Novel Process for the Manufacturing of High Purity Linagliptin
Field of the Invention
The present invention relates to a process for the manufacture of Linagliptin represented by the formula (I).
Background of the Invention
The present invention relates to novel cost effective process for the manufacture of highly pure Linagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor and is chemically known as 8-[(3/?)-3-aminopiperidin-l-yl]-7-but-2-ynyl-3-methyl-1 -[(4-methylquinazolin-2-yl) methyl] purine-2,6-dione represented by the formula(I)
Linagliptin is currently marketed under the trade name Tradjenta, Trajenta and others.
US7407955 (US '955) discloses Linagliptin as a dipeptidyl peptidase IV, related compounds and their pharmaceutical compositions. It describes a process for the preparation of Linagliptin, wherein tert-butyloxy carbonyl (Boe) Linagliptin represented by formula-II is deprotected using hydrochloric acid in 2-propanol. Then crude Linagliptin is purified using column chromatography. The process disclosed in US '955 is schematically represented in Scheme-1.

US7820815 (US '815) discloses a process for the preparation of Linagliptin, by deprotectingl-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-l-y[)-8-(3-(R)-phthalimidopiperidin-1 -yl)-xanthine of formula (V) in presence of ethanolamine, wherein l-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-(3-(R) phthalimidopiperidin-l-yl)-xanthine of formula (V) is prepared by N-alkylation of (R)-3-phthalimidopiperidine of formula (IV) with 1 -[(4-methylquinazolin-2-yl) methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromo xanthine of formula (III) using a base in N-methyl-2-pyrrolidine as represented in the scheme-2.

The processes disclosed in US '955 and US '815 involve protection, de-protection of amino group, leading to the increase in cost due to the long manufacturing cycle with low yield. Further, the above processes require purification of Linagliptin (I) by chromatography. Thus, the processes disclosed in US '955 and US '815 are not suitable for commercial manufacturing of Linagliptin (I). In addition, these processes led to the formation of an impurity l-[(4-Methyl-quinazolin-2-yl) methyl]-3-methyl-7-(3-bromobut-2- l-[(4-Methyl-quinazolin-2-yl) methyl]-3-methyl-7-(2-butyn-I-yl)-8-(3-(R)-amino-piperidin-l-yl)- xanthine) represented by formula (VI) generally referred as impurity bromo-butene
WO 2013/098775 describes a process for the preparation of Linagliptin(I) by the reaction of (R)-3-aminopiperidine (or its dihydrochloride (VII)) with l-[(4-methyl-quinazolin-2-yl) methyl]- 3-methyl-7-(2-butyn-l-yl)-8-bromo-xanthine represented by the formula (III) in the presence of a suitable base in a solvent, wherein, the crude Linagliptin (I) was further purified by crystallization as

Linagliptin tartrate using tartaric acid and then basified to get Linagliptin (I) as represented by the scheme-3,
WO2016207364A1 describes a fiirther process for preparation of Linagliptin of formula (I), wherein (R)-piperidine-3- amine (or its dihydrochloride(VII)) was reacted with l-[(4-methyl-quinazolin-2-yl) methyl]- 3-methyl-7-(2-butyn-l-yl)-8-haloxanthine represented by the formula (VIII) in the presence of a base in a solvent to give Linagliptin (I) as represented by following scheme -4

The processes disclosed in WO 2013/098775 and in WO2016207364A1,
when practiced lead to Linagliptin with a regioisomeric impurity, namely 8-((S)-piperidin-3-ytamino)-7-(but-2-ynyl)-3-methyI-l-((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6(3H,7H)-dione, represented by the formula (IX) in higher amounts (more than 0.2) with lower yield, thus making it difficult to use the processes for the manufacture of Linagliptin (I)

EP 2 468 749 Al discloses the preparation of Linagliptin(l) by converting the
intermediate 7-(but-2-ynyl)-8- (3-(ethoxycarbonyl)piperidin-1 -yl} -3-methyl-
l-((4-methylquinazolin-2-yl) methyl)-lH-purine-2,6(3H,7H)-dione
represented by the formula (X) to 7-(but-2-ynyl)-8-(3-isocyanatopiperidin-l-
yl)-3-methyl-1-((4-methylquinazolin-2-yl) methyl)-1 H-purine-2,6 -(3H,7H)-
dione represented by the formula (XI) by Curtis rearrangement foliowed by
hydrolysis as represented by Scheme-5, wherein 7-(but-2-ynyl)-8-{3-
(ethoxycarbonyl)piperidin-l-yl}-3-methyl-l-((4-methylquinazolin-2-yl)
methyl)-1 H-purine-2,6 (3H,7H)-dione (X) is prepared by reacting l-[(4-methyl-
quinazolin-2-yl) methyl]- 3-methyl-7-(2-butyn-l-yl)-8-haloxanthine
represented by the formula (VIII) with (R) 3-(ethoxycarbonyl)piperidine represented by the formula (XII).

