Preparation of .alpha.-arylalkanoic acids
AssigneeSyntex Pharmaceuticals International Ltd.
InventorGeorge C. Schloemer
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Abstract
Pharmaceutically useful optically active .alpha.-arylalkanoic acids or esters, ortho esters, or amides thereof are stereoselectively prepared by contacting an aryl magnesium Grignard reagent with an optically active .alpha.-substituted acyl halide to form the optically active aryl .alpha.-substituted alkyl ketone, which is ketalized and rearranged to the desired optically active .alpha.-arylalkanoic acid or the corresponding ester, ortho ester or amide. In an alternate embodiment, the aryl .alpha.-substituted alkyl ketone is reduced to the corresponding alkanol, which is rearranged to the .alpha.-arylalkanal. The alkanal so produced is converted to the desired optically active .alpha.-arylalkanoic acid by conventional methods.
Claims24
A process for producing a stereoisomer of the compound of the formula:
- ##STR48## in the substantial absence of any other stereoisomer of said compound which comprises contacting an organometallic compound of the formula:
- ArMX
- with an optically active acyl halide, acyl amine or acid anhydride of the formula:
- ##STR49## wherein Ar is substituted or unsubstituted naphthyl, M is magnesium, R.sub.1 is methyl, X is halogen, Y is halogen, the group of the formula:
- ##STR50## wherein R' and R" are alkyl or aryl or when taken together with N form a heterocyclic moiety which optionally can contain other hetero atoms, or acyloxy, and Z is a protected hydroxy group or a sulfonyloxy group of the formula:
- ##STR51## wherein R.sub.2 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl or arylalkyl.
A process for producing a material consisting essentially of a single stereoisomer of a compound of the formula:
- ##STR52## which comprises contacting an organometallic compound of the formula:
- ArMX
- with a material consisting essentially of a single stereoisomer of an acyl halide, acyl amine or acid anhydride of the formula:
- ##STR53## wherein Ar is substituted or unsubstituted naphthyl, M is magnesium, R.sub.1 is methyl, X is halogen, Y is halogen, the group of the formula:
- ##STR54## wherein R' and R" are alkyl or aