Indian Patents. 198386:AN IMPROVED PROCESS FOR THE PREPARATION OF HETEROCYCLIC ANTIDIABETIC COMPOUNDS

Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF HETEROCYCLIC ANTIDIABETIC COMPOUNDS
Abstract	The present invention relates to a process for the preparation of antidiabetic compounds having the formula (1), where R represents (C1-C6) alkyl group.

Full Text	where R represents (C1-C6)alkyl group. The compound of formula (1) is useful in lowering the plasma glucose, triglyceride, total cholesterol (TC); increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL). The compound of formula (1) is also useful in reducing body weight and for the treatment and / or propiiylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. The compound of formula (I) is also useful for the treatment and/or prophylaxis of insulin resistance (type 11 diabetes). Background of invention In our WTO mailbox application No. 569/MAS/2001 we have described a process for the preparation of free acid of compound of formula (1). The process described therein comprises of reacting the pyrazolo pyrimidine of the formula (4) with compound of formula (5) to produce a compound of formula (6) and hydtolyzing the compound of formula (6) to obtain an acid of formula (7), convening the acid of formula (7) to an amide of the formula (8) and hydrolyzing the amide to produce the free acid of compound of formula (la). The piocess is shown in the scheme-1 given below Objective of present invention The main objective of the present invention is to provide a simple and robust process for the preparation of the compound of formula (1) with high chemical and chiral purity. Another objective of the present invention is also to provide a process for the preparation of the compound of formula (11). Detailed description oftlie invention Accordingly, the present invention provides a process for the preparation of compounds of the formula (1), where R represents (C1-C6)alkyl group, which comprises: i) cyclizing the 4-amino-l-methyl-3-propyl-lH-5-pyrazolecarboxamide of the formula (2) with propionic acid of the formula (3) in neat or in the presence of a solvent or an acid at a temperature in the range of 20 to 160°C for a period in the range of 2 to 30 h, to yield compound of formula (4), ii) reacting the compound of formula (4) with haloethanol of formula (9) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, in the presence of a solvent and a base at a temperature in the range of 40 to 150 °C for and the duration may range from 4 to 30 h, to yield compound of formula (10), iii) converting the compound of formula (10) to halo compound of formula (11), where X represents halogen atom such as fluorine, chlorine, bromine or iodine using halogenating agent in the presence of a solvent and a base at a temperature in the range of -20 to 60 "C preferably in the range of 0 to 25C, for a period in the range of 4 lo24 h, iv) condensing the pyrazolo[4,3-d]pyrimidin-7-one of the formula (II) where X is defined as above with compound of formula (12) where R' represents t- butyldimethyl siiyi, trimethyl silyl or alkoxyalkyl group; R^ represents (Ci-C6)alkyi group in the presence of a base and a solvent at a temperature in the range of 5 to 150 "C, for a period in the range of 2 to 30 h, to give compound of the formula (13) where R2 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R represents (C1-C6)alkyl group, v) hydrolyzing the compound of formula (13) to yield the compound of the formula (14) in the presence of a base or an acid and a solvent at a temperature in the range of 10 to 80 °C and for a period in the range of 4 to 24 h, vi) elherifying the compound of formula (14) to a compound of formula (la) using alkylating agent in the presence of a base and a solvent wherein R represents (C1-C6)alkyl group at a temperature in the range of 0 to 30 °C and for a period in the range of 30 min. to 24 h, vii) reacting the compound of formula (la) with tromethamine in the presence of a solvent at a temperature in the range of 10 to 150 °C, for a period in the range of 2 to 24 h, to yield compound of formula (1) where R is as defined above and viii) isolating the compound of formula (1) by conventional methods. Scheme-2 The cyclization of compound of formula (2) with propionic acid of the formula (3) may be carried out in neat or in the presence of a solvent such as DMF, THF, toluene, xylene and the like or a mixture thereof. The reaction may be carried out in the presence or absence of an acid such as POCI3, PPA, p-toluenesulfonic acid TFA, P205-xylene and the like. The reaction may be carried out at a temperature in the range of 20 to 160 °C for a period in the range of 2 to 30 h with azeotropic removal of water. The reaction of compound of formula (4) with haloethanol of formula (9) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, may be carried out in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride, DBU, DABCO, DBN, cesium carbonate, lithium hydroxide, triethyl amine, diisopropyl amine and the like. The reaction may be carried out using a solvent such as THF, DMF, dichloromethane, acetonitrile. NMP, toluene and the like or mixtures thereof. The temperature of the reaction may range from 40 to 150 "C for and the duration may range from 4 to 30 h. The conversion of compound of formula (10) to a compound of formula (11) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, may be carried out using halogenating agent such as cone. HCl, HBr, PBrj, POClj, MeS02Cl, thionyi chloride, oxalyl chloride, para toluene sulfonyl chloride and the like in the presence of base such as triethyl amine, diisopropyl amine, pyridine and the like. The reaction may also be carried out using a solvent such as DCM, DCE, pyridine and the like or mixtures thereof. The reaction temperature may be in the range of -20 °C to 60 X, preferably from 0 °C to 25 °C. The reaction time may range from 4 to 24 h. The condensation of compound of the formula (11) where X is defined as above, with compound of the formula (8) where R represents t-butyldimethyl silyl, trimethyl silyl and the like; or alkoxyalkyl groups such as methoxy, ethoxy, propoxy, isopropoxy and the like, R^ represents (C1-C5) alkyl groups such as methyl, ethyl, propyl, butyl, t-bulyl and the like, to provide a compound of the formula (13) where R1 and R2 are as defined above, may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, using a solvent such as toluene, xylene, THF, DMF, DME, DMSO, NMP or alcohols such as methanol, ethanol, propanol, isopropanol and the like or mixture thereof The reaction may be carried out at a temperature in the range of 5 to 150 °C and the duration of the reaction may range from 2 to 30 h. The hydrolysis of compound of the formula (13) where R1 and R2 are as defined above, to yield compound of formula (14) may be carried out using an acid such as methane sulfonic acid, HCl, H2SO4, trifluoroacetic acid, para toluene sulfonic acid and the like in the presence or absence of a solvent such as methanol, ethanol, propanol, isopropanol and the like or mixture thereof Further hydrolysis to yield compound of formula (14) may be carried out using a base such as NaH, NaOH, KOH, LiOH, t-BuOK, K2CO3, NaHCO3 and the like in the presence of a solvent such as water, methanol, ethanol, propanol, isopropanol and the like or mixture [hereof. The reaction may be carried out at a temperature in the range of 10 to SO "C and the duration of the reaction may range from 4 to 24 h. The etherification of compound of formula (14) to obtain compound of fonnula (la) where R represents (C\|-C6)alkyl groups such as methyl, ethyl, propyl, butyl, t-butyl and the like, may be carried out using dialkyi sulfate such as diethyl sulfate, dimethyl sulfate and the like or (C1-C6)alkyl halides such as ethyl iodide, methyl iodide and the like, in the presence of a base such as NaH, NaOH, KOil, t-BuOK, K2CO3, NaHCO3 and the like, in the presence of a solvent such as toluene, xylene, benzene, DMF, DMSO, MIBK, ethyl acetate, N-methyl pyrrolidone (NMP) and the like or a mixture thereof. The reaction may be carried out at a temperature in the range of 0 °C to 30 °C and the duration of the reaction may range from 30 min. to 24 h. The reaction of compound of formula (la) where R is defined as above, with tromethamine may be carried out in the presence of a solvent such as alcohols like methanol, elhanol, propanol, isopropanol and the like; acetonilrile, DMF, DMSO, acetone, 1,4-dioxane and the like or a mixture thereof, at a temperature in the range of 10 lo 150 °C, for a period in the range of 1 to 24 h to provide compound of the formula (1). Another embodiment of the present invention provides a process for the preparation of the compound of fonnula (11) where X represents halogen atom such as fluorine, chlorine, bron\ine or iodine, which comprises: i) cyclizjng the 4-amino-I-melhyl-3-propyl-lH-5-pyrazolecarboxamide of the formula (2) with propionic acid of the formula (3) in neat or in the presence of a solvent or an acid at a temperature in the range of 20 to 160°C for a period in the range of 2 to 30 h, to yield compound of formula (4), ii) reacting the compound of fonnula (4) with haloethanol of formula (9) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, in the presence of a solvent and a base at a temperature in the range of 40 to 150 "C for and the duration may range from 4 to 30 h, to yield compound of formula (10), iii) converting the compound of formula {10} to halo compound of formula (11), where X represents halogen atom such as fluorine, chlorine, bromine or iodine using halogenaling agent in the presence of a solvent and a base at a temperature in the range of-20 to 60 °C for a period in the range of 4 to24 h, iv) isolating the compound of formula (11) by conventional methods. The cyclization of compound of formula (2) with propionic acid of the formula (3) may be carried out in neat or in the presence of a solvent such as DMF, THF, toluene, xylene and the like or a mixture thereof. The reaction may be carried out in the presence or absence of an acid such as POCI3, PPA, p-toluenesulfonic acid TFA, PzOs-xylene and the like. The reaction may be carried out at a temperature in the range of 20 °C to 160 °C for a period in the range of 2 to 30 h with azeotropic removal of water. The reaction of compound of formula (4) with haloethanol of formula (9) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, may be carried out in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride, DBU, DABCO, DBN, cesium carbonate, lithium hydroxide, triethyl amine, diisopropyl amine and the like. The reaction may be carried out using a solvent such as THF, DMF, dichloromethane, acetonitrile, NMP, toluene and llie like or mixtures thereof. The temperature of the reaction may range from 40 to 150 °C for and the duration may range from 4 to 30 h. The conversion of compound of formula (10) to a compound of formula (11) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, may be carried out using halogenating agents such as cone. HCl, HBr, PBrj, POCh, MeS02CI, thionyl chloride, oxalyl chloride, p-toluenesulfonyl chloride and the like in the presence of a base such as triethyl amine, diisopropyl amine, pyridine and the like. The reaction may also be carried out using a solvent such as DCM, DCE, pyridine and the like or mixture thereof. The reaction temperature may be in the range of -20 °C to 60 "C, preferably from 0 °C to 25 °C. The reaction time may range from 4 to 24 h. The present invention is described in detail with example given below that are provided by way of illustration only and therefore should not be construed to limit ihe scope of the invention. Example 1 Step (i) Preparation of 5-Ethyl-l-methylr3-propyl-6,7-dihydro-llHl-pyrazolo-[4,3dl- pyrimidin-T-oue 4-Amino-l-m6thyl-3-ptopyl-lH-5-pyrazolecarboxamide (2.0 g, 0.0108 M), propionic acid (10 ml) and xylene (20 ml) were taken in a round bottomed flask fitted with Dean-Stark apparatus and refluxed for 24 h. After completion of reaction, xylene was distilled off and poured in water and stirred for 1 h at room temperature. The precipitated compound was filtered and dried to yield the title compound, (weighs 390 mg, yield 16%, purity 85%). IR(KBr): 2960,2870, 1699, 1609, 1489,1455, 1394, 1315, 1018. 'H NMR (CDCU): 5 11.22 (br s, IH, D2O exchangeable), 4.25 (s, 3H), 2.87 (t, J - 7.1 Hz, 2H), 2.78 (q, i= 7.3 Hz, 2H), f.95-1,70 (m, 2H), 1.39 (t, y = 7.6 Hz, 3H), 1.00(t,J=7.3Hz, 3H). Mass m/z (CI): 221 (M++1, 100%), 192 (17%), 191 (15%), 122 (5%), 105 (6%). 93 (11%), 91 (22%). Step (ii) Preimration of 5-ctliyI-6{2-hydroxyethyrj-l-iiietliyIO-\|>ropyl-6,7-ditydro-lH-pyrazolo \|4,3d\|-pyniiii(Iine-7-one 5-Ethyl-1 -methyl-3-propyl-6,7-dihydro-l [Hl-pyrazolo-[4,3d]-pyrimidin-7-one (5.0 g, 0.022 M), dimethylformamide {100 ml), potassium carbonate {9.3 g, 0.032 M). and chloroethanol {3.6 g, 0.04 M) were taken in a round bottomed flask and heated at 110 °C for 18 to 24 h. After completion of reaction, the reaction mass was poured into ice cold water and extracted with ethylacetate. The organic layer was evaporated to get the title compound, {weighs 5 g, yield 83.2%, purity 95.6%). IR (KBr): 3333, 2964, 1685, 1575, 1485, 1453, 1320, 1196, 1082, 1022, 885. 1HNMR(CDCI3):5 4.31 (t,y=5.1 Hz, 2H), 4.21 {s, 3H), 3.99 (br s, 2H), 2.92 (t, J - 7.3 Hz, 2H), 2.86 (q, 7=7,1 Hz, 2H), 1.90-1.72 (m, 2H), 1.35 (t, J=7.\ Hz, 3H), 0.99(t,J=7.3Hz,3H). Mass m/z (CI): 265 (M++1, 100%), 247 (9%), 236 (8%) 192 (3%). Step (iii) Preparation of 5-ethyl-6(2-chloro ethyl)-l-methyl-3-propyi-6,7-dihydro-lH- pyrazolo (4,3 d]-pyrimidine-7-one 5-Ethyl-6{2-hydroxyethyl)-l-methy[-3-pvopyl-6,7-dihydro-lH-pyrazolo[4,3-d]-pyrimidine-7-one (4.0 g, 0.015 M), dichloromethane (20 ml), triethylamine (3.16 ml) were placed in a round bottomed flask and cooled to 0 to 5 °C. Then melhanesulfony! chloride (2.43 g, 0.016 M) dissolved in dichloromethane (10 ml) was added slowly. After complete addition, the reaction mass was raised to ambient temperature and maintained for 8 to 12 h. After completion of the reaction, the reaction mass was washed with water and the organic layer was evaporated to get the title compound (weighs 3.5 g, yield 83%, purity 97%). IR(KBr): 3439, 2954, 2872, 1684, 1575, 1445, 1369, 1315, 1268, 1183,1160,973. 1H NMR {CDCi3): S 4.04 (t, J= 6.6 Hz, 2H), 4.22 (s, 3H), 3.82 (t, J = 6.6 Hz. 2H), 2.96-2.8! (m, 4H), 1.90-1.73 (m, 2H), 1.36 {t, 7= 7.3 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H). Mass m/z: 284 37c1-M+ 14%), 282 (35c1-M+ 27%), 267 (21%), 254 (100%), 247 (50%), 192 (41%), 191 (42%), 136 (14%). Step (iv) Preparation of methyl (-) 3-[4-(2-(5-ethyl-l-inelhyI-7-oxo-3-propyl-6, 7-dihydro- lH-pyrazolo-[4,3-d\|pyrinii(lin-6-yl)ethoxy)plienyl]-2-tertiarybutyI dimethyl siiyloxy propionate in a 500 ml four necked round bottom flask, fitted with a Dean Stark apparatus, reflux condenser and efficient stirrer, powdered KICOB (35 g, 0.25 M) and toluene (180 ml) was added at 30 to 35 "C under stirring. The reaction mixture was heated to 110 to 120 °C and maintained at reflux temperature of toluene for 2 to 3 h. After azeotropic removal of water, tlie reaction mixture was brought to 70 to 80 "C and methyl 2(S)-tertiary butyl dimethyl siIyloxy-3-(4-hydroxyphenyl)propionaIe (15.5 g, 0.05 M) and 5-ethyl-6-(2-thloroethyl)-l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-7-one (18 g^ 0.05 M) were added at the same temperature under stirring. The reaction mixture was refluxed for 15 to 18 h under stirring. The reaction mixture was brought to 30 to 35 °C and cooled tolO to 15 °C and water (100 ml) was added and separated the organic layer. The aqueous layer was extracted with toluene (50 ml x 2) and the combined toluene layers were washed with demineralised water (50 ml x 2). The toluene layer was concentrated to yield the title compound as an oily liquid (weighs 30 g, yield 93%, purity 94 to 96%). IR (Neat) cm': 3120, 2910, 1756,1686, 1574. 'H NMR (200 MHz, CDCh) 6 : 7.13 (d, J=8.4 Hz, 2H), 6.77 (d, J-8.6 Hz, 2H), 4.50 (t, J=5.0 Hz, 2H), 4.29-4.22 (m, 3H), 4.01 (t, J=3.7 Hz, IH), 3.81 (s, 3H), 3.1-2.94 (m, 4H), 2.84 (t, J=7.5 Hz, 2H), 1.9-1.78 (m, 4H), 1.30 (t, J=7.3 Hz, 3H), 1.16 (t, J=7.0 Hz, 3H), 0.85 (s, 9H). Mass m/z (CI): 557 (M++I). Step (v) Preparation of (-) 3-\|4-(2-(5-ethyl-l-metliyl-7-Dxo-3-propyl-6,7-diliy(Iro-lH-pyrazolo-\|4,3-dJpyrimi(liil-6-yl)ethoxy)phenyI\|-2-hydroxypropanoicacid In a 2 L four necked round bottom flask, fitted with a reflux condenser and mechanical stirrer, methyl (-) 3-[4-(2-(5-ethyl-l-methy!-7-oxo-3-propyl-6,7-dihydro-I H-pyrazolo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-tertiarybutyl dimethyl silyloxy propionate (96 g, 0.1729 M) and methanol (480 ml, 1:5 w/v) were added at 25 to 35 'C under stirring. p-Toluene sulfonic acid (3.28 g) was added to the reaction mixture at 30 to 35 "C. After complete addition, the reaction mixture was heated to 65 to 75 °C for 10 to 15 h under stirring. After completion of the reaction, the reaction mixture was cooled to 5 to 10 °C and 5% NaOH solution (276 ml) was added slowly under stirring. After addition, the reaction mixture was brought to 25 to 35 °C and maintained for 6 to 8 h under stirring. After completion of the reaction, the reaction mixture was diluted with demineralised water (500 ml) and washed with toluene (300 ml X 3). The aqueous layer was acidified with cone. HCl (30-32%) at 5 to 10 °C to pH 1,5 lo 2.0 and maintained at the same temperature for Ihr. The precipitated product was filtered, washed with demineralised water (100 ml x 2), dried to yield the pure title compound as off white to cream colored solid (weighs 62 g, yield 84%, purity 95.87% by HPLC, mp: 208 to 211 "C). IR(KBr)cm-':3400-3300,3120,2970, 1710, 1680, 1570. 'H NMR (200 MHz, DMS0-d6) 5 : 713 (d, J - 8.4 Hz, 2H), 6.77 (d, i = 8.6 Hz, 2H), 4.50 (t, J - 5.0 Hz, 2H), 4.29-4.22 (m, 4H), 4.01 (t, J - 3.7 Hz, IH), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (t, I = 7.5 Hz, 2H), 1,9-1.78 (m, 2H), 1.38 (t, J - 7.3 Hz, 3H), 1.16(t,J = 7.0Hz,3H). Anal. Calcd. C22H28N4O5 %C 61.68, %H 6.54, %N 13.08; Found %C 61.55, %H 6.35, %N 12.90 Massm/z(CI):429(M+l). step (vi) Preparation of (-) 3-\|4-(2-(S-ethyl-l-methyI-7-oxo-3-propy\|-6,7-diliy(lro-lH- pyrazolo-[4,3-d)pyriniidin-6-yl)ethoxy)phenyl\|-2-etlioxypropanoicacid In a 500 ml four necked round bottom flask, fitted with a plain condenser and mechanical stirrer, toluene (80 ml) and sodium hydride (8.25 g, 60%) were added and cooled to 10 to 15 "C. To the reaction mixture, diethyl sulfate (8.99 g) was added slowly at 10 to 15 °C in about 10 to 15 min. under stirring. The reaction mixture was maintained at 10 to 15 °C for 30 min. under stirring. A solution of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-IH-pyrazolo-\|;4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-hydroxypropanoic acid (10 g) dissolved in N-methyl-pyrrolidone (NMP) (40 ml) was added to the reaction mixture at 10 to 15 °C in about 1 to 2 h. After complete addition, the reaction mixture was maintained at 10 to 15 "C for 5 to 6 h under stirring. Then the reaction mixture was brought to 25 to 35 °C and maintained for 12 to 15 h. After completion, the reaction mixture was slowly poured into ice-cold demineralised water (50 ml) and stirred for 30 min. The organic layer was separated and the aqueous layer was washed with toluene (50 ml x 2) and pooled the toluene washings. The aqueous layer was acidified slowly with 25% H2SO4 at 10 to 15 °C, in about 30 min. to pH 2.0 to 2.5 and maintained at the same temperature for 30 min. The precipitated product was filtered, washed with demineraUsed water (50 ml), and dried to yield the crude title compound as off white colored solid (weighs 9.2 g, yield 86%). The crude compound (8.8 g) was dissolved in toluene (180 ml) under reflux condition and filtered off the insoluble fibrous particles or salt through Hiflow bed. The toluene layer was concentrated below 110 °C. Isopropanol (40 ml) was added to the residue and stirred for 30 min. at 10 to 15 "C. The residue was filtered and dried to yield the title compound as ofT-white to white colored solid (weighs 6.4 g, yield 60%, purity 90.23% by HPLC, mp: 149 - 153 X). IR (KBr) cm': 3400-3300, 3120, 2970, and 1720. 'H NMR (200 MHz, DMS0-d6) 6 : 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.50 (t, J = 5.0 Hz, 2H), 4.29-4.22 (m, 5H), 4.01 (t, J = 3.7 Hz, IH), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (t, J = 7.5 Hz, 2H), 1.9-1.78 (m, 2H), 1.38 (t, J = 7.3 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H), 0.97 (I, J = 7.4 Hz, 3H). Anal. Calcd. C24H32N4O5 %C 63.15, %H 7.01, %N 12.82; Found %C 63.00, %H 6.90, %N 12,15. Mass m/z(Cl):457{M+l). Step tvii) Preparation of (-) 3-[4-(2-(5-ethyl-I-methyl-7-oxo-3-propyl-6,7-dihydro-l H- py razolo-I4,3-d) pyrimidiii-6-yI)ethoxy)phenylI-2-ethoxy prop anoic acid tromethainine salt In a 250 ml four-necked round bottom flask, fitted with a reflux condenser and mechanical stirrer, {-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxypropanoic acid (3 g, 0.0065 M) and isopropanol (45 ml) were added at 25 to 35 °C under stirring. The reaction mixture was heated slowly to 80 to 90 °C and maintained for 1 to 2 h for complete dissolution of the mass. The solution was filtered through Hiflow bed at 80 to 90 °C. The filtrate was recharged in a separate 250 ml four necked RB flask fitted with a mechanical stirrer and reflux condenser. Tromethamine (0.8 g) was added to the RB flask at 55 to 65 "^C in a single lot, under stirring and heated to reflux temperature and maintained gentle reflux for 8 to 10 h. The reaction mass was cooled to 25 to 35 °C under stirring and maintained for 2 to 3 h. The reaction mixture was further cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for complete precipitation. The precipitated product was filtered, washed with chilled isopropanol and dried at 60 "C to yield pure title compound as off white crystalline solid (weighs 4.61 g, yield 79,8 %, purity 97.82%, Chemical 99.72%, Chiral (+) isomer 0.28%, mp: 115toI19°C). IR (KBr) cm"': 3300-3250, 3120, 2935,1693, 1575. 'H NMR (200 MHz, DMSO-de) 5 : 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.1 Hz, 2H), 4.50 (t, J = 5,0 Hz, 2H), 4.29-4.22 (m, 5H), 4.01 (t, J = 3.70 Hz, IH), 4.0 (s, 6H), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (t, J = 7.5 Hz, 2H), 1.9-1.78 (m, 2H), 1.38 (t, J = 7.3 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H), 0.97 (t, J - 7.4 Hz, 3H). Mass m/z(CI):457(M++l), Anal. Calcd: C28H43N3O8; % C 61.20; % H: 7.83; % N 7.65; Found % C 61.05; % H 7.70; %N 7.50, Example 2 Step (i) Preparation of 5-Ethyl-l-methyI-3-propyl-6,7-dihydro-llHl-pyrazolo-l4,3di-pyrimidin-7-oiie 4-Amino-l-methyl-3-propyl-lH-5-pyrazolecarboxamide (300 g, 1.65 M), propionic acid (1.5 L) and para toluene sulfonic acid (catalytic) were taken in a round bottomed flask filled with Dean-Stark apparatus and refluxed for i 0 to 24 h. After completion of reaction, the reaction mass was poured into water, filtered and dried to yield the title compound, (weighs 314 g, yield 86%, purity 98%). Step (ii) Preparation of 5-ethyl-6{2-hydroxyethyI}-l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo (4,3 d)-pyrimidine-7-one 5-EtIiyl-l-methyI-3-propyl-6,7-dihydra-l[H]-pyrazolo-[4,3d]-pyrimidin-7-one (20.0 g, 90 M). NMP (200 ml), potassium carbonate (37.6 g, 0.272 M), and chloro ethanoi (14.5 g, 0.184 M) were taken in a round bottomed flask and heated at 90 to 110 °C for 16 to 20 h. After completion of reaction, the reaction mass was into ice cold water. The precipitated compound filtered and dried to get the title compound, (weighs 16,8 g, yield 70.2%, purity 96%). Step (ill) Preparation of 5-ethyI-6(2-chloro ethyl)-l-methyl-3-prop yl-6,7-dihydro-lH- pyrazolo 14,3 d]-pyrimidiiie-7-one 5-Ethyl-6{2-hydroxyethyl}-l-methyl-3-propyl-6,7-dihydro-IH-pyrazolo[4,3-d]-pyrimidine-7-one (4.0 g, 0.015 M), dichloromethane (20 ml), triethylamine (3.16 ml) were placed in a round bottomed flask and cooled to 0 to 5 "C. Then methaneaulfonyl chloride (2.43 g, 0.016 M) dissolved in dichloromethane (10 ml) was added slowly. After complete addition, the reaction mass was raised to ambient temperature and maintained for 12 (o 14 h. After completion of the reaction, the reaction mass was washed with water aad the organic layer was evaporated to gel the title compound (weighs 3.5 g, yield 83%, purity 97%). Slep (iv) Preparation of methyl (-) 3-(4-(2-(5-ethyl-l-methyI-7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo-[4,3-d]py rim id in-6-yl)ethoxy)phenyl]-2-tertiary butyl dimethyl sllyloxy propionate in a 500 ml four necked round bottom flask, fitted with a Dean Stark apparatus, reflux condenser and eficient stirrer, powdered K2CO3 (35 g, 0.25 M) and toluene (180 ml) was added at 30 to 35 "C under stirring. The reaction mixture was heated to 110 to 120 "C and maintained at reflux temperature of toluene for 2 to 3 h. After azeotropic removal of water, the reaction mixture was brought to 70 to 80 °C and methyl 2(S)-tertiary butyl dimethyl siiyloxy-3-(4-hydroxyphenyl)propionale (15,5 g, 0.05 M) and 5-ethyl-6-(2-chloroethyl)-l-methyl-3-propyl-6,7-dihydro-iH-pyrazolo[4,3-d]pyrimidin-7-one (18 g, 0.05 M) were added at the same temperature under stirring. The reaction mixture was refluxed for 15 to 18 h under stirring. The reaction mixture was brought to 30 to 35 °C and cooled tolO to 15 "C and water (lOO ml) was added and separated the organic layer. The aqueous layer was extracted with toluene (50 ml x 2) and the combined toluene layers were washed with demineralised water (50 ml x 2). The toluene layer was concentrated to yield the title compound as an oily liquid (weighs 30 g, yield 93%, purity 94-96%). IR (Neat) cm': 3120, 2910, 1756, 1686,1574. 'H NMR (200 MHz, CDCI3) 5 : 7.13 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 4.50 (t, J=5.0 Hz, 211), 4.29-4.22 (m, 3H), 4.01 (t, J=3.7 Hz, IH), 3.81 (s, 3H), 3.1-2.94 (m, 4H), 2.84 {t, J=7.5 Hz, 2H), 1.9-1.78 (m, 4H), 1.30 (t, J=7.3 Hz, 3H), 1.16 (t, J=7.0 Hz, 3H), 0.85 (s, 9H). Massm/z{Cl):557(M+ 1). step (V) Preparation of (-) 3-(4-(2-(5-cthyl-l-methyl-7-oxo-3-propyl-6,7-thydro-lH- pyrazolo-[4,3-d]pyrimidin-6-yl)etlioxy)phenyl\|-2-liydroxypropaiioic acid In a 2 L four necked round bottom flask, fitted with a reflux condenser and mechanical stirrer, methyl (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7'dihydro-1 H-pyrazolo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-tertiarybutyl dimethyl silyloxy propionate {96 g, 0.1729 M) and methanol (480 ml, 1:5 w/v) were added at 25 to 35 °C under stirring, p-Toluenesulfonic acid (3.28 g) was added to the reaction mixture at 30 to 35 °C. After complete addition, the reaction mixture was heated to 65 to 75 °C for 10 to 15 h under stirring. After completion of the reaction, the reaction mixture was cooled to 5 to 10 °C and 5% NaOH solution (276 ml) was added slowly under stirring. After addition, the reaction mixture was brought to 25 to 35 "C and maintained for 6 to 8 h under stirring. After completion of the reaction, the reaction mixture was diluted with demineralised water (500 ml) and washed with toluene (300 ml X 3). The aqueous layer was acidified with cone. HCl (30-32%) at 5 to 10 °C to pH 1.5-2.0 and maintained at the same temperature for Ihr, The precipitated product was fdtered, washed with demineralised water (100 ml x 2), dried lo yield the pure title compound as off white to cream colored solid (weighs 62 g, yield 84%, purity 95.87% by HPLC,mp: 208-211 °C). IR (KBr) cm-': 3400-3300, 3120, 2970, 1710, 1680, 1570. 'H NMR (200 MHz, DMS0-d6) 5 : 7.13 (d, J = 8,4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.50 (t, J = 5.0 Hz, 2H), 4.29-4.22 (m, 4H), 4.01 (t, J = 3.7 Hz, IH), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (t, J = 7.5 Hz, 2H), 1.9-1.78 (m, 2H), 1.38 (t, J = 7.3 Hz, 3H), 1.16(t,J = 7.0Hz,3H). Anal. Calcd, C22H2BN4O5 %C 61.68, %H 6.54, %N 13.08; Found %C 61.55, %H 6.35, %N 12.90 Massm/z(Cl):429CM+l). step (vl) Preparation of {-) 3-\|4-(2-(5-ethyl-l-metIiyI-7-oxo-3-propyl-6,7-(Iihydro-lH- pyrazolo-[4,3-d]pyrimiditi-6-yl)ethoxy)phenyl]-2-ethoxypropanoic acid In a 500 ml round bottom flask, diethyl sulfate (45 g) was added to sodium hydroxide in toluene (100 ml) followed by a solution of (-) 3-t4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazoIo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-hydroxypropanoic acid (50 g) in N-methyl- pyrrolidone (200 ml) at 10 to 15 °C in about 1 to 2 h. After complete addition, the reaction mixture was maintained at room temperature for 20 to 24 h under stirring. The reaction mixture was diluted with water (250 ml). The aqueous layer was washed with toluene and acidified with cone, HCl maintaining the temperature in the range of 10 to 15 °C under stirring. Stirring was continued further for 1 h under the same temperature. The solid product obtained was filtered and washed with demineralised water. The product obtained was then taken In isopropanol (152 ml) and stirred for 1 to 2 h at 10 to 15 °C. The solid was filtered and dried under vacuum to yield the title compound (weighs 39 g, yield 73 %, purity 90.23% by HPLC, mp: 149-153 °C). Ill (KBr) cm"': 3400-3300, 3120, 2970, 1720. 'H NMR(200 MHz, DMSO-dfi) 5:7.13 (d, 5 = 8.4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.50 (t, J = 5.0 Hz, 2H), 4.29-4.22 (m, 5H), 4.01 (1, J = 3.7 Hz, IH), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (I, J = 7.5 Hz. 2H), 1.9-1.78 (m, 2H), 1.38 (t, J = 7.3 Hz, 311), 1.16 (t, J = 7.0 Hz, 3?I), 0.97 (t, J = 7,4 Hz, 3H). Anal. Calcd. C24H32N40s %C 63.15, %H 7.01, %N 12.82; Found %C 63.00, %H 6.90, %N 12.15. Mass m/z (CI): 457 (M+1). Step(vii) Preparation of (-) 3-\|4-(2-(5-ethyl-l-methyi-7-oxo-3-propyl-6,7-dihydro-lH- pyrazolo-14,3-dlpyrimidin-6-yl)ethoxy)plienyll-2-etlioxypropanolc acid trometiiamine salt In a 250 ml four-necked round bottom flask, fitted with a reflux condenser and mechanical stirrer, (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyiimidin-6-yl)ethoxy)phenyl]-2-ethoxypropanoic acid (3 g, 0.0065 M) and isopropanol (45 ml) were added at 25 to 35 °C under stirring. The reaction mixture was heated slowly to 80 to 90 °C and maintained for 1 to 2 h for complete dissolution of the mass. The solution was filtered through Hiflow bed at 80 to 90 "C. The filtrate was recharged in a separate 250 ml four necked RB flask fitted with a mechanical stirrer and reflux condenser. Tromethamine (0.8 g) was added to the RB flask at 55 to 65 °C in a single lot, under stirring and heated to reflux temperature and maintained gentle reflux for 8 to 10 h. The reaction mass was cooled to 25 to 35 °C under stirring and maintained for 2 to 3 h. The reaction mixture was further cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for complete precipitation. The precipitated product was filtered, washed with chilled isopropanol and dried at 60 °C to yield pure title compound as off white crystalline solid (weighs 4.61 g, yield 79,8 %, purity 97,82%, Chemical 99.72%, Chital (+) isomer 0.28%, mp: 115-119 X). lR(KBr)cm"':3300-3250, 3120, 2935, 1693, 1575. 'H NMR (200 MHz, DMSO-dfi) 5 : 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.1 Hz, 2H), 4.50 (t. J = 5.0 Hz, 2H), 4.29-4.22 (m, 5H), 4.01 (t. J = 3.70 Hz, IH), 4.0 (s, 6H), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (t, J = 7.5 Hz, 2H), 1.9-1.78 (m, 2H), 1.38 (t, J - 7.3 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H). Mass nVz (CI): 457 (M+ + 1), Anal. Calcd: C28H43N3O8; % C 61.20; % H: 7.83; % N 7.65; Found % C 61,05; % H 7.70; % N 7.50. Example 3 Step (i) Preparation of 5-Ethyl-l-metliyl-3-propyl-6,7-diiiydro-l[H\|-pyrazolo-14,3d]- pyrimi(Iiii-7-one 4-Amino-1 -melhy 1-3-propyl-1 H-5-pyrazolecarboxamide (2,0 g, 0.0108 M), propionic acid (10 ml) and xylene (20 ml) were taken in a round bottomed flask fitted with Dean-Stark apparatus and refluxed for 24 h. After completion of reaction, xylene was distilled off and poured in water and stined for 1 hi at room temperature. The precipitated compound was filtered and dried to yield the title compound, (weighs 390 mg, yield 16%, purity 85%). IR (KBr): 2960, 2870, 1699, 1609, 1489,1455, 1394, 1315, 1018. 'H NMR (CDCI3): 5 11.22 (br s, IH, D2O exchangeable), 4.25 (s, 3H), 2.87 (t, j = 7.1 Hz, 2H), 2.78{q,/=7.3 Hz, 2H), 1.95-1.70 (m, 2H), 1.39 (t, J = 7.6 Hz, 3H), 1.00 (t, J-7.3 Hz, 3H). Mass m/z (CI); 22] (MV], J00%), i92 (17%), 191 (15%), J22 (5%), 105 (6%), 93 (11%), 91 (22%). Step (ii) Preparation of S-ethyl-6{2-hydroxyethyl}-l-methy!