US 4,677,211 AGranted

Preparation of lactones

AssigneeSandoz Pharmaceuticals Corp.

InventorsCharles F. Jewell, Jr., James R. Wareing

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Abstract

7-Substituted lower alkyl hept-6-enoates and 4-hydroxytetrahydropyran-2-ones bearing 6-olefinic substituents (e.g.,) ethyl erythro-3,5-dihydroxy-7-phenyl-hept-6-enoates are prepared by a multi-step process. The process involves 3-protected-lower alkyl 3,5-dihydroxy-hept-6-enoates, which are obtained by cleaving corresponding 6.alpha.-vinyl-4.beta.-protected hydroxy-tetrahydro 2H-pyran-2-ones. The final products are useful as anti hypercholesteremic agents.

Claims16

Dependent claims

A method of preparing a compound of formula D:

##STR33## in single enantiomeric form in which P.sup.1 is a trisubstituted silyl radical having at least 2 bulky radicals selected from the group consisting of (a) tertiary alkyl (C.sub.4 to C.sub.8) groups, and (b) phenyl which may be unsubstituted or substituted by up to 2 of any of lower alkyl (C.sub.1 -C.sub.4), chloro, nitro, trifluoromethyl, or mono-substituted in the para-position by phenyl or benzyl which may be unsubstituted, or in turn substituted by one or two of such substituted groups as defined, and any non-bulky radical is unbranched alkyl having from 1 to 4 carbon atoms;
and
R.sub.6, is alkyl having from 1 to 3 carbon atoms, n-butyl, i-butyl, t-butyl or benzyl;
comprising
(a) reacting a compound of formula V:
##STR34## wherein each of R.sub.7 and R.sub.8 is, independently, a hydrogen atom or alkyl having from 1 to 6 carbon atoms;
and P.sup.1 is as defined;
under essentially anhydrous conditions, at about -10.degree. to +10.degree. C., with a compound of the formula
M--OR.sub.6 '
in which R.sub.6 ' is as defined and M is an alkali metal, in an alcohol of the formula
R.sub.6 '--OH
in which R.sub.6 ' is as defined to form a reaction product;
(b) quenching said reaction product with an aqueous solution, to form the corresponding compound of formula A:
##STR35## in which P.sup.1, R.sub.6 ', R.sub.7 and R.sub.8 are as defined;
(c) reacting said compound A with a compound of the formula B:
P.sup.1 --L B
in which P.sup.1 is as defined and L is a leaving group, in the presence of an acid acceptor, in an inert medium, at a temperature of from about +5.degree. to +40.degree., under essentially anhydrous conditions;
said leaving group being chloro, bromo, or iodo, or an alkyl and aryl sulfonyl radical, in which alkyl is C.sub.1 -C.sub.6 alkyl and aryl is phenyl which may be unsubstituted or mono-substituted by a C.sub.1 -C.sub.4 alkyl, to form the corresponding compound of formula C:
##STR36## in which P.sup.1, R.sub.6 ', R.sub.7 and R.sub.8 are as defined;
and (d) oxidizing said compound C by reacting which ozone at a temperature of from about -50.degree. to +80.degree. C., in an inert medium to form the corresponding ozonide;
and (e) reacting said ozonide with a mild reducing agent to form the corresponding compound D;
with the proviso that compound V has the 4R,6S form and each of compounds A, C, and D have the 3R,5S form.

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Dependencies are inferred from the claim text.

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Abstract

A method of preparing a compound of formula D:

##STR33## in single enantiomeric form in which P.sup.1 is a trisubstituted silyl radical having at least 2 bulky radicals selected from the group consisting of (a) tertiary alkyl (C.sub.4 to C.sub.8) groups, and (b) phenyl which may be unsubstituted or substituted by up to 2 of any of lower alkyl (C.sub.1 -C.sub.4), chloro, nitro, trifluoromethyl, or mono-substituted in the para-position by phenyl or benzyl which may be unsubstituted, or in turn substituted by one or two of such substituted groups as defined, and any non-bulky radical is unbranched alkyl having from 1 to 4 carbon atoms;
and
R.sub.6, is alkyl having from 1 to 3 carbon atoms, n-butyl, i-butyl, t-butyl or benzyl;
comprising
(a) reacting a compound of formula V:
##STR34## wherein each of R.sub.7 and R.sub.8 is, independently, a hydrogen atom or alkyl having from 1 to 6 carbon atoms;
and P.sup.1 is as defined;
under essentially anhydrous conditions, at about -10.degree. to +10.degree. C., with a compound of the formula
M--OR.sub.6 '
in which R.sub.6 ' is as defined and M is an alkali metal, in an alcohol of the formula
R.sub.6 '--OH
in which R.sub.6 ' is as defined to form a reaction product;
(b) quenching said reaction product with an aqueous solution, to form the corresponding compound of formula A:
##STR35## in which P.sup.1, R.sub.6 ', R.sub.7 and R.sub.8 are as defined;
(c) reacting said compound A with a compound of the formula B:
P.sup.1 --L B
in which P.sup.1 is as defined and L is a leaving group, in the presence of an acid acceptor, in an inert medium, at a temperature of from about +5.degree. to +40.degree., under essentially anhydrous conditions;
said leaving group being chloro, bromo, or iodo, or an alkyl and aryl sulfonyl radical, in which alkyl is C.sub.1 -C.sub.6 alkyl and aryl is phenyl which may be unsubstituted or mono-substituted by a C.sub.1 -C.sub.4 alkyl, to form the corresponding compound of formula C:
##STR36## in which P.sup.1, R.sub.6 ', R.sub.7 and R.sub.8 are as defined;
and (d) oxidizing said compound C by reacting which ozone at a temperature of from about -50.degree. to +80.degree. C., in an inert medium to form the corresponding ozonide;
and (e) reacting said ozonide with a mild reducing agent to form the corresponding compound D;
with the proviso that compound V has the 4R,6S form and each of compounds A, C, and D have the 3R,5S form.

19 more elements