Pyranones

Details Pyranones Pyranones

1994-08-01

1996-06-18

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548236, 5483111, 549214, 549218, 549291, C07D27704, C07D30930

Patent

active

055279163

DESCRIPTION:

BRIEF SUMMARY
This invention relates to processes for the preparation of tetrahydropyran-2-ones which involve a kinetic resolution stage for producing at least one optically active isomer of a tetrahydro pyran-2-one having at least two chiral centres from a mixture of isomers, such as a cis or trans racemate or a mixture of cis and trans racemates, to certain novel isomers, particularly single enantiomers, of the tetrahydropyran-2-one, and to certain novel dihydropyran-2-ones and pyran-2-ones.
Optically active materials such as tetrahydropyran-2-ones may be used as intermediates in the manufacture of compounds such as pharmaceuticals, agrochemicals and chemicals for use in electronics industry. The optically active tetrahydropyran-2-ones of the present invention are particularly useful as intermediates in the manufacture of HMG-CoA reductase inhibitors. Available processes for the production of tetrahydropyran-2-ones are typically lengthy, require reagents which are expensive or difficult to handle on a large scale, give poor overall yields, and do not give access to all optical isomers.
According to the present invention there is provided a process for the separation of at least one isomer from a mixture of isomers of a tetrahydropyran-2-one, having at least two chiral centres, which comprises selective reaction of at least one isomer with a reagent catalysed by a hydrolase enzyme whereby at least one isomer is preferentially converted into a distinct chemical species from the other isomers so that it is susceptible of separation by an appropriate chemical or physical separation process in which the tetrahydropyran-2-one is of Formula (1): ##STR2## wherein: Z is --H or a protecting group susceptible of reaction with the reagent under the influence of the enzyme; and
The protecting group, Z, is preferably a readily displaceable protecting group. Examples of suitable readily displaceable protecting groups include --PO.(OR.sup.3).sub.2, --CO.R.sup.3 ; --SO.OR.sup.3 ; --NO.sub.2 and --(CO).OR.sup.3 in which each R.sup.3 is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted phenyl. Preferred examples of the protecting group, Z, include benzoyl, --COCH.sub.3, --CO(n--C.sub.3 H.sub.7) and --(CO)OCH.sub.3.
Where the group represented by Y is protected formyl it is preferably of the formula --CH(OR).sub.2, --CH(SR).sub.2 or --CH(OR)(SR) wherein each R independently is --H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted phenyl or two groups --OR or --SR attached to the same carbon atom, together with the carbon atom to which they are attached, form a 5- to 7-membered heterocycle. Examples of such groups are: ##STR3## in which each T is a divalent group. Examples of suitable groups represented by T are --C.sub.2 H.sub.4 --, --(CH.sub.2).sub.3 --, --CH(CH.sub.3)--CH(CH.sub.3)-- and --CH(Ph)--CH(Ph)--. Alternatively, the formyl group may be protected by conversion into an oxazolidine, imidazolidine, thiazolidine, bisulphite, O-substituted cyanohydrin such as O-acyl, O-tetrahydropyran-2-yl and O--SiR.sup.3 in which R.sup.3 is as hereinbefore defined, cyanohydrin, hydrazone or oxime derivative. It is preferred that the formyl group is protected by conversion into an oxazolidine.
Where R or R.sup.3 is or contains an alkyl group this is preferably C.sub.1-12 -alkyl, more preferably C.sub.1-6 -alkyl and especially methyl, ethyl, propyl or butyl.
Where R or R.sup.3 is or contains an alkenyl group this is preferably C.sub.2-12 -alkenyl, more preferably C.sub.2-6 -alkenyl and especially vinyl. Where any R or R.sup.3 is alkyl or alkenyl it may be in the form of a straight or R.sup.3 branched chain.
Where the group represented by R or is optionally R.sup.3 is optionally substituted alkyl or alkenyl, the substituent is preferably selected from C.sub.1-6 -alkoxy; halogen, such as --Cl, --Br or --F; hydroxy; cyano; --NR.sub.2 in which R is as hereinbefore defined such as --NMe.sub.2 ; cyclohexyl; phenyl; and protected primary and secondary amino groups suc

REFERENCES:
patent: 4625039 (1986-11-01), Jewell, Jr. et al.
Cardani et al, S. Tetrahedron 46(20) pp. 7283-7288 (1990).

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