| Title of Invention | AN IMPROVED PROCESS FOR PREPARATION OF ROSUVASTATIN CALCIUM |
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| Abstract | The present invention relates to an improved process for preparing (E)-7-[4-(4-fluorophenyl)- 6-isopropl-2-methyslsulfony amino pyrimdin-5-yl 3R,5S-,5-dihydroxyhept-6--enoic acid calcium of Formula I, |
| Full Text | FIELD OF THE INVENTION The present invention relates to an improved process for preparing (E)-7-[4-(4-fluorophenyl)' 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrirnidin-5-yl](3R,5S)-3,5-dihydroxy^ enoic acid calcium of Formula I, F H3C. Formula I and its intermediates with high purity starting from the compound of Formula II, F Formula II BACKGROUND OF THE INVENTION Rosuvastatin, which is an antihyperchlolesterolemic drug, is chemically known as (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methyIsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5- dihydroxyhept-6-enoic acid calcium (2:1) salt of Formula 1. Rosuvastatin was for the first time disclosed in US 5,260,440. Rosuvastatin is being marketed under the proprietary name CRESTOR, as an oral tablet, for the treatment of hypercholesterolemia. In view of the importance of Rosuvastatin as a lipid-lowering agent, several synthetic methods have been reported in the literature to prepare Rosuvastatin, some of which are summarized below: us 5,260,440 discloses a process for preparing Rosuvastatin in examples. The process is as shown below: C-C-CHyCOOCiHs F Base H.C Q DDQ NaH (60%) Methanesulfonyl chloride Methyl (3R)-3-(tert-butyldi methylsiIyloxy-5-oxo-6-tri OSi(CH3)2t-Bu COOCH3 SO2CH3 CH3 phenylphosphoranylidene Uiethy NaBH, 10 Diethylmethoxyborane F COO-i'^Ca H3C^ 12 i. Saponification^ ii. CaCl2 ^ The difficulties in the above process are that the intermediate (A) is not obtained in pure form readily. Further, its purification is tedious and overall yield is extremely low. Even when intermediate (A) is obtained in pure form, further condensation with intermediate (X) to form Rosuvastatin, does not result in Rosuvastatin of right quality as the product contains unacceptable quantity of impurity levels. WO 03/097614 describes a modified procedure for the preparation of the starting material 4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-carbaxldehyde and further conversion to Rosuvastatin by condensing with methyl (3R)-3-[(tert- butyldimethylsilyl)oxy]-5-oxo-6-triphenylphosphoranylidene hexanoate. The condensed product was deprotected using methanesulfonic acid and subsequently converted to Rosuvastatin calcium (2:1) salt. WO 2004/052867 describes a process to prepare Rosuvastatin by condensing 1-cyano (2S)-2- [(tert-butyldimethylsilyl)oxy]-4-oxo-5-triphenylphosphoranylidenepentane with 4-(4- fluorophenyl)-6-isopropyl-2[methyl(methylsulfonyl)amino]pyrimidin-5-carbaldehyde and subsequent deprotection of silyl group, followed by reduction and hydrolysis. WO 2000/049014 discloses a novel chemical process for the manufacture of tert-butyl (E)-(6- {2-[4-(4-fluorophenyl)-6-isopropyl-2-methyl(methyIsulfonyl)amino]pyrimidin-5-yl]vinyl}- (4R,6S)-2,2-dimethyl[l,3]dioxan-4-yl)acetate which comprises reaction of diphenyl {4-(4- flurophenyl)-6-isopropyl-2[methyl(methylsulfonyl)amino]pyrimidin-5-yl- methyl }phosphineoxide with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4- yl]acetate and its further conversion to Rosuvastatin. WO 2004/014872 describes a process for the manufacture of Rosuvastatin calcium (2:1) salt which comprises mixing a solution of calcium chloride with a solution of water soluble salt of (E)7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl](3R,5S)-3,5-dihydroxyhept"6-enoic acid. This process for the preparation of Rosuvastatin employs the use of phosphorane side chain, the preparation of side chain requires eight synthetic steps and involves expensive reagents. The process is both uneconomical and time consuming, hence not appropriate for commercial scale operation. WO 2006/100689 A1 discloses a process for preparation of Rosuvastatin as shown below : R. R4 / R HjC^ S02CH3 CH3 Oxidation HjC^ CHO