FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See Section 10 and Rule 13)
AN IMPROVED PROCESS FOR THE PREPARATION OF LINAGL1PTIN
M/S AMOL1 ORGANICS PVT. LTD, 407 DALAMAL HOUSE, J.B.ROAD. NARIMAN POINT, MUMBAI-400021, INDIA, an Indian company incorporated under the companies Act,
1956
The following specification particularly describes and ascertains the nature of this invention and
the manner in which it is to be performed

Field Of Invention
The present invention relates to an improved processes for the preparation of (R)-8-(3-aminopiperidine-1-yl)-7-(but-2-ynyl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione (Linagliptin).
Background of the invention
Linagliptin, namely (R)-8-(3-aminopiperidine-l-yl)-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6(3H,7H)-dione as presented by Formula I, is a long acting inhibitor of dipeptidylpeptidase-IV (DPP-IV) activity, for the treatment of type II diabetes mellitus. Linagliptin is known from US Patent No 7,407,955.

Several processes for the preparation of Linagliptin are known in the literature such as those described in US Patent Nos. 7,407,955 and 7,820,815, US Patent Publication No. 2012/0195525 and PCT Publication No. 2013/098775.
US Patent No. 7,407,955 discloses Linagliptin, related compounds, their method of preparation and their use as pharmaceutical compositions. The synthesis of Linagliptin as reported in the patent can be described as the scheme-1 below, where Linagliptin is prepared by deprotecting (R)-tert-butyl 1 -(7-(but-2-ynyl)-3-methyl-1 -((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purine-8-yl)piperidine-3-ylcarbamate of Formula-Ill in presence of an acid such as Trifluoroacetic acid or hydrochloric acid. The (R)-tert-butyl 1-(7-(but-2-ynyl)-3-methyLl-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purine-8-yl)piperidine-3-ylcarbamate is prepared by condensing 8-bromo-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)- lH-purine-2,6(3H,7H)-dione of Formula-II with (R)-3-tert-

Butoxycarbonyl aminopiperidine of Formula IV. The compound 8-bromo-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yI)methyl)- lH-purine-2,6(3H,7H)-dione according to Formula-11 is prepared by coupling reaction between 2-(chloromethyl)-4-methylquinazoline of Formula-V and 8-bromo-7-(but-2-ynyl)-3-methyl-3,4,5,7-tetrahydro-lH-purine-2.6-dione of Formula-VI.

The Trifluoroacetic acid used in the synthesis is commercially expensive, hazardous and difficult to handle. Hence, there is a need to develop deprotection reaction for the synthesis of Linagliptin at commercially feasible expenses. Moreover, the purity of the product obtained by

the process of US 7,407.955 is not reported in the said patent. The present invention makes use of organic acids such as formic acid, sulfonic acids such as 4-methyfbenzenesulfonic acid (PTSA), methanesulfonic acid (MSA), ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-chlorobenzenesulfonic acid and inorganic acids such as orthophosphoric acid which are commercially available at considerably lower costs and providing improved purity and yield of the resulting product (Linagliptin).
Object of the invention
The object of the present invention is to provide an improved process for the deprotection of tert-butyloxy carbonyl (Boc) protected Linagliptin to produce Linagliptin of Formula-I.

Summary of the invention
The invention encompasses an improved process for the synthesis of Linagliptin, denoted by Formula-I, by deprotecting a tert-butyloxy carbonyl (Boc)-protected compound of Formula-Ill:


In this process, the acid used is organic acids such as formic acid, sulfonic acids such as 4-methylbenzenesulfonic acid (PTSA), methanesulfonic acid (MSA), ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-chlorobenzenesulfonic acids or inorganic acids such as orthophosphoric acid which are commercially available at considerably lower costs and providing improved purity and yield of the resulting product (Linagliptin).
Detailed Description of the Invention
The present invention gives an improved process for the preparation of (R)-8-(3-aminopiperidine-1 -yl)-7-(but-2-ynyI)-3-methyl-1 -((4-methylquinazoline-2-yl)methyl)-l H-purine-2,6(3H,7H)-dione (Linagliptin), denoted by Formula-I, by deprotecting a tert-butyloxy carbonyl (Boc)-protected compound of Formula-Ill.