Astheprocessdisclosed inScheme-5 involves multiple steps, highercycle time and uses costly reagents resulting poor yield and more impurities, is not suitable for industrial scale preparation of Linagliptin(I).
WO2019/219620 teaches a method of synthesis of Linagliptin(l) by de-protectionof (R)- imine derivatives of Linagliptin represented by the general formula(XIII), more particularly N-benzylidene Linagliptin by using N-hydroxylamine. Further it teaches, the synthesis of imine derivatives of Linagliptin(XIII) by reacting of imine derivatives of (R)-3-amino-piperidine represented by the general formula(XIV) (more particularly (R)-N-benzylidenepiperidin-3-amine) with l-[(4-methylquinazolin-2-yl) methyl]-3-methyl-7-(2-butyn-l-yl)-8-haloxanthine (VIII), as represented by the scheme-6

The disclosed process in WO2019/219620, is difficult to practice in larger scale, as the process involves preparation, isolation and purification of N-benzylidene Linagliptin(XIII)(R=H, Rl=Phenyl,) foliowed by de-protection of benzyl dine group to crude Linagliptin, foliowed by purification.
It is clear from above described prior art processes; there is a need for a simple cost effective process to manufacture of high purity Linagliptin (I).
Objects of the Invention
The primary object of the invention is to provide cost effective process suitable for the larger scale manufacture of Linagliptin (I).

Another aspect of the present invention is to provide an efficiënt, operationally
simple process, which does not require isolation of imine derivative of
Linagliptin.
Yet another objective is to provide process for manufacture of highly pure
Linagliptin (I).
Field of the Invention
The present invention relates to the preparation of Linagliptin represented by the formula (I).
Summary of the Invention
The present invention provides an alternate simple, one pot reaction for the
larger scale manufacture of Linagliptin (I) comprising of; reaction of
alkylidenepiperidin-3-amine represented by a general formula( XIV) with 1-
[(4-methyl-quinazolin-2-yl) methyl]-3-methyl-7-(2-butyn-l-yl)-8-
haloxanthine (VIII), using a suitable solvents, with or without phase transfer catalyst and a base with instantaneous hydrolysis imine to Linagliptin(l) as represented by scheme-7 Scheme-7

X=Br,CLI.
R, Rl=alkylCl-C5orH
Detailed Description of the Invention
The primary aspect of the present invention is to provide a cost effective process for the manufacture of Linagliptin(I), namely 8-[(3^)-3-aminopiperidin-l-yl]-7-but-2-ynyl-3-methyl-l-[(4-methylquinazolin-2-yl) methyl] purine-2,6-dione(I), which comprise of:
a) N-arylation of (R)-N-alkylidenepiperidin-3-amine represented by a formula (XIV);

using a base, with or without phase transfer catalyst in a suitable solvent with instantaneous hydrolysis of imine of Linagliptin to Linagtiptin(I) and corresponding carbonyl compound by water generated insitu in the reaction by the neutralization of acid by the base , at ambient temperature as represented by Scheme-7,
a) Wherein fïrst aspect of the present invention is the selection of 7-but-2-ynyl-8-halo-3-methylpurine-2,6-dione represented by formula (VIII), wherein, halogen is selected from group consists of chlorine, bromine and iodine, and most preferably bromine.
b) Wherein second aspect of the present invention is the selection (R)-N-alkylidenepiperidin-3-amine represented by formula XIV, wherein Rl, R is selected from a group consistof H, methyl, ethyl, propyl, 2-propyl, and butyl, more preferably from a group consist of methyl, ethyl, and 2-propyl; and most preferably Rl=methyl or 2-propyl, R= methyl or 2-propyl
c) Wherein third aspect of the present invention is the selection of the solvent, selected from a group consist of toluene, xylene, heptanes, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, ethyl methyl ketone, methyl isobutyl ketone, DMF, DMSO, methyl THF, and NMP; more preferably selected from a group consist of ethyl toluene, ethyl methyl ketone, and methyl isobutyl ketone; and most preferably methyl isobutyl ketone.

