FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A process for preparation of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-
piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyI-l-[(4-methyI-2quinazo!inyl)
methyl] and its pharmaceutically acceptable salts"
2. APPLICANT:
(a) NAME: HARMAN FINOCHEM LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: 107, Vinay Bhavya Complex, 159-A , C.S.T. Road, Kalina,
Mumbai - 400098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION:
The present invention relates to process for preparation of 1 H-Purine-2.6-dione. 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyI-l-[(4-methyl-2quinazolinyl) methyl] (Formula-1) with high purity and high yield.
BACKGROUND OF INVENTION:
DPP-IV inhibitor is described chemically as lH-Purine-2.6-dione. 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-1 -yl)-3,7-dihydro-3-methyl-1 -[(4-methyl-2quinazolinyl) methyl] (Forumula-1). 1H-purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] is used for the treatment of type-

II diabetes mellitus.
US 7,407,955 describes synthesis of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] and its pharmaceutically,tolerable salts which involves condensation reaction of 8-bromo xanthine with 3-(R)-BOC amino piperidine resulting in protected 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] which is converted to 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] by deprotection process.


Scheme-1
The said process is tedious, time consuming and expensive. Further the said process
involves impurities which are difficult to remove on industrial scale.
PCT publication WO2013098775 discloses process for preparation of lH-Purine-2,6-
dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-
methyl-2quinazolinyl) methyl] comprising reacting (R)-piperidine-3-amine of formula II or an acid addition salt thereof with 1 -[(4-methyl-quinazolin-2-yl)methyl]-3- methyl-7-(2-butyn-I -yl)-8-bromoxanthine of formula III in presence of a suitable base in an inert organic solvent. The reaction reported in this publication has disadvantages such as longer reaction periods, less yields and purity.
Thus there is a need in the art to develop cost-effective, time saving and eco-friendly process for preparing lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yI)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazoiinyl) methyl].
Therefore, the object of the present invention is to provide an insitu process for preparing lH-Purine-2,6-dione, 8-[(3R)-3-amino-I-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] -(D)-tartrate salt to avoid multistep synthesis reported in prior art. Another object of the present invention is to provide suitable catalyst which increases the rate of reaction and decreases the reaction time which results in obtaining Formula-1 with high yield and high purity.

Thus the present invention provides economical, safe and commercially applicable process for preparing 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] .
SUMMARY OF THE INVENTION:
The present invention discloses cost-effective and improved process for preparation of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] of formula-1.
In a preferred aspect, the invention provides insitu process for preparing lH-Purine-2,6-
dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-
methyl-2quinazolinyl) methyl] -(D)-Tartrate salt which comprises:
(a) Reacting 8-bromo-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methylquinazolin-2-
yl)methyl]-3,7-dihydro-lH-purine-2,6-dione of formula-2 with (3R)-piperidin-3-
amine dihydrochloride of formula-3 in presence of base, wherein, the reaction is
characterized by the use of suitable catalyst and ester solvent or mixture of ester
solvents with dipolar aprotic solvents at 85-125°C;
(b) Reacting the crude 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-
butyn-1 -y l)-3,7-dihydro-3-methyl-1 -[(4-methyl-2quinazolinyl) methyljwith D-
tartaric acid using mixture of alcohol solvent with 0.5 to 50% denatured alcohol
(herein after DNS) at a temperature from 35 to 75°C; and
(c) Isolating lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-
3,7-dihydro-3-methyl-1-[(4-methyl-2quinazolinyl) methyl] -D-tartrate salt.
In another aspect, the invention provides a process for isolation of pure lH-Purine-2,6-
dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-
methyl-2quinazolinyl) methyl] from 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyI) methyl] -(D)-Tartrate salt which comprises:
(a) hydrolyzing the Tartrate salt of 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] in presence of solvent by maintaining pH at 11-12 with a suitable base in water at a temperature range of 25-55°C;

(b) optionally repeating the process of preparing lH-Purine-2,6-dione, 8-[(3R)-3-
amino-1 -piperidinyl]-7-(2-butyn-l -yl)-3,7-dihydro-3-methyl-1 -[(4-methyl-
2quinazolmyl) methyl] -(D)-tartrate salt obtained from step (a), isolating tartrate
salt and hydrolyzing tartrate salt and
(c) Isolating pure lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-
1 -yl)- 3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl].
DETAILED DESCRIPTION OF THE INVENTION:
The present invention discloses a process for preparing lH-Purme-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl)


methyl]. (Forumula-1)
In an embodiment, the invention discloses insitu process for preparing lH-Purme-2,6-
dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-I-yl)-3,7-dihydro-3-methyl-l-[(4-
methyl-2quinazolinyl) methyl] -(D)-Tartrate salt which comprises:
(a) Reacting 8-bromo-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methylquinazolin-2-
yl)methyl]-3,7-dihydro-lH-purine-2,6-dione of formuIa-2 with (3R)-piperidin-3-
amine dihydrochloride of formula-3 in presence of a base, wherein, the reaction
is characterized by the use of suitable catalyst and ester solvent or mixture of
ester solvents with dipolar aprotic solvents at 85-125°C to obtain crude 1H-
Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-
3-methyl-l-[(4-methyl-2quinazolinyl) methyl];
(b) Reacting the crude lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-
butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazoliny!) methyl] with D-
Tartaric acid using mixture of alcohol solvent with 0.5 to 50% DNS at a
temperature from 35 to 75°C; and
(c) Isolating 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-
3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] -D-tartrate salt.

The ester solvent in the said process is selected from the group consisting of N-Butyl acetate, Ethyl acetate, Methyl acetate, Isopropyl acetate. The dipolar aprotic solvent is selected from N-methylmorpholine, Morpholine, N-methyl-2-pyrrolidone, Dimethylformamide, Dimethylacetamide, Dimethylsulfoxide. The base is selected from alkali and alkaline earth metal carbonates like Potassium carbonate, Sodium carbonate, Potassium bi carbonate, Sodium bi carbonate. The suitable catalyst is selected from Potassium iodide and Sodium iodide.
The alcohol solvent is selected from Methanol, Ethanol, n-Propanol, Isopropanol, n-Butanol. The denatured alcohol (DNS) is with 0.5-50% Ethyl acetate, 0.5-50% Toluene, 0.5-50% Acetone or mixture of them.
The HPLC purity of the 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazo!inyl) methyl] -(D)-Tartrate salt thus obtained is 99-99.95%.
In another embodiment, the invention discloses process for isolation of pure lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methy!-2quinazolinyl) methyl] from lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyI-2quinazolinyl) methyl] -(D)-Tartrate salt which comprises:
(a) hydrolyzing the Tartrate salt of 1 H-Purine-2;6-dione, 8-[(3R)-3-amino-l -
piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl)
methyl] in presence of solvent by maintaining pH 11-12 with a suitable base in water
at a temperature range of 25-55°C;
(b) optionally repeating the process of preparing lH-Purine-2,6-dione, 8-[(3R)-3-
amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-
2quinazolinyI) methyl] -(D)-tartrate salt obtained from step (a), isolating tartrate salt
and hydrolyzing tartrate salt and
(c) Isolating of pure lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-
butyn-l-yI)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl].
The suitable base is selected from Sodium hydroxide, Potassium hydroxide, Lithium hydroxide, Calcium hydroxide. The solvent is selected from toluene, 1,4-dioxane, Chloroform, Diethylether, Dichloromethane.

The HPLC purity of the pure lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyI]-7-(2-
butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] thus obtained is
99-99.95%.
The present invention discloses process for preparing Formula-1 according to scheme-2.

The following examples, which include preferred embodiments, will serve to illustrate the
practice of this invention, it being understood that the particulars shown are by way of
example and for purpose of illustrative discussion of preferred embodiments of the
invention.
Examples:
Example: 1 Preparation of lH-Purine-2,6-dione, 8-[(3R)-3-arnino-l-piperidinyl]-7-
(2-butyn-l-yl)-3,7-dihydro-3-methyI-l-[(4-methyI-2quinazolinyl) methyl] -(D)-
Tartrate salt
To the 1500cc N-butyl acetate charged 0.55 moles Potassium carbonate, O.Olmoles
Potassium iodide and 0.275 moles (3R)-piperidin-3-amine dihydrochloride and 0.22
moles 8-bromo-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7-
dihydro-lH-purine-2,6-dione. Stirred the reaction mixture for 4-8hrs at 85-125°C. After

completion of the reaction, reaction mixture cooled to 5-10°C and charged lOOOcc 10% Acetic acid solution. After stirred for 10-30 min aqueous layer was washed with 300cc Methyl isobutyl ketone and 300 cc Toluene at 15-45°C. Aqueous layer cooled to 5-10 °C and charged 350cc 10% Sodium hydroxide. Then charged lOOOcc Methylene dichloride and stirred for 20 min. aqueous layer extracted with 350cc Methylene dichloride two times. Organic layer washed with water and brine solution. Solvent distilled out completely. Charged lOOcc Methanol to degassed mass and distilled out Methanol under vaccum.
To thereaction mass added 2500 cc Methanol and 0.5-50% Denatured alcohol charged 0.13mole D-tartaric acid at reflux temperature for 1 to 3 hrs. Cooled the reaction mixture at 5-15°C and stirred for 2-4 hrs. Filtered the product and washed with solvent. Wet product dried at 25-45°C for 4-8hrs to obtain lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-tnethyl-2quinazolinyl) methyl] Tartrate salt with 78-85% yield. HPLC purity: 99-99.5%
Example: 2 Preparation of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] -(D)-Tartrate salt
To the mixture of 1300 cc n-butyl acetate and 200 cc n-Methylmorpholine charge 0.55
mole Potassium carbonate, 0.01 mole Potassium iodide, 0.275 mole (3R)-piperidin-3-
amine dihydrochloride, 0.22 mole 8-bromo-7-(but-2-yn-l-yl)-3-methyl-l-[(4-
methylquinazoIin-2-yl)methyI]-3,7-dihydro-lH-purine-2,6-dione. Maintained the
reaction mixture for 4-8hrs at 85-I25°C. After completion of the reaction, reaction mixture cooled to 5-10°C and charged lOOOcc of 10% Acetic acid solution. After stirred for 10-30 min aqueous layer was washed with 300cc Methyl isobutyl ketone and 300 cc Toluene at 15-45°C. Aqueous layer cooled to 5-10 °C and charged 350cc 10% Sodium hydroxide. Then charged lOOOcc Methylene dichloride and stirred for 20 min. aqueous layer extracted with 350cc Methylene dichloride two times. Organic layer washed with water and brine solution. Solvent distilled out completely. Charged lOOcc Methanol to degassed mass and distilled out Methanol under vaccum.
To the reaction mass added 2500 cc Methanol and 0.5-50% Denatured alcohol .charged 0.13mole D-tartaric acid at reflux temperature for 1 to 3 hrs. Cooled the reaction mixture at 5-15°C and stirred for 2-4 hrs. Filtered the product and washed with solvent. Wet

product dried at 25-45°C for 4-8hrs to obtain lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-
piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl]
Tartrate salt with 78-85% yield.
HPLC purity: 99-99.5%
Example: 3 Preparation of pure lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-
piperidinyl]-7-(2-butyn-l-yI)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl)
methyl]
In 1500cc water, charged lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-
butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] Tartrate salt and
2000cc Toluene at temperature of 25-55°C.pHwas adjusted to 1,1-12 with 10% Sodium
hydroxide solution. Stirred for 45-75 min and washed organic layer with water and brine
solution. Distilled out the organic layer at 40-45°C.
To the reaction mass added 1650cc Methanol and 0.5-50% DNS charged 0.14 mole
purified 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-
dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] in first purification at a
temperature 35-75 oC. Charged 0.1 mole D-tartaric acid in 350 cc Methanol with 0.5-50%
DNS at reflux temperature for 1 to 3 hrs. Cooled the reaction mixture at 5-15°C and
stirred for 2-4 hrs. Filtered the product and washed with solvent. Wet product dried at 25-
45°C for 4-8hrs to obtain lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-
butyn-l-yI)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] Tartrate salt. In
975cc water charge lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-I-
yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazoliny[) methyl] Tartrate salt and 1300cc
Toluene at temperature 25-55°C.pH adjusted 11-12 with 10% Sodium hydroxide solution.
Stirred for 45-75 min and washed organic layer with water and brine solution. Distilled
out solvent at 40-45°C. Charged DNS at a temperature 45-85°C and stirred for 30 min.
cooled the mixture at 15-35 °C and filtered to obtain pure lH-Purine-2,6-dione, 8-[(3R)-
3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-337-dihydro-3-methyl-l-[(4-methyl-
2quinazolinyl) methyl] with 47% yield.
HPLC purity: 99-99.95%
Single large unknown impurity: less than 0.07 %

We claim,
(1) A process for preparation of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-
piperidinyl]-7-(2-butyn-l-yl)-3l)-dihydro-3-rnethyl-l-[(4-rnethyl-2quinazolinyl)

(a) Reacting insitu 8-bromo-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methylquinazolin-2-
yl)methyl]-3,7-dihydro-lH-purine-2,6-dione of formula-2 with (3R)-piperidin-3-
amine dihydrochloride of formula-3 in presence of base, wherein the reaction is
characterized by the use of suitable catalyst and ester solvent or mixture of ester
solvents with dipolar aprotic solvents at 85-125°C to obtain crude lH-Purine-2,6-
dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-
[(4-methyl-2quinazolinyl) methyl];
(b) Reacting insitu crude lH-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-
butyn-l-yI)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] with D-
tartaric acid in mixture of alcohol solvent and 0.5 to 50% DNS at a temperature
from35 to 75°C;and
(c) Isolating lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazoIinyl) methyl] -D-tartrate salt.
(2) The process according to claim 1, wherein the process for preparing pure 1H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] which comprises: (a) hydrolyzing tartrate salt of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l'-piperidinyl]-7-(2-butyn-l-y])-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] in presence of solvent by maintaining pH at 11-12 with a suitable base in water at a temperature range of 25-55°C;

(b) optionally repeating the process of preparing lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] -(D)-tartrate salt obtained from step (a), isolating tartrate salt and hydrolyzing tartrate salt and
(c) Isolating pure 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl].

(3) The process according to claim 1, wherein the ester solvent is selected from the group consisting of N-butyl acetate, Ethyl acetate, Methyl acetate and Isopropyl acetate.
(4) The process according to claim 1, wherein the dipolar aprotic solvent is selected from the group consisting of N-methylmorpholine, Morpholine, N-methyl-2-pyrrolidone, Dimethylformamide, Dimethylacetamide and Dimethylsulfoxide.
(5) The process according to claim 1, wherein the base used in step (a) is selected from the group consisting of alkali and alkaline earth metal carbonates like Potassium carbonate, Sodium carbonate, Potassium bi carbonate and Sodium bi carbonate.
(6) The process according to claim 1, wherein the suitable catalyst is selected from Potassium iodide or Sodium iodide.
(7) The process according to claim 1, wherein the alcohol solvent used in step(b) is selected from Methanol or Ethanol.
(8) The process according to claim 1, wherein the DNS used in step (b) is selected from denatured alcohol with 0.5 to 50% Ethyl acetate, 0.5-50 %ToIuene, 0.5-50%Acetone or mixture of them.
(9) The process according to any of the preceding claims, wherein purity of 1H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyI-2quinazolinyl) methyl] -(D)-tartrate salt and pure IH-Purine-

2,6-dione, 8-[(3R)-3-amino-]-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-I-[(4-methyi-2quinazoIinyl) methyl] is 99-99.95%.
(10) The process according to any of the preceding claims, wherein single largest unknown impurity is less than 0.07%.