Title of Invention	"A PROCESS FOR THE PREPRATION OF A NOVEL 3-TETRAHYDRO -2H-2-PYRANYLOXY-5- (TERT.BUTYLDIMETHYLSILYLOXY)-1S,3R,5R)-CYCLO-HEXYLACETATE USEFUL AS AN INTERMEDIATE FOR ß-HYDROXY r-LACTONE"
Abstract	A process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclo-hexylacetate useful as an intermediate for ß-hydroxy δ-lactone A process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclo-hexylacetate useful as an intermediate for p-hydroxy 5-lactone by reacting a compound 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R, 5R)-cyclohexylacetate with dihydropyran in an organic solvent in the presence of p-toluene sulphonic acid at a temperature ranging from 5-10°C for a period ranging from 2 to 5 hrs, quenching the above reaction with an aqueous sodium bicarbonate, separating the organic layer, drying, on evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsllyloxy)-(1S,3R,5R)-cyclohexylacetate.

Title of Invention

"A PROCESS FOR THE PREPRATION OF A NOVEL 3-TETRAHYDRO -2H-2-PYRANYLOXY-5- (TERT.BUTYLDIMETHYLSILYLOXY)-1S,3R,5R)-CYCLO-HEXYLACETATE USEFUL AS AN INTERMEDIATE FOR ß-HYDROXY r-LACTONE"

Abstract

A process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclo-hexylacetate useful as an intermediate for ß-hydroxy δ-lactone A process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclo-hexylacetate useful as an intermediate for p-hydroxy 5-lactone by reacting a compound 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R, 5R)-cyclohexylacetate with dihydropyran in an organic solvent in the presence of p-toluene sulphonic acid at a temperature ranging from 5-10°C for a period ranging from 2 to 5 hrs, quenching the above reaction with an aqueous sodium bicarbonate, separating the organic layer, drying, on evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsllyloxy)-(1S,3R,5R)-cyclohexylacetate.

Full Text	The present relates to a process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyioxy)-(1S,3R,5R)-cyclohexylacetate useful as an intermediate for ß-hydroxy δ-lactone. More particularly it relates to a process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylace-tate having formula 6 from a compound 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclo-hexylacetate having formula 5 (Formula Removed) useful as an intermediate for 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone having formula 1. (Formula Removed) The compound ß-hydroxy-δ-lactone (1) is an important intermediate in the synthesis of biologically active drugs e.g. compactin, atorvastatin, fluvastatin , cholesterol lowering drugs. Hitherto known processes for the synthesis of P-hydroxy-5-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. Chetn., 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. 1SP4739,073) 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, 21, 2279-82 e) Racemic and optically active p-hydroxy-5-lactone from cis-cyclohexane-1,3,5-triol (K. Prasad & O. Repic, Tet. Lett., 1984, 21, 2435-38; H. Suemune, M. Takahashi, S. Maeda, Z. Fxi & K. Sakai, Tet. Asymm. 1990, 1, 425-8, M. Cauda, V.Eyken & M. Vandewalle, Tet. Asymmetry 1990, i, 17-20). f) Enzymatic kinetic resolution of racemic p-hydroxy-6-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 dilTicult 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-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate useful as an intermediate for 6-hydroxymethyi-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone. Yet another object is to provide a process for the preparation of 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone 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-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclo-hexylacetate having formula 6 (Formula Removed) useful as an intermediate for 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R, 6S)-tetrahydro-2H-2-pyranone which comprises reacting a compound 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(15,3R,5R)- cyclohexylacetate (5) with dihydropyran in an organic solvent in the presence of p- toluene sulphonic acid at a temperature ranging from 5 -10 °C for a period ranging from 2 to 5 hrs, quenching the above reaction with an aqueous sodium bicarbonate, separating the organic layer, drying, on evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)- cyclohexylacetate. In an embodiment of the present invention the organic solvent used is selected from the group consisting of ethyl acetate, chloroform, dichloromethane, methanol or diethyl ether. The compound 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1 S,3R,5R) cyclohexylacetate (5) is prepared by a procedure as described and claimed in our earlier co-pending patent application no. NF 27/01 The process of the present invention is described herein below with references to the following examples, which are illustrative only and should not be construed to unit the scope of the present invention in any maimer. Example 1 Preparation of cis, cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate 3: Finely powdered cis, cis-3,5-di(methylcarbonyloxy)cyclohexylacetate 2 (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 1N 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 (CDCl3): 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 C10H16O5: C 55.56%, H 7.40% Found : C 55.30%, H 8.00% Example 2 Preparation of cis,cis-3-(methylcarbonyloxy)-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. HCl 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), 2.2 (m, 3H), 3.38 (m, 1H), 4.73 (m, 2H). 2.3 13C NMR (CDCl3): 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)cyclohexylacetate (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 1N 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)-(1S,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(CHCl3): 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 C14H28O4Si: C 58.33%, H 9.72% Found : C 58.15%, H 10.20% Specific rotation [α]D = -4.8 (c 1, CHCl3) e.e. >95%) (determined by chiral HPLC of corresponding Mosher ester. Column: Whelk-O1 [4.0 mm Id x 25 cm] AT-256; =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). Example 4: Preparation of 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)- (1S,3R,5R)-cyclohexylacetate (6) 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate (5, 2.9 parts, 9.73 mmol) was dissolved in dry dichloromethane (30 parts). The solution was cooled below 0°C in ice-salt bath. To the stirred solution, dihydropyran (1 part, 12 mmol) was added and p-toluenesulfonic acid monohydrate (0.1 part) was added as catalyst. Reaction mixture was stirred at -10°C for 2 hr. Reaction was quenched by adding aqueous sodium bicarbonate solution. Both the layers were separated. Aqueous layer was extracted dichloromethane (10 part). Organic layers were combined and washed with water followed by brine wash. It was then dried on anhydrous sodium sulfate and solvent was removed under vacuum. Residue was purified by flash column chromatography to yield 3-tetrahydro-2H-2-pyranyloxy-5- (tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate 6 (yield 3.7 parts, 99.5%). 1H NMR (CDCl3): δ 0.07 (s, 6H), 0.87 (s, 9H), 1.25-1.90 (m, 9H), 2.04 (s, 3H), 2.05-40 (m, 3H), 3.40-3.7S (m, 3H), 3.86 (m, 1H), 4.55-4.80 (m, 2H) 13C NMR (CDCl3): δ -4.90, 18.00, 19.40, 19.50, 25.20, 25.80, 30.90, 36.80, 40.70, 41.00, 42.80, 62.00, 62.50, 66.00, 68.00, 69.70, 95.00, 96.80 IR(CHCl3): 752.08, 768.22, 838.35, 1029.76, 1114.56, 1215.63, 1251.94, 1727.19, 2858.86, 2950.80, 3016.74 Mass: Base m/e = 85 other m/e: 231,211, 171, 159, 129, 117, 105, 101,85,79,75, 67,55 Elemental analysis: calculated for C19H36O5Si: C 61.29%, H 9.68%) Found : C 61.37%,, H 10.03% Specific rotation [α]D = +1.39 (c 1, CHCl3) We ciaim : 1. A process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5- (tert.butyldimethylsiiyloxy)-(1S,3R,5R)-cyclo-hexylacetate having formula 6 (Formula Removed) useful as an intermediate for ß-hydroxy 5-iactone which comprises reacting a compound 3-hydroxy-5-(tert.butyldimethyisilyloxy)-(1S,3R, 5R) -cyclohexylacetate having formula 5 as described in the specification with dihydropyran in an organic solvent in the presence of p-toluene sulphonic acid at a temperature ranging from 5-10°C for a period ranging from 2 to 5 hrs, quenching the above reaction with an aqueous sodium bicarbonate, separating the organic layer, drying, on evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilytoxy)-(1S.3R,5R)-cyclohexyiacetate. 2. A process as claimed in claims 1-2 wherein the organic solvent used for the reaction is selected from the group consisting of ethyl acetate, chloroform, dichloromethane, methanol or diethyl ether. 3, A process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5- (tert.butyldimethylsityloxy)-(1S,3R,5R)-cyciohexylacetate useful as an intermediate for ß-hydroxy 5-lactone substantially as herein described with reference to the examples.

Full Text

The present relates to a process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyioxy)-(1S,3R,5R)-cyclohexylacetate useful as an intermediate for ß-hydroxy δ-lactone.
More particularly it relates to a process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylace-tate having formula 6
from a compound 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclo-hexylacetate having formula 5
(Formula Removed)
useful as an intermediate for 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone having formula 1.
(Formula Removed)
The compound ß-hydroxy-δ-lactone (1) is an important intermediate in the synthesis
of biologically active drugs e.g. compactin, atorvastatin, fluvastatin , cholesterol lowering drugs.
Hitherto known processes for the synthesis of P-hydroxy-5-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. Chetn., 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. 1SP4739,073)
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, 21, 2279-82
e) Racemic and optically active p-hydroxy-5-lactone from cis-cyclohexane-1,3,5-triol (K. Prasad & O. Repic, Tet. Lett., 1984, 21, 2435-38; H. Suemune,
M. Takahashi, S. Maeda, Z. Fxi & K. Sakai, Tet. Asymm. 1990, 1, 425-8, M.
Cauda, V.Eyken & M. Vandewalle, Tet. Asymmetry 1990, i, 17-20).
f) Enzymatic kinetic resolution of racemic p-hydroxy-6-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 dilTicult 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-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate useful as an intermediate for 6-hydroxymethyi-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone.
Yet another object is to provide a process for the preparation of 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone 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-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclo-hexylacetate having formula 6
(Formula Removed)
useful as an intermediate for 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,
6S)-tetrahydro-2H-2-pyranone which comprises
reacting a compound 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(15,3R,5R)-
cyclohexylacetate (5) with dihydropyran in an organic solvent in the presence of p-
toluene sulphonic acid at a temperature ranging from 5 -10 °C for a period ranging
from 2 to 5 hrs, quenching the above reaction with an aqueous sodium bicarbonate,
separating the organic layer, drying, on evaporating and column chromatography to
obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-
cyclohexylacetate.
In an embodiment of the present invention the organic solvent used is selected from the group consisting of ethyl acetate, chloroform, dichloromethane, methanol or diethyl ether.
The compound 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1 S,3R,5R)
cyclohexylacetate (5) is prepared by a procedure as described and claimed in our earlier co-pending patent application no. NF 27/01
The process of the present invention is described herein below with references to the following examples, which are illustrative only and should not be construed to unit the scope of the present invention in any maimer.
Example 1
Preparation of cis, cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate 3:
Finely powdered cis, cis-3,5-di(methylcarbonyloxy)cyclohexylacetate 2 (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
1N 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 (CDCl3): 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 C10H16O5: C 55.56%, H 7.40%
Found : C 55.30%, H 8.00%
Example 2
Preparation of cis,cis-3-(methylcarbonyloxy)-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. HCl 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),
2.2 (m, 3H), 3.38 (m, 1H), 4.73 (m, 2H).
2.3 13C NMR (CDCl3): 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)cyclohexylacetate (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 1N 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)-(1S,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(CHCl3): 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 C14H28O4Si: C 58.33%, H 9.72%
Found : C 58.15%, H 10.20%
Specific rotation [α]D = -4.8 (c 1, CHCl3) e.e. >95%) (determined by chiral HPLC of corresponding Mosher ester. Column: Whelk-O1 [4.0 mm Id x 25 cm] AT-256; =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).
Example 4:
Preparation of 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-
(1S,3R,5R)-cyclohexylacetate (6)
3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate (5, 2.9 parts, 9.73 mmol) was dissolved in dry dichloromethane (30 parts). The solution was cooled below 0°C in ice-salt bath. To the stirred solution, dihydropyran (1 part, 12 mmol) was added and p-toluenesulfonic acid monohydrate (0.1 part) was added as catalyst. Reaction mixture was stirred at -10°C for 2 hr. Reaction was quenched by
adding aqueous sodium bicarbonate solution. Both the layers were separated.
Aqueous layer was extracted dichloromethane (10 part). Organic layers were
combined and washed with water followed by brine wash. It was then dried on
anhydrous sodium sulfate and solvent was removed under vacuum. Residue was
purified by flash column chromatography to yield 3-tetrahydro-2H-2-pyranyloxy-5-
(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate 6 (yield 3.7 parts, 99.5%).
1H NMR (CDCl3): δ 0.07 (s, 6H), 0.87 (s, 9H), 1.25-1.90 (m, 9H), 2.04 (s, 3H), 2.05-40 (m, 3H), 3.40-3.7S (m, 3H), 3.86 (m, 1H), 4.55-4.80 (m, 2H)
13C NMR (CDCl3): δ -4.90, 18.00, 19.40, 19.50, 25.20, 25.80, 30.90, 36.80, 40.70, 41.00, 42.80, 62.00, 62.50, 66.00, 68.00, 69.70, 95.00, 96.80
IR(CHCl3): 752.08, 768.22, 838.35, 1029.76, 1114.56, 1215.63, 1251.94, 1727.19, 2858.86, 2950.80, 3016.74
Mass: Base m/e = 85 other m/e: 231,211, 171, 159, 129, 117, 105, 101,85,79,75, 67,55
Elemental analysis: calculated for C19H36O5Si: C 61.29%, H 9.68%)
Found : C 61.37%,, H 10.03%
Specific rotation [α]D = +1.39 (c 1, CHCl3)

We ciaim :
1. A process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-
(tert.butyldimethylsiiyloxy)-(1S,3R,5R)-cyclo-hexylacetate having formula 6
(Formula Removed)
useful as an intermediate for ß-hydroxy 5-iactone which comprises reacting a compound 3-hydroxy-5-(tert.butyldimethyisilyloxy)-(1S,3R, 5R) -cyclohexylacetate having formula 5 as described in the specification with dihydropyran in an organic solvent in the presence of p-toluene sulphonic acid at a temperature ranging from 5-10°C for a period ranging from 2 to 5 hrs, quenching the above reaction with an aqueous sodium bicarbonate, separating the organic layer, drying, on evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilytoxy)-(1S.3R,5R)-cyclohexyiacetate.
2. A process as claimed in claims 1-2 wherein the organic solvent used for the
reaction is selected from the group consisting of ethyl acetate, chloroform,
dichloromethane, methanol or diethyl ether.
3, A process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-
(tert.butyldimethylsityloxy)-(1S,3R,5R)-cyciohexylacetate useful as an intermediate
for ß-hydroxy 5-lactone substantially as herein described with reference to the
examples.

Documents:

82-del-2001-abstract..pdf

82-del-2001-claims.pdf

82-del-2001-complete specification(granted).pdf

82-del-2001-correspondence-others.pdf

82-del-2001-correspondence-po.pdf

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

82-del-2001-form-1.pdf

82-del-2001-form-2.pdf

82-del-2001-form-4.pdf

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Patent Number

195688

Indian Patent Application Number

82/DEL/2001

PG Journal Number

31/2009

Publication Date

31-Jul-2009

Grant Date

21-Apr-2006

Date of Filing

31-Jan-2001

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG NEW DELHI.110001 INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SANDEEP RAGHUNATH GHORPADE	NATIONAL CHEMICAL LABORATORY PUNE 411 008 MAHARASHTRA INDIA.
2	UTTAM RAMRAO KALKOTE	NATIONAL CHEMICAL LABORATORY PUNE 411 008 MAHARASHTRA INDIA.
3	SUBHASH PRATAPRAO CHAVAN	NATIONAL CHEMICAL LABORATORY PUNE 411 008 MAHARASHTRA INDIA.
4	SUNIL RAMCHANDRA BHIDE	NATIONAL CHEMICAL LABORATORY PUNE 411 008 MAHARASHTRA INDIA.
5	THOTT APPILLIL RAVINDRANATHAN	NATIONAL CHEMICAL LABORATORY PUNE 411 008 MAHARASHTRA INDIA.

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