SO2CH3 CH3 OH CH. + CH. H3Q CH SO2CH3 CHj S02CH3 CH3 CH3 CH3 Hydrolysis CHj H3C. S02CH3 CH3 Rosuvastatin SO2CH3 CH3 SO2CH3 CH3 In the above scheme Ri, R2, R3 represent substituted or unsubstituted phenyl and R4 represents an aliphatic residue selected from C1-C4 alkyl, R5 represents C1-C4 alkyl which is optionally substituted by hydroxyl, R6 represents hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R7 represents aliphatic residue, Rg represents C1-C4 alkyl WO 2006/106526 A1 describes the preparation of Rosuvastatin as shown below : T H3Q CH, HjC^ SO2CH3 CH3 CHO N" ^N' ^CHj r/ SO2CH3 CH3 t CH F OM o H3Q HjC^ S02CH3 CH3 Reduction S02CH3 CH3 Acid activating group 'l H^cr'^a--^ OM or ^ CH3 CH3 Hydrolysis CH3 S02CH3 CH3 Rt R6 NH2 Resolution Acid activating Rroup H3C. j^A^CHj HjCk SO2CH3 CH3 Esterification SO2CH3 CH3 SO2CH3 CHj Hydrolysis 2+ Ca HjC^ H3C. S02CH3 CH3 SO2CH3 CHJ In the above mentioned scheme Ri, R2, R3 are substituted or unsubstituted phenyl and R4 is an aliphatic residue selected from Ci-C^ alkyl, R5 represents C1-C4 alkyl, M is an alkali metal salt, X represents a halogen, Ke represents C1-C4 alkyl which is optionally substituted by hydroxyl, R7 represents hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, Rg is an aliphatic residue selected from C1-C4 alkyl. As mentioned above though there are number of processes available still there is a continuing need to identify alternative processes for the manufacture of Rosuvastatin and its pharmaceutically acceptable salts. Such processes may, for example, when compared to previously known processes, be more convenient to use, be more suitable for large scale manufacture, give the product in a better yield, reduce the number of steps involved, use intermediates which are more easily isolated, require less complex purification techniques, use less expensive reagents and/or be more environmentally friendly. We have now found an improved process for preparing (E)-7-[4-(4-fluorophenyl)-6-isopropyl- 2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium of Formula I OBJECTIVE The main objective of the present invention is to provide an improved process for preparing (E)-7-[4-(4-fluorophenyl)-6-isopropyi-2-[methyl(methyisulfonyl)amino]pyrimidin-5- yi](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium of Formula 1. SUMMARY OF THE INVENTION The present invention relates to an improved process for preparing (E)-7-[4-(4-fluorophenyl)- 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6- enoic acid calcium of Formula I, F H3C. Formula I which comprises, a) protecting the compound of Formula III with a suitable hydroxy protecting group F Formula III in an organic solvent to obtain a compound of Formula IV, Formula IV wherein R2 represents a hydroxy protecting group b) activating the acid group of the compound of Formula IV with acid activator, followed by treating the resulting intermediate with neutral magnesium salt of malonic acid of Formula V o Formula V R3 represents C1-C4 straight chain or branched chain alkyl, aryl, substituted aryl, aralkyl in an organic solvent to obtain a compound of Formula VI, Formula VI H3Q CH3 :h3 Mg 2 wherein R3 is as defined above, c) deprotecting the compound of Formula VI with a suitable reagents to obtain compound of Formula VII, Formula VII SO2CH3 CH3 wherein R3 is as defined above, in an organic solvent, water or mixtures thereof, wherein R3 is as defined above, d) reducing the compound of Formula VII to obtain a compound of Formula VIII, H3Q N Formula VIII wherein R3 is as defined above, e) hydrolyzing the compound of Formula VIII and converting into a salt of Formula I thereof DETAILED DESCRIPTION OF THE INVENTION The main objective of the present invention is to provide a new improved process for the preparation of Rosuvastatin in high yield and high purity. The compound of Formula III is protected with a suitable hydroxy protecting group selected from tertiary butyldimethylsilyl chloride, 2,3-dihydropyran, trimethylsilylchloride, methoxymethyl chloride, more preferably tertiary butyldimethylsilyl chloride. The hydroxy protection is carried out in an organic