Title of Invention	A process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(1S,3R,5R)-cyclohexylacetate useful as an intermediate for veta-hydroxy delta-lactone.
Abstract	The present invention provides a process for the preparation of a novel 3-hydroxy-5- (tert.butyldimethylsilyloxy)-(15,3R,5R)-cyciohexylacetate useful as an intermediate for 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2- pyranone (ß-hydroxy-δ-lactone) having formula 1. (Formula Removed) More particularly the present invention provides a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(15,3R,5R)-cyclohexylacetate having formula 5 (Formula Removed) from a compound cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy) cyclohexylacetate having formula 4. (Formula Removed)

Title of Invention

A process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(1S,3R,5R)-cyclohexylacetate useful as an intermediate for veta-hydroxy delta-lactone.

Abstract

The present invention provides a process for the preparation of a novel 3-hydroxy-5- (tert.butyldimethylsilyloxy)-(15,3R,5R)-cyciohexylacetate useful as an intermediate for 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2- pyranone (ß-hydroxy-δ-lactone) having formula 1. (Formula Removed) More particularly the present invention provides a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(15,3R,5R)-cyclohexylacetate having formula 5 (Formula Removed) from a compound cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy) cyclohexylacetate having formula 4. (Formula Removed)

Full Text	The present invention relates to a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(1S,3R,5R)-cyclohexyjacetate useful as an intermediate for p-hydroxy 5-lactone having formula 1. (Formula Removed) More particularly it relates to a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate having formula 5 (Formula Removed from a compound cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy) cyclohexylacetate having formula 4 (Formula Removed) The compound cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy) cyclohexylacetate having formula 4 is prepared from the compound cis.cis-3- hydroxy-5-(methylcarbonyloxy-cyclohexylacetate having formula 3 (Formula Removed)by a procedure as described and claimed in our co-pending application No.87/D/2001 The compound ß-hydroxy-δ-lactone (1) is an important intermediate in the synthesis of biologically active drugs e.g. compacting atorvastatin, fluvastatin , cholesterol lowering drugs. Hitherto known processes for the synthesis of ß-hydroxy-δ-lactone (1) involves a) Addition of lithium enolate of ethylacetate to (S)-2,2-dimethyl-1,3-dioxlane-4-ethanol, which in derived from L-malic acid, followed by acid treatment. (T. Rosen, M.J. Taschner & C.H. Heathcock, J. Org. Chem., 1984, 49, 3994-4003) b) Multistep chemical manipulation of tri-acetyl-D-glucal (T. Rosen, M.J. Taschner, C.H. Heathcock, J. Org. Chem., 1984, 49, 3994; F.G. Kathawala, Mountain Lake N.J. USP 4739,073) c) Coupling of (S)-2,2-dimethyl-l,3-dioxalane-4-ethanal with optically active (R)-methyl-p-tolylsulphoxide which in turn obtained by oxidation of methyl- p-tolylsulphide with baker yeast, followed by desulphurization and few chemical manipulation (J. Beecher, I. Brackerridge, S.M. Roberts, J. Tang & A.J. Willetts, J. Chem. Soc. Perkin Tran.I 1995, 1641; Tetrahedron 1995, 51,13217) d) Deprotection and hydrolysis of 6-cyanomethyl-2,2-dimethyl-l,3-dioxane-4-acetate, which in turn obtained by two carbon homologation on optically active ethyl-3-hydroxy-4-cyanobutyrate and followed by stereoselective reduction (P.L. Brower, D.E. Butler, C.F. Deering, T.V. Le, A. Millar, T.N. Nanninga & B.D. Roth, Tet. Lett, 1992, 33, 2279-82 e) Racemic and optically active p-hydroxy-8-lactone from cis-cyclohexane-1,3,5-triol (K. Prasad & O. Repic, Tet. Lett., 1984, 25., 2435-38; H. Suemune, M. Takahashi, S. Maeda, Z. Fxi & K. Sakai, Tet. Asymm. 