-3-propyl-6,7-dihy(lro-lI1- pyrazolo [4,3 d\|-pyrimidine-7-one 5-Ethyl-l-melliyl-3-propyl-6,7-dihydro-l[H]-pyrazolo-[4,3d]-pyrimidin-7-onc (5.0 g, 0.022 M), dimethylformaraide (100 ml), potassiun) carbonate (9.3 g, 0.032 M), and chloroethanol (3,6 g, 0.04 M) were taken in a round bottomed flask and heated at 110 X for 18 to 24 h. After completion of reaction, the reaction mass was poured into ice cold water and extracted with ethylacetate. The organic layer was evaporated to get tlie title compound, (weighs 5 g, yield 83.2%, purity 95.6%). IR (KBr): 3333, 2964, 1685, 1575, 1485, 1453, 1320, 1196, 1082, 1022, 885, 'HNMR(CDCl3): 8 4.31 (t,/=5.1 Hz, 2H), 4.21 (s, 3H), 3.99 (br s, 2H), 2,92 {X,J -7,3 Hz, 2H), 2.86(q, J=7.1 Hz, 2H), 1,90-1.72 (m, 2H), 1.35 (t, 7=7.1 Hz, 3H), 0.99(t,J=7.3Hz,3H), Mass m/z (CI): 265 (M^I, 100%), 247 (9%), 236 (8%) 192 (3%). Step (iii) Preparation of 5-ethyl-6(2-chloro ethyl)-l-metliyi-3-pro pyl-6,7-dihy dro-III- pyrazolo [4,3 d\|-pyrimidine-7-one 5-Etbyl-6{2-hydroxyelhyl}-l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]-pyrimidine-7-one (4.0 g, 0.015 M), d-chloromethane (20 ml), triethylamine (3,16 ml) were placed in a round bottomed flask and cooled to 0 to 5 "C. Then methanesulfonyl chloride (2.43 g, 0.016 M) dissolved in dichloromethane (10 ml) was added slowly. After complete addition, the reaction mass was raised to ambient temperature and maintained for 8 to 12 h. After completion of the reaction, the reaction mass was washed with water and the organic layer was evaporated to get the title compound (weighs 3.5 g, yield 83%, purity 97%). IR(KBr}:3439,2954,2872, 1684, 1575, 1445, 1369,1315, 1268,1183, 1160,973. 'H NMR (CDCh) : 6 4.04 (t, J- 6.6 Hz, 2H), 4.22 (s, 3H), 3.82 (t, J = 6.6 Hz, 2H), 2.96-2.81 (m, 4H), 1.90-1.73 (m, 2H), 1.36 (t, J-7.3 Hz, 3H), 0.99 (t, 7 = 7.3 Hz, 3H). Mass m/z: 284 (37Cl-M+ 14%), 282 (35C1-M+ 27%), 267 (21%), 254 (100%), 247 (50%), 192 (41%), 191 (42%), 136 (14%). Example 4 Step (i) Preparation of 5-Ethyl-l-iiicthyl-3-propyl-6,7-diliydro-l[H]-pyrazolo-[4,3d]- pyrimidin~7-one 4-Amino-I-niethy(-3-propyl-IH-5-pyrazolecarboxamide (300 g, i.65 M), propionic acid (1,5 L) and p-toluenesulfonic acid (catalytic) were taken in a round bottomed flask fitted with Dean-Stark apparatus and refluxed for 10 to 24 h. After completion of reaction, the reaction mass was poured into water, filtered and dried to yield the title compound, (weighs 314 g, yield 86%, purity 98%). Step (ii) Preparation of 5-etliyl-6{2-hydroxyethyl}-l-methyl-3-propyl-6,7-diliydro-lH- pyrazolo [4,3 d\|-pyrimidine-7-one 5-Ethyl-l-melhyl-3-propyl-6,7-dihydro-l[H]-pyrazolo-[4,3d]-pyrimidin-7-one (20.0 g, 90 M), NMP (200 ml), potassium carbonate (37.6 g, 0.272 M), and chloroethanol (14.5 g, 0.184 M) were taken in a round bottomed flask and heated at 90 to 110 oC for 16 to 20 h. After completion of reaction, the reaction mass was into ice cold water. The precipitated compound filtered and dried to get the i\l\e compound, (weighs 16.8 g, yield 70.2%, purity 96%). step (iii) Preparation of 5-ethyl-6(2-chloro ethyl)-l-methyl-3-propyl-6,7-dihydro-111 pyrazolo [4,3 d]-pyrimidine-7-one 5-Et))yJ-6{2-hydroxyethylf-)-me!hy]-3-propy)-6,7-dihydro-]H-pyrazo]o[4,3-dJ-pyrimidine-7-one (4.0 g, O.OiS M), dichloromethane (20 ml), triethylamine (3.16 ml) were placed in a round bottomed flask and cooled to 0 to 5 °C. Then methanesulfonyl chloride (2.43 g, 0.016 M) dissolved in dichloromethane (10 ml) was added slowly. After complete addition, the reaction mass was raised to ambient temperature and maintained for 12 to 14 h. After completion of the reaction, the reaction mass was washed with water and the organic layer was evaporated to get the title compound (weighs 3.5 g, yield 83%, purity 97%). Claims: 1. A process for the preparation of compounds of the formula (1), where R represents (C1-C6) alkyl group, which comprises: i) cyclizing the 4-amino-l-melhyl-3-propyl-lH-5-pyrazolecarboxamide of the formula (2) with propionic acid of the formula (3) in neat or in the presence of a solvent or an acid at a temperature in the range of 20 to 160 "C for a period in the range of 2 to 30 h, to yield compound of formula (4), ii) reacting Ihe compound of formula (4) with haloethano! of formula (9) where X represents halogen atom in the presence of a solvent and a base at a temperature in the range of 40 to 150 'C for a period in the range of 4 to 30 h, lo yield compound of formula (10), iii) converting the compound of fonnula (10) to halo compound of formula (11) where X represents halogen atom, using halogenating agent in the presence of a solvent and a base at a temperature in the range of -20 to 60 "C preferably from 0 to 250, for a period in the range of 4 to 24 h, iv) condensing the pyrazolo[4,3-d]pyrimidin-7-one of the formula (11) where X represents halogen atom with compound of formula (12) where R' represents t-butyldimelhyl silyl, trimethyl siiyi or alkoxyaikyl group; R2 represents (C1-C6)alkyl group in (he presence of a base and a solvent at a (emperatitre in (he range of 5 (o 150 °C, for a period in the range of 2 to 30 h, to give compound of the formula (13) where R1 and R2 are as defined above where R1 represents t-butyldimethyj silyl, trimethyl siiyi or alkoxyaikyl group; R1 represents {C1-C6)alkyl group, V) hydrolysing the compound of formula (13) to yield the compound of the fonuula (14) in the presence of a base or an acid and a solvent at a temperature in the range of 10 to 80 °c for a period in the range of 4 to 24 h, vi) etherifying the compound of formula (14) to a compound of fonuula (la) where R represents (C1-C2)alkyl group using an alkylating agent in the presence of a base and a solvent at a temperature in the range of 0 to 30 "C for a period in the range of 4 to 24 h, vii) reacting the compound of formula (la) where R is defined as above, with tromethamine in the presence of a solvent at a temperature in the range of 10 to 150 "C, for a period in the range of 2 to 24 h, to yield compound of formula (I) where R is as defined above and viii) isolating the compound of formula (1) by conventional methods. 2. The process as described in claim 1, wherein the solvent used in step (i) is selected from DMF, THF, toluene, xylene or a mixture thereof. 3. The process as described in claims 1 and 2, wherein the acid used in step (i) is selected from POCI3, PPA or p-toluenesulfonic acid. 4. The process as described in claims 1 to 3, wherein the base used in step (ii) is selected from potassium carbonate, sodium carbonate, sodium hydride, DBU, DABCO, DBN, iriethyl amine or diisopropyl amine. 5. The process as described in claims 1 to 4, wherein the solvent used in step (ii) is selected from THF, DMF, dichloromethane, acetonitrile, NMP, toluene or mixture thereof 6. The process as described in claims 1 to 5, wherein the halogenating agent used in step (lii) is selected from cone. HCI, HBr, PBrs, POCI3 or MeSOzCI. 7. The process as described in claims I to 6, wherein the base used in step (iii) is selected from (riethyl amine, diisopropyl amine or pyridine. 8. The process as described in claims 1 to 7, wherein the solvent used in step (iii) is selected from DCM, DCE, pyridine or a mixture thereof. 9. The process as described in claims I to 8, wherein the reaction in step (iii) is carried out at a temperature in the range of 0 to 25 °C and the duration in the range of and 4 to 20 h, 10. The process as described in claims 1 to 9, wherein the base used in step (iv) is selected from sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide. 11. The process as described in claims 1 to 10, wherein the solvent used in step (iv) is selected from toluene, xylene, THF, DMF, DME, DMSO, NMP or alcohol selected from methanol, ethanol, propanol, isopropanol or mixture thereof. 12. The process as described in claims 1 to 11, wherein the acid used in step (v) is selected from methane sulfonic acid, HCI, H2SO4, trifluoroacetic acid or para toluene sulfonic acid. 13. The process as described in claims I to 12, wherein the solvent used in step (v) is selected from water, methanol, ethanol, propanol, isopropanol or mixture thereof. 14. The process as described in claims 1 to 13, wherein the base used in step (v) is selected from NaH, NaOH, KOH, t-BuOK, K2CO3 or NaHCOj. 15. The process as described in claims 1 to 14, wherein the alkylating agent used in step (vi) is selected from (Ci-Cb) alkyl sulfate or alkyl halide. 16. The process as described in claims 1 to 15, wherein the base used in step (vi) is selected from NaH, NaOH, KOH, t-BuOK, K2CO1 or NaHCO3- 17. The process as described in claims 1 to 16, wherein the solvent used in step (vi) is selected from toluene, xylene, benzene, DMF, DMSO, MIBK, ethyl acetate, NMP or a mixture thereof. 18. The process as described in claims 1 to 17, wherein the solvent used in step (vii) is selected from acetonitrile, DMF, DMSO, acetone, 1,4-dioxane or aicohoi selected from methanol, elhano), propaiiol, jsopropanol or mixture thereof. 19. The process as described in claim 15, wherein dialkyl sulfate is selected from dimethyl sulfate or diethyl sulfate, 20. A process for the preparation of compound of the formula (11), where X represents halogen atom such as fluorine, chlorine, bromine or iodine, which comprises: i) cyclizing the 4-amino-l-methyl-3-propyl-lH-5-pyrazolecarboxamide of the formula (2) with piopionic acid of the fonnula (3) in neat or in the presence of 3 solvent or an acid at a temperature in the range of 20 to 160 °C for a period in the range of 2 to 30 h, to yield compound of formula (4), ii) reacting the compound of formula (4) with haioethanol of formula (9) where X represents halogen atom in the presence of a solvent and a base at a temperature in the range of 40 to 150 °C for a period in the range of 4 to 30 h, to yield compound of formula (10), iii) converting the compound of fonnula (10) to halo compound of formula (II) where X is defined as above using halogenating agent in the presence of a solvent and a base at a temperature in the range of-20 to 60 "C C preferably from 0 to 25°C, for a period in the range of 4 to 24 h, iv) isolating the compound of formula (11) by conventional methods. 21. The process as described in claim 20, wherein the solvent used in step (i) is selected from DMF, THF, toluene, xylene or a mixture thereof. 22. The process as described in claims 20 and 21, wherein the acid used in step (i) is selected from POCl3, PPA or p-loluenesulfonic acid. 23. The process as described in claims 20 to 22, wherein the base used in step (ii) is selected from potassium carbonate, sodium carbonate, sodium hydride, DBU, DABCO, DBN, trietiiyl amine or diisopropyl amine. 24. The process as described in claims 20 to 23, wherein (he solvent used in step (ii) is selected from THF, DMF, dichloromethane, acetonitrile, NMP, toluene or mixture thereof. 25. The process as described in claims 20 to 24, wherein the halogenating agent used in step (iii) is selected from cone. HCl, HBr, PBr3, POCI3 or MeS02Cl. 26. The process as described in claims 20 to 25, wherein the base used in step (iii) is selected from triethyl amine, diifeopropyl amine or pyridine. 27. The process as described in claims 20 to 26, wherein the solvent used in step (iii) is selected from DCM, DCE, pyridine or a mixture thereof, 28. The process as described in claims 20 to 27, wherein the reaction in step (iii) is carried out at a temperature in the range of 0 to 25 °C and the duration in the range ofand 4 to 20 h, 29. A process for the preparation of compounds of formula (1) and (11) substantially as herein described with reference to the examples.

Full Text

where R represents (C1-C6)alkyl group.
The compound of formula (1) is useful in lowering the plasma glucose, triglyceride, total cholesterol (TC); increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL).
The compound of formula (1) is also useful in reducing body weight and for the treatment and / or propiiylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. The compound of formula (I) is also useful for the treatment and/or prophylaxis of insulin resistance (type 11 diabetes).
Background of invention
In our WTO mailbox application No. 569/MAS/2001 we have described a process for the preparation of free acid of compound of formula (1). The process described therein comprises of reacting the pyrazolo pyrimidine of the formula (4) with compound of formula (5) to produce a compound of formula (6) and hydtolyzing the compound of formula (6) to obtain an acid of formula (7), convening the acid of formula (7) to an amide of the formula (8) and hydrolyzing the amide to produce the free acid of compound of formula (la). The piocess is shown in the scheme-1 given below

Objective of present invention
The main objective of the present invention is to provide a simple and robust process for the preparation of the compound of formula (1) with high chemical and chiral purity.
Another objective of the present invention is also to provide a process for the preparation of the compound of formula (11).
Detailed description oftlie invention
Accordingly, the present invention provides a process for the preparation of compounds of the formula (1),

where R represents (C1-C6)alkyl group, which comprises:
i) cyclizing the 4-amino-l-methyl-3-propyl-lH-5-pyrazolecarboxamide of the
formula (2) with propionic acid of the formula (3) in neat or in the presence of a

solvent or an acid at a temperature in the range of 20 to 160°C for a period in the
range of 2 to 30 h, to yield compound of formula (4),
ii) reacting the compound of formula (4) with haloethanol of formula (9) where
X represents halogen atom such as fluorine, chlorine, bromine or iodine, in the
presence of a solvent and a base at a temperature in the range of 40 to 150 °C for and
the duration may range from 4 to 30 h, to yield compound of formula (10),
iii) converting the compound of formula (10) to halo compound of formula (11),
where X represents halogen atom such as fluorine, chlorine, bromine or iodine using
halogenating agent in the presence of a solvent and a base at a temperature in the
range of -20 to 60 "C preferably in the range of 0 to 25C, for a period in the range of
4 lo24 h,
iv) condensing the pyrazolo[4,3-d]pyrimidin-7-one of the formula (II) where X
is defined as above with compound of formula (12) where R' represents t-
butyldimethyl siiyi, trimethyl silyl or alkoxyalkyl group; R^ represents (Ci-C6)alkyi
group in the presence of a base and a solvent at a temperature in the range of 5 to 150
"C, for a period in the range of 2 to 30 h, to give compound of the formula (13)
where R2 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R
represents (C1-C6)alkyl group,
v) hydrolyzing the compound of formula (13) to yield the compound of the
formula (14) in the presence of a base or an acid and a solvent at a temperature in
the range of 10 to 80 °C and for a period in the range of 4 to 24 h,
vi) elherifying the compound of formula (14) to a compound of formula (la)
using alkylating agent in the presence of a base and a solvent wherein R represents
(C1-C6)alkyl group at a temperature in the range of 0 to 30 °C and for a period in the
range of 30 min. to 24 h,
vii) reacting the compound of formula (la) with tromethamine in the presence of
a solvent at a temperature in the range of 10 to 150 °C, for a period in the range of 2
to 24 h, to yield compound of formula (1) where R is as defined above and
viii) isolating the compound of formula (1) by conventional methods.

Scheme-2
The cyclization of compound of formula (2) with propionic acid of the formula (3) may be carried out in neat or in the presence of a solvent such as DMF, THF, toluene, xylene and the like or a mixture thereof. The reaction may be carried out in the presence or absence of an acid such as POCI3, PPA, p-toluenesulfonic acid TFA, P205-xylene and the like. The reaction may be carried out at a temperature in the range of 20 to 160 °C for a period in the range of 2 to 30 h with azeotropic removal of water.
The reaction of compound of formula (4) with haloethanol of formula (9) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, may be carried out in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride, DBU, DABCO, DBN, cesium carbonate, lithium hydroxide, triethyl amine, diisopropyl amine and the like. The reaction may be

carried out using a solvent such as THF, DMF, dichloromethane, acetonitrile. NMP, toluene and the like or mixtures thereof. The temperature of the reaction may range from 40 to 150 "C for and the duration may range from 4 to 30 h.
The conversion of compound of formula (10) to a compound of formula (11) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, may be carried out using halogenating agent such as cone. HCl, HBr, PBrj, POClj, MeS02Cl, thionyi chloride, oxalyl chloride, para toluene sulfonyl chloride and the like in the presence of base such as triethyl amine, diisopropyl amine, pyridine and the like. The reaction may also be carried out using a solvent such as DCM, DCE, pyridine and the like or mixtures thereof. The reaction temperature may be in the range of -20 °C to 60 X, preferably from 0 °C to 25 °C. The reaction time may range from 4 to 24 h.
The condensation of compound of the formula (11) where X is defined as above, with compound of the formula (8) where R represents t-butyldimethyl silyl, trimethyl silyl and the like; or alkoxyalkyl groups such as methoxy, ethoxy, propoxy, isopropoxy and the like, R^ represents (C1-C5) alkyl groups such as methyl, ethyl, propyl, butyl, t-bulyl and the like, to provide a compound of the formula (13) where R1 and R2 are as defined above, may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, using a solvent such as toluene, xylene, THF, DMF, DME, DMSO, NMP or alcohols such as methanol, ethanol, propanol, isopropanol and the like or mixture thereof The reaction may be carried out at a temperature in the range of 5 to 150 °C and the duration of the reaction may range from 2 to 30 h.
The hydrolysis of compound of the formula (13) where R1 and R2 are as defined above, to yield compound of formula (14) may be carried out using an acid such as methane sulfonic acid, HCl, H2SO4, trifluoroacetic acid, para toluene sulfonic acid and the like in the presence or absence of a solvent such as methanol, ethanol, propanol, isopropanol and the like or mixture thereof Further hydrolysis to yield compound of formula (14) may be carried out using a base such as NaH, NaOH, KOH, LiOH, t-BuOK, K2CO3, NaHCO3 and the like in the presence of a solvent such as water, methanol, ethanol, propanol, isopropanol and the like or mixture

[hereof. The reaction may be carried out at a temperature in the range of 10 to SO "C and the duration of the reaction may range from 4 to 24 h.
The etherification of compound of formula (14) to obtain compound of fonnula (la) where R represents (C|-C6)alkyl groups such as methyl, ethyl, propyl, butyl, t-butyl and the like, may be carried out using dialkyi sulfate such as diethyl sulfate, dimethyl sulfate and the like or (C1-C6)alkyl halides such as ethyl iodide, methyl iodide and the like, in the presence of a base such as NaH, NaOH, KOil, t-BuOK, K2CO3, NaHCO3 and the like, in the presence of a solvent such as toluene, xylene, benzene, DMF, DMSO, MIBK, ethyl acetate, N-methyl pyrrolidone (NMP) and the like or a mixture thereof. The reaction may be carried out at a temperature in the range of 0 °C to 30 °C and the duration of the reaction may range from 30 min. to 24 h.
The reaction of compound of formula (la) where R is defined as above, with tromethamine may be carried out in the presence of a solvent such as alcohols like methanol, elhanol, propanol, isopropanol and the like; acetonilrile, DMF, DMSO, acetone, 1,4-dioxane and the like or a mixture thereof, at a temperature in the range of 10 lo 150 °C, for a period in the range of 1 to 24 h to provide compound of the formula (1).
Another embodiment of the present invention provides a process for the preparation of the compound of fonnula (11)

where X represents halogen atom such as fluorine, chlorine, bron\ine or iodine,
which comprises:
i) cyclizjng the 4-amino-I-melhyl-3-propyl-lH-5-pyrazolecarboxamide of the
formula (2) with propionic acid of the formula (3) in neat or in the presence of a solvent or an acid at a temperature in the range of 20 to 160°C for a period in the range of 2 to 30 h, to yield compound of formula (4),
ii) reacting the compound of fonnula (4) with haloethanol of formula (9) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, in the

presence of a solvent and a base at a temperature in the range of 40 to 150 "C for and
the duration may range from 4 to 30 h, to yield compound of formula (10),
iii) converting the compound of formula {10} to halo compound of formula (11),
where X represents halogen atom such as fluorine, chlorine, bromine or iodine using
halogenaling agent in the presence of a solvent and a base at a temperature in the
range of-20 to 60 °C for a period in the range of 4 to24 h,
iv) isolating the compound of formula (11) by conventional methods.

The cyclization of compound of formula (2) with propionic acid of the formula (3) may be carried out in neat or in the presence of a solvent such as DMF, THF, toluene, xylene and the like or a mixture thereof. The reaction may be carried out in the presence or absence of an acid such as POCI3, PPA, p-toluenesulfonic acid TFA, PzOs-xylene and the like. The reaction may be carried out at a temperature in the range of 20 °C to 160 °C for a period in the range of 2 to 30 h with azeotropic removal of water.
The reaction of compound of formula (4) with haloethanol of formula (9) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, may be carried out in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride, DBU, DABCO, DBN, cesium carbonate, lithium hydroxide, triethyl amine, diisopropyl amine and the like. The reaction may be carried out using a solvent such as THF, DMF, dichloromethane, acetonitrile, NMP,

toluene and llie like or mixtures thereof. The temperature of the reaction may range from 40 to 150 °C for and the duration may range from 4 to 30 h.
The conversion of compound of formula (10) to a compound of formula (11) where X represents halogen atom such as fluorine, chlorine, bromine or iodine, may be carried out using halogenating agents such as cone. HCl, HBr, PBrj, POCh, MeS02CI, thionyl chloride, oxalyl chloride, p-toluenesulfonyl chloride and the like in the presence of a base such as triethyl amine, diisopropyl amine, pyridine and the like. The reaction may also be carried out using a solvent such as DCM, DCE, pyridine and the like or mixture thereof. The reaction temperature may be in the range of -20 °C to 60 "C, preferably from 0 °C to 25 °C. The reaction time may range from 4 to 24 h.
The present invention is described in detail with example given below that are provided by way of illustration only and therefore should not be construed to limit ihe scope of the invention.
Example 1
Step (i)
Preparation of 5-Ethyl-l-methylr3-propyl-6,7-dihydro-llHl-pyrazolo-[4,3dl-
pyrimidin-T-oue
4-Amino-l-m6thyl-3-ptopyl-lH-5-pyrazolecarboxamide (2.0 g, 0.0108 M),
propionic acid (10 ml) and xylene (20 ml) were taken in a round bottomed flask
fitted with Dean-Stark apparatus and refluxed for 24 h. After completion of reaction,
xylene was distilled off and poured in water and stirred for 1 h at room temperature.
The precipitated compound was filtered and dried to yield the title compound,
(weighs 390 mg, yield 16%, purity 85%).
IR(KBr): 2960,2870, 1699, 1609, 1489,1455, 1394, 1315, 1018.
'H NMR (CDCU): 5 11.22 (br s, IH, D2O exchangeable), 4.25 (s, 3H), 2.87 (t, J -
7.1 Hz, 2H), 2.78 (q, i= 7.3 Hz, 2H), f.95-1,70 (m, 2H), 1.39 (t, y = 7.6 Hz, 3H),
1.00(t,J=7.3Hz, 3H).
Mass m/z (CI): 221 (M++1, 100%), 192 (17%), 191 (15%), 122 (5%), 105 (6%). 93
(11%), 91 (22%).

Step (ii)
Preimration of 5-ctliyI-6{2-hydroxyethyrj-l-iiietliyIO-|>ropyl-6,7-ditydro-lH-pyrazolo |4,3d|-pyniiii(Iine-7-one
5-Ethyl-1 -methyl-3-propyl-6,7-dihydro-l [Hl-pyrazolo-[4,3d]-pyrimidin-7-one (5.0 g, 0.022 M), dimethylformamide {100 ml), potassium carbonate {9.3 g, 0.032 M). and chloroethanol {3.6 g, 0.04 M) were taken in a round bottomed flask and heated at 110 °C for 18 to 24 h. After completion of reaction, the reaction mass was poured into ice cold water and extracted with ethylacetate. The organic layer was evaporated to get the title compound, {weighs 5 g, yield 83.2%, purity 95.6%). IR (KBr): 3333, 2964, 1685, 1575, 1485, 1453, 1320, 1196, 1082, 1022, 885. 1HNMR(CDCI3):5 4.31 (t,y=5.1 Hz, 2H), 4.21 {s, 3H), 3.99 (br s, 2H), 2.92 (t, J - 7.3 Hz, 2H), 2.86 (q, 7=7,1 Hz, 2H), 1.90-1.72 (m, 2H), 1.35 (t, J=7.\ Hz, 3H), 0.99(t,J=7.3Hz,3H). Mass m/z (CI): 265 (M++1, 100%), 247 (9%), 236 (8%) 192 (3%).
Step (iii)
Preparation of 5-ethyl-6(2-chloro ethyl)-l-methyl-3-propyi-6,7-dihydro-lH-
pyrazolo (4,3 d]-pyrimidine-7-one
5-Ethyl-6{2-hydroxyethyl)-l-methy[-3-pvopyl-6,7-dihydro-lH-pyrazolo[4,3-d]-pyrimidine-7-one (4.0 g, 0.015 M), dichloromethane (20 ml), triethylamine (3.16 ml) were placed in a round bottomed flask and cooled to 0 to 5 °C. Then melhanesulfony! chloride (2.43 g, 0.016 M) dissolved in dichloromethane (10 ml) was added slowly. After complete addition, the reaction mass was raised to ambient temperature and maintained for 8 to 12 h. After completion of the reaction, the reaction mass was washed with water and the organic layer was evaporated to get the title compound (weighs 3.5 g, yield 83%, purity 97%).
IR(KBr): 3439, 2954, 2872, 1684, 1575, 1445, 1369, 1315, 1268, 1183,1160,973. 1H NMR {CDCi3): S 4.04 (t, J= 6.6 Hz, 2H), 4.22 (s, 3H), 3.82 (t, J = 6.6 Hz. 2H), 2.96-2.8! (m, 4H), 1.90-1.73 (m, 2H), 1.36 {t, 7= 7.3 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H).

Mass m/z: 284 37c1-M+ 14%), 282 (35c1-M+ 27%), 267 (21%), 254 (100%), 247 (50%), 192 (41%), 191 (42%), 136 (14%).
Step (iv)
Preparation of methyl (-) 3-[4-(2-(5-ethyl-l-inelhyI-7-oxo-3-propyl-6, 7-dihydro-
lH-pyrazolo-[4,3-d|pyrinii(lin-6-yl)ethoxy)plienyl]-2-tertiarybutyI dimethyl
siiyloxy propionate
in a 500 ml four necked round bottom flask, fitted with a Dean Stark apparatus, reflux condenser and efficient stirrer, powdered KICOB (35 g, 0.25 M) and toluene (180 ml) was added at 30 to 35 "C under stirring. The reaction mixture was heated to 110 to 120 °C and maintained at reflux temperature of toluene for 2 to 3 h. After azeotropic removal of water, tlie reaction mixture was brought to 70 to 80 "C and methyl 2(S)-tertiary butyl dimethyl siIyloxy-3-(4-hydroxyphenyl)propionaIe (15.5 g, 0.05 M) and 5-ethyl-6-(2-thloroethyl)-l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-7-one (18 g^ 0.05 M) were added at the same temperature under stirring. The reaction mixture was refluxed for 15 to 18 h under stirring. The reaction mixture was brought to 30 to 35 °C and cooled tolO to 15 °C and water (100 ml) was added and separated the organic layer. The aqueous layer was extracted with toluene (50 ml x 2) and the combined toluene layers were washed with demineralised water (50 ml x 2). The toluene layer was concentrated to yield the title compound as an oily liquid (weighs 30 g, yield 93%, purity 94 to 96%). IR (Neat) cm': 3120, 2910, 1756,1686, 1574.
'H NMR (200 MHz, CDCh) 6 : 7.13 (d, J=8.4 Hz, 2H), 6.77 (d, J-8.6 Hz, 2H), 4.50 (t, J=5.0 Hz, 2H), 4.29-4.22 (m, 3H), 4.01 (t, J=3.7 Hz, IH), 3.81 (s, 3H), 3.1-2.94 (m, 4H), 2.84 (t, J=7.5 Hz, 2H), 1.9-1.78 (m, 4H), 1.30 (t, J=7.3 Hz, 3H), 1.16 (t, J=7.0 Hz, 3H), 0.85 (s, 9H). Mass m/z (CI): 557 (M++I).

Step (v)
Preparation of (-) 3-|4-(2-(5-ethyl-l-metliyl-7-Dxo-3-propyl-6,7-diliy(Iro-lH-pyrazolo-|4,3-dJpyrimi(liil-6-yl)ethoxy)phenyI|-2-hydroxypropanoicacid
In a 2 L four necked round bottom flask, fitted with a reflux condenser and mechanical stirrer, methyl (-) 3-[4-(2-(5-ethyl-l-methy!-7-oxo-3-propyl-6,7-dihydro-I H-pyrazolo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-tertiarybutyl dimethyl silyloxy propionate (96 g, 0.1729 M) and methanol (480 ml, 1:5 w/v) were added at 25 to 35 'C under stirring. p-Toluene sulfonic acid (3.28 g) was added to the reaction mixture at 30 to 35 "C. After complete addition, the reaction mixture was heated to 65 to 75 °C for 10 to 15 h under stirring. After completion of the reaction, the reaction mixture was cooled to 5 to 10 °C and 5% NaOH solution (276 ml) was added slowly under stirring. After addition, the reaction mixture was brought to 25 to 35 °C and maintained for 6 to 8 h under stirring. After completion of the reaction, the reaction mixture was diluted with demineralised water (500 ml) and washed with toluene (300 ml X 3). The aqueous layer was acidified with cone. HCl (30-32%) at 5 to 10 °C to pH 1,5 lo 2.0 and maintained at the same temperature for Ihr. The precipitated product was filtered, washed with demineralised water (100 ml x 2), dried to yield the pure title compound as off white to cream colored solid (weighs 62 g, yield 84%, purity 95.87% by HPLC, mp: 208 to 211 "C). IR(KBr)cm-':3400-3300,3120,2970, 1710, 1680, 1570.
'H NMR (200 MHz, DMS0-d6) 5 : 713 (d, J - 8.4 Hz, 2H), 6.77 (d, i = 8.6 Hz, 2H), 4.50 (t, J - 5.0 Hz, 2H), 4.29-4.22 (m, 4H), 4.01 (t, J - 3.7 Hz, IH), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (t, I = 7.5 Hz, 2H), 1,9-1.78 (m, 2H), 1.38 (t, J - 7.3 Hz, 3H), 1.16(t,J = 7.0Hz,3H).
Anal. Calcd. C22H28N4O5 %C 61.68, %H 6.54, %N 13.08; Found %C 61.55, %H 6.35, %N 12.90 Massm/z(CI):429(M+l).

step (vi)
Preparation of (-) 3-|4-(2-(S-ethyl-l-methyI-7-oxo-3-propy|-6,7-diliy(lro-lH-
pyrazolo-[4,3-d)pyriniidin-6-yl)ethoxy)phenyl|-2-etlioxypropanoicacid In a 500 ml four necked round bottom flask, fitted with a plain condenser and mechanical stirrer, toluene (80 ml) and sodium hydride (8.25 g, 60%) were added and cooled to 10 to 15 "C. To the reaction mixture, diethyl sulfate (8.99 g) was added slowly at 10 to 15 °C in about 10 to 15 min. under stirring. The reaction mixture was maintained at 10 to 15 °C for 30 min. under stirring. A solution of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-IH-pyrazolo-|;4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-hydroxypropanoic acid (10 g) dissolved in N-methyl-pyrrolidone (NMP) (40 ml) was added to the reaction mixture at 10 to 15 °C in about 1 to 2 h. After complete addition, the reaction mixture was maintained at 10 to 15 "C for 5 to 6 h under stirring. Then the reaction mixture was brought to 25 to 35 °C and maintained for 12 to 15 h. After completion, the reaction mixture was slowly poured into ice-cold demineralised water (50 ml) and stirred for 30 min. The organic layer was separated and the aqueous layer was washed with toluene (50 ml x 2) and pooled the toluene washings. The aqueous layer was acidified slowly with 25% H2SO4 at 10 to 15 °C, in about 30 min. to pH 2.0 to 2.5 and maintained at the same temperature for 30 min. The precipitated product was filtered, washed with demineraUsed water (50 ml), and dried to yield the crude title compound as off white colored solid (weighs 9.2 g, yield 86%). The crude compound (8.8 g) was dissolved in toluene (180 ml) under reflux condition and filtered off the insoluble fibrous particles or salt through Hiflow bed. The toluene layer was concentrated below 110 °C. Isopropanol (40 ml) was added to the residue and stirred for 30 min. at 10 to 15 "C. The residue was filtered and dried to yield the title compound as ofT-white to white colored solid (weighs 6.4 g, yield 60%, purity 90.23% by HPLC, mp: 149 - 153 X). IR (KBr) cm': 3400-3300, 3120, 2970, and 1720.
'H NMR (200 MHz, DMS0-d6) 6 : 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.50 (t, J = 5.0 Hz, 2H), 4.29-4.22 (m, 5H), 4.01 (t, J = 3.7 Hz, IH), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (t, J = 7.5 Hz, 2H), 1.9-1.78 (m, 2H), 1.38 (t, J = 7.3 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H), 0.97 (I, J = 7.4 Hz, 3H).

Anal. Calcd. C24H32N4O5 %C 63.15, %H 7.01, %N 12.82; Found %C 63.00, %H
6.90, %N 12,15.
Mass m/z(Cl):457{M+l).
Step tvii)
Preparation of (-) 3-[4-(2-(5-ethyl-I-methyl-7-oxo-3-propyl-6,7-dihydro-l H-
py razolo-I4,3-d) pyrimidiii-6-yI)ethoxy)phenylI-2-ethoxy prop anoic acid
tromethainine salt
In a 250 ml four-necked round bottom flask, fitted with a reflux condenser and mechanical stirrer, {-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxypropanoic acid (3 g, 0.0065 M) and isopropanol (45 ml) were added at 25 to 35 °C under stirring. The reaction mixture was heated slowly to 80 to 90 °C and maintained for 1 to 2 h for complete dissolution of the mass. The solution was filtered through Hiflow bed at 80 to 90 °C. The filtrate was recharged in a separate 250 ml four necked RB flask fitted with a mechanical stirrer and reflux condenser. Tromethamine (0.8 g) was added to the RB flask at 55 to 65 "^C in a single lot, under stirring and heated to reflux temperature and maintained gentle reflux for 8 to 10 h. The reaction mass was cooled to 25 to 35 °C under stirring and maintained for 2 to 3 h. The reaction mixture was further cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for complete precipitation. The precipitated product was filtered, washed with chilled isopropanol and dried at 60 "C to yield pure title compound as off white crystalline solid (weighs 4.61 g, yield 79,8 %, purity 97.82%, Chemical 99.72%, Chiral (+) isomer 0.28%, mp: 115toI19°C).
IR (KBr) cm"': 3300-3250, 3120, 2935,1693, 1575.
'H NMR (200 MHz, DMSO-de) 5 : 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.1 Hz, 2H), 4.50 (t, J = 5,0 Hz, 2H), 4.29-4.22 (m, 5H), 4.01 (t, J = 3.70 Hz, IH), 4.0 (s, 6H), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (t, J = 7.5 Hz, 2H), 1.9-1.78 (m, 2H), 1.38 (t, J = 7.3 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H), 0.97 (t, J - 7.4 Hz, 3H). Mass m/z(CI):457(M++l),

Anal. Calcd: C28H43N3O8; % C 61.20; % H: 7.83; % N 7.65; Found % C 61.05; % H 7.70; %N 7.50,
Example 2 Step (i)
Preparation of 5-Ethyl-l-methyI-3-propyl-6,7-dihydro-llHl-pyrazolo-l4,3di-pyrimidin-7-oiie
4-Amino-l-methyl-3-propyl-lH-5-pyrazolecarboxamide (300 g, 1.65 M), propionic acid (1.5 L) and para toluene sulfonic acid (catalytic) were taken in a round bottomed flask filled with Dean-Stark apparatus and refluxed for i 0 to 24 h. After completion of reaction, the reaction mass was poured into water, filtered and dried to yield the title compound, (weighs 314 g, yield 86%, purity 98%).
Step (ii)
Preparation of 5-ethyl-6{2-hydroxyethyI}-l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo (4,3 d)-pyrimidine-7-one
5-EtIiyl-l-methyI-3-propyl-6,7-dihydra-l[H]-pyrazolo-[4,3d]-pyrimidin-7-one (20.0 g, 90 M). NMP (200 ml), potassium carbonate (37.6 g, 0.272 M), and chloro ethanoi (14.5 g, 0.184 M) were taken in a round bottomed flask and heated at 90 to 110 °C for 16 to 20 h. After completion of reaction, the reaction mass was into ice cold water. The precipitated compound filtered and dried to get the title compound, (weighs 16,8 g, yield 70.2%, purity 96%).
Step (ill)
Preparation of 5-ethyI-6(2-chloro ethyl)-l-methyl-3-prop yl-6,7-dihydro-lH-
pyrazolo 14,3 d]-pyrimidiiie-7-one
5-Ethyl-6{2-hydroxyethyl}-l-methyl-3-propyl-6,7-dihydro-IH-pyrazolo[4,3-d]-pyrimidine-7-one (4.0 g, 0.015 M), dichloromethane (20 ml), triethylamine (3.16 ml) were placed in a round bottomed flask and cooled to 0 to 5 "C. Then methaneaulfonyl chloride (2.43 g, 0.016 M) dissolved in dichloromethane (10 ml) was added slowly. After complete addition, the reaction mass was raised to ambient temperature and maintained for 12 (o 14 h. After completion of the reaction, the

reaction mass was washed with water aad the organic layer was evaporated to gel the title compound (weighs 3.5 g, yield 83%, purity 97%).
Slep (iv)
Preparation of methyl (-) 3-(4-(2-(5-ethyl-l-methyI-7-oxo-3-propyl-6,7-dihydro-
1 H-pyrazolo-[4,3-d]py rim id in-6-yl)ethoxy)phenyl]-2-tertiary butyl dimethyl
sllyloxy propionate
in a 500 ml four necked round bottom flask, fitted with a Dean Stark apparatus, reflux condenser and eficient stirrer, powdered K2CO3 (35 g, 0.25 M) and toluene (180 ml) was added at 30 to 35 "C under stirring. The reaction mixture was heated to 110 to 120 "C and maintained at reflux temperature of toluene for 2 to 3 h. After azeotropic removal of water, the reaction mixture was brought to 70 to 80 °C and methyl 2(S)-tertiary butyl dimethyl siiyloxy-3-(4-hydroxyphenyl)propionale (15,5 g, 0.05 M) and 5-ethyl-6-(2-chloroethyl)-l-methyl-3-propyl-6,7-dihydro-iH-pyrazolo[4,3-d]pyrimidin-7-one (18 g, 0.05 M) were added at the same temperature under stirring. The reaction mixture was refluxed for 15 to 18 h under stirring. The reaction mixture was brought to 30 to 35 °C and cooled tolO to 15 "C and water (lOO ml) was added and separated the organic layer. The aqueous layer was extracted with toluene (50 ml x 2) and the combined toluene layers were washed with demineralised water (50 ml x 2). The toluene layer was concentrated to yield the title compound as an oily liquid (weighs 30 g, yield 93%, purity 94-96%). IR (Neat) cm': 3120, 2910, 1756, 1686,1574.
'H NMR (200 MHz, CDCI3) 5 : 7.13 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 4.50 (t, J=5.0 Hz, 211), 4.29-4.22 (m, 3H), 4.01 (t, J=3.7 Hz, IH), 3.81 (s, 3H), 3.1-2.94 (m, 4H), 2.84 {t, J=7.5 Hz, 2H), 1.9-1.78 (m, 4H), 1.30 (t, J=7.3 Hz, 3H), 1.16 (t, J=7.0 Hz, 3H), 0.85 (s, 9H). Massm/z{Cl):557(M*+ 1).

step (V)
Preparation of (-) 3-(4-(2-(5-cthyl-l-methyl-7-oxo-3-propyl-6,7-thydro-lH-
pyrazolo-[4,3-d]pyrimidin-6-yl)etlioxy)phenyl|-2-liydroxypropaiioic acid
In a 2 L four necked round bottom flask, fitted with a reflux condenser and mechanical stirrer, methyl (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7'dihydro-1 H-pyrazolo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-tertiarybutyl dimethyl silyloxy propionate {96 g, 0.1729 M) and methanol (480 ml, 1:5 w/v) were added at 25 to 35 °C under stirring, p-Toluenesulfonic acid (3.28 g) was added to the reaction mixture at 30 to 35 °C. After complete addition, the reaction mixture was heated to 65 to 75 °C for 10 to 15 h under stirring. After completion of the reaction, the reaction mixture was cooled to 5 to 10 °C and 5% NaOH solution (276 ml) was added slowly under stirring. After addition, the reaction mixture was brought to 25 to 35 "C and maintained for 6 to 8 h under stirring. After completion of the reaction, the reaction mixture was diluted with demineralised water (500 ml) and washed with toluene (300 ml X 3). The aqueous layer was acidified with cone. HCl (30-32%) at 5 to 10 °C to pH 1.5-2.0 and maintained at the same temperature for Ihr, The precipitated product was fdtered, washed with demineralised water (100 ml x 2), dried lo yield the pure title compound as off white to cream colored solid (weighs 62 g, yield 84%, purity 95.87% by HPLC,mp: 208-211 °C). IR (KBr) cm-': 3400-3300, 3120, 2970, 1710, 1680, 1570.
'H NMR (200 MHz, DMS0-d6) 5 : 7.13 (d, J = 8,4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.50 (t, J = 5.0 Hz, 2H), 4.29-4.22 (m, 4H), 4.01 (t, J = 3.7 Hz, IH), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (t, J = 7.5 Hz, 2H), 1.9-1.78 (m, 2H), 1.38 (t, J = 7.3 Hz, 3H), 1.16(t,J = 7.0Hz,3H).
Anal. Calcd, C22H2BN4O5 %C 61.68, %H 6.54, %N 13.08; Found %C 61.55, %H 6.35, %N 12.90 Massm/z(Cl):429CM+l).

step (vl)
Preparation of {-) 3-|4-(2-(5-ethyl-l-metIiyI-7-oxo-3-propyl-6,7-(Iihydro-lH-
pyrazolo-[4,3-d]pyrimiditi-6-yl)ethoxy)phenyl]-2-ethoxypropanoic acid
In a 500 ml round bottom flask, diethyl sulfate (45 g) was added to sodium hydroxide in toluene (100 ml) followed by a solution of (-) 3-t4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazoIo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-hydroxypropanoic acid (50 g) in N-methyl- pyrrolidone (200 ml) at 10 to 15 °C in about 1 to 2 h. After complete addition, the reaction mixture was maintained at room temperature for 20 to 24 h under stirring. The reaction mixture was diluted with water (250 ml). The aqueous layer was washed with toluene and acidified with cone, HCl maintaining the temperature in the range of 10 to 15 °C under stirring. Stirring was continued further for 1 h under the same temperature. The solid product obtained was filtered and washed with demineralised water. The product obtained was then taken In isopropanol (152 ml) and stirred for 1 to 2 h at 10 to 15 °C. The solid was filtered and dried under vacuum to yield the title compound (weighs 39 g, yield 73 %, purity 90.23% by HPLC, mp: 149-153 °C). Ill (KBr) cm"': 3400-3300, 3120, 2970, 1720.
'H NMR(200 MHz, DMSO-dfi) 5:7.13 (d, 5 = 8.4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.50 (t, J = 5.0 Hz, 2H), 4.29-4.22 (m, 5H), 4.01 (1, J = 3.7 Hz, IH), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (I, J = 7.5 Hz. 2H), 1.9-1.78 (m, 2H), 1.38 (t, J = 7.3 Hz, 311), 1.16 (t, J = 7.0 Hz, 3?I), 0.97 (t, J = 7,4 Hz, 3H).
Anal. Calcd. C24H32N40s %C 63.15, %H 7.01, %N 12.82; Found %C 63.00, %H 6.90, %N 12.15. Mass m/z (CI): 457 (M+1).
Step(vii)
Preparation of (-) 3-|4-(2-(5-ethyl-l-methyi-7-oxo-3-propyl-6,7-dihydro-lH-
pyrazolo-14,3-dlpyrimidin-6-yl)ethoxy)plienyll-2-etlioxypropanolc acid
trometiiamine salt
In a 250 ml four-necked round bottom flask, fitted with a reflux condenser and mechanical stirrer, (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyiimidin-6-yl)ethoxy)phenyl]-2-ethoxypropanoic acid (3 g, 0.0065

M) and isopropanol (45 ml) were added at 25 to 35 °C under stirring. The reaction mixture was heated slowly to 80 to 90 °C and maintained for 1 to 2 h for complete dissolution of the mass. The solution was filtered through Hiflow bed at 80 to 90 "C. The filtrate was recharged in a separate 250 ml four necked RB flask fitted with a mechanical stirrer and reflux condenser. Tromethamine (0.8 g) was added to the RB flask at 55 to 65 °C in a single lot, under stirring and heated to reflux temperature and maintained gentle reflux for 8 to 10 h. The reaction mass was cooled to 25 to 35 °C under stirring and maintained for 2 to 3 h. The reaction mixture was further cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for complete precipitation. The precipitated product was filtered, washed with chilled isopropanol and dried at 60 °C to yield pure title compound as off white crystalline solid (weighs 4.61 g, yield 79,8 %, purity 97,82%, Chemical 99.72%, Chital (+) isomer 0.28%, mp: 115-119 X).
lR(KBr)cm"':3300-3250, 3120, 2935, 1693, 1575.
'H NMR (200 MHz, DMSO-dfi) 5 : 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.1 Hz, 2H), 4.50 (t. J = 5.0 Hz, 2H), 4.29-4.22 (m, 5H), 4.01 (t. J = 3.70 Hz, IH), 4.0 (s, 6H), 3.69-3.35 (m, 2H), 3.1-2.94 (m, 4H), 2.84 (t, J = 7.5 Hz, 2H), 1.9-1.78 (m, 2H), 1.38 (t, J - 7.3 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H). Mass nVz (CI): 457 (M+ + 1),
Anal. Calcd: C28H43N3O8; % C 61.20; % H: 7.83; % N 7.65; Found % C 61,05; % H 7.70; % N 7.50.
Example 3
Step (i)
Preparation of 5-Ethyl-l-metliyl-3-propyl-6,7-diiiydro-l[H|-pyrazolo-14,3d]-
pyrimi(Iiii-7-one
4-Amino-1 -melhy 1-3-propyl-1 H-5-pyrazolecarboxamide (2,0 g, 0.0108 M), propionic acid (10 ml) and xylene (20 ml) were taken in a round bottomed flask fitted with Dean-Stark apparatus and refluxed for 24 h. After completion of reaction, xylene was distilled off and poured in water and stined for 1 hi at room temperature.

The precipitated compound was filtered and dried to yield the title compound,
(weighs 390 mg, yield 16%, purity 85%).
IR (KBr): 2960, 2870, 1699, 1609, 1489,1455, 1394, 1315, 1018.
'H NMR (CDCI3): 5 11.22 (br s, IH, D2O exchangeable), 4.25 (s, 3H), 2.87 (t, j =
7.1 Hz, 2H), 2.78{q,/=7.3 Hz, 2H), 1.95-1.70 (m, 2H), 1.39 (t, J = 7.6 Hz, 3H),
1.00 (t, J-7.3 Hz, 3H).
Mass m/z (CI); 22] (MV], J00%), i92 (17%), 191 (15%), J22 (5%), 105 (6%), 93
(11%), 91 (22%).
Step (ii)
Preparation of S-ethyl-6{2-hydroxyethyl}-l-methy!-3-propyl-6,7-dihy(lro-lI1-
pyrazolo [4,3 d|-pyrimidine-7-one
5-Ethyl-l-melliyl-3-propyl-6,7-dihydro-l[H]-pyrazolo-[4,3d]-pyrimidin-7-onc (5.0 g, 0.022 M), dimethylformaraide (100 ml), potassiun) carbonate (9.3 g, 0.032 M), and chloroethanol (3,6 g, 0.04 M) were taken in a round bottomed flask and heated at 110 X for 18 to 24 h. After completion of reaction, the reaction mass was poured into ice cold water and extracted with ethylacetate. The organic layer was evaporated to get tlie title compound, (weighs 5 g, yield 83.2%, purity 95.6%). IR (KBr): 3333, 2964, 1685, 1575, 1485, 1453, 1320, 1196, 1082, 1022, 885, 'HNMR(CDCl3): 8 4.31 (t,/=5.1 Hz, 2H), 4.21 (s, 3H), 3.99 (br s, 2H), 2,92 {X,J -7,3 Hz, 2H), 2.86(q, J=7.1 Hz, 2H), 1,90-1.72 (m, 2H), 1.35 (t, 7=7.1 Hz, 3H), 0.99(t,J=7.3Hz,3H), Mass m/z (CI): 265 (M^I, 100%), 247 (9%), 236 (8%) 192 (3%).
Step (iii)
Preparation of 5-ethyl-6(2-chloro ethyl)-l-metliyi-3-pro pyl-6,7-dihy dro-III-
pyrazolo [4,3 d|-pyrimidine-7-one
5-Etbyl-6{2-hydroxyelhyl}-l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]-pyrimidine-7-one (4.0 g, 0.015 M), d-chloromethane (20 ml), triethylamine (3,16 ml) were placed in a round bottomed flask and cooled to 0 to 5 "C. Then methanesulfonyl chloride (2.43 g, 0.016 M) dissolved in dichloromethane (10 ml) was added slowly. After complete addition, the reaction mass was raised to ambient

temperature and maintained for 8 to 12 h. After completion of the reaction, the reaction mass was washed with water and the organic layer was evaporated to get the title compound (weighs 3.5 g, yield 83%, purity 97%).
IR(KBr}:3439,2954,2872, 1684, 1575, 1445, 1369,1315, 1268,1183, 1160,973. 'H NMR (CDCh) : 6 4.04 (t, J- 6.6 Hz, 2H), 4.22 (s, 3H), 3.82 (t, J = 6.6 Hz, 2H), 2.96-2.81 (m, 4H), 1.90-1.73 (m, 2H), 1.36 (t, J-7.3 Hz, 3H), 0.99 (t, 7 = 7.3 Hz, 3H).
Mass m/z: 284 (37Cl-M+ 14%), 282 (35C1-M+ 27%), 267 (21%), 254 (100%), 247 (50%), 192 (41%), 191 (42%), 136 (14%).
Example 4
Step (i)
Preparation of 5-Ethyl-l-iiicthyl-3-propyl-6,7-diliydro-l[H]-pyrazolo-[4,3d]-
pyrimidin~7-one
4-Amino-I-niethy(-3-propyl-IH-5-pyrazolecarboxamide (300 g, i.65 M), propionic acid (1,5 L) and p-toluenesulfonic acid (catalytic) were taken in a round bottomed flask fitted with Dean-Stark apparatus and refluxed for 10 to 24 h. After completion of reaction, the reaction mass was poured into water, filtered and dried to yield the title compound, (weighs 314 g, yield 86%, purity 98%).
Step (ii)
Preparation of 5-etliyl-6{2-hydroxyethyl}-l-methyl-3-propyl-6,7-diliydro-lH-
pyrazolo [4,3 d|-pyrimidine-7-one
5-Ethyl-l-melhyl-3-propyl-6,7-dihydro-l[H]-pyrazolo-[4,3d]-pyrimidin-7-one (20.0 g, 90 M), NMP (200 ml), potassium carbonate (37.6 g, 0.272 M), and chloroethanol (14.5 g, 0.184 M) were taken in a round bottomed flask and heated at 90 to 110 oC for 16 to 20 h. After completion of reaction, the reaction mass was into ice cold water. The precipitated compound filtered and dried to get the i\l\e compound, (weighs 16.8 g, yield 70.2%, purity 96%).

step (iii)
Preparation of 5-ethyl-6(2-chloro ethyl)-l-methyl-3-propyl-6,7-dihydro-111 pyrazolo [4,3 d]-pyrimidine-7-one
5-Et))yJ-6{2-hydroxyethylf-)-me!hy]-3-propy)-6,7-dihydro-]H-pyrazo]o[4,3-dJ-pyrimidine-7-one (4.0 g, O.OiS M), dichloromethane (20 ml), triethylamine (3.16 ml) were placed in a round bottomed flask and cooled to 0 to 5 °C. Then methanesulfonyl chloride (2.43 g, 0.016 M) dissolved in dichloromethane (10 ml) was added slowly. After complete addition, the reaction mass was raised to ambient temperature and maintained for 12 to 14 h. After completion of the reaction, the reaction mass was washed with water and the organic layer was evaporated to get the title compound (weighs 3.5 g, yield 83%, purity 97%).

Claims:
1. A process for the preparation of compounds of the formula (1),

where R represents (C1-C6) alkyl group, which comprises:
i) cyclizing the 4-amino-l-melhyl-3-propyl-lH-5-pyrazolecarboxamide of the
formula (2)
with propionic acid of the formula (3)

in neat or in the presence of a solvent or an acid at a temperature in the range of 20 to 160 "C for a period in the range of 2 to 30 h, to yield compound of formula (4),

ii) reacting Ihe compound of formula (4) with haloethano! of formula (9)

where X represents halogen atom in the presence of a solvent and a base at a temperature in the range of 40 to 150 'C for a period in the range of 4 to 30 h, lo yield compound of formula (10),

iii) converting the compound of fonnula (10) to halo compound of formula (11)

where X represents halogen atom, using halogenating agent in the presence of a solvent and a base at a temperature in the range of -20 to 60 "C preferably from 0 to 250, for a period in the range of 4 to 24 h,
iv) condensing the pyrazolo[4,3-d]pyrimidin-7-one of the formula (11) where X represents halogen atom with compound of formula (12)

where R' represents t-butyldimelhyl silyl, trimethyl siiyi or alkoxyaikyl group; R2 represents (C1-C6)alkyl group in (he presence of a base and a solvent at a (emperatitre in (he range of 5 (o 150 °C, for a period in the range of 2 to 30 h, to give compound of the formula (13) where R1 and R2 are as defined above

where R1 represents t-butyldimethyj silyl, trimethyl siiyi or alkoxyaikyl group; R1 represents {C1-C6)alkyl group,
V) hydrolysing the compound of formula (13) to yield the compound of the fonuula (14)

in the presence of a base or an acid and a solvent at a temperature in the range of 10 to 80 °c for a period in the range of 4 to 24 h,
vi) etherifying the compound of formula (14) to a compound of fonuula (la) where R represents (C1-C2)alkyl group using an alkylating agent in the presence of a base and a solvent at a temperature in the range of 0 to 30 "C for a period in the range of 4 to 24 h,

vii) reacting the compound of formula (la) where R is defined as above, with tromethamine in the presence of a solvent at a temperature in the range of 10 to 150 "C, for a period in the range of 2 to 24 h, to yield compound of formula (I) where R is as defined above and
viii) isolating the compound of formula (1) by conventional methods.
2. The process as described in claim 1, wherein the solvent used in step (i) is
selected from DMF, THF, toluene, xylene or a mixture thereof.
3. The process as described in claims 1 and 2, wherein the acid used in step (i) is
selected from POCI3, PPA or p-toluenesulfonic acid.

4. The process as described in claims 1 to 3, wherein the base used in step (ii) is selected from potassium carbonate, sodium carbonate, sodium hydride, DBU, DABCO, DBN, iriethyl amine or diisopropyl amine.
5. The process as described in claims 1 to 4, wherein the solvent used in step (ii) is selected from THF, DMF, dichloromethane, acetonitrile, NMP, toluene or mixture thereof
6. The process as described in claims 1 to 5, wherein the halogenating agent used in step (lii) is selected from cone. HCI, HBr, PBrs, POCI3 or MeSOzCI.
7. The process as described in claims I to 6, wherein the base used in step (iii) is selected from (riethyl amine, diisopropyl amine or pyridine.
8. The process as described in claims 1 to 7, wherein the solvent used in step (iii) is selected from DCM, DCE, pyridine or a mixture thereof.
9. The process as described in claims I to 8, wherein the reaction in step (iii) is carried out at a temperature in the range of 0 to 25 °C and the duration in the range of and 4 to 20 h,
10. The process as described in claims 1 to 9, wherein the base used in step (iv) is selected from sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide.
11. The process as described in claims 1 to 10, wherein the solvent used in step (iv) is selected from toluene, xylene, THF, DMF, DME, DMSO, NMP or alcohol selected from methanol, ethanol, propanol, isopropanol or mixture thereof.
12. The process as described in claims 1 to 11, wherein the acid used in step (v) is selected from methane sulfonic acid, HCI, H2SO4, trifluoroacetic acid or para toluene sulfonic acid.
13. The process as described in claims I to 12, wherein the solvent used in step (v) is selected from water, methanol, ethanol, propanol, isopropanol or mixture thereof.
14. The process as described in claims 1 to 13, wherein the base used in step (v) is selected from NaH, NaOH, KOH, t-BuOK, K2CO3 or NaHCOj.
15. The process as described in claims 1 to 14, wherein the alkylating agent used in step (vi) is selected from (Ci-Cb) alkyl sulfate or alkyl halide.

16. The process as described in claims 1 to 15, wherein the base used in step (vi) is selected from NaH, NaOH, KOH, t-BuOK, K2CO1 or NaHCO3-
17. The process as described in claims 1 to 16, wherein the solvent used in step (vi) is selected from toluene, xylene, benzene, DMF, DMSO, MIBK, ethyl acetate, NMP or a mixture thereof.
18. The process as described in claims 1 to 17, wherein the solvent used in step (vii) is selected from acetonitrile, DMF, DMSO, acetone, 1,4-dioxane or aicohoi selected from methanol, elhano), propaiiol, jsopropanol or mixture thereof.
19. The process as described in claim 15, wherein dialkyl sulfate is selected from dimethyl sulfate or diethyl sulfate,
20. A process for the preparation of compound of the formula (11),
where X represents halogen atom such as fluorine, chlorine, bromine or iodine, which comprises:
i) cyclizing the 4-amino-l-methyl-3-propyl-lH-5-pyrazolecarboxamide of the
formula (2)

with piopionic acid of the fonnula (3)*

in neat or in the presence of 3 solvent or an acid at a temperature in the range of 20 to 160 °C for a period in the range of 2 to 30 h, to yield compound of formula (4),

ii) reacting the compound of formula (4) with haioethanol of formula (9)

where X represents halogen atom in the presence of a solvent and a base at a temperature in the range of 40 to 150 °C for a period in the range of 4 to 30 h, to yield compound of formula (10),

iii) converting the compound of fonnula (10) to halo compound of formula (II) where X is defined as above using halogenating agent in the presence of a solvent and a base at a temperature in the range of-20 to 60 "C C preferably from 0 to 25°C, for a period in the range of 4 to 24 h, iv) isolating the compound of formula (11) by conventional methods.
21. The process as described in claim 20, wherein the solvent used in step (i) is selected from DMF, THF, toluene, xylene or a mixture thereof.
22. The process as described in claims 20 and 21, wherein the acid used in step (i) is selected from POCl3, PPA or p-loluenesulfonic acid.
23. The process as described in claims 20 to 22, wherein the base used in step (ii) is selected from potassium carbonate, sodium carbonate, sodium hydride, DBU, DABCO, DBN, trietiiyl amine or diisopropyl amine.

24. The process as described in claims 20 to 23, wherein (he solvent used in step (ii) is selected from THF, DMF, dichloromethane, acetonitrile, NMP, toluene or mixture thereof.
25. The process as described in claims 20 to 24, wherein the halogenating agent used in step (iii) is selected from cone. HCl, HBr, PBr3, POCI3 or MeS02Cl.

26. The process as described in claims 20 to 25, wherein the base used in step (iii) is selected from triethyl amine, diifeopropyl amine or pyridine.
27. The process as described in claims 20 to 26, wherein the solvent used in step (iii) is selected from DCM, DCE, pyridine or a mixture thereof,
28. The process as described in claims 20 to 27, wherein the reaction in step (iii)
is carried out at a temperature in the range of 0 to 25 °C and the duration in the range
ofand 4 to 20 h,
29. A process for the preparation of compounds of formula (1) and (11)
substantially as herein described with reference to the examples.

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Patent Number

198386

Indian Patent Application Number

400/MAS/2002

PG Journal Number

20/2006

Publication Date

19-May-2006

Grant Date

24-Jan-2006

Date of Filing

23-May-2002

Name of Patentee

DR. REDDY'S LABORATORIES LTD

Applicant Address

7-1-27, AMEERPET HYDERABAD-500 016,

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. REDDY'S LABORATORIES LTD	7-1-27, AMEERPET HYDERABAD-500 016,

PCT International Classification Number

C07D261/20

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA