Title of Invention	PROCESS FOR THE PREPARATION OF TROMETHAMINE SALT OF (-) 3-[4-(2-(5-ETHYL-1-METHYL-7-OXO-3-PROPYL-6,7-DIHYDRO-1H-PYRAZOLO-[4,3-D]PYRIMIDIN-6-YL)ETHOXY)PHENYL]-2-ALKOXYPROPIONIC ACID
Abstract	A present invention relates to a process for the preparation of tromethamine salt of (-) 3-[ 4-(2-(5-ethyl-1-methyl- 7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo- [4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-alkoxypropionic acid of the formula (1), where R represents (C<SUB>1</SUB>-C<SUB>6<SUB>) alkyl group, comprising three step processes: i) condensing the pyrazolo [4, 3-d]pyrimidin- 7-one of the formula (3), with alkyI3-(4-hydroxyphenyl)-(2S)-2-hydroxy propionate of the formula (4) in the presence of a base and an organic solvent, ii) hydrolysing and etherifying the resulting alkyl (-) 3-[4-(2-( 5-ethyl-l-methyl.- 7- oxo-3-propyl-6, 7 -dihydro-l H -pyrazolo-[ 4,3-d]pyrimidin-6-yl)ethoxy )phenyl]-2- hydroxy propanoate of the formula (5) iii) reacting the resulting (-) 3-[4-(2-(5-ethyl-1-methyl- 7-oxo-3-propyl-6, 7- dihydro-1H -pyrazolo-[ 4,3-d]pyrimidin-6- yl)ethoxy )phenyl]- 2- alkoxypropanoic acid of formula (6) with tromethamine in presence of temperature.

Title of Invention

PROCESS FOR THE PREPARATION OF TROMETHAMINE SALT OF (-) 3-[4-(2-(5-ETHYL-1-METHYL-7-OXO-3-PROPYL-6,7-DIHYDRO-1H-PYRAZOLO-[4,3-D]PYRIMIDIN-6-YL)ETHOXY)PHENYL]-2-ALKOXYPROPIONIC ACID

Abstract

A present invention relates to a process for the preparation of tromethamine salt of (-) 3-[ 4-(2-(5-ethyl-1-methyl- 7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo- [4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-alkoxypropionic acid of the formula (1), where R represents (C<SUB>1</SUB>-C<SUB>6<SUB>) alkyl group, comprising three step processes: i) condensing the pyrazolo [4, 3-d]pyrimidin- 7-one of the formula (3), with alkyI3-(4-hydroxyphenyl)-(2S)-2-hydroxy propionate of the formula (4) in the presence of a base and an organic solvent, ii) hydrolysing and etherifying the resulting alkyl (-) 3-[4-(2-( 5-ethyl-l-methyl.- 7- oxo-3-propyl-6, 7 -dihydro-l H -pyrazolo-[ 4,3-d]pyrimidin-6-yl)ethoxy )phenyl]-2- hydroxy propanoate of the formula (5) iii) reacting the resulting (-) 3-[4-(2-(5-ethyl-1-methyl- 7-oxo-3-propyl-6, 7- dihydro-1H -pyrazolo-[ 4,3-d]pyrimidin-6- yl)ethoxy )phenyl]- 2- alkoxypropanoic acid of formula (6) with tromethamine in presence of temperature.