1990,1, 425-8, M. Canda, V.Eyken & M. Vandewalle, Tet. Asymmetry 1990,1, 17-20). f) Enzymatic kinetic resolution of racemic (3-hydroxy-5-lactone by transesterification with vinyl acetate in THF using Chromobacteriun viscosum lipase as catalyst at 40 °C. [Crosby, J. B.; Andrew, J. H.; John, A. L. WO 9306235 Al CA 119:936292 (1993)] g) Chemoenzymatic route involving kinetic resolution through lactone formation in ether catalyzed by PPL [Bonini, C; Pucci, P.; Viggiani, L. J. Org. Chem. 1991,56,4050] h) Chemoenzymatic route involing enzymatic desymmetrization of intermediate diacetate, followed by chemical conversions. [Bonni, C; Racioppi, R.; Righi, G.; Viggiani, L. J. Org. Chem. 1991, 58, 802] i) Chemoenzymatic synthesis starting from endohydroxylacto which is obtained by enzymatic resolution [MaCague, R.; Olivo, H. F.; Roberts, S. M. Tetrahedron Lett. 1993, 34, 3785] j) Diastereoselective synthesis of lactone based on Eu(fod)3 catalyzed highly diastereoselective [4+2] cycloaddition of l-methoxybuta-l,3-diene to (2R)-N- glyoxyloxyborane-10,2-sultam and further chemical transformations [ Bauer, T.; Kozak, J.; Chauis, C; Jurczak, J. J. Chem. Soc.; Chem. Commun. 1990, 1178 and Tetrahedron: Asymmetry 1996, 7, 1391] k) Chiral synthesi using (R)-O-benzylglycidol as starting material [Takano, S.; Shimazaki, Y.; Sekiguchi, Y.; Ogasawara, K. Synthesis 1989, 539] 1) Asymmetric synthesis based on Red-Al promoted intramolecular reductive cleavage of Benzyl 4-hydroxy-2-butenyl ether structures. [Hatakeyama, S.; Satoh, K.; Takano, S. Tetrahedron Lett. 1993, 34, 7425] The prior art processes have following drawbacks : 1. The processes use chemicals such as butyl lithium, lithium aluminium hydride, methoxy-diethylborane which are costly and difficult to handle and therefore make the process difficult. 2. All known process are however involves large number of synthetic steps resulting in low over all yields. The main object of the present invention is to provide a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate useful as an intermediate for the preparation of 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone (ß-hydroxy-δ-lactone). Another object of the present invention is to provide a process for the preparation of 6-hydroxymethyl-4-(tert.butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone (ß-hydroxy-δ-lactone) having formula 1 which obviates the drawbacks of the prior art processes and use cheaper and easily accessible chemicals. Accordingly, the present invention provides a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(1S,3R,5R)-cyclohexylacetate having formula 5 (Formula Removed) useful as an intermediate for (3-hydroxy 5-lactone which comprises reacting a compound cis,cis-3,5-di(methylcarbonyloxy)-5-tert.butyldimethylsilyloxy) cyclohexyl-acetate of formula 4 with a lipase enzyme in a buffer having pH ranging from 5 to 7, at a temperature ranging from 25 to 30°C for a period ranging between 24 to 30 hours, extracting the mixture with an organic solvent, removing the solvent by evaporation and on column chromatography to obtain 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate. In an