Process for the preparation of N-(4-hydroxyphenyl)-retinamide
AssigneeOrtho Pharmaceutical Corporation
InventorCynthia A. Maryanoff
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Abstract
This invention is directed to an efficient, mild, high yield process for the large scale synthesis of N-(4-hydroxyphenyl)-retinamide comprising the preferred steps of reacting retinoic acid with dimethylchloroformamidinium chloride to from retinoyl chloride which in turn is reacted with bis-(N,O)-trimethylsilyl-p-aminophenol to eventually form N-(4-hydroxyphenyl)-retinamide and to the novel use of bis-(N,O)-trimethylsilyl-p-aminophenol to eventually form a hydroxyphenylamide, particularly N-(4-hydroxyphenylretinamide and methods of recrystallizing N-(4-hydroxyphenyl)-retinamide to obtain the stable "A" polymorph thereof.
Claims20
A mild, high yield process for the large scale synthesis of N-(4-hydroxyphenyl)-retinamide comprising the steps of:
- reacting retinoic acid with dimethylchloroformamidinium chloride at ambient temperature to form retinoyl chloride;
- and
- reacting retinoyl chloride with a tertiary substituted, bis-(N,O)-(silyl)-p-aminophenol of the formula bis-(R.sub.1,R.sub.2, R.sub.3 silyl)-p-aminophenol wherein R.sub.1-3 are the same or different and are phenyl or C.sub.1-5 alkyl, at a temperature of below 20.degree. C. to eventually form N-(4-hydroxyphenyl)-retinamide.
A method of using bis-(R.sub.1,R.sub.2,R.sub.3 silyl)-p-aminophenol as an intermediate to eventually produce N-(4-hydroxyphenyl)-retinamide wherein R.sub.1-3 are the same or different and are phenyl or C.sub.1-5 alkyl.
A method of using bis-(R.sub.1,R.sub.2,R.sub.3 silyl)-p-aminophenol as an intermediate to eventually produce a hydroxyphenylamide.
Dependencies are inferred from the claim text.