d) Wherein fourth aspect of the present invention is the temperature range for the reaction, selected from 30°C to 150°C, more preferably 60°C to 90°C and most preferably 75°C to 90°C.
e) Wherein fifth aspect of the present invention is the selection of the base selected from a group consist of alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonate; more preferably alkali metal carbonates and most preferably sodium carbonates
f) Wherein sixth aspect of the present invention is 7-but-2-ynyl-8-bromo-3-methylpurine-2,6-dione(III) prepared by reaction of 7-but-2-ynyl-8-bromo-3-methylpurine-2,6-dione represented by the formula (XV),
with 2-chloromethyl-4-methyl-quinazoline represented by the formula (XVI),
in the presence of potassium carbonate in DMSO; wherein 7-but-2-ynyl-8-bromo-3-methylpurine-2)6-dione(III) prepared and used with or without isolation from the solvent to react with (R)-N-

alkylidenepiperidin-3-amine represented by formula XIV, to form Linagliptin(I)
g) Wherein seventh aspect of the present invention is the preparation of (R)-N-alkylidenepiperidin-3-amine represented by formula XIV by treating (R)3-aminopiperidine with a alkyl carbonyl compounds represented by genera! formula R-CO-Ri (wherein R, Rl= H or Ci to Cs-alkyl) in the presence of base in a suitable solvent with the removai of water by azeotropic distillation, wherein solvent can be selected from a group consist of toluene, xylene, ethyl methyl ketone, and methyl isopropyl ketone and the base is selected from a group consist of alkali metal hydroxides, alkali metal carbonates and alkalimetal bicarbonate; more preferably alkali metal carbonates, most preferably sodium carbonates. The general procedure adopted in the present invention is similar to the one described in literature described in Organic Process Research & Development 2005, 9, 102-104 for selective alkylation secondary amino group of 4-amino piperidine.
h) Wherein eighth aspect of the present invention is the instantaneous insitu hydrolysis of imine of Linagliptin carried out with water generated in the reaction i.e. without addition of water. In fact alkylidine Linagliptin (imine of Linagliptin) is not detected by HPLC even in the in-process monitoring of the reaction. According to literature (Organic Process Research & Development 2005,9, 102-104 ) l-alkyI-4-aminopiperidine was selectively prepared by the alkylation of 4-(alkyl-2-ylidene)aminopiperidine foliowed by hydrolysis of alkylidene group at 50-55°C by the addition of water.
i) Wherein ninth aspect of the present invention, is the selection of phase transfer catalyst selected from preferably from a group consist of tetra alkyl ammonium halides, more preferably from tetra alkyl ammonium bromides and most preferably te tra butyl ammonium bromide

Examples
Reference is now made to the following examples, which together with the
above descriptions; illustrate the invention in a non-limiting fashion.
Experiment-1:
Preparation of (R)N-(4-methylpentan-2-ylidene) piperidin-3-amine
(XVII)
Methyl isobutyl ketone (lOOOmL), R-piperidine-3-amine.2HCl (lOOg, 0.57mol) and sodium carbonate (153.07g, 1.44mol) were charged into a reaction flask at 25-30°C. The reaction mass temperature was raised to reflux temperature with the azeotropic separation of water. The progress of the reaction was monitored by GC. After complete conversion of R-piperidine-3-amine, the reaction mixture was cooled to 25-30°C, inorganic salts were filtered out. Methyl isobutyl ketone was distilled out completely under vacuüm to obtained crude N-(4-methylpentan-2-ylidene) piperidin-3-amine (XVII) and was used without further purification. Yield: 98 gms (93%), purity 98% by GC
Experiment-2:
Preparation of 8-bromo-7-(but-2-ynyI)-3-methyl-I-((4-methylquinazoIin-
2-yl)methyl)-lH-purine-2,6(3H,7H)-dione(III):
Dimethyl sulfoxide (500 mL), 8-bromo-7-(but-2-ynyl)-3-methyl-lH-purine-
2,6(3H,7H)-dione (100 g, 0.33 mol) (XV), 2-(chlorormethyl)-4-
methylquinazoline (77.8g, 0.40mol)(XVI) potassium carbonate (69.8g,
0.49mol) were charged into a reaction flask at 25-30°C and the mass temperature was raised to 80°C to 85°C over a period of 1-2 hr under stirring.