solvent in presence of bases like imidazole, triethylamine. The usage of base is essential for completion of silylation. The organic solvent used for the above silylation reaction is selected from tetrahydrofuran, dimethoxy ethane, dioxane, dichloromethane, ethylene dichloride, N,N-dimethylformamide, dimethylsulfoxide. N-methylpyrrolidine, sulfolane, more preferably N,N-dimethylformamide etc. Also during this silylation reaction a suitable additive is added to accelerate silylation which is selected from sodium iodide, potassium iodide, lithium iodide etc. The reaction is conducted at a temperature in the range of 0°-128°C, more preferably 50-80°C. The compound of Formula IV is isolated as an oily mass which is sufficiently pure for the next step. The hydroxy protected compound of Formula IV is treated with acid activator like 1,1- carbonyldiimidazole, or methyl chloroformate, ethyl chloroformate, phenyl chloroformate, 4- methoxyphenylchloroformate, 4-chlorophenylchloroformate, 2,4-dinitrophenylchloroformate, 4-trifluoromethylphenylchloroformate, 4-nitrophenylchloroformate, 2- nitrophenylchloroformate, etc in presence of organic base more preferably 1,1- carbonyldiimidazole in the presence or absence of organic base. The organic base is selected from triethyl amine, pyridine etc. The resulting activated imidazolimide intermediate is subsequently treated with magnesium salt of monoalkyl malonate of Formula V. Magnesium salt of Formula V can be prepared by treating 2 moles of malonic acid mono alkyl ester with 1 mole of magnesium ethoxide. This homologation is conducted at a temperature between 0- 100°C, preferably at ambient temperature. The organic solvent used in the homologation is selected from tetrahydrofuran, N,N-dimethylformamide, methylene dichloride, acetonitrile or mixtures thereof During the workup compound of Formula VI a which is generated in situ F COOR3 Formula VI a gets decarboxylated giving directly ketoester of Formula VI. The deprotection of the compound of Formula VI is carried out using acids having a general Formula HX wherein X represents halogen or MX wherein X represents halogen, M is cation derived from like inorganic metal like Na"^, K"^, Li^ etc or organic amine like N'^(R)4 where in R represents C1-C4 alkyl, straight chain, branched chain alkyl, sulfonic acids such as para toluene sulfonic acids, methanesulfonic acids, trifluormethane sulfonic acid, organic acids such as formic acid, trifluroacetic acid, acetic acid in aqueous solvent or in a mixture of organic solvent at room temperature. The reaction is preferably conducted in a organic solvent, water or mixtures thereof. The organic solvent can be selected from tetrahydrofuran, acetonitrile, methanol, ethanol, dichloromethane, ethylene dichloride, toluene, xylene etc. The compound of Formula VII is stereoselectively reduced with metal borohydride in presence of chelating agent like trialkylborane or boronates like dialkyl alkoxy borane more preferably diethyl methoxy borane. The stereoselective reduction is carried out in a mixture of inert solvent preferably tetrahydrofuran and lower alkanol, more preferably methanol at -TS^C-O'^C. The metal borohydride employed is selected from sodium borohydride, potassium borohydride, calcium borohydride, more preferably sodium borohydride. After completion of reaction, excess borohydride is destroyed by acetic acid and resulting compound of Formula VIII is extracted into an organic solvent. The organic layer is concentrated under reduced pressure to give crude compound of Formula VIII that is utilized for hydrolysis step as such. Saponification of compound of Formula VIII is carried out using a base, such as alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, more preferably sodium hydroxide. The sodium salt of Rosuvastatin thus obtained can be optionally isolated or the solution containing of Rosuvastatin sodium is treated with Benzathaizine acetate to get the corresponding Benzathaizine salt which can be fiirther converted to Rosuvastatin calcium. Alternatively, aqueous sodium salt of Rosuvastatin can be treated with calcium ion source to give Rosuvastatin calcium. The preparation of compound of Formula III is elaborated in our co-pending application number 1994/CHE/2006 filed in Chennai, India. The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. Example 1 Preparation of (4E)-5-{4-(4-Fluorophenyl)-6-isopropyl-2-[methyl- (methylsulfonyl)amino]pyrimidin-5-yl}-(3S)-3-(0-tertbutyldimethylsiI^^^ acid Tert-butyldimethylsilyl chloride (7.6 g, 0.05 m.) was dissolved in N,N-dimethylformamide (25 ml) and anhydrous potassium iodide (8.4 g, 0,05 ml) was added to it at 25®C. The mixture was heated to 60®C and stirred for 30 min. Triethylamine (7 g, 0.06 m) was added to the above hot reaction mixture and stirred for 10 min at Subsequently (4E)-5-{4-(4-fluorophenyl)-6- isopropyl"2-[methyl(methylsulfonyl)amino]pyridin«5-yl-(3S)-3"hydroxy-4-pentanoic acid (10 g, 0.02 m) was dissolved in N,N-dimethylformamide (25 ml) and added to the above reaction mixture dropwise over a period of 30 min at 60°C. The reaction mass was further stirred at 60®C for 2 h and cooled to room temperature. The reaction mass was quenched by adding DM water (50 ml) and product was extracted in toluene (2 x 50 ml). The toluene layer was washed with aqueous sodium bicarbonate (50 ml) followed by aqueous saturated sodium chloride (50 ml). The solvent was removed under reduced pressure to yield product (4E)-5-{4-(4- fluorophenyl)-6-isopropyl-2-[methyl-(methylsulfonyl)amino]pyrimidin-5-yI}-(3S)-3-(0- tertbutyldimethylsilyl)-4-pentanoic acid was isolated as an oily mass, which was pure enough for the subsequent reaction. YIELD: 12 g (95%) ^HNMR (300 MHz, CDCb) : 0.05 (s, 6H (CH3)2), 0.89 (s, 9H (CH3)3), 1.27-1.30 (m, 6H (CH3)2), 2.38-2.50 (m, 2H, CH2X 3.40 (m, IH, CH), 3.54 (s, 3H, CH3), 3.59 (s, 3H, CH3), 4.52 (brs, IH, CH), 5.50-5.61 (m, IH, CH), 6.58 (d, J=15Hz, CH), 7.0-7.18 (m, 2H, ArH), 7.60-7.66 (m, 2H, ArH). Example 2 Preparation of Ethyl (6E)-7-{4-(4-Fluorophenyl)-6-isopropyl-2-[methyl- (methyIsuIfonyl)amino]pyrimidin-5-yI}-(5S)-S-(0-tertbutyldimethylsilyl)-3-oxo-hept-6- enoate (4E)-5"{4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin (3S)-3-(0-tertbutyldimethylsilyl)-4-pentanoic acid (10 g, 0.018 m) was dissolved in tetrahydrofuran (180 ml) and a solution of 1,1-carbonyldiimidazole (5.3 g, 0.03 m) in tetrahydrofuran (30 ml) was added to the above reaction mass drop wise over a period of 30 min. The reaction mass was stirred overnight and magnesium salt of ethyl malonate (prepared \n situ by stirring 2.27 g of magnesium alkoxide and monomethyi maolonate 5.0 g in tetrahydrofuran 30 ml at 25 °C) was added dropwise into the reaction mass. The reaction mass was stirred for additional 20 h. After completion of the reaction, tetrahydrofuran was distilled out and redissolved the mass in a mixture of toluene (500 ml) and ethyl acetate (100 ml). The resulting organic layer was washed with aqueous sodium carbonate (500 ml) followed by DM water (2 x 500 ml). Thereafter, the organic layer was concentrated completely at 45-50°C under reduced pressure to obtain the crude product. The crude product obtained in the above process was used for the subsequent reaction without further purification. YIELD: 8.75 g Example 3 Preparation of Ethyl (6E)-7-{4-(4-Fluorophenyl)-6-isopropy 1-2-[methyl- (methyIsuIfonyI)amino]pyrimidin-5-yl}-(5S)-5-hydroxy-3-oxo-heptenoate Ethyl (6E)-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyI)amino]pyrimidin-5-yl}- (5S)-5-(0-tertbutyldimethylsilyl)-3-oxo-hept-6-enoate (10 g, 0.016 m) was dissolved in acetonitrile (250 ml) at 25°C and the reaction mixture was cooled to O^C. Hydrofluoric acid (48%, 15 ml) was diluted in acetonitrile (250 ml) and added slowly to the above reaction mass over a period of 20 min at 0-5°C. After addition, the reaction mass was quenched by addition of 10% aqueous sodium bicarbonate solution (50 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was washed with DM water (50 ml) and solvent distilled out under vacuum at 40-45°C to obtain the product as an oily mass. YIELD: 8.25 g (66%) 'HNMR (300 MHz, CDCb) : 1.25-1.32 (m, 9H(CH3)2 & CH3), 2.67 (d, J-6Hz, 2H, CHa), 