The process comprises of deprotecting a compound (R)-tert-butyl I-(7-(but-2-ynyJ)-3-methyl-1-((4-methylquinazolin-2-y))methyl)-2,6-dioxo-2.3.6,7-tetrahydro-lH-purine-8-yl)piperidine-3-ylcarbamate of Formula-Ill, where, the tert-butyloxycarbonyl group is cleaved by treatment with an acid such as formic acid, sulfonic acids such as 4-methylbenzenesulfonic acid (PTSA), methanesulfonic acid (MSA), ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-chlorobenzenesulfonic acids or inorganic acids such as orthophosphoric acid which are commercially available at considerably lower costs in presence or absence of Tetra Butyl Ammonium Bromide (TBAB) as phase transfer catalyst using solvents such as methylene chloride, methanol or ethyl acetate. The process also yields improved purity and yield of the product (Linagliptin).
Another aspect of the invention comprises One pot process for the synthesis of Linagliptin wherein the deprotection is carried out using an acid such as formic acid, sulfonic acids such as 4-methylbenzenesulfonic acid (PTSA), methanesulfonic acid (MSA), ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-chlorobenzenesulfonic

acids or inorganic acids such as orthophosphoric acid which are commercially available at considerably lower costs.
The invention can be illustrated in detail as follows:
The compound (R)-tert-butyl l-(7-(but-2-ynyI)-3-methyI-!-((4-methyIquinazolin-2-yI) methyl)-2,6-dioxo-2,3,6,7-tetrahydro-l H-purine-8-yI)piperidine-3-ylcarbamate of Formula-Ill is obtained following the procedure explained in US Patent No. 7,407,955. 2-(ch!oromethyl)-4-methylquinazoline of Formula-V is added to a mixture of 8-bromo-7-(but-2-ynyl)-3-methyl-3,4,5,7-tetrahydro-lH-purine-2.6-dione of Formula-VI and potassium carbonate in Dimethylformamide. The reaction mixture is stirred at room temperature for eight hours and the product is further purified to obtain compound 8-bromo-7-(but-2-ynyI)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)- lH-purine-2,6(3H,7H)-dione according to Formula-II. 8-bromo-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)- lH-purine-2,6(3H.7H)-dione of Formula-Il is reacted with (R)-3-tert-Butoxycarbonyl aminopiperidine of Formula IV in presence of N, N-Dimethy[formamide and the mixture is heated to 110-115°C. Potassium carbonate and N,N-Dimethylformamide are added and the reaction mixture is stirred and then cooled to 55-60°C. The resulting crude product is further purified using methanol and water and dried to obtain (R)-tert-butyl l-(7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purine-8-yl)piperidine-3-ylcarbamate of Formula-Ill. The compound according to Formula-Ill is dissolved in organic solvents such as methylene chloride, methanol or ethyl acetate and further combined with an acid such as formic acid, sulfonic acids such as 4-methylbenzenesulfonic acid (PTSA), methanesulfonic acid (MSA), ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-chlorobenzenesulfonic acids or inorganic acids such as orthophosphoric acid and Tetra Butyl Ammonium Bromide (TBAB) optionally. After the completion of reaction, the solution is cooled to 15-20°C and pH 8-9 of the solution is adjusted using 30% NaOH. Organic phase is separated and distilled. Further, the crude product is purified by acid-base treatment. The product pure Linagliptin as denoted by Formula-I is obtained.
Another process for the synthesis of Linagliptin follows One pot synthesis by reacting methyl-7-(-2-butin-l-yl)-8-bromoxanthine and 2-chloromethyl-4-methyl quinazoline in presence of N,N-Dimethylformamide and potassium carbonate at 110-115°C which is further reacted with (R)-3-tert-Butyloxycarbonyl aminopiperidine in presence of potassium carbonate. The reaction mixture