Then the mass temperature was maintained at 80°C to 85°C for 5-6 hours. The progress of the reaction was monitored by HPLC, on complete conversion of 8-bromo-7-(but-2-ynyl)-3-methyl-lH-purine-2,6(3H,7H)-dione (XV), the reaction mixture was cooled to 50-55°C. methanol (500 ml) was charged slowly to the reaction mass under stirring and the reaction mass was further cooled to 25-30 °C. The formed solid 8-bromo-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl) methyl)-lH-purine-2, 6(3H, 7H)-dione (III) was fïltered, washed with water, dried. Yield: I28gms (84%) purity 99.4% by HPLC. m.pt:245-246°C
Experiment-3:
Preparation of 8-((R)-3-aminopiperidin-l-yl)-7-(but-2-ynyl)-3-methyl-l-((4-methylquinoIin-2-yl)methyl)-lH-purine-2,6(3H, 7H)-dione(l) (Linagliptin):
Methyl isobutyl ketone (lOOOmL), 8-bromo-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6(3H,7H)-dione (III) (lOOg, 0.22mol), (R)-N-(4-methylpentan-2-ylidene) piperidin-3-amine (XVII)(48.26 g, 0.26 mol), sodium carbonate (35.07g, 0.33mol), tetrabutylammonium bromide (5g, 0.01 mol) were charged into a reaction flaskof reaction assembly at 25-30°C. Then the mass temperature was raised slowly to 90°C to 95°Cand maintained at 90°C to 95°C under stirring for 16-18 hrs. On completion of reaction, (monitored by HPLC), the reaction mixture was cooled. The inorganic salts were fïltered and the Linagliptin was extracted into aqueous phase using dilute acetic acid. Then pH of the separated aqueous layer was basified using sodium hydroxide solution and extracted into dichloromethane. The dichloromethane was distilled out and the product was crystallized in 2-propanol to yield pure Linagliptin (I). Yield: 88g (85%), Purity: 99.76% with regioisomer (IX) 0.04%

Experiment-4:
Preparation of 8-((R)-3-aniinopiperidin-l-yl)-7-(but-2-ynyl)-3-methyl-l-((4-methylquinolin-2-yl) methyl)-lH-purine-2,6(3H, 7H)-dione(l) (Linagliptin):
Methyl isobutyl ketone (lOOOmL, 10V), 8-bromo-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6(3H,7H)-dione (III) (lOOg, 0.22mol), N-(4-methylpentan-2-ylidene) piperidin-3-amine (XVII) (48.26 g, 0.26 mol), potassium carbonate (45.73g, 0.33mol), tetrabutylammonium bromide (5g, 0.01 mol) were charged into a reaction flask of reaction assembly at 25-30°C and the mass temperature was raised slowly to 90°C to 95°Cand was maintained at 90°C to 95°C under stirring for 16-18 hrs. The completion of reaction, (monitored by HPLC), the reaction mixture was cooled The inorganic salts were filtered, and the Linagliptin was extracted into aqueous phase using dilute acetic acid. Then the separated aqueous layer was basified using sodium hydroxide solution and the product was extracted using dichloromethane. The dichloromethane was distilled out and the product was crystallized in 2-propanol to yield pure Linagliptin (I) Yield: 86g (83%), Purity: 99.75% Regioisomer (IX): 0.06%
Experiment-5: Preparation of 8-((R)-3-aminopiperidin-l-yl)-7-(but-2-ynyl)-3-methyl-l-((4-methylquinolin-2-yl) methyl)-lH-purine-2, 6(3H, 7H)-dione (I) (Linagliptin):
Methyl isobutyl ketone (lOOOmL ), R-piperidine-3-amine dihydrochloride (48.81g, 0.28mol) and sodium carbonate (74.7lg, 0.70 mol) were added into a reaction vessel at 25°C and slowly raised the reflux temperature under stirring with removal water by azeotropic distillation. The progress of the reaction was monitored by GC, after complete cor.version of R-piperidine-3-amine, the reaction mixture was cooled to 25-30°C, and inorganic salts were filtered out. The filtered solution was charged back to the reaction flask. 8-bromo-7-(but-2-ynyl)-3-methy]-l-((4-methylquinazoIin-2-yl)methyl)-lH-purine-2,6(3H,7H)-