Full Text	Field of the invention The present invention relates to a process for the preparation of antidiabetic compound having the formula (1). 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 prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. The compound of formula (1) is also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes). Background of invention In our WTO mailbox application No. 569/MAS/2001 we have disclosed and described novel antidiabetic compounds having the formula (2) where R1 represents hydrogen atom, halogen, hydroxy, lower alkyl, alkoxy, substituted or unsubstituted aralkyl group or forms a bond together with the adjacent group R3; R3 represents hydrogen, hydroxy, halogen, lower alkyl, alkoxy, alkanoyl, aroyl, aralkanoyl, substituted or unsubstituted aralkyl or R forms a bond together with R1; R3 may be hydrogen atom or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, alkanoyl, aroyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups, with a provision that R3 does not represent hydrogen when R1 represents hydrogen or lower alkyl group; R4 may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen or NR3 where R3 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R4 and R3 together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, a nitrogen atom and which may optionally contain one or more additional heteroatoms selected from oxygen, sulfur or nitrogen; n is an integer ranging from 1- 4; Ar represents substituted or unsubstituted, divalent, single or fused. where X represents O or S; R6 when attached to the carbon atom represents hydrogen, halogen, hydroxy, nitre, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl, aroyl, alkanoyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R3 when attached to nitrogen atom represents hydrogen, hydroxy, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl, aroyl, alkanoyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R and R when attached to carbon atom may be same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl or substituted or unsubstituted groups selected from alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxyalkyl, thioalkyl, alkylthio groups; R3 and R3 when attached to nitrogen may be same or different and represent hydrogen, hydroxy or substituted or unsubstituted groups selected from alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, arylamino groups. 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. where R represents (C1-C6) alkyl group, which comprises: i) condensing the pyrazolo[4,3-d]pyrimidin-7-one of the formula (3) where X represents halogen atom such as fluorine, chlorine, bromine or iodine with compound of the formula (4) wherein R1 represents (C1-C6) alkyl group, m the presence of a base and a solvent at a temperature in the range of 0 to 150 °C for a period in the range of 5 to 30 h to give compound of the formula (5) where R1 represents (C1-C6) alkyl group, li) hydrolysing and etherifying the compound of formula (5) m the presence of a base and a solvent using an alkylating agent to obtain compound of formula (6) where R represent (CpCe) alkyl group at a temperature in the range of 5 to 50 °C for a period in the range of 4 to 30 h, iii). reacting the compound of formula (6) with tromethamine in the presence of a solvent at a temperature in the range of 5 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 iv). isolating the compound of formula (1) formed by conventional methods. the formula (4) may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, using a solvent such as toluene, xylene, THF, DMF, DME, DMSO or alcohols such as methanol, ethanol, propanol, isopropanol and the like or a mixture thereof. The reaction may be carried out at a temperature in the range of 0°Cto 150°C and the duration of the reaction may range from 5 to 30 h. The hydrolysis and etherification of compound of the formula (5) may be carried out in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCOs and the like; using a solvent such as hydrocarbons like toluene, xylene, benzene and the like or DMF, DMSO, MIBK, ethyl acetate, N-methyl pyrrolidone (NMP) and the like or a mixture thereof The alkylatmg agent may be selected from (R)2-sulfates such as diethyl sulfate, dimethyl sulfate and the like or R- halides such as ethyl iodide, methyl iodide and the like. The reaction may be carried out at a temperature in the range of 0 °C to 50 °C and the duration of the reaction may range from 4 to 30 h. The reaction of compound of formula (6) with tromethamine may be carried out in the presence of a solvent such as alcohols like methanol, ethanol, propanol, isopropanol, n-butanol, t-butanol and the like; acetonitrile, where X represents halogen atom such as fluorine, chlorine, bromine or iodine with compound of formula (7) where R3 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R1 represents (C1-C6)alkyl 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 (8) where R3 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R1 represents (C1-C6)alkyl group, (ii) converting the compound of formula (8) to yield the compound of the formula (5) in the presence of an acid and a solvent, further hydrolysis yields compound of formula (9) in the presence of a base and a solvent at a temperature in the range of 10 to 80 °C, for a period in the range of 4 to 30 h, (iii). etherifying the compound of formula (9) to a compound of formula (6) 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 150 °C, for a period in the range of 8 to 30 h, iv). reacting the compound of formula (6) with tromethamme m the presence of a solvent at a temperature in the range of 5 to 150 °C, for a period The condensation of compound of the formula (3) with compound of the formula (7) may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and the like, using a solvent such as toluene, xylene, THF, DMF, DME, DMSO or alcohols such as methanol, ethanol, propanol, isopropanol and the like. The reaction may be carried out at a temperature in the range of 20 to 150 °C and the duration of the reaction may range from 2 to 30 h. Converting compound of the formula (8) to yield compound of formula (5) using an acid such as methane sulfonic acid, HCl, H2SO4, trifluoroacetic acid, p-toluenesulfonic acid and the like in the presence of a solvent such as methanol, ethanol, propanol, isopropanol and the like. Further hydrolysis to yield compound of formula (5) may be carried out using a base such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCOj and the like in the presence of a solvent such as water, methanol, ethanol, propanol, isopropanol and the like. The reaction may be carried out at a temperature in the range of 10 °C to 80 °C and the duration of the reaction may range from 4 to 30 h. The etherification of compound of formula (9) to obtain compound of formula (6) may be carried out using (R)2-sulfates such as diethyl sulfate, dimethyl sulfate and the like or R-halides such as ethyl iodide, methyl iodide and the like, in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHC03 and the like, in 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 150 °C and the duration of the reaction may range from 8 to 30 h. The reaction of compound of formula (6) with tromethamine may be carried out in the presence of a solvent such as alcohols like methanol, ethanol, propanol, isopropanol and the like; acetonitrile, DMF, DMSO, acetone, 1,4-dioxane and the like or a mixture thereof, at a temperature in the range of 5 to 150 °C, for a period in the range of 2 to 24 h. with compound of the formula (10) wherein R and R1 may be same or different and represent (C1-C6)alkyl group, in the presence of a base and a solvent at a temperature in the range of 0 to 150 °C for a period in the range of 5 to 30 h to give compound of the formula (11) where R and R1 are as defined above, ii) hydrolysing the compound of formula (11) in the presence of a base and a solvent to obtain compound of formula (6) where R represents (C\- C6)alkyl group at a temperature in the range of 0 to 40 °C, for a period in the range of 4 to 10 h, iii). reacting the compound of formula (6) with tromethamine in the presence of a solvent at a temperature in the range of 5 to 150 °C, for a period in the range of 1 to 24 h, to yield compound of formula (1) where R is as defined above and iv). isolating the compound of formula (1) formed by conventional methods. The condensation of compound of the formula (3) with compound of the formula (10) may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like, using a solvent such as toluene, xylene, THF, DMF, DME, DMSO or alcohols such as methanol, ethanol, propanol, isopropanol and the like or a mixture thereof. The reaction may be carried out at a temperature in the range of 0 °C to 150 °C and the duration of the reaction may range from 5 to 30 h. The hydrolysis of compound of the formula (11) may be carried out in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCOj and the like; using solvents such as hydrocarbons like toluene, xylene, benzene and the like; alcohol such as methanol, ethanol, propanol, isopropanol and the like; water, DMF, DMSO, MIBK, ethyl acetate, N-methyl pyrrolidone (NMP), water and the like or a mixture thereof The reaction may be carried out at a temperature in the range of 0 °C to 40 °C and the duration of the reaction may range from 4 to 10 h. The reaction of compound of formula (6) with tromethamine may be carried out in the presence of a solvent such as alcohols like methanol, ethanol, propanol, isopropanol and the like; acetonitrile, DMF, DMSO, acetone, 1,4-dioxane and the like or a mixture thereof, at a temperature in the range of 10 to 150 °C, for a period in the range of 2 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 the scope of the invention. Example 1 Step (i) Preparation of isopropyl (-) 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-hydroxy propanoate In a 500 ml four necked round bottom flask, fitted with a Dean Stark apparatus, reflux condenser and an efficient stirrer, powdered K2CO3 (20.75 g, 0.15 M) and toluene (70 ml) were added at 30-35 °C under stirring. The reaction mixture was refluxed for 2 to 3 h. After azeotropic removal of water, the reaction mixture was cooled to 70 to 80 °C and added isopropyl 3-(4-hydroxyphenyl)-2(S)-hydroxy propionate (5.575 g, 0.025 M) and 5-ethyl-6-(2-chloroethyl)-l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-7-one (7.05 g, 0.025 M) under stirring. The reaction mixture was maintained under reflux for 8 to 10 h. The reaction mixture was cooled to 10 to 15 °C. Demineralised water was added and separated the toluene layer. The aqueous layer was extracted with toluene and the combined toluene layers were washed with demineralised water. The combined toluene layers were concentrated under vacuum. To the residue, petroleum ether was added at room temperature, under stirring. The precipitate was allowed to stir at room temperature for 10 to 15 min., followed by cooling at 5 to 10 °C for 2 h. The solid obtained was filtered and dried to yield the pure title compound as off-white crystalline sohd (weighs 9.4 g, yield 80%, purity 98.52%, mp: 120-125 °C). IR (KBr) (cm") 3450-3400, 3120, 2970, 1730, 1690, 1570. "H NMR (200 MHz, DMSO-de) 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 = 7.0 Hz, 3H), 0.97 (m, 6H). Anal. Calcd. C25H34N4O5 %C 63.82, %H 7.23, %N 11.91; Found %C 63.70, %H7.10,%,N 11.75. Mass m/z (CI): 471 (M+1). step (ii) Preparation of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro- lH-pyrazoIo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxypropanoic acid In a 250 ml four necked round bottom flask, fitted with a plain condenser and a mechanical stirrer, toluene (38 ml) and sodium hydride (2.0g, 60%) were added and cooled to 10 to 15 °C. To the reaction mixture, diethyl sulfate (4.026 g) was added slowly under stirring and maintained at 10 to 15 °C for 30 min. Isopropyl (-) 3-[4-(2-(5-ethyI-l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-6-yl) ethoxy)phenyl]-2-hydroxy propanoate (4.7 g) dissolved in N-methyl pyrrolidone (NMP) (10 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 this temperature 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 and stirred for 30 min. The organic layer was separated and the aqueous layer washed with toluene and pooled the toluene washings. The aqueous layer was acidified with cone. HCl at 10 to 15 °C, in about 30 min., to pH 2.0-2.5 and maintained at the same temperature for 30 min. under stirring. The precipitated product was filtered, washed with demineralised water and dried to yield the pure title compound as off white colored solid (weighs 4.4 g, yield 96%, purity 91.41% chemical 92.30%, chiral 7.7% (+) isomer, mp: 149-153 °C. IR (KBr) (cm-"): 3400-3300, 3120, 2970, 1720. "H NMR (200 MHz, DMSO-dfi) 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, 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 (t, 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. Massm/z(CI):457(M+l). Step (iii) Preparation of (-) 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 tromethamine 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 stirrmg. The reaction mixture was heated slowly to 80 to 90 °C and maintained for 1 to 2 h for complete dissolution of the mass. Tromethamine (0.8 g) was added at 55 to 65 °C in a single lot, under stirring. The reaction mixture was refluxed for 8 to 10 h. The reaction mass was cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for precipitation. The precipitated product was filtered, washed with chilled isopropanol and dried 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: 115-119 °C). IR (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 (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+ + 1), 122 (C4H,,N03+1) Anal. Calcd : C28H43N5O8; % C 58.23; % H : 7.45; % N 12.13; Found % C 58.10; %H 7.31; %N 12.0. Example 2 Step (i) Preparation of methyl (-) 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- tertiarybutyl dimethyl silyloxy propionate In a 500 ml four necked round bottom flask, fitted with a Dean Stark apparatus, reflux condenser and an efficient stirrer, powdered K2CO3 (35 g, 0.25 M) and toluene (180 ml) were added at 30 to 35 °C under stirring. The reaction mixture refluxed 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 silyloxy-3-(4-hydroxyphenyl)propanoate (15.5 g, 0.05 M) and 5- ethyl-6-(2-chloroethyl)-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. The reaction mixture was cooled to 10 to 15 °C and water was added to separate the organic layer. The aqueous layer was extracted with toluene and the combined toluene layers were washed with demineralised water. The toluene layer was concentrated under vacuum 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, 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). Massm/z(CI):557(M++l). step (ii) Preparation of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro- lH-pyrazolo-[4,3-d]pyriinidin-6-yl)ethoxy)phenyl]-2-hydroxypropanoic 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-lH-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 hrs 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 and washed with toluene. 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 filtered, washed with demineralised water and dried to yield the pure title compound as off white to cream colored solid (weighs 62 g, yield 84%, purity 95.87% by HPLCmp: 208-211 °C). IR (neat) cm"": 3400-3300, 3120, 2970, 1710, 1680, 1570. "H NMR (200 MHz, DMSO-dfi) S : 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 = 7.0 Hz, 3H). Anal. Calcd. C22H28N4O5 %C 61.68, %H 6.54, %N 13.08; Found %C 61.55, %H 6.35, %N 12.90 Mass m/z (CI) : 429 (M+1). Step (iii) Preparation of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro- lH-pyrazoIo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxypropanoic acid 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 10-15 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-lH-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 and pooled the toluene washings. The aqueous layer was acidified with 25% H2SO4 at 10 to 15 °C, in about 30 min, to pH 2.0-2.5 and maintained at the same temperature for 30 min. The precipitated product was filtered, washed with demineralised water 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 through Hiflow bed. The toluene layer was concentrated below 110 °C under vacuum. 