Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-15
2002-07-09
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C560S128000, C556S482000
Reexamination Certificate
active
06417374
ABSTRACT:
This invention relates to a process for the preparation of optically active 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone (&bgr;-hydroxy-&dgr;-lactone) having formula 1.
More particularly it relates to a process for the preparation of the said compound using Cis,cis-3,5-di(methylcarbonyloxy)cyclohexylacetate having formula 2
The compound &bgr;-hydroxy-&dgr;-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 &bgr;-hydroxy-&dgr;-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-1,3-dioxalane-4-ethanal with optically active (R)-methyl-p-tolylsulphoxide which in turn obtained by oxidation of methyl-p-tolysulphide 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-1,3-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 &bgr;-hydroxy-&dgr;-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 &bgr;-hydroxy-&dgr;-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 A1 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 1-methoxybuta-1,3-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]
l) 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 aluminum 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 new process for the preparation of &bgr;-hydroxy-&dgr;-lactone (1), which obviates the drawbacks of the prior art processes and use cheaper and easily accessible chemicals.
Another object of the present invention is to provide (i) selective Baeyer-Villiger rearrangement of 3-hydroxy-5-t-butyldimethylsilyloxy-1-cyclohexanone (9) with chemical reagent or Baeyer Villiger oxidase and (ii) enantioselective hydrolysis of cis-3-(methylcarbonyloxy)-5-(tert-butyldimethylsilyloxy)cyclohexylacetate with enzyme.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly the present invention provides a process for the preparation of &bgr;-hydroxy-&dgr;-lactone of formula 1 using novel intermediates which comprises
a) reacting a compound of formula 2 with a lipase enzyme in a buffer having
pH ranging between 5 to 7, at a temperature ranging from 25 to 30° C. for a period ranging between 19 to 30 hrs. extracting the reaction mixture with an organic solvent, removing the solvent by evaporation to obtain cis,cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate having formula (3),
b) reacting a compound of formula 3 with tert-butyldimethylsilylchloride in an organic solvent in the presence of an organic base at a temperature ranging from −15 to 20° C. for a period ranging from 6 to 12 hrs, separating the organic solvent, to obtain cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate having formula 4,
c) reacting a compound 4 with a lipase enzyme in a buffer having pH in the range of 5 to 8, at a temperature ranging from 25 to 30° C. for a period ranging between 24 to 60 hrs., 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)-cyclohexylace-tate having formula 5,
d) reacting a compound of formula 5 with dihydropyran in an organic solvent in the presence of p-toluene sulphonic acid at a temperature ranging from 5 to 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 having formula 6,
e) reacting a compound of formula 6 with an anhydrous potassium carbonate in methanol at room temperature for a period ranging from 2 to 6 hrs, evaporating the solvent, extracting with an organic solvent, washing with brine solution, drying, evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexan-1-ol having formula 7,
f) reacting a compound of formula 7 with pyridinium chlorochromate in an organic solvent at room temperature for a period ranging from 6 to 8 hours, extracting the above mixture with an ether, washing with brine, drying, on evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexan-1-one having formula 8,
g) reacting a compound of formula 8 with magnesium bromide in an organic solvent at a temperature ranging from 5 to 30° C. for a period ranging from 1 to 12 hours, quenching the above reaction ammonium chloride, separating the organic layer, drying and on evaporating to obtain 3-hydroxy-5-(tert-butyldimethyl silyloxy)-(3S,5R)-cyclohexan-1-one having formula 9,
h) reacting a compound of formula 9 with m-chloroperbenzoic acid at room temperature for a period ranging from 16-24 hours, extracting the compound with an orgainc layer, washing with sodium metabisulphite, brine, drying and on evaporation to obtain 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone having formula 1.
In an embodiment of the present invention the organic solvent used in steps a, c, e and h for the extraction of the product is selected from the group consisting of ethyl acetate, chloroform, dichloromethane and t-butanol.
In an a
Bhide Sunil Ramchandra
Chavan Subhash Prataprao
Ghorpade Sandeep Raghunath
Kalkote Uttam Ramrao
Ravindranathan Thottappillil
Council of Scientific & Industrial Research
Owens Amelia
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