dione(III) (100 g, 0.22 mol), sodium carbonate (35.07g, 0.33mol), tetrabutylammonium bromide (5g, 0.01 mol) were added into the flask and the mass temperature was raised slowly to 90°C to 95°Cand was maintained at 90°C to 95°C under stinïng for 16-18 hrs. The completion of reaction, (monitored by HPLC), the reaction mixture was cooled. The inorganic salts were filtered, and the Linagliptin was extracted into aqueous phase using dilute acetic acid. Then pH of the separated aqueous layer was basified using sodium hydroxide solution and the product was extracted using dichloromethane. Then dichloromethane was distilled out and the product was crystallized in 2-propanol to yield pure Linagliptin (I), Yield: 89g (85%) Purity: 99.75% with regioisomer (IX): 0.06%.
Experiment-6: Preparation of 8-((R)-3-aminopiperidin-l-yl)-7-(but-2-ynyl)-3-methyl-l-((4-methylquinolin-2-yl) methyl)- lH-purine-2, 6(3H, 7H)-dione (I) (Linagliptin):
Methyl isobutyl ketone (lOOOmL ), R-piperidine-3-amine dihydrochloride (48.81g, 0.28mol) and sodium carbonate (74.7lg, 0.70 mol) were added into a reaction vessel at 25°C and slowly raised the reflux temperature under stirring with removal water by azeotropic distillation. The progress of the reaction was monitored by GC, after complete conversion of R-piperidine-3-amine, the reaction mixture was cooled to 25-30°C, and inorganic salts were filtered out. The filtered solution was charged back to the reaction flask. 8-bromo-7-(but-2-ynyl)-3-methyl-1 -((4-methylquinazolin-2-yl)methyl)-l H-purine-2,6(3H,7H)-dione(III) (100 g, 0.22 mol), sodium carbonate (35.07g, 0.33mol) was added into the flask and the mass temperature was raised slowly to 90°C to 95°C and was maintained at 90°C to 95°C under stirring for 16-18 hrs. The completion of reaction, (monitored by HPLC), the reaction mixture was cooled. The inorganic salts were filtered, and the Linagliptin was extracted into aqueous phase using dilute acetic acid. Then pH of the separated aqueous layer was basified using sodium hydroxide solution and the product was extracted using dichloromethane. Then dichloromethane was distilled out and the product was

crystallized in 2-propanol to yield pure Linagliptin (I), Yield: 88g (85%) Purity: 99.75% with regio isomer (IX): 0.05%.
Experiment-7:
Preparation of 8-((R)-3-aminopiperidin-l-yl)-7-(but-2-ynyI)-3-methyl-l-((4-methylquinolin-2-yI) methyl)-lH-purine-2, 6(3H, 7H)-dione (I) (Linagliptin):
Toluene( 1 OOOmL), 8-bromo-7-(but-2-ynyl)-3-methyl-1 -((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6(3H,7H)-dione (III) (lOOg, 0.22mol), (R)-N-(4-methylpentan-2-ylidene) piperidin-3-amine (XVII) (48.26 g, 0.26 mol), Sodium carbonate (35.07g, 0.33mol), tetrabutylammonium bromide (5g, 0.01 mol) were charged into a reaction flask of reaction assembly at 25-30°C and the mass temperature was raised slowly to 90°C to 95°C and was maintained at 90°C to 95°C under stirring for 35-38hours. The completion of reaction, (monitored by HPLC), the reaction mixture was cooled, the inorganic salts were fïltered, and the Linagliptin was extracted into aqueous phase using dilute acetic acid. Then the separated aqueous layer was basified using sodium hydroxide solution and the product was extracted using dichloromethane. Then dichloromethane was distilled out and the product was crystallized in 2-propanol to yield pure Linagliptin (I) Yield: 75g (72%), Purity: 99.23%; with regioisomer (IX): 0.08%
Experiment-8:
Preparation of (R)-N-butylidenepiperidin-3-amine (XVIII);