embodiment of the present invention the organic solvent used for the extraction of the product is selected from the group consisting of ethyl acetate, chloroform, and dichloromethane. In another embodiment the buffer used is selected from phosphate buffer and citrate buffer. In yet another embodiment the lipase used is selected from the group consisting of pig procain lipase (PPL), pig liver esterase (PLE) and chicken liver acetone powder (CLAP). Cis,cis-3,5-di(methylcarbonyloxy)cyclohexylacetate is prepared by treatment of acetic anhydride with cis-l,3,5-cyclohexantriol which is made by known literature procedure (Strong, P. N.; Keana, J. F. W. J. Org. Chem.1975, 40, 956). The process of the present invention is described herein below with reference to the following examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner. Example 1 Preparation of cis, cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate Finely powdered cis, cis-3,5-di(methylcarbonyloxy)cyclohexylacetate (6.5 parts, 25.19 mmol parts) was suspended in 0.1 M sodium phosphate buffer (pH 7) (135 parts) and stirred vigorously. To the stirred suspension Porcine Liver Esterase (0.110 parts) was added and reaction mixture was stirred vigorously at 30°C for 20 hr. pH of the reaction mixture was monitored at every 2 hrs and was maintained at pH 7 using IN NaOH solution. After completion of reaction (20 hr), it was extracted with ethyl acetate (2 x 150 parts). Organic layers were combined and washed with brine, dried on anhydrous sodium sulfate and concentrated under vacuum to yield cis,cis-3- hydroxy-5-methylcarbonyloxycyclohexylacetate 3 yield (4.8 g parts, 88%). 1H NMR (CDCl3): δ 1.20-1.58 (qn, 3H), 2.08 (s, 6H), 2.28 (m, 3H), 3.78 (m, 1H), 4.78 (m, 2H) 13C NMR (CDC13): δ 21.15, 36.33, 39.93, 64.83, 67.65, 170.42 IR(KBr): 754.60, 884.15, 1029.29, 1140.34, 1250.00, 1367.64, 1738.92,2871.17, 2953.14,3445.47 Mass: Base m/e = 96 other m/e: 156, 138, 114, 73, 67, 67, 60, 55 Elemental analysis: calculated for C10Hl6O5: C 55.56%, H 7.40% Found : C 55.30%, H 8.00% Example 2 Preparation of cis,cis-3-(methyIcarbonyloxy)-5-(tert.butyldimethylsilyloxy) cyclo- hexylacetate 4 Cis, cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate (3, 2 parts, 9.26 mmol) and DMAP (0.113 parts, 0.926 mmol) were placed in 100 ml two-necked round bottom flask equipped with dropping funnel and two-way stopcock. It was evacuated and flushed with argon. To it, dry dichloromethane (10 parts) and dry HMPA (2 part) was added and stirred to dissolve. The solution was cooled to -10°C with stirring. To it, solution of tert-butyldimethylsilyl chloride in 10 part dry dichloromethane was added dropwise while maintaining temperature below 0°C. Reaction mixture was stirred for 15 min and to it dry triethylamine (2.02 g, 20 mmol) was added dropwise. Reaction mixture was stirred at room temperature for 12 hr. It was then transferred to a separating funnel and washed successively with cold, dil. HC1 water, aq. NaHCO3 and then brine. Organic layer was dried on anhydrous sodium sulfate and solvent was removed under vacuum. Residue was purified by flash column chromatography. (eluent 2-4% ethyl acetate in petroleum ether) to yield Cis,cis-3- (methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate (4, yield 2.85 parts, 90%). 1H NMR (CDCl3): δ 0.06(s, 9H), 0.87 (s, 6H), 1.20-1.45 (m, 3H), 2.03 (s, 6H), (m, 3H), 3.38 (m, 1H), 4.73 (m, 2H-). 2.2 13C NMR (CDC13): δ -5.07, 17.61, 25.40, 36.17,40.40, 65.43, 67.01, 169.64 IR(CHCl3): 758.90, 838.05, 1034.91, 1106.32, 1246.82, 1368.91, 1734.01,2858.81, 2955.07 Mass: Base m/e= 117 other m/e: 273, 213, 171, 159, 129, 117,97,79,75,57 Elemental analysis: calculated for C26H30O5Si: C 58.185%, H 9.10% Found :C 58.19%, H 9.50% Example 3 Preparation of 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(lS,3R,5R)-cyclohexyl acetate (5) Cis, cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cycIohexylacetate (4, 5 patrs, 147 mmol) was dissolved in tert-butanol (20 parts). To the solution, 0.1 M sodium phosphate buffer (230 parts, pH 8) was added and mixture was stirred vigorously. To the stirred emulsion, Porcine liver esterase (0.150 parts) was added and the mixture was stirred vigorously at 30°C for 54 hrs. During reaction pH was maintained at 8 using IN sodium hydroxide solution. Reaction mixture was extracted with ethyl acetate (3 x 200 parts). Organic layers were combined and washed with brine. It was then dried on anhydrous sodium sulfate and solvent was removed under vacuum. Oily residue contained 3-hydroxy-5-(tert.butyldimethylsilyloxy)- (lS,3R,5R)-cyclohexylacetate 5 along with unreacted 4. Both were separated by flash column chromatography. Cis,cis-3-(methylcarbonyloxy)-5- (tert.butyldimethylsilyloxy)cyclo- hexylacetate recovered: 1.07 parts; 3-hydroxy-5- (tert.butyldimethylsilyloxy)-(15',3R,5R)-cyclohexylacetate (5, yield 2.8 parts, 70% based on recovered starting material. 1H NMR (CDCl3): δ 0.06 (s, 9H), 0.87 (s, 6H), 1.35-1.60, (m, 3H), 2.06 (s, 3H), 2.15 (m, 3H), 3.7 (m, 2H), 4.75 (m, 1H) 13C NMR (CDCl3): δ -4.60, 18.15, 21.38, 25.90, 39.98, 40.31, 43.93, 65.45, 66.40, 68.17, 170.68 IR(CHC13): 758.43,838.93, 1049.42, 1109.15, 1218.09, 1254.01, 1370.09, 1725.03, 2859.8, 2887.95,2952.33, 3017.48 Mass: Base m/e = 75 other m/e: 231, 171, 129, 117, 105,97,79,75,67,59 Elemental analysis: calculated for C14H2804Si: C 58.33%, H 9.72% Found :C 58.15%, H 10.20% Specific rotation [α]D = -4.8 (c 1, CHC13) e.e. >95% (determined by chiral HPLC of corresponding Mosher ester. Column: Whelk-Ol [4.0 mm Id x 25 cm] AT-256; A. =254 nm, flow rate: 1 ml/min; mobile phase: Hexane:isopropanol 98:02; retention time for Mosher ester of 5 = 4.59, for Mosher ester of ent-5 = 4.34). We claim : 1. A process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(1S,3R,5R)-cyclohexylacetate having formula 5 (Formula Removed) useful as an intermediate for ß-hydroxy δ-lactone which comprises reacting a compound cis,cis-3,5-di(methylcarbonyloxy)-5-tert.'butyldimethylsilyloxy) cyclohexyl-acetate of formula 4 with a lipase enzyme in a buffer having pH ranging from 5 to 7, at a temperature ranging from 25 to 30°C for a period ranging between 24 to 30 hours, extracting the mixture with an organic solvent, removing the solvent by evaporation and on column chromatography to obtain 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate. 2. A process as claimed in claim 1, wherein the organic solvent used is selected from the group consisting of ethyl acetate, chloroform and dichloromethane. 3. An improved process as claimed in claims 1-2, wherein the buffer used is selected from phosphate buffer and citrate buffer. 4. A process as claimed in claims I-3, wherein the lipase used is selected from the group consisting of pig procain lipase (PPL), pig liver esterase (PLE) and chicken liver acetone powder (CLAP). 5. A process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(1S,3R,5R)-cyclohexylacetate useful as an intermediate for ß-hydroxy δ-lactone substantially as herein described with reference to the examples.

Full Text

The present invention relates to a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(1S,3R,5R)-cyclohexyjacetate useful as an intermediate for p-hydroxy 5-lactone having formula 1. (Formula Removed)
More particularly it relates to a process for the preparation of a novel
3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate having
formula 5
(Formula Removed
from a compound cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy) cyclohexylacetate having formula 4
(Formula Removed)
The compound cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy) cyclohexylacetate having formula 4 is prepared from the compound cis.cis-3- hydroxy-5-(methylcarbonyloxy-cyclohexylacetate having formula 3
(Formula Removed)by a procedure as described and claimed in our co-pending application No.87/D/2001
The compound ß-hydroxy-δ-lactone (1) is an important intermediate in the synthesis of biologically active drugs e.g. compacting atorvastatin, fluvastatin , cholesterol lowering drugs.
Hitherto known processes for the synthesis of ß-hydroxy-δ-lactone (1) involves
a) Addition of lithium enolate of ethylacetate to (S)-2,2-dimethyl-1,3-dioxlane-4-ethanol, which in derived from L-malic acid, followed by acid treatment. (T. Rosen, M.J. Taschner & C.H. Heathcock, J. Org. Chem., 1984, 49, 3994-4003)
b) Multistep chemical manipulation of tri-acetyl-D-glucal (T. Rosen, M.J. Taschner, C.H. Heathcock, J. Org. Chem., 1984, 49, 3994; F.G. Kathawala, Mountain Lake N.J. USP 4739,073)
c) Coupling of (S)-2,2-dimethyl-l,3-dioxalane-4-ethanal with optically active
(R)-methyl-p-tolylsulphoxide which in turn obtained by oxidation of methyl-
p-tolylsulphide with baker yeast, followed by desulphurization and few
chemical manipulation (J. Beecher, I. Brackerridge, S.M. Roberts, J. Tang &
A.J. Willetts, J. Chem. Soc. Perkin Tran.I 1995, 1641; Tetrahedron 1995,
51,13217)
d) Deprotection and hydrolysis of 6-cyanomethyl-2,2-dimethyl-l,3-dioxane-4-acetate, which in turn obtained by two carbon homologation on optically active ethyl-3-hydroxy-4-cyanobutyrate and followed by stereoselective reduction (P.L. Brower, D.E. Butler, C.F. Deering, T.V. Le, A. Millar, T.N. Nanninga & B.D. Roth, Tet. Lett, 1992, 33, 2279-82
e) Racemic and optically active p-hydroxy-8-lactone from cis-cyclohexane-1,3,5-triol (K. Prasad & O. Repic, Tet. Lett., 1984, 25., 2435-38; H. Suemune,
M. Takahashi, S. Maeda, Z. Fxi & K. Sakai, Tet. Asymm. 1990,1, 425-8, M. Canda, V.Eyken & M. Vandewalle, Tet. Asymmetry 1990,1, 17-20).
f) Enzymatic kinetic resolution of racemic (3-hydroxy-5-lactone by transesterification with vinyl acetate in THF using Chromobacteriun viscosum lipase as catalyst at 40 °C. [Crosby, J. B.; Andrew, J. H.; John, A. L. WO 9306235 Al CA 119:936292 (1993)]
g) Chemoenzymatic route involving kinetic resolution through lactone formation in ether catalyzed by PPL [Bonini, C; Pucci, P.; Viggiani, L. J. Org. Chem. 1991,56,4050]
h) Chemoenzymatic route involing enzymatic desymmetrization of intermediate
diacetate, followed by chemical conversions. [Bonni, C; Racioppi, R.; Righi,
G.; Viggiani, L. J. Org. Chem. 1991, 58, 802] i) Chemoenzymatic synthesis starting from endohydroxylacto which is obtained
by enzymatic resolution [MaCague, R.; Olivo, H. F.; Roberts, S. M.
Tetrahedron Lett. 1993, 34, 3785] j) Diastereoselective synthesis of lactone based on Eu(fod)3 catalyzed highly
diastereoselective [4+2] cycloaddition of l-methoxybuta-l,3-diene to (2R)-N-
glyoxyloxyborane-10,2-sultam and further chemical transformations [ Bauer,
T.; Kozak, J.; Chauis, C; Jurczak, J. J. Chem. Soc.; Chem. Commun. 1990,
1178 and Tetrahedron: Asymmetry 1996, 7, 1391] k) Chiral synthesi using (R)-O-benzylglycidol as starting material [Takano, S.;
Shimazaki, Y.; Sekiguchi, Y.; Ogasawara, K. Synthesis 1989, 539] 1) Asymmetric synthesis based on Red-Al promoted intramolecular reductive
cleavage of Benzyl 4-hydroxy-2-butenyl ether structures. [Hatakeyama, S.;
Satoh, K.; Takano, S. Tetrahedron Lett. 1993, 34, 7425]
The prior art processes have following drawbacks :
1. The processes use chemicals such as butyl lithium, lithium aluminium hydride, methoxy-diethylborane which are costly and difficult to handle and therefore make the process difficult.
2. All known process are however involves large number of synthetic steps resulting in low over all yields.
The main object of the present invention is to provide a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate useful as an intermediate for the preparation of 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone (ß-hydroxy-δ-lactone).
Another object of the present invention is to provide a process for the preparation of 6-hydroxymethyl-4-(tert.butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone (ß-hydroxy-δ-lactone) having formula 1 which obviates the drawbacks of the prior art processes and use cheaper and easily accessible chemicals.
Accordingly, the present invention provides a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(1S,3R,5R)-cyclohexylacetate having formula 5
(Formula Removed)
useful as an intermediate for (3-hydroxy 5-lactone which comprises reacting a compound cis,cis-3,5-di(methylcarbonyloxy)-5-tert.butyldimethylsilyloxy) cyclohexyl-acetate of formula 4 with a lipase enzyme in a buffer having pH ranging from 5 to 7, at a temperature ranging from 25 to 30°C for a period ranging between 24 to 30 hours, extracting the mixture with an organic solvent, removing the solvent by evaporation and on column chromatography to obtain 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate.
In an embodiment of the present invention the organic solvent used for the extraction of the product is selected from the group consisting of ethyl acetate, chloroform, and dichloromethane.
In another embodiment the buffer used is selected from phosphate buffer and citrate buffer.
In yet another embodiment the lipase used is selected from the group consisting of pig procain lipase (PPL), pig liver esterase (PLE) and chicken liver acetone powder (CLAP).
Cis,cis-3,5-di(methylcarbonyloxy)cyclohexylacetate is prepared by treatment of acetic anhydride with cis-l,3,5-cyclohexantriol which is made by known literature procedure (Strong, P. N.; Keana, J. F. W. J. Org. Chem.1975, 40, 956).
The process of the present invention is described herein below with reference to the following examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.

Example 1
Preparation of cis, cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate
Finely powdered cis, cis-3,5-di(methylcarbonyloxy)cyclohexylacetate (6.5 parts,
25.19 mmol parts) was suspended in 0.1 M sodium phosphate buffer (pH 7) (135
parts) and stirred vigorously. To the stirred suspension Porcine Liver Esterase (0.110
parts) was added and reaction mixture was stirred vigorously at 30°C for 20 hr. pH of
the reaction mixture was monitored at every 2 hrs and was maintained at pH 7 using
IN NaOH solution. After completion of reaction (20 hr), it was extracted with ethyl
acetate (2 x 150 parts). Organic layers were combined and washed with brine, dried
on anhydrous sodium sulfate and concentrated under vacuum to yield cis,cis-3-
hydroxy-5-methylcarbonyloxycyclohexylacetate 3 yield (4.8 g parts, 88%).
1H NMR (CDCl3): δ 1.20-1.58 (qn, 3H), 2.08 (s, 6H), 2.28 (m, 3H), 3.78 (m, 1H), 4.78 (m, 2H)
13C NMR (CDC13): δ 21.15, 36.33, 39.93, 64.83, 67.65, 170.42
IR(KBr): 754.60, 884.15, 1029.29, 1140.34, 1250.00, 1367.64, 1738.92,2871.17, 2953.14,3445.47
Mass: Base m/e = 96 other m/e: 156, 138, 114, 73, 67, 67, 60, 55 Elemental analysis: calculated for C10Hl6O5: C 55.56%, H 7.40%
Found : C 55.30%, H 8.00%
Example 2
Preparation of cis,cis-3-(methyIcarbonyloxy)-5-(tert.butyldimethylsilyloxy) cyclo-
hexylacetate 4
Cis, cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate (3, 2 parts, 9.26 mmol) and DMAP (0.113 parts, 0.926 mmol) were placed in 100 ml two-necked round bottom flask equipped with dropping funnel and two-way stopcock. It was evacuated and flushed with argon. To it, dry dichloromethane (10 parts) and dry HMPA (2 part)
was added and stirred to dissolve. The solution was cooled to -10°C with stirring. To
it, solution of tert-butyldimethylsilyl chloride in 10 part dry dichloromethane was
added dropwise while maintaining temperature below 0°C. Reaction mixture was
stirred for 15 min and to it dry triethylamine (2.02 g, 20 mmol) was added dropwise.
Reaction mixture was stirred at room temperature for 12 hr. It was then transferred to
a separating funnel and washed successively with cold, dil. HC1 water, aq. NaHCO3
and then brine. Organic layer was dried on anhydrous sodium sulfate and solvent was
removed under vacuum. Residue was purified by flash column chromatography.
(eluent 2-4% ethyl acetate in petroleum ether) to yield Cis,cis-3-
(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate (4, yield 2.85
parts, 90%).
1H NMR (CDCl3): δ 0.06(s, 9H), 0.87 (s, 6H), 1.20-1.45 (m, 3H), 2.03 (s, 6H), (m, 3H), 3.38 (m, 1H), 4.73 (m, 2H-).
2.2 13C NMR (CDC13): δ -5.07, 17.61, 25.40, 36.17,40.40, 65.43, 67.01, 169.64
IR(CHCl3): 758.90, 838.05, 1034.91, 1106.32, 1246.82, 1368.91, 1734.01,2858.81, 2955.07
Mass: Base m/e= 117 other m/e: 273, 213, 171, 159, 129, 117,97,79,75,57
Elemental analysis: calculated for C26H30O5Si: C 58.185%, H 9.10%
Found :C 58.19%, H 9.50%
Example 3
Preparation of 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(lS,3R,5R)-cyclohexyl
acetate (5)
Cis, cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cycIohexylacetate (4, 5 patrs, 147 mmol) was dissolved in tert-butanol (20 parts). To the solution, 0.1 M sodium phosphate buffer (230 parts, pH 8) was added and mixture was stirred vigorously. To the stirred emulsion, Porcine liver esterase (0.150 parts) was added
and the mixture was stirred vigorously at 30°C for 54 hrs. During reaction pH was
maintained at 8 using IN sodium hydroxide solution. Reaction mixture was extracted
with ethyl acetate (3 x 200 parts). Organic layers were combined and washed with
brine. It was then dried on anhydrous sodium sulfate and solvent was removed under
vacuum. Oily residue contained 3-hydroxy-5-(tert.butyldimethylsilyloxy)-
(lS,3R,5R)-cyclohexylacetate 5 along with unreacted 4. Both were separated by
flash column chromatography. Cis,cis-3-(methylcarbonyloxy)-5-
(tert.butyldimethylsilyloxy)cyclo- hexylacetate recovered: 1.07 parts; 3-hydroxy-5-
(tert.butyldimethylsilyloxy)-(15',3R,5R)-cyclohexylacetate (5, yield 2.8 parts, 70%
based on recovered starting material.
1H NMR (CDCl3): δ 0.06 (s, 9H), 0.87 (s, 6H), 1.35-1.60, (m, 3H), 2.06 (s, 3H), 2.15 (m, 3H), 3.7 (m, 2H), 4.75 (m, 1H)
13C NMR (CDCl3): δ -4.60, 18.15, 21.38, 25.90, 39.98, 40.31, 43.93, 65.45, 66.40, 68.17, 170.68
IR(CHC13): 758.43,838.93, 1049.42, 1109.15, 1218.09, 1254.01, 1370.09, 1725.03, 2859.8, 2887.95,2952.33, 3017.48
Mass: Base m/e = 75 other m/e: 231, 171, 129, 117, 105,97,79,75,67,59 Elemental analysis: calculated for C14H2804Si: C 58.33%, H 9.72%
Found :C 58.15%, H 10.20%
Specific rotation [α]D = -4.8 (c 1, CHC13) e.e. >95% (determined by chiral HPLC of
corresponding Mosher ester. Column: Whelk-Ol [4.0 mm Id x 25 cm] AT-256; A.
=254 nm, flow rate: 1 ml/min; mobile phase: Hexane:isopropanol 98:02; retention
time for Mosher ester of 5 = 4.59, for Mosher ester of ent-5 = 4.34).

We claim :
1. A process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(1S,3R,5R)-cyclohexylacetate having formula 5 (Formula Removed)
useful as an intermediate for ß-hydroxy δ-lactone which comprises reacting a compound cis,cis-3,5-di(methylcarbonyloxy)-5-tert.'butyldimethylsilyloxy) cyclohexyl-acetate of formula 4 with a lipase enzyme in a buffer having pH ranging from 5 to 7, at a temperature ranging from 25 to 30°C for a period ranging between 24 to 30 hours, extracting the mixture with an organic solvent, removing the solvent by evaporation and on column chromatography to obtain 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate.
2. A process as claimed in claim 1, wherein the organic solvent used is selected from the group consisting of ethyl acetate, chloroform and dichloromethane.
3. An improved process as claimed in claims 1-2, wherein the buffer used is selected from phosphate buffer and citrate buffer.
4. A process as claimed in claims I-3, wherein the lipase used is selected from the group consisting of pig procain lipase (PPL), pig liver esterase (PLE) and chicken liver acetone powder (CLAP).
5. A process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(1S,3R,5R)-cyclohexylacetate useful as an intermediate for ß-hydroxy δ-lactone substantially as herein described with reference to the examples.

Documents:

0081-del-2001-abstract.pdf

0081-del-2001-claims.pdf

0081-del-2001-complete specification granted.pdf

0081-del-2001-correspondence-others.pdf

0081-del-2001-correspondence-po.pdf

0081-del-2001-description (complete).pdf

0081-del-2001-form-1.pdf

0081-del-2001-form-2.pdf

0081-del-2001-form-4.pdf

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Patent Number

199866

Indian Patent Application Number

0081/DEL/2001

PG Journal Number

33/2008

Publication Date

15-Aug-2008

Grant Date

12-Jan-2007

Date of Filing

31-Jan-2001

Name of Patentee

Council of Scientific and Industrial Research

Applicant Address

Rafi Marg, New Delhi - 110 001.

Inventors:

#	Inventor's Name	Inventor's Address
1	Sandeep Raghunath Ghorpade	National Chemical Laboratory, Pune 411 008, Maharastra.
2	Uttam Ramrao Kalkote	National Chemical Laboratory, Pune 411 008, Maharastra.
3	Subhash Prataprao Chavan	National Chemical Laboratory, Pune 411 008, Maharastra.
4	Sunil Ramchandra Bhide	National Chemical Laboratory, Pune 411 008, Maharastra.
5	Thottappillil Ravindranathan	National Chemical Laboratory, Pune 411 008, Maharastra.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA