US 5,278,313 AGranted

Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors

AssigneeE. R. Squibb & Sons, Inc.

InventorsJohn K. Thottathil, Yadagiri Pendri, Wen-Sen Li, David R. Kronenthal

Life of this patent

Estimating the term…

Abstract

A novel, overall process for the preparation of a compound of the formula I: ##STR1## where R.sup.1 and R.sup.2 are each independently hydrogen, an alkyl group, a cycloalkyl group, an aryl group or, taken together with the carbon atom to which they are attached, form a cycloalkyl group; and R.sup.3 is hydrogen, an alkyl group, or an aryl group, or salts thereof, useful as intermediates in the preparation of HMG-CoA reductase inhibitors; novel methods within the overall process; and novel intermediates produced by those methods.

Claims4

Dependent claims

A process for the preparation of a compound of the formula I:

##STR40## where R.sup.1 and R.sup.2 are each independently hydrogen, an alkyl group, a cycloalkyl group, an aryl group or, taken together with the carbon atom to which they are attached, form a cycloalkyl group;
and
R.sup.3 is hydrogen, an alkyl group, or an aryl group;
or a salt thereof;
comprising the steps of:
(a) at a temperature of from about 25.degree. C. to about -90.degree. C., condensing a compound of the formula II:
##STR41## where X is a halogen atom;
and
R.sup.4 is an alkyl group, a cycloalkyl group or an aryl group,
with a compound of the formula III:
##STR42## where R.sup.3 is as defined above for the formula I, or a salt thereof, such that the molar ratio of the compound of the formula III to the compound of the formula II is from about 8:1 to 3:1, in the presence of a condensation agent such that the molar ratio of the condensation agent to the compound of the formula II is from about 8:1 to about 3:1, to form a compound of the formula IV:
##STR43## where X is as defined in formula II and R.sup.3 is as defined in formula I, or a salt thereof;
(b) at a temperature of from about -30.degree. C. to about -90.degree. C., reducing, in the presence of a reducing agent such that the molar ratio of the reducing agent to the compound of the formula IV is from about 1:1 to about 4:1, the compound of the formula IV or a salt thereof prepared in step (a) to form a compound of the formula V:
##STR44## where X is as defined in formula II and R.sup.3 is as defined in formula I, or a salt thereof;
(c) preparing a compound of the formula VII, or a salt thereof:
##STR45## where R.sup.1, R.sup.2 and R.sup.3 are as defined in formula I;
and
X is as defined in formula II, comprising the step of reacting, at a temperature of from about 0.degree. C. to about 60.degree. C., the compound of the formula V or a salt thereof prepared in step (b) with a compound of the formula VIa, VIb, or VIc:
##STR46## where R.sup.1 and R.sup.2 are as defined in formula I;
R.sup.1b and R.sup.2b are each independently hydrogen, an alkyl group, a cycloalkyl group, an aryl group or, taken together with the carbon atoms to which they are attached, form a 1,2- cycloalkenyl group;
and
R.sup.5 and R.sup.6 are each independently an alkyl group, such that the molar ratio of the compound of the formula VIa, VIb or VIc to the compound of the formula V is from about 1:1 to about 20:1, in the presence of an acidic condensation agent such that the molar ratio of the acidic condensation agent to the compound of the formula V is from about 1:1 to about 0.001:1;
(d) at a temperature of from about 0.degree. C. to about 130.degree. C., preparing a compound of the formula VIII:
##STR47## where R.sup.1, R.sup.2 and R.sup.3 are as defined in formula I;
and
R.sup.7 is an alkyl group or an aryl group;
or a salt thereof,
by displacing the group X of the compound of the formula VII or a salt thereof prepared in step (c) with an acyloxy group of the formula --O--C(O)--R.sup.7 by use of a displacement agent such that the molar ratio of the displacement agent to the compound of the formula VII is from about 1:1 to about 5:1;
and
(e) at a temperature of from about 0.degree. C. to about 100.degree. C., hydrolyzing in a mildly basic medium the compound of the formula VIII or a salt thereof prepared in step (d) with a hydrolyzing agent such that the molar ratio of hydrolyzing agent to the compound of the formula VIII is from about 2:1 to about 1:2, to produce the compound of the formula I or a salt thereof.

27 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…

Abstract

A process for the preparation of a compound of the formula I:

##STR40## where R.sup.1 and R.sup.2 are each independently hydrogen, an alkyl group, a cycloalkyl group, an aryl group or, taken together with the carbon atom to which they are attached, form a cycloalkyl group;
and
R.sup.3 is hydrogen, an alkyl group, or an aryl group;
or a salt thereof;
comprising the steps of:
(a) at a temperature of from about 25.degree. C. to about -90.degree. C., condensing a compound of the formula II:
##STR41## where X is a halogen atom;
and
R.sup.4 is an alkyl group, a cycloalkyl group or an aryl group,
with a compound of the formula III:
##STR42## where R.sup.3 is as defined above for the formula I, or a salt thereof, such that the molar ratio of the compound of the formula III to the compound of the formula II is from about 8:1 to 3:1, in the presence of a condensation agent such that the molar ratio of the condensation agent to the compound of the formula II is from about 8:1 to about 3:1, to form a compound of the formula IV:
##STR43## where X is as defined in formula II and R.sup.3 is as defined in formula I, or a salt thereof;
(b) at a temperature of from about -30.degree. C. to about -90.degree. C., reducing, in the presence of a reducing agent such that the molar ratio of the reducing agent to the compound of the formula IV is from about 1:1 to about 4:1, the compound of the formula IV or a salt thereof prepared in step (a) to form a compound of the formula V:
##STR44## where X is as defined in formula II and R.sup.3 is as defined in formula I, or a salt thereof;
(c) preparing a compound of the formula VII, or a salt thereof:
##STR45## where R.sup.1, R.sup.2 and R.sup.3 are as defined in formula I;
and
X is as defined in formula II, comprising the step of reacting, at a temperature of from about 0.degree. C. to about 60.degree. C., the compound of the formula V or a salt thereof prepared in step (b) with a compound of the formula VIa, VIb, or VIc:
##STR46## where R.sup.1 and R.sup.2 are as defined in formula I;
R.sup.1b and R.sup.2b are each independently hydrogen, an alkyl group, a cycloalkyl group, an aryl group or, taken together with the carbon atoms to which they are attached, form a 1,2- cycloalkenyl group;
and
R.sup.5 and R.sup.6 are each independently an alkyl group, such that the molar ratio of the compound of the formula VIa, VIb or VIc to the compound of the formula V is from about 1:1 to about 20:1, in the presence of an acidic condensation agent such that the molar ratio of the acidic condensation agent to the compound of the formula V is from about 1:1 to about 0.001:1;
(d) at a temperature of from about 0.degree. C. to about 130.degree. C., preparing a compound of the formula VIII:
##STR47## where R.sup.1, R.sup.2 and R.sup.3 are as defined in formula I;
and
R.sup.7 is an alkyl group or an aryl group;
or a salt thereof,
by displacing the group X of the compound of the formula VII or a salt thereof prepared in step (c) with an acyloxy group of the formula --O--C(O)--R.sup.7 by use of a displacement agent such that the molar ratio of the displacement agent to the compound of the formula VII is from about 1:1 to about 5:1;
and
(e) at a temperature of from about 0.degree. C. to about 100.degree. C., hydrolyzing in a mildly basic medium the compound of the formula VIII or a salt thereof prepared in step (d) with a hydrolyzing agent such that the molar ratio of hydrolyzing agent to the compound of the formula VIII is from about 2:1 to about 1:2, to produce the compound of the formula I or a salt thereof.

27 more elements