Toluene (lOOOmL), R-piperidine-3-amine.2HCl (lOOg, O.57mol), Butaraldehyde (83.36g, 1.15mol) and sodium carbonate (I53.07g, 1.44 mol) were charged into a reaction flask at 25-30°C. The reaction mass temperature was raised to reflux temperature (110-115°C) with the azeotropic separation of water. The progress of the reaction was monitored by GC, after complete conversion of R-piperidine-3-amine, the reaction mixture was cooled to 25-30°C, and inorganic salts were filtered out. Methyl isobutyl ketone was distilled out completely under vacuüm to obtained crude (R)-N-butylidenepiperidin-3-amine (XVIII) and was used without further purification. Yield: 80 gms (95%).
Experiment-9:
Preparation of 8-((R)-3-aminopiperidin-l-yl)-7-(but-2-ynyl)-3-methyl-l-((4-
methylquinolin-2-yl)methyl)-lH-purine-2,6(3H, 7H)-dione (I) (Linagliptin):
Toluene (1 OOOmL), 8-bromo-7-(but-2-ynyl)-3-methyl-1 -((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6(3H,7H)-dione (III)(100 g, 0.22 mol), (E)-N-butylidenepiperidin-3-amine (XVIII)(41.26 g, 0.26 mol), sodium carbonate (35.07g, 0.33mol), Tetra Butyl ammonium Bromide (5g, 0.01 mol) wereadded into a reaction vessel at ambient temperature and the mass temperature was raised slowly to 90°C to 95°C and was maintained at 90°C to 95°C under stirring for 35-38hours. The completion of reaction, (monitored by HPLC), the reaction mixture was cooled, the inorganic salts were filtered, and the Linagliptin was extracted into aqueous phase using dilute acetic acid. Then the separated aqueous layer was basified using sodium hydroxide solution and the product was extracted using dichloromethane. The dichloromethane was distilled out and the product was crystallized in 2-propanol to yield pure Linagliptin (I) Yield: 70g (67%) Purity: 99.20% with regio isomer (IX): 0.6%

We Claim:
1. A process for preparing Linagliptin a compound of the formula (I) in a single pot reaction comprising of:
N-arylation of (R)-N-alkylidenepiperidin-3-amine represented by a formula (XIV),
with 7-but-2-ynyl-8-halo-3-methylpurine-2,6-dione represented by the formula (VIII),

using a inorganic base, vvith or without phase transfer catalyst in a suitable solvent at ambient temperature, with the instantaneous, in-situ hydrolysis of formed Linagliptin imine with water generaled in the reaction to high purity Linagliptin (I) with regioisomerO.04%.
2. Theprocessasclaimed in claim-1 wherein, the selection of halogen in 7-but-2-ynyl-8-halo-3-methylpurine-2, 6-dione represented by formula (VIII), is from group consist of chlorine, bromine and iodine, and most preferably bromine.
3. The process as claimed in claim-1 wherein, (alkylidene)amino-3-(R)piperidine represented by formula XIV, wherein, Rl, R are selected from a group consist of H, methyl, ethyl, propyl, 2-propyl, butyl, more preferably Rl,R=methyl, ethyl, 2-propyl, and most preferably Rl=methyl or 2-propyl, R= methyl or 2-propyl
4. The process as claimed in claim-1 wherein, the solvent is selected from a group consist of toluene, heptanes, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, ethyl methyl ketone, methyl isobutyl ketone, DMF, DMSO, and methyl THF, NMP; more preferably selected from a group consist of toluene, ethyl methyl ketone, and methyl isobutyl ketone, and most preferably methyl isobutyl ketone.
5. The process as claimed in claim-1 wherein, the temperature range for the reaction, is in the range of 30°C to 150°C, more preferably in the range of 60°C to 90°C and most preferably in the range of 75°C to 90°C.
6. The process as claimed in claim-1 wherein, the inorganic base is selected from a group consist of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonate, and alkali metal alkoxide more preferably alkali metal carbonates and most preferably sodium carbonates.

7. The process as claimed in claim -1 wherein, the phase transfer caïalyst is selected from a group consist of tetraalkylammonium halides, more preferably from a group consist of tetraalkylammonium bromides and most preferably tetrabutylammonium bromide
8. The process as claimed in claim-2 wherein, the 7-but-2-ynyI-8-bromo-3-methylpurine-2, 6-dione (III) is prepared and used with or without isolation from solvent.
9. The process as claimed in claim-3, wherein, the compound of formula of (XIV) is prepared and used with or without isolation from solvent.
10. The process as claimed in claim-1 wherein, the phase transfer catalyst is selected from preferably from a group consist of tetraalkylammonium halides, more preferably from tetraalkylammonium bromides and most preferably tetrabutylammonium bromide.