US 5,177,239 AGranted

Method for preparing a phosphonic acid ester

AssigneeE. R. Squibb & Sons, Inc.

InventorsJanak Singh, Richard H. Mueller

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Abstract

A method is provided for preparing a phosphonic acid ester having the structure ##STR1## wherein R.sup.1 is farnesyl or a derivative or analog thereof, and R.sup.2 is lower alkyl, by treating a farnesyl halide R.sup.1 Hal(Hal.dbd.Cl,Br,I) with an alkoxide of the structure ##STR2## wherein M is an alkali metal and R.sup.2c is lower alkyl. The resulting phosphonic acid ester is an intermediate in preparing a squalene synthetase inhibitor which is used for inhibiting cholesterol biosynthesis.

Claims10

Dependent claims

A method for preparing a phosphonic acid ester compound having the structure ##STR20## wherein R.sup.2a is C.sub.1 to C.sub.8 alkyl or C.sub.3 to C.sub.12 alkenyl;

R.sup.1 is R.sup.5 -Q.sup.1 -Q.sup.2 -Q.sup.3 - wherein Q.sup.1, Q.sup.2 and Q.sup.3 are the same or different and are independently ##STR21## --CH.sub.2 --C.dbd.C--CH.sub.2 -- or a single bond, with the proviso that if Q.sup.1 is a bond, then Q.sup.2 and Q.sup.3 are bonds;
and if Q.sup.2 is a bond then Q.sup.3 is a bond;
and R.sup.1 must include at least one double bond;
and wherein R.sup.6 is H, lower alkyl, halo or haloalkyl;
R.sup.7 is H, halogen, lower alkyl or lower alkylthio;
R.sup.8 is H, halogen, trimethylsilyl or lower alkyl;
and R.sup.9 is H or lower alkyl;
##STR22## CH.sub.3 (CH.sub.2).sub.p where p is an integer from 2 to 7, or R.sup.16 --C.dbd.C--CH.sub.2 --where R.sup.16 is H or lower alkyl;
R.sup.10 and R.sup.11 are the same or different and are independently H, lower alkyl, haloalkyl, halogen or lower alkenyl or R.sup.10 and R.sup.11 can be taken together to form (CH.sub.2).sub.s where s is an integer from 2 to 7;
R.sup.12 is H, lower alkyl, halogen or lower alkenyl;
and R.sup.13 and R.sup.14 are the same or different and are independently lower alkyl;
with the proviso that if all of Q.sup.1, Q.sup.2 and Q.sup.3 are bonds, then both R.sup.10 and R.sup.11 cannot be H, and R.sup.5 cannot be CH.sub.3 (CH.sub.2).sub.p --with p less than or equal to 4, and including all stereoisomers thereof, which comprises treating a solution of a carbinol of the structure. ##STR23## in an inert organic solvent, with a strong base which has the structure
KN[Si(alkyl).sub.3 ].sub.2
at a temperature of within the range of from about -20.degree. C. to about 20.degree. C., under an inert atmosphere, to form an alkoxide of the structure. ##STR24## reacting an allylic halide of the structure
R.sup.1 Hal
wherein Hal is Cl, Br or I, wherein R.sup.1 is as defined above, with said alkoxide, at a temperature within the range of from about -20.degree. to about 20.degree. C., to form the phosphonic acid ester of the structure ##STR25## wherein lower alkyl by itself or as part of another group has 1 to 8 carbons in the normal chain.

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Dependencies are inferred from the claim text.

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Abstract

A method for preparing a phosphonic acid ester compound having the structure ##STR20## wherein R.sup.2a is C.sub.1 to C.sub.8 alkyl or C.sub.3 to C.sub.12 alkenyl;

R.sup.1 is R.sup.5 -Q.sup.1 -Q.sup.2 -Q.sup.3 - wherein Q.sup.1, Q.sup.2 and Q.sup.3 are the same or different and are independently ##STR21## --CH.sub.2 --C.dbd.C--CH.sub.2 -- or a single bond, with the proviso that if Q.sup.1 is a bond, then Q.sup.2 and Q.sup.3 are bonds;
and if Q.sup.2 is a bond then Q.sup.3 is a bond;
and R.sup.1 must include at least one double bond;
and wherein R.sup.6 is H, lower alkyl, halo or haloalkyl;
R.sup.7 is H, halogen, lower alkyl or lower alkylthio;
R.sup.8 is H, halogen, trimethylsilyl or lower alkyl;
and R.sup.9 is H or lower alkyl;
##STR22## CH.sub.3 (CH.sub.2).sub.p where p is an integer from 2 to 7, or R.sup.16 --C.dbd.C--CH.sub.2 --where R.sup.16 is H or lower alkyl;
R.sup.10 and R.sup.11 are the same or different and are independently H, lower alkyl, haloalkyl, halogen or lower alkenyl or R.sup.10 and R.sup.11 can be taken together to form (CH.sub.2).sub.s where s is an integer from 2 to 7;
R.sup.12 is H, lower alkyl, halogen or lower alkenyl;
and R.sup.13 and R.sup.14 are the same or different and are independently lower alkyl;
with the proviso that if all of Q.sup.1, Q.sup.2 and Q.sup.3 are bonds, then both R.sup.10 and R.sup.11 cannot be H, and R.sup.5 cannot be CH.sub.3 (CH.sub.2).sub.p --with p less than or equal to 4, and including all stereoisomers thereof, which comprises treating a solution of a carbinol of the structure. ##STR23## in an inert organic solvent, with a strong base which has the structure
KN[Si(alkyl).sub.3 ].sub.2
at a temperature of within the range of from about -20.degree. C. to about 20.degree. C., under an inert atmosphere, to form an alkoxide of the structure. ##STR24## reacting an allylic halide of the structure
R.sup.1 Hal
wherein Hal is Cl, Br or I, wherein R.sup.1 is as defined above, with said alkoxide, at a temperature within the range of from about -20.degree. to about 20.degree. C., to form the phosphonic acid ester of the structure ##STR25## wherein lower alkyl by itself or as part of another group has 1 to 8 carbons in the normal chain.

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