3.30-3.39 (m, IH, CH), 3.46 (s, 2H, CH2), 3.53(s, 3H, CH3), 3.59 (s, 3H, CH3), 4.12-4.20 (m, 2H, CH2), 4.56 (brs, 1H,CH), 5.40 (dd, J=15Hz, 6Hz, CH), 6.68 (d, J=15Hz, IH, CH), 7.09- 7.28 (m, 2H, ArH), 7.62-7.67 (m, 2H, ArH). Example 4 Preparation of Ethyl (6E)-7-{4-(4-fluorophenyI)-6-isopropy 1-2-[methyl- (methylsuIfonyI)amino]pyrimidin-5-yI}(3R,5E)-3,5-dihydroxy-hept-6-enoate Ethyl (6E)-7-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl-(methylsulfonyl)amino]pyrimidin-5- yl}(5S)-3-oxo-heptenoate (10 g, 0.02 m) was dissolved in a mixture of tetrahydrofuran (500 ml) and methanol (70 ml) at 25'C. The mixture was cooled to -78'C and diethylmethoxyborane (48% in tetrahydrofuran, 5 ml, 0.02 m) was added to the above cooled reaction mass at -IS to -78®C over a period of 20 min. The reaction mass was stirred at -75 to -78®C for 30 min before adding sodium borohydride (1 g, 0.02 m). The mixture was stirred for another 2 h at -78®C and quenched by adding acetic acid (13 g). Thereafter, saturated sodium bicarbonate (500 ml) was added to it and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with ethyl acetate (250 ml) and the combined organic layer was washed with DM water (250 ml). The organic layer obtained during the above process was concentrated at 40-45°C under vacuum to get the crude product, which was used for hydrolysis as such without further purification. YIELD: 10g(99%) ^HNMR (300 MHz, CDCI3) : 1.22-1.30 (m, 9H (CH3)2 & CH3), 1.46-1.53 (m, 2H, CH2), 2.46 (d, J=6Hz, 2H, CH2), 3.34-3.38 (m, IH, CH), 3.52 (s, 3H, CH3), 3.58 (s, 3H, CH3), 4.15-4.28 (m, 2H, CH2), 4.95 (brs, IH, CH), 5.45 (dd, J-15Hz, 6Hz). Example 5 Preparation of Ethyl (6E)-7-(4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methyIsulfonyI)aminopyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoate Benzthiazine salt Ethyl-(6E)-7-(4-(4-fIuorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)aminopyrimidin-5- yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate (1 g) was dissolved in ethanol (12 ml) at 25-30'C and added O.IN NaOH (16 ml) in 15 min at 25-30^C under reduced pressure. The reaction mixture was stirred for iVi hr at 25«30®C and ethanol was removed completely. Under reduce pressure DM water (25 ml) was added to the concentrated mass and washed with toluene (2 x 50 ml). Finally the aqueous layer was washed with 30% ethyl acetate and toluene mixture (2 x 50 ml). To the aqueous layer added a solution of benzthiene diacetate (1 g) dissolved in DM water (10 ml) at 25-30®C and stirred for 3 hrs at 25-30°C, the resulting product was filtered, washed with DM water (5 ml) and dried to constant weight. YIELD : 10.6 g. Example 6 Preparation of Rosuvastatin calcium N,N'-Dibenzylethylenediamine rosuvastatin salt (2 g) was dissolved in a mixture of ethyl acetate (30 ml) and DM water (30 ml) and cooled to 0-5°C. The above cold mixture was treated with aqueous hydrochloric acid (3 ml) at 0-5°C. The resulting clear solution was stirred for 10 min. The organic layer was separated, washed with water and cooled to 0-5°C. Aqueous sodium hydroxide (1 N, 30 ml) was added to the above organic layer and stirred at room temperature for 30 min for conversion of Rosuvasatin acid to it sodium salt. Toluene (70 ml) was added to the above mixture and stirred for 10 min. The aqueous layer was separated and traces of solvent was removed at 40-45°C under vacuum. The resulting clear aqueous layer was treated with an aqueous solution of calcium chloride (IN, 3 ml) and resulting Rosuvastatin calcium was filtered and dried. Dry Wt. 0.6 g Chromatographic purity: 993%, WE CLAIM 1) An improved process for preparing (E)-7-[4-(4-fluorophenyi)-6-isopropyl-2- [niethyl(niethylsulfonyl)aniino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyh^ acid calcium of Formula I, F Formula I -l2 which comprises, a) protecting the compound of Formula III with a suitable hydroxy protecting group F H3Q Formula III SO2CH3 CH3 in an organic solvent to obtain a compound of Formula IV, F Formula IV wherein R2 represents a hydroxy protecting group b) activating the acid group of the compound of Formula IV with acid activator, followed by treating the resulting intermediate with neutral magnesium salt of malonic acid of Formula V R3 represents CrC4 straight chain or branched chain alkyl, aryl, substituted aryl, aralkyl in an organic solvent to obtain a compound of Formula VI, Formula VI CH3 SO2CH3 CH3 wherein R2 and R3 is as define above Mg 2 Formula V c) deprotecting the compound of Formula VI with a suitable reagents to obtain compound of Formula VII, F Formula VII wherein R3 is as defined above, in an organic solvent, water or mixtures thereof, wherein R3 is as defined above, d) reducing the compound of Formula VII to obtain a compound of Formula VIII, COOR3 N' wherein R3 as defined above e) hydrolyzing the compound of Formula VIII and converting into a salt of Formula I thereof. 2) The process according to claim 1, wherein protecting group employed is selected from tert.butyldimethylsilyl chloride, dihydropyran, trimethylsilyl chloride, methoxy methyl chloride, more preferably tert.butyl dimethylsilylchloride. 3) The process according to claim 1, wherein the solvent employed in step (a) is selected from tetrahydrofuran, dioxane, dimethoxy ethane, dichloromethane, ethylene dichloride, dimehyl formamide, dimethyl sulfoxide, N-methyl pyrrolidine, sulfolane or mixtures thereof more preferably N,N-dimethylformamide. 4) The process according to claim 1, wherein the activating group employed in step (b) is 1,1-carbonyldiimidazole, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, 4-methoxyphenylchloroformate, 4-chlorophenylchloroformate, 2,4- dinitrophenylchloroformate, 4-trifluoromethylphenylchloroformate, 4- nitrophenylchloroformate, 2-nitrophenylchloroformate, more preferably 1,1- carbonyldiimidazole. 5) The process according to claim 1, wherein the solvent employed in step (b) is selected from tetrahydrofiiran, methyl tert.butylether, isopropyl ether, diisopropyl ether, N,N- dimethylformamide, methylene dichloride, acetonitrile, more preferably tetrahydrofuran. 6) The process according to claim 1, wherein the deprotection reaction is carried out using hydrofluoric acid, lithium fluoride, potassium fluoride, sodium fluoride, sulfonic acids such as para toluene sulfonic acids, methane sulfonic acids, trifluormethane sulfonic acid, organic acids such as formic acid, trifluro acetic acid, acetic acid, tetrabutyl ammonium fluoride, more preferably hydrofluoric acid. 7) The process according to claim 1, wherein the organic solvent used in step (c) is selected from tetrahydrofuran, acetonitrile, methanol, ethanoi, methylene chloride, ethylene dichloride, toluene, xylene, or mixtures thereof more preferably acetonitrile, 8) The process according to claim 1, wherein the reduction in step (d) is carried out using metal borohydrides selected from sodium borohydride, potassium borohydride, calcium borohydrate, more preferably sodium borohydride. 9) The process according to claim 1, wherein the reduction in step (d) is carried out in an inert solvent selected from tetrahydrofuran, lower alkanol or mixtures thereof. 10) The process according to claim 1, wherein the hydrolysis of step (e) is carried out using alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, more preferably sodium hydroxide. |
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| Patent Number | 278066 | |||||||||||||||||||||
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| Indian Patent Application Number | 277/CHE/2007 | |||||||||||||||||||||
| PG Journal Number | 52/2016 | |||||||||||||||||||||
| Publication Date | 16-Dec-2016 | |||||||||||||||||||||
| Grant Date | 09-Dec-2016 | |||||||||||||||||||||
| Date of Filing | 08-Feb-2007 | |||||||||||||||||||||
| Name of Patentee | AUROBINDO PHARMA LIMITED | |||||||||||||||||||||
| Applicant Address | AUROBINDO PHARMA LIMITED PLOT NO.2 MAITRIVIHAR AMEERPET HYDERABAD - 500 038 AP INDIA. | |||||||||||||||||||||
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| PCT International Classification Number | C07D239/42 | |||||||||||||||||||||
| PCT International Application Number | N/A | |||||||||||||||||||||
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