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 off-white to white colored solid (weighs 6.4 g, yield 60%, purity 90.23% by HPLC, mp : 149-153 °C). IR (neat) cm"" : 3400-3300, 3120, 2970, 1720. "H NMR (200 MHz, DMSO-ds) 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, 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 (t, 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 (CI) : 457 (M+1). Step (iv) Preparation of (-) 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 tromethamine 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. Tromethamine (0.8 g) was added at 55 to 65 °C in a single lot, under stirring. The reaction mixture was refluxed for 8 to 10 h. The reaction mass was cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for precipitation. The precipitated product was filtered, washed with chilled isopropanol and dried 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 : 115-119 °C). IR (neat) cm"": 3300-3250, 3120, 2935 (-C-H aliphatic), 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 nVz (CI) : 457 (M+ + 1), 122 (C4HnN03+l) Anal. Calcd : C28H43N5O8; % C 58.23; % H : 7.45; % N 12.13; Found % C 58.10; %H 7.31; %N 12.0. Example 3 Step (i) Preparation of (-) isopropyl 3-[4-(2-(5-ethyI-l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxy-propionate In a 5 L four necked round bottom flask, fitted with a Dean-Stark apparatus, reflux condenser and an efficient stirrer, powdered K2CO3 (391 g, 2.837 M) and toluene (2 L) were added at 25 to 35 °C under stirring. The reaction mixture was refluxed for 2 to 3 hours. After azeotropic removal of water, the reaction mixture was cooled to 75 to 85 °C and added (-) isopropyl 2-ethoxy-3-(4-hydroxyphenyl)propionate (160 g, 0.638 M) and 5-ethyl-6-(2-chloroethyl)-l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-7one (200 g, 0.709 M), sequentially, in one lot. The reaction mixture was further refluxed for 5 to 6 hours. The reaction mixture was brought to room temperature and cooled to 10 to 15 °C and water (1.5 L) was added to separate the organic layer. The organic layer was washed with demineralised water. The toluene layer was concentrated under vacuum. Isopropyl alcohol (2 L) was added to the residue under stirring and cooled the reaction mixture to 5 to 10 °C and maintained for 2 hrs. The precipitated product was filtered and dried to afford pure title compound as off-white crystalline solid (mp: 98-100 °C, weighs 282 g, yield 80%, purity 98-99%). IR (neat) cm"": 3120, 2930, 1732, 1660, 1587. "H NMR (200 MHz, DMSOA) 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), 4.50 (t, J = 5.0 Hz, 2H), 4.29-4.22 (m, 6H), 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), 1.01 (d, 6H), 0.97 (t, J = 7.4 Hz, 3H). Mass m/z (CI): 499 (M+ + 1). Anal. Calcd : C27H38N4O5; % C 65.06; % H 7.63; % N 11.24; Found % C 64.90; % H 7.52; % N 11.04. Step (ii) Preparation of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyI-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxypropionic acid In a 10 L four necked round bottom flask, fitted with a plain aerial condenser and mechanical stirrer, (-) isopropyl 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propy]-6,7-dihydro-lH-pyrazoIo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxy-propionate (817 g, 1.64 M) and methanol (5.72 L) were added at 25 to 35 °C under stirring. The reaction mixture was cooled to 10 to 15 °C and added 20% NaOH solution (1.64 L) slowly maintaining the temperature below 20 °C in about 20-30 min. After complete addition, the reaction mixture was brought to 25 to 35 °C and maintained under stirring. After completion of the reaction, water (3 L) was added to the reaction mixture and washed with toluene. The aqueous layer was acidified with cone, hydrochloric acid at 15 to 20 °C under stirring and maintained at 5 to 10 °C for 2 hrs. The precipitated product was filtered and dried to afford pure title compound as off-white crystalline solid (mp: 151-154 °C, weighs 600 g, yield 80%, purity 99% by HPLC). IR (neat) cm"": 3450, 3120, 2930, 1720, 1587. "H NMR (200 MHz, DMSO-de) 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), 4.50 (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), 0.97 (t, J = 7.4 Hz, 3H). Mass m/z (CI): 457 (M+ + 1). Anal. Calcd : C24H32N4O5; % C 63.15; % H 7.01; % N 12.28; Found % C 63.0; % H 6.89; % N 12.13 Step (iii) Preparation of tromethamine salt of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3- propyl-6,7-dihydro-lH-pyrazoIo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2- ethoxypropionic acid In a 10 L four-necked round bottom flask, fitted with a reflux condenser and a 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-ethoxypropionic acid (600 g, 1.135 M) and isopropyl alcohol (6 L) were added at 25 to 35 °C under stirring. The reaction mixture was heated slowly at 80 to 90 °C and maintained for 1 to 2 hrs for complete dissolution of the mass. Tromethamine (159 g, 1.315 M) in isopropyl alcohol (210 ml) was added at 55 to 65 °C in a single lot, under stirring. The reaction mixture was refluxed for 8 to 10 hrs. The reaction mixture was then cooled to 25 to 35 °C under stirring and maintained for 6 hr to get the precipitated solid. The reaction mixture was further cooled to 10 to 15 °C under stirring and maintained for 2 to 3 hrs for complete precipitation. The precipitated product was filtered and dried to yield pure title compound as off-white crystalline solid (weighs 640 g, yield 84%, purity 99.2% by HPLC, mp 117-120 °C). IR (neat) cm" 3400-3200, 3120, 2935, 1585. "H NMR (200 MHz, DMSO-dfi) § : 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"" + 1), 122 (C4H\|,N03+1) Anal. Calcd : C28H43N5O8; % C 58.23; % H : 7.45; % N 12.13; Found % C 58.10; %H 7.31; %N 12.0. We claim: 1. A process for the preparation of tromethamine salt of (-) 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-alkoxypropionic acid of the formula (1), wherein R1 represents (C1-C6) alkyl group, in the presence of a base and an organic solvent at a temperature in the range of 0 to 150 °C for a period in the range of 5 to 30 h to give alkyl (-) 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-hydroxy propanoate of the formula (5) where R1 represents (C1-C6) alkyl group, ii) hydrolysing and etherifying the compound of formula (5) in the presence of a base and a solvent using an alkylating agent to obtain (-) 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-alkoxypropanoic acid of formula (6) at a temperature in the range of 5 to 50 °C for a period in the range of 4 to 30 h iii). reacting the compound of formula (6) 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 iv). isolating the compound of formula (1) formed by conventional methods. 2. The process as described in claim 1, wherein the base used in step (i) is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide. 3. The process as claimed in claims 1 and 2, wherein the solvent used in step (i) is selected from toluene, xylene, THF, DMF, DME, DMSO, alcohols or a mixture thereof. 4. The process as claimed in claims 1 to 3, wherein the base used in step (ii) is selected from NaH, NaOH, KOH, t-BuOK, K2CO3 or NaHCOa. 5. The process as claimed in claims 1 to 4, wherein the solvent used in step (ii) is selected from hydrocarbons, DMF, DMSO, MIBK, ethyl acetate, N- methyl pyrrolidone or a mixture thereof 6. The process as claimed in claims 1 to 5, wherein the alkylating used in step (ii) is (R)2-sulfate selected from diethyl sulphate, dimethylsulphate; or R-halide.

Full Text

Field of the invention
The present invention relates to a process for the preparation of antidiabetic compound having the formula (1).

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 prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. The compound of formula (1) is also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes).
Background of invention
In our WTO mailbox application No. 569/MAS/2001 we have disclosed and described novel antidiabetic compounds having the formula (2)

where R1 represents hydrogen atom, halogen, hydroxy, lower alkyl, alkoxy, substituted or unsubstituted aralkyl group or forms a bond together with the adjacent group R3; R3 represents hydrogen, hydroxy, halogen, lower alkyl, alkoxy, alkanoyl, aroyl, aralkanoyl, substituted or unsubstituted aralkyl or R forms a bond together with R1; R3 may be hydrogen atom or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, alkanoyl, aroyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, alkoxyalkyl, alkoxycarbonyl,

aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups, with a provision that R3 does not represent hydrogen when R1 represents hydrogen or lower alkyl group; R4 may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen or NR3 where R3 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R4 and R3 together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, a nitrogen atom and which may optionally contain one or more additional heteroatoms selected from oxygen, sulfur or nitrogen; n is an integer ranging from 1- 4; Ar represents substituted or unsubstituted, divalent, single or fused.

where X represents O or S; R6 when attached to the carbon atom represents hydrogen, halogen, hydroxy, nitre, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl, aroyl, alkanoyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R3 when attached to nitrogen atom represents hydrogen, hydroxy, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl, aroyl, alkanoyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R and R when attached to carbon atom may be same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl or substituted or unsubstituted groups selected from alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxyalkyl, thioalkyl, alkylthio groups; R3 and R3 when attached to nitrogen may be same or different and represent hydrogen, hydroxy or substituted or unsubstituted groups selected from alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, arylamino groups.

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.

where R represents (C1-C6) alkyl group, which comprises:
i) condensing the pyrazolo[4,3-d]pyrimidin-7-one of the formula (3)
where X represents halogen atom such as fluorine, chlorine, bromine or iodine
with compound of the formula (4) wherein R1 represents (C1-C6) alkyl group,
m the presence of a base and a solvent at a temperature in the range of 0 to 150
°C for a period in the range of 5 to 30 h to give compound of the formula (5)
where R1 represents (C1-C6) alkyl group,
li) hydrolysing and etherifying the compound of formula (5) m the
presence of a base and a solvent using an alkylating agent to obtain compound
of formula (6) where R represent (CpCe) alkyl group at a temperature in the
range of 5 to 50 °C for a period in the range of 4 to 30 h,
iii). reacting the compound of formula (6) with tromethamine in the
presence of a solvent at a temperature in the range of 5 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
iv). isolating the compound of formula (1) formed by conventional
methods.

the formula (4) may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, using a solvent such as toluene, xylene, THF, DMF, DME, DMSO or alcohols such as methanol, ethanol, propanol, isopropanol and the like or a mixture thereof. The reaction may be carried out at a temperature in the range of 0°Cto 150°C and the duration of the reaction may range from 5 to 30 h.
The hydrolysis and etherification of compound of the formula (5) may be carried out in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCOs and the like; using a solvent such as hydrocarbons like toluene, xylene, benzene and the like or DMF, DMSO, MIBK, ethyl acetate, N-methyl pyrrolidone (NMP) and the like or a mixture thereof The alkylatmg agent may be selected from (R)2-sulfates such as diethyl sulfate, dimethyl sulfate and the like or R- halides such as ethyl iodide, methyl iodide and the like. The reaction may be carried out at a temperature in the range of 0 °C to 50 °C and the duration of the reaction may range from 4 to 30 h.
The reaction of compound of formula (6) with tromethamine may be carried out in the presence of a solvent such as alcohols like methanol, ethanol, propanol, isopropanol, n-butanol, t-butanol and the like; acetonitrile,

where X represents halogen atom such as fluorine, chlorine, bromine or iodine with compound of formula (7) where R3 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R1 represents (C1-C6)alkyl 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 (8) where R3 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R1 represents (C1-C6)alkyl group,
(ii) converting the compound of formula (8) to yield the compound of the formula (5) in the presence of an acid and a solvent, further hydrolysis yields compound of formula (9) in the presence of a base and a solvent at a temperature in the range of 10 to 80 °C, for a period in the range of 4 to 30 h, (iii). etherifying the compound of formula (9) to a compound of formula (6) 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 150 °C, for a period in the range of 8 to 30 h,
iv). reacting the compound of formula (6) with tromethamme m the presence of a solvent at a temperature in the range of 5 to 150 °C, for a period

The condensation of compound of the formula (3) with compound of the formula (7) may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and the like, using a solvent such as toluene, xylene, THF, DMF, DME, DMSO or alcohols such as methanol, ethanol, propanol, isopropanol and the like. The reaction may be carried out at a temperature in the range of 20 to 150 °C and the duration of the reaction may range from 2 to 30 h.
Converting compound of the formula (8) to yield compound of formula (5) using an acid such as methane sulfonic acid, HCl, H2SO4, trifluoroacetic acid, p-toluenesulfonic acid and the like in the presence of a solvent such as methanol, ethanol, propanol, isopropanol and the like. Further hydrolysis to

yield compound of formula (5) may be carried out using a base such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCOj and the like in the presence of a solvent such as water, methanol, ethanol, propanol, isopropanol and the like. The reaction may be carried out at a temperature in the range of 10 °C to 80 °C and the duration of the reaction may range from 4 to 30 h.
The etherification of compound of formula (9) to obtain compound of formula (6) may be carried out using (R)2-sulfates such as diethyl sulfate, dimethyl sulfate and the like or R-halides such as ethyl iodide, methyl iodide and the like, in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHC03 and the like, in 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 150 °C and the duration of the reaction may range from 8 to 30 h.
The reaction of compound of formula (6) with tromethamine may be carried out in the presence of a solvent such as alcohols like methanol, ethanol, propanol, isopropanol and the like; acetonitrile, DMF, DMSO, acetone, 1,4-dioxane and the like or a mixture thereof, at a temperature in the range of 5 to 150 °C, for a period in the range of 2 to 24 h.

