride (Formula-III, 5.73 gm) were charged into RBF under nitrogen atmosphere at room temperature. The reaction mass is heated to 100 0C and maintained for 4-5 hours. Reaction mixture was cooled to 25-30 0C filtered and washed with MIBK (100 ml). The filtrate was treated with 20% Acetic acid solution (150 ml) and stirred for 30 minutes at room temperature. The layers were separated. The aqueous layer is basified in presence of MDC (100 ml) by treating with 24% sodium hydroxide solution (100 ml). The mixture was stirred for 30-60 minutes. Aqueous layer was again extracted with MDC (50 ml). Combined organic layers washed with brine solution. Charcoal treatment was carried out for MDC layer; MDC layer dried over sodium sulphate and solvent evaporated under reduced pressure to get wet cake. Wet cake poured in mixture of acetonitrile (20 ml) and MTBE (20 ml). The reaction mixture was stirred for 1-2 hours at Room temperature. Reaction mass filtered and washed with Acetonitrile (10 ml) and MTBE (10 ml), and dried under vacuum to get pure Linagliptin (Formula-I, 8 gm) with 98.25% purity by HPLC and Regioisomer (Formula-IV) is 1.04%.

Example 4: Process for the preparation of Formula I:

1-[(4-methyl-quinazoline-2yl) methyl]-3methyl-7-(2-butyn-1-yl)-8-bromoxanthine (Formula–II, 10 gm) and MIBK (100 ml), potassium carbonate (24.4 gm) and R-amino Piperidine dihydrochloride (Formula-III, 5.73 gm) were charged into RBF under nitrogen atmosphere at room temperature. The reaction mass is heated to 80 0C and maintained for 8-9 hours. Reaction mixture was cooled to 25-30 0C filtered and washed with MIBK (100 ml). The filtrate was treated with 20% Acetic acid solution (150 ml) and stirred for 30 minutes at room temperature. The layers were separated. The aqueous layer is basified in presence of MDC (100 ml) by treating with 24% sodium hydroxide solution (100 ml). The mixture was stirred for 30-60 minutes. Aqueous layer was again extracted with MDC (50 ml). Combined organic layers washed with brine solution. Charcoal treatment was carried out for MDC layer; MDC layer dried over sodium sulphate and solvent evaporated under reduced pressure to get wet cake. Wet cake poured in mixture of acetonitrile (20 ml) and MTBE (20 ml). The reaction mixture was stirred for 1-2 hours at Room temperature. Reaction mass filtered and washed with Acetonitrile (10 ml) and MTBE (10 ml), and dried under vacuum to get pure Linagliptin (Formula-I, 8.5 gm) with 99.09% purity by HPLC and Regioisomer (Formula-IV) is 0.52%.
Example 5: Process for the preparation of Formula I:

1-[(4-methyl-quinazoline-2yl) methyl]-3methyl-7-(2-butyn-1-yl)-8-bromoxanthine (Formula–II, 10 gm) and MIBK (100 ml), potassium carbonate (24.4 gm) and R-amino Piperidine dihydrochloride (Formula-III, 5.73 gm) were charged into RBF under nitrogen atmosphere at room temperature. The reaction mass is heated to 50-55 0C and maintained for 30-35 hours. Reaction mixture was cooled to 25-30 0C filtered and washed with MIBK (100 ml). The filtrate was treated with 20% Acetic acid solution (150 ml) and stirred for 30 minutes at room temperature. The layers were separated. The aqueous layer is basified in presence of MDC (100 ml) by treating with 24% sodium hydroxide solution (100 ml). The mixture was stirred for 30-60 minutes. Aqueous layer was again extracted with MDC (50 ml). Combined organic layers washed with brine solution. Charcoal treatment was carried out for MDC layer; MDC layer dried over sodium sulphate and solvent evaporated under reduced pressure to get wet cake. Wet cake poured in mixture of acetonitrile (20 ml) and MTBE (20 ml). The reaction mixture was stirred for 1-2 hours at Room temperature. Reaction mass filtered and washed with Acetonitrile (10 ml) and MTBE (10 ml), and dried under vacuum to get pure Linagliptin (Formula-I, 5.5 gm) with 98.66% purity by HPLC and Regioisomer (Formula-IV) is 0.17%.

Example 6: Process for the preparation of Formula I:

1-[(4-methyl-quinazoline-2yl) methyl]-3methyl-7-(2-butyn-1-yl)-8-bromoxanthine (Formula–II, 10 gm) and MIBK (100 ml), potassium carbonate (24.4 gm) and R-amino Piperidine dihydrochloride (Formula-III, 5.73 gm) were charged into RBF under nitrogen atmosphere at room temperature. The reaction mass is heated to 60-65 0C and maintained for 20-25 hours. Reaction mixture was cooled to 25-30 0C filtered and washed with MIBK (100 ml). The filtrate was treated with 20% Acetic acid solution (150 ml) and stirred for 30 minutes at room temperature. The layers were separated. The aqueous layer is basified in presence of MDC (100 ml) by treating with 24% sodium hydroxide solution (100 ml). The mixture was stirred for 30-60 minutes. Aqueous layer was again extracted with MDC (50 ml). Combined organic layers washed with brine solution. Charcoal treatment was carried out for MDC layer; MDC layer dried over sodium sulphate and solvent evaporated under reduced pressure to get wet cake. Wet cake poured in mixture of acetonitrile (20 ml) and MTBE (20 ml). The reaction mixture was stirred for 1-2 hours at Room temperature. Reaction mass filtered and washed with Acetonitrile (10 ml) and MTBE (10 ml), and dried under vacuum to get pure Linagliptin (Formula-I, 7.1 gm) with 99.27% purity by HPLC and Regioisomer (Formula-IV) is 0.22%.
,CLAIMS:
1. An improved process for the preparation of Linagliptin of formula (I) comprising the steps of:

reacting 1-[(4-methyl-quinazoline-2yl) methyl]-3methyl-7-(2-butyn-1-yl)-8-bromoxanthine of Formula–II

with (R)-piperidine-3-amine of formula (III) or an acid addition salt thereof

in presence of a suitable base in an inert organic solvent and inert atmosphere at a temperature ranging from 50°C to 75°C and maintained for a time period of about 90-120 Hrs to obtain Linagliptin of formula (I),

with purity greater than 98%, wherein the regioisomer impurity (Formula-IV) is controlled below 0.25%.

2. The process for the preparation of Linagliptin of formula (I) as claimed in claim 1 wherein the acid addition salt of (R)-piperidine-3-amine of formula (III) is R-amino Piperidine dihydrochloride.

3. The process for the preparation of Linagliptin of formula (I) as claimed in claim 1 wherein the suitable base is selected from a group consisting of Potassium carbonate, Sodium Bicrabonate, Sodium Carbonate, Sodium hydroxide, Triethyl amine or mixtures thereof.

4. The process for the preparation of Linagliptin of formula (I) as claimed in claim 1 wherein the organic solvent is selected from a group consisting of methylisobutylketone (MIBK), Acetone, Dimethyl sulfoxide (DMSO), Dimethylformamide (DMF) or mixtures thereof.

5. The process for the preparation of Linagliptin of formula (I) as claimed in claim 1 further comprising the step of preparing the compound of formula (II) comprising the steps of:

reacting 8-Bromo-7-but-2-ynyl-3-methyl-3,7-dihydro-purine-2,6-dione, compound of formula V with 2-(Chloromethyl)-4-methylquinazoline in presence of base such as Potassium carbonate and solvent such as Dimethyl sulfoxide (DMSO).

6. The process for the preparation of Linagliptin of formula (I) as claimed in claim 1 wherein the said Linagliptin of formula (I) is obtained with purity greater than 99.40% and wherein regioisomer impurity (Formula-IV) is controlled below 0.15% which is as per ICH limit.