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US 5,210,262 AGranted
Method for preparing a phosphonic acid ester
AssigneeE. R. Squibb & Sons, Inc.
InventorsJanak Singh, Richard H. Mueller
Life of this patent
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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=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.
Claims9
A method for preparing a compound having the structure ##STR42## wherein Y.sup.1 and Y.sup.2 are H or halogen;
- R.sup.2a, R.sup.3a and R.sup.4a may be the same or different and are independently 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 ##STR43## 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 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;
- ##STR44## CH.sub.3 (CH.sub.2).sub.p where p is an integer from 2 to 7 or R.sup.16 --C.tbd.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 ##STR45## 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 ##STR46## 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. C. to about 20.degree. C., to form the phosphonic acid diester of the structure ##STR47## treating the phosphonic acid diester with a strong aqueous base, an alkali metal cyanide or an alkali metal halide or treating said diester with bromotrimethylsilane or iodotrimethylsilane, under an inert atmosphere, in the presence of 2,4,6-collidine, and then treating with an alcohol of the formula
- R.sup.2a OH
- and dicyclohexylcarbodiimide to form the monoester ##STR48## treating the monoester with diethyl(trimethylsilyl)amine, under an inert atmosphere, treating and resulting reaction product with oxalyl chloride to form the acid chloride, and treating the acid chloride with a metal salt of the structure ##STR49## where M.sub.1 is Li.sup.+, Na.sup.+, K.sup.+, MgHal, .sup.+ ZnHal, Ce(Hal).sub.2 or Cu.sup.+, and R.sup.3a and R.sup.4a are independently selected from C.sub.1 -C.sub.8 alkyl or C.sub.3 -C.sub.12 alkenyl, to form the phosphinyl-phosphonate of the formula ##STR50##
13 more elements
A method for preparing a compound having the structure ##STR54## wherein Y.sup.1 and Y.sup.2 are H or halogen;
- R.sup.2a, R.sup.3a and R.sup.4a may be the same or different and are independently 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 ##STR55## 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 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;
- ##STR56## CH.sub.3 (CH.sub.2).sub.p where p is an integer from 2 to 7, or R.sup.16 --C.tbd.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 can 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 ##STR57## 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 ##STR58## 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. C. to about 20.degree. C., to form the phosphonic acid diester of the structure ##STR59## treating the phosphonic acid diester with a strong aqueous base, an alkali metal cyanide or an alkali metal halide or treating said diester with bromotrimethylsilane or iodotrimethylsilane, under an inert atmosphere, in the presence of 2,4,6-collidine, and then treating with an alcohol of the formula
- R.sup.2a OH
- and dicyclohexylcarbodiimide to form the monoester ##STR60## treating said monoester in pyridine, with p-nitrophenol and 4-dimethylaminopyridine and dicyclohexylcarbodiimide, under an inert atmosphere, to form the nitrophenol of the formula ##STR61## and treating the nitrophenol with a metal salt of the structure ##STR62## where M.sub.1 is Li.sup.+, Na.sup.+, K.sup.+, MgHal, .sup.+ ZnHal, Ce(Hal).sub.2 or Cu.sup.+, and R.sup.3a and R.sup.4a are independently selected from C.sub.1 -C.sub.8 alkyl or C.sub.3 -C.sub.12 alkenyl, to form the phosphinyl-phosphonate of the formula ##STR63##
11 more elements
Dependencies are inferred from the claim text.