with compound of the formula (10) wherein R and R1 may be same or
different and represent (C1-C6)alkyl group, in the presence of a base and a
solvent at a temperature in the range of 0 to 150 °C for a period in the range of
5 to 30 h to give compound of the formula (11) where R and R1 are as defined
above,
ii) hydrolysing the compound of formula (11) in the presence of a base
and a solvent to obtain compound of formula (6) where R represents (C\-
C6)alkyl group at a temperature in the range of 0 to 40 °C, for a period in the
range of 4 to 10 h,
iii). reacting the compound of formula (6) with tromethamine in the
presence of a solvent at a temperature in the range of 5 to 150 °C, for a period
in the range of 1 to 24 h, to yield compound of formula (1) where R is as
defined above and
iv). isolating the compound of formula (1) formed by conventional
methods.

The condensation of compound of the formula (3) with compound of the formula (10) may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like, using a solvent such as

toluene, xylene, THF, DMF, DME, DMSO or alcohols such as methanol, ethanol, propanol, isopropanol and the like or a mixture thereof. The reaction may be carried out at a temperature in the range of 0 °C to 150 °C and the duration of the reaction may range from 5 to 30 h.
The hydrolysis of compound of the formula (11) may be carried out in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCOj and the like; using solvents such as hydrocarbons like toluene, xylene, benzene and the like; alcohol such as methanol, ethanol, propanol, isopropanol and the like; water, DMF, DMSO, MIBK, ethyl acetate, N-methyl pyrrolidone (NMP), water and the like or a mixture thereof The reaction may be carried out at a temperature in the range of 0 °C to 40 °C and the duration of the reaction may range from 4 to 10 h.
The reaction of compound of formula (6) with tromethamine may be carried out in the presence of a solvent such as alcohols like methanol, ethanol, propanol, isopropanol and the like; acetonitrile, DMF, DMSO, acetone, 1,4-dioxane and the like or a mixture thereof, at a temperature in the range of 10 to 150 °C, for a period in the range of 2 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 the scope of the invention.
Example 1
Step (i)
Preparation of isopropyl (-) 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-hydroxy
propanoate
In a 500 ml four necked round bottom flask, fitted with a Dean Stark
apparatus, reflux condenser and an efficient stirrer, powdered K2CO3 (20.75 g,
0.15 M) and toluene (70 ml) were added at 30-35 °C under stirring. The

reaction mixture was refluxed for 2 to 3 h. After azeotropic removal of water, the reaction mixture was cooled to 70 to 80 °C and added isopropyl 3-(4-hydroxyphenyl)-2(S)-hydroxy propionate (5.575 g, 0.025 M) and 5-ethyl-6-(2-chloroethyl)-l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-7-one (7.05 g, 0.025 M) under stirring. The reaction mixture was maintained under reflux for 8 to 10 h. The reaction mixture was cooled to 10 to 15 °C. Demineralised water was added and separated the toluene layer. The aqueous layer was extracted with toluene and the combined toluene layers were washed with demineralised water. The combined toluene layers were concentrated under vacuum. To the residue, petroleum ether was added at room temperature, under stirring. The precipitate was allowed to stir at room temperature for 10 to 15 min., followed by cooling at 5 to 10 °C for 2 h. The solid obtained was filtered and dried to yield the pure title compound as off-white crystalline sohd (weighs 9.4 g, yield 80%, purity 98.52%, mp: 120-125 °C).
IR (KBr) (cm") 3450-3400, 3120, 2970, 1730, 1690, 1570. "H NMR (200 MHz, DMSO-de) 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 = 7.0 Hz, 3H), 0.97 (m, 6H). Anal. Calcd. C25H34N4O5 %C 63.82, %H 7.23, %N 11.91; Found %C 63.70, %H7.10,%,N 11.75. Mass m/z (CI): 471 (M+1).

step (ii)
Preparation of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-
lH-pyrazoIo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxypropanoic
acid
In a 250 ml four necked round bottom flask, fitted with a plain condenser and a mechanical stirrer, toluene (38 ml) and sodium hydride (2.0g, 60%) were added and cooled to 10 to 15 °C. To the reaction mixture, diethyl sulfate (4.026 g) was added slowly under stirring and maintained at 10 to 15 °C for 30 min. Isopropyl (-) 3-[4-(2-(5-ethyI-l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-6-yl) ethoxy)phenyl]-2-hydroxy propanoate (4.7 g) dissolved in N-methyl pyrrolidone (NMP) (10 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 this temperature 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 and stirred for 30 min. The organic layer was separated and the aqueous layer washed with toluene and pooled the toluene washings. The aqueous layer was acidified with cone. HCl at 10 to 15 °C, in about 30 min., to pH 2.0-2.5 and maintained at the same temperature for 30 min. under stirring. The precipitated product was filtered, washed with demineralised water and dried to yield the pure title compound as off white colored solid (weighs 4.4 g, yield 96%, purity 91.41% chemical 92.30%, chiral 7.7% (+) isomer, mp: 149-153 °C. IR (KBr) (cm-"): 3400-3300, 3120, 2970, 1720.
"H NMR (200 MHz, DMSO-dfi) 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, 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 (t, 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.
Massm/z(CI):457(M+l).
Step (iii)
Preparation of (-) 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 tromethamine 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 stirrmg. The reaction mixture was heated slowly to 80 to 90 °C and maintained for 1 to 2 h for complete dissolution of the mass. Tromethamine (0.8 g) was added at 55 to 65 °C in a single lot, under stirring. The reaction mixture was refluxed for 8 to 10 h. The reaction mass was cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for precipitation. The precipitated product was filtered, washed with chilled isopropanol and dried 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: 115-119 °C). IR (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 (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+ + 1), 122 (C4H,,N03+1)
Anal. Calcd : C28H43N5O8; % C 58.23; % H : 7.45; % N 12.13; Found % C 58.10; %H 7.31; %N 12.0.