is extracted with organic solvent and further treated with an acid such as organic acid such as formic acid, sulfonic acids such as 4-methylbenzenesulfonic acid (PTSA), methanesulfonic acid (MSA), ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-chforobenzenesulfonic acids and inorganic acids such as orthophosphoric acid. The solution is then made basic with help of a base the organic phase is separated and distilled to obtain dry product (Crude Linagliptin).
EXAMPLE 1 (Reference Example)
Preparation of (R)-8-(3-aminopiperidine-l-yl)-7-(but-2-ynyl)-3-methyl-l-((4-
methylquinazoline-2-yl) methyl)-lH-purine-2,6(3H,7H)-dione (Crude Linagliptin) (Formula-I)
A solution of 50 g of compound of Formula-Ill in 250 mL methylene chloride is combined with 150 ml Trifluoroacetic acid (TFA) and 250 mL methylene chloride is added and stirred for half an hour at 15-20°C. After the completion of the reaction, it is diluted with 100 mL methylene chloride and pH=9-10 is adjusted by 30% NaOH at 15-20°C. The organic layer is separated and subjected to distillation under vacuum to obtain crude Linagliptin. Dry weight-40 g (97.6%) Purity = 98.13%
EXAMPLE 2
Preparation of (R)-8-(3-aminopiperidine-l-y[)-7-(but-2-ynyl)-3-methy[-l-((4-
metbylquinazo!ine-2-yl)methyl)-lH-purine-2,6(3H,7H)-dione (Crude Linagliptin) (Formula-I)
A solution of 50.0 g of compound of Formula-Ill in 500 mL methylene chloride is combined with 150 mL of formic acid and 0.5 gm of Tetra Butyl Ammonium Bromide (TBAB) and Potassium iodide 5 gm and stirred for half an hour at 25-30°C. The reaction mixture is heated and maintained at 40-45°C for 24 hours. After the completion of the reaction, it is diluted with 100 mL methylene chloride and 250 mL DM water. The solution is cooled to I5-20°C and 30% NaOH is added to make the pH of the solution up to 9-10. The organic layer is separated and subjected to distillation under vacuum to obtain crude Linagliptin. Dry weight = 40 g (97.6%) Purity = 91.61%

EXAMPLE 3
Preparation of (R)-8-(3-aminopiperidine-l-yl)-7-(but-2-ynyl)-3-methyl-l-((4-
methylquinazoline-2-yl) methyl)-lH-purine-2, 6 (3H, 7H)-dione (Crude Linagliptin) (Formula-I)
A solution of 50.0 g of compound of Formula-Ill in 500 mL methylene chloride is combined with 150 ml methanesulfonic acid (MSA) and stirred for half an hour at 15-20°C. After the completion of reaction, it is diluted with 100 mL methylene chloride and 250 mL DM water. pH 9-10 of the resulting solution is adjusted by 30% NaOH. The material gets extracted in organic methylene chloride layer which is separated and distilled to obtain crude Linagliptin. Dry weight-40 g (97.6%) Purity = 97.44%
EXAMPLE 4
Preparation of (R)-8-(3-aminopiperidine-l-yl)-7-(but-2-ynyl)-3-methyI-l-((4-
methyIquinazoline-2-yl) methyI)-lH-purine-2, 6 (3H, 7H) - dione (Crude Linagliptin) (Formula-I)
A solution of 50.0 g of compound of Formula-Ill in 500 mL methylene chloride is combined with 150 mL orthophosphoric acid and stirred for half an hour at 15-20°C. After the completion of the reaction, it is diluted with 500 mL methylene chloride and 500 mL DM water. pH 9-10 of the resulting solution is adjusted by 30% NaOH at 15-35°C. The solution is stirred for half an hour at 30-35°C. The organic layer is separated and subjected to distillation under vacuum to obtain crude Linagliptin. Dry weight = 39 g (95%) Purity-98.07%
EXAMPLE 5
Preparation of (R)-8-(3-aminopiperidine-l-yl)-7-(but-2-ynyl)-3-methyl-l-((4-
methylquinazoline-2-yI)methyl)-lH-purinc-2,6(3H,7H)-dione (Crude Linagliptin)
(Formula-I)
A solution of 50.0 g of compound of Formula-Ill in 500mL methylene chloride is combined with 150 gm of 4-methylbenzene sulfonic acid (PTSA) and stirred for half an hour at 15-20°C. After the completion of the reaction, it is diluted with 100 mL methylene chloride and 500 mL DM

water. 30% NaOH is added to adjust the pH of the solution up to 9-10 at 15-25°C. The organic phase is separated and subjected to distillation under vacuum to obtain crude Linagliptin. Dry weight = 40.0 g (97.6%) Purity-89.22%
EXAMPLE 6 Purification of crude Linagliptin
The crude Linagliptin obtained as product of processes explained in above examples is further treated with acid and base for purification. For this, the crude product is dissolved in 250 mL toluene and 250 mL water. Then, 6-8 mL acetic acid and 10 mL DM water is added and the reaction mixture is stirred for half an hour at 40-45°C. The aqueous layer is then separated; toluene 100 mL is added to the aqueous layer and stirred for half an hour at 40-45°C. The aqueous layer is separated and 500 mL methylene chloride is added to it. The pH of the reaction mixture is adjusted 9-10 by 30% NaOH at 20-25°C. The organic methylene chloride phase is separated, dried over Na2SO4 and solvent is evaporated to obtain the product (Pure Linagliptin).
The % purity and % yield of the product obtained after acid base treatment of the final product is tabulated in Table I.
Table 1

SrNo. Example No. % Purity % Yield
1 Example 1 (TFA) 99.53 % 88%
2 Example 2 (Formic acid) 98.85 % 85%
Example 3 (MSA) 99.38% 82%
4 Example 4 (Orthophosphoric
acid) 99.54% 92%
5 Example 5 (PTSA) 97.59 % 85%
EXAMPLE 7 One pot synthesis for the preparation of Linagliptin
25.00 g of rnethyl-7-(-2-butin-l-yI)-8-bromoxanthine, 17.23 g of 2-chloromethyl-4-methyl quinazoline and 200 mL of N,N-Dimethylformamide are charged in Round bottom flask.

Potassium carbonate (15.0 g) and N.N-Dimethylformamide (50 mL) are added and the reaction mass is heated to 110-115°C and maintained for 2 hours. After completion of the reaction, reaction mixture is cooled to 90°C and 21.74 g of (R)-3-tert-Butyloxycarbonyl aminopiperidine and 11.5 g of Potassium carbonate are added. Again the reaction mass is heated slowly upto 110-115°C and maintained for 2 hours. After completion of the reaction, reaction mixture is cooled to 25-30°C, diluted with 250 mL DM water and subsequently with 250 mL of methylene chloride. The solution is stirred at 25-30°C for 30 minutes and layers are separated. The aqueous layer is extracted with 250 mL methylene chloride and methylene chloride layer is washed with DM water. To the methylene chloride layer, 250 mL TFA (Trifluoroacetic acid) is added at 15-20°C and the reaction mass is stirred for 30 minutes. After the completion of reaction, it is cooled to 15-20°C and pH= 9-10 is adjusted by 30 % NaOH. The reaction mass is stirred for 30 minutes. The layers are separated and methylene chloride layer is washed with DM water, dried over Na2SO4 and subjected to distillation under vacuum below 45°C. To the residue, 250 mL TBME is added at 25-30°C and stirred for an hour. The product is filtered and washed with TBME 25 mL.
To the wet product obtained, toluene 100 mL and DM water 100 mL is added and stirred for 10 minutes at 45-50°C. The pH of the solution is adjusted to 3.5-4.0 by acetic acid. The reaction mass is stirred for 30 minutes, the layers are separated and aqueous layer is washed with 40 mL toluene. To the aqueous layer, 400 mL methylene chloride is added, cooled to 15-20°C and pH is adjusted up to 9-10 by 30 % NaOH. The reaction mass is stirred for 30 minutes and the layers are separated. The methylene chloride layer is dried over Na2SO4 and subjected to distillation under vaccum to obtain final Linaglitin. Dry weight- 28 g (71 %) Purity = 96.42 %
EXAMPLE 8 One pot synthesis for the preparation of Linagliptin
25.0 g of methyl-7-(-2-butin-l-yl)-8-bromoxanthine, 17.23 g of 2-chloromethyl-4-methyl quinazoline and 200 mL of N.N-Dimethylformamide are charged in Round bottom flask. Potassium carbonate (15.0 g) and N,N-Dirnethylforrnamide (50 mL) are added and the reaction

mass is heated to 110-115°C and maintained for 2 hours. After completion of the reaction, reaction mixture is cooled to 90°C and 21.74 g of (R)-3-tert-Butyloxycarbonyl aminopiperidine and 11.5 g of Potassium carbonate are added. Again the reaction mass is heated slowly upto 110-115°C and maintained for 2 hours. After completion of the reaction, reaction mixture is cooled to 25-30°C. diluted with 250 mL DM water and subsequently with 250 mL of methylene chloride. The solution is stirred at 25-30°C for 30 minutes and layers are separated. The aqueous layer is extracted with 250 mL methylene chloride and methylene chloride layer is washed with DM water. To the methylene chloride layer, 150 mL Orthophosphoric acid is added at 15-20°C and the reaction mass is stirred for 30 minutes at 25-30°C. After the completion of reaction, the reaction mass is diluted with 500 mL methylene chloride and 500 mL DM water, cooled to 15-20°C and pH = 9-10 is adjusted by 30 % NaOH. The layers are separated and methylene chloride layer is washed with DM water, dried over Na2S04 and subjected to distillation under vacuum below 45°C. To the residue, 250 mL TBME is added at 25-30°C and stirred for an hour. The product is filtered and washed with TBME 25 mL.
To the wet product obtained, toluene 200 mL and DM water 200 mL is added and stirred for 10 minutes at 45-50°C. The pH of the solution is adjusted to 3.5-4.0 by acetic acid. The reaction mass is stirred for 30 minutes, the layers are separated and aqueous layer is washed with 40 mL toluene. To the aqueous layer, 400 mL methylene chloride is added, cooled to 15-20°C and pH is adjusted up to 9-10 by 30 % NaOH. The reaction mass is stirred for 30 minutes and the layers are separated. The methylene chloride layer is dried over Na2S04 and subjected to distillation under vaccum to obtain final Linagliptin. Dry weight = 28 g (71 %) Purity = 96.96%

We Claim:
1) A process for preparation of Linagliptin of Formula-I by deprotecting a compound of Formula-Ill comprising

a) the solution of the compound of Formula-Ill in an organic solvent is combined with an acid such as organic acid such as formic acid, sulfonic acids such as 4-methylbenzenesulfonic acid (PTSA), methanesulfonic acid (MSA), ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-chlorobenzenesulfonic acids and inorganic acids such as orthophosphoric acid, and stirred;
b) the solution is then made basic with help of a base:
c) the organic phase is separated and distilled to obtain crude Linagliptin;
d) the crude Linagliptin is further purified by acid base treatment to obtain pure Linagliptin.

2) The process according to claim 1, where the solution is combined with an acid prefereably formic acid, methylbenzenesuifonic acid (PTSA), methanesulfonic acid (MSA), or orthophosphoricacid.
3) The process according to claim 2, where the acid is more preferably orthophosphoric acid.
4) The process according to claim 3, where the purity of pure Linagliptin is greater than 99.50 %.
5) The process according to claim 1, where the pH of the solution is adjusted preferably up to 8-9.
6) The process according to claim 1, where the yield of crude Linagliptin is greater than 95 %.
7) The process according to claim 3. where the yield of pure Linagliptin is greater than 90 %.
8) A one pot process for preparation of Linagliptin of formula I comprising

a) reacting methyl-7-(-2-butin-l-yl)-8-bromoxanthine and 2-chloromethyl-4-methyl quinazoline in presence of N.N-Dimethylformamide and potassium carbonate;
b) which is further reacted with (R)-3-tert-Butyloxycarbonyl aminopiperidine in presence of potassium carbonate;
c) the reaction mixture is extracted with organic solvent and further treated with an acid such as organic acid such as formic acid, sulfonic acids such as 4-methylbenzenesulfonic acid (PTSA), methanesulfonic acid (MSA), ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-chlorobenzenesulfonic acids and inorganic acids such as orthophosphoric acid;
d) the solution is then made basic with help of a base;
e) the organic phase is separated and distilled to obtain dry product (Crude Linagliptin).
9) The one pot process according to claim 5, where the solution is combined with an acid
preferably formic acid, methylbenzenesuifonic acid (PTSA), methanesulfonic acid (MSA), or
orthophosphoric acid.
10)The one pot process according to claim 6, where the acid is more preferably orthophosphoric acid.