Example 2
Step (i)
Preparation of methyl (-) 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-
tertiarybutyl dimethyl silyloxy propionate
In a 500 ml four necked round bottom flask, fitted with a Dean Stark
apparatus, reflux condenser and an efficient stirrer, powdered K2CO3 (35 g,
0.25 M) and toluene (180 ml) were added at 30 to 35 °C under stirring. The
reaction mixture refluxed 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 silyloxy-3-(4-hydroxyphenyl)propanoate (15.5 g, 0.05 M) and 5-
ethyl-6-(2-chloroethyl)-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. The reaction
mixture was cooled to 10 to 15 °C and water was added to separate the organic
layer. The aqueous layer was extracted with toluene and the combined toluene
layers were washed with demineralised water. The toluene layer was
concentrated under vacuum 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, 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).
Massm/z(CI):557(M++l).

step (ii)
Preparation of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-
lH-pyrazolo-[4,3-d]pyriinidin-6-yl)ethoxy)phenyl]-2-hydroxypropanoic
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-lH-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 hrs 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 and washed with toluene. 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 filtered, washed with demineralised water and dried to yield the pure title compound as off white to cream colored solid (weighs 62 g, yield 84%, purity 95.87% by HPLCmp: 208-211 °C). IR (neat) cm"": 3400-3300, 3120, 2970, 1710, 1680, 1570. "H NMR (200 MHz, DMSO-dfi) S : 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 = 7.0 Hz, 3H).
Anal. Calcd. C22H28N4O5 %C 61.68, %H 6.54, %N 13.08; Found %C 61.55, %H 6.35, %N 12.90 Mass m/z (CI) : 429 (M+1).

Step (iii)
Preparation of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyl-6,7-dihydro-
lH-pyrazoIo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxypropanoic
acid
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 10-15 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-lH-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 and pooled the toluene washings. The aqueous layer was acidified with 25% H2SO4 at 10 to 15 °C, in about 30 min, to pH 2.0-2.5 and maintained at the same temperature for 30 min. The precipitated product was filtered, washed with demineralised water 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 through Hiflow bed. The toluene layer was concentrated below 110 °C under vacuum. 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 off-white to white colored solid (weighs 6.4 g, yield 60%, purity 90.23% by HPLC, mp : 149-153 °C).

IR (neat) cm"" : 3400-3300, 3120, 2970, 1720.
"H NMR (200 MHz, DMSO-ds) 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, 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 (t, 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 (CI) : 457 (M+1).
Step (iv)
Preparation of (-) 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 tromethamine 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. Tromethamine (0.8 g) was added at 55 to 65 °C in a single lot, under stirring. The reaction mixture was refluxed for 8 to 10 h. The reaction mass was cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for precipitation. The precipitated product was filtered, washed with chilled isopropanol and dried 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 : 115-119 °C). IR (neat) cm"": 3300-3250, 3120, 2935 (-C-H aliphatic), 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 nVz (CI) : 457 (M+ + 1), 122 (C4HnN03+l)
Anal. Calcd : C28H43N5O8; % C 58.23; % H : 7.45; % N 12.13; Found % C
58.10; %H 7.31; %N 12.0.
Example 3 Step (i)
Preparation of (-) isopropyl 3-[4-(2-(5-ethyI-l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxy-propionate
In a 5 L four necked round bottom flask, fitted with a Dean-Stark apparatus, reflux condenser and an efficient stirrer, powdered K2CO3 (391 g, 2.837 M) and toluene (2 L) were added at 25 to 35 °C under stirring. The reaction mixture was refluxed for 2 to 3 hours. After azeotropic removal of water, the reaction mixture was cooled to 75 to 85 °C and added (-) isopropyl 2-ethoxy-3-(4-hydroxyphenyl)propionate (160 g, 0.638 M) and 5-ethyl-6-(2-chloroethyl)-l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-7one (200 g, 0.709 M), sequentially, in one lot. The reaction mixture was further refluxed for 5 to 6 hours. The reaction mixture was brought to room temperature and cooled to 10 to 15 °C and water (1.5 L) was added to separate the organic layer. The organic layer was washed with demineralised water. The toluene layer was concentrated under vacuum. Isopropyl alcohol (2 L) was added to the residue under stirring and cooled the reaction mixture to 5 to 10 °C and maintained for 2 hrs. The precipitated product was filtered and dried to afford pure title compound as off-white crystalline solid (mp: 98-100 °C, weighs 282 g, yield 80%, purity 98-99%). IR (neat) cm"": 3120, 2930, 1732, 1660, 1587.

"H NMR (200 MHz, DMSOA) 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), 4.50 (t, J = 5.0 Hz, 2H), 4.29-4.22 (m, 6H), 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), 1.01 (d, 6H), 0.97 (t, J = 7.4 Hz, 3H).
Mass m/z (CI): 499 (M+ + 1). Anal. Calcd : C27H38N4O5; % C 65.06; % H 7.63; % N 11.24; Found % C 64.90; % H 7.52; % N 11.04. Step (ii)
Preparation of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propyI-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxypropionic acid In a 10 L four necked round bottom flask, fitted with a plain aerial condenser and mechanical stirrer, (-) isopropyl 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-propy]-6,7-dihydro-lH-pyrazoIo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-ethoxy-propionate (817 g, 1.64 M) and methanol (5.72 L) were added at 25 to 35 °C under stirring. The reaction mixture was cooled to 10 to 15 °C and added 20% NaOH solution (1.64 L) slowly maintaining the temperature below 20 °C in about 20-30 min. After complete addition, the reaction mixture was brought to 25 to 35 °C and maintained under stirring. After completion of the reaction, water (3 L) was added to the reaction mixture and washed with toluene. The aqueous layer was acidified with cone, hydrochloric acid at 15 to 20 °C under stirring and maintained at 5 to 10 °C for 2 hrs. The precipitated product was filtered and dried to afford pure title compound as off-white crystalline solid (mp: 151-154 °C, weighs 600 g, yield 80%, purity 99% by HPLC).
IR (neat) cm"": 3450, 3120, 2930, 1720, 1587.
"H NMR (200 MHz, DMSO-de) 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), 4.50 (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), 0.97 (t, J = 7.4 Hz, 3H).

Mass m/z (CI): 457 (M+ + 1). Anal. Calcd : C24H32N4O5; % C 63.15; % H
7.01; % N 12.28; Found % C 63.0; % H 6.89; % N 12.13
Step (iii)
Preparation of tromethamine salt of (-) 3-[4-(2-(5-ethyl-l-methyl-7-oxo-3-
propyl-6,7-dihydro-lH-pyrazoIo-[4,3-d]pyrimidin-6-yl)ethoxy)phenyl]-2-
ethoxypropionic acid
In a 10 L four-necked round bottom flask, fitted with a reflux condenser and a
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-ethoxypropionic acid
(600 g, 1.135 M) and isopropyl alcohol (6 L) were added at 25 to 35 °C under
stirring. The reaction mixture was heated slowly at 80 to 90 °C and maintained
for 1 to 2 hrs for complete dissolution of the mass. Tromethamine (159 g,
1.315 M) in isopropyl alcohol (210 ml) was added at 55 to 65 °C in a single
lot, under stirring. The reaction mixture was refluxed for 8 to 10 hrs. The
reaction mixture was then cooled to 25 to 35 °C under stirring and maintained
for 6 hr to get the precipitated solid. The reaction mixture was further cooled
to 10 to 15 °C under stirring and maintained for 2 to 3 hrs for complete
precipitation. The precipitated product was filtered and dried to yield pure title
compound as off-white crystalline solid (weighs 640 g, yield 84%, purity
99.2% by HPLC, mp 117-120 °C).
IR (neat) cm" 3400-3200, 3120, 2935, 1585.
"H NMR (200 MHz, DMSO-dfi) § : 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"" + 1), 122 (C4H|,N03+1)
Anal. Calcd : C28H43N5O8; % C 58.23; % H : 7.45; % N 12.13; Found % C
58.10; %H 7.31; %N 12.0.

We claim:
1. A process for the preparation of tromethamine salt of (-) 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-alkoxypropionic acid of the formula
(1),

wherein R1 represents (C1-C6) alkyl group, in the presence of a base and an organic solvent at a temperature in the range of 0 to 150 °C for a period in the range of 5 to 30 h to give alkyl (-) 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-hydroxy propanoate of the formula
(5)

where R1 represents (C1-C6) alkyl group,
ii) hydrolysing and etherifying the compound of formula (5) in the
presence of a base and a solvent using an alkylating agent to obtain (-) 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-alkoxypropanoic acid of formula (6) at a temperature in
the range of 5 to 50 °C for a period in the range of 4 to 30 h

iii). reacting the compound of formula (6) 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
iv). isolating the compound of formula (1) formed by conventional
methods.
2. The process as described in claim 1, wherein the base used in step (i) is
selected from sodium carbonate, potassium carbonate, sodium hydroxide or
potassium hydroxide.
3. The process as claimed in claims 1 and 2, wherein the solvent used in
step (i) is selected from toluene, xylene, THF, DMF, DME, DMSO, alcohols
or a mixture thereof.

4. The process as claimed in claims 1 to 3, wherein the base used in step
(ii) is selected from NaH, NaOH, KOH, t-BuOK, K2CO3 or NaHCOa.
5. The process as claimed in claims 1 to 4, wherein the solvent used in
step (ii) is selected from hydrocarbons, DMF, DMSO, MIBK, ethyl acetate, N-
methyl pyrrolidone or a mixture thereof
6. The process as claimed in claims 1 to 5, wherein the alkylating used in step (ii) is (R)2-sulfate selected from diethyl sulphate, dimethylsulphate; or R-halide.

Documents:

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Patent Number

221875

Indian Patent Application Number

399/MAS/2002

PG Journal Number

37/2008

Publication Date

12-Sep-2008

Grant Date

08-Jul-2008

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	GADDAM OM REDDY	C/O. DR. REDDY'S LABORATORIES LTD., 7-1-27, MEERPET, HYDERABAD 500 016,
2	BATCHU CHANDRASEKHAR	C/O. DR. REDDY'S LABORATORIES LTD., 7-1-27, MEERPET, HYDERABAD 500 016,
3	KOTRA NARASIMHA MURTHY	C/O. DR. REDDY'S LABORATORIES LTD., 7-1-27, MEERPET, HYDERABAD 500 016,
4	POTLAPALLY RAJENDER KUMAR	C/O. DR. REDDY'S LABORATORIES LTD., 7-1-27, MEERPET, HYDERABAD 500 016,
5	SIRISILLA RAJU	C/O. DR. REDDY'S LABORATORIES LTD., 7-1-27, MEERPET, HYDERABAD 500 016,
6	TETALI SATYANARAYANA VARA PRASAD REDDY	C/O. DR. REDDY'S LABORATORIES LTD., 7-1-27, MEERPET, HYDERABAD 500 016,
7	CHANDAR BHAR	C/O. DR. REDDY'S LABORATORIES LTD., 7-1-27, MEERPET, HYDERABAD 500 016,

PCT International Classification Number

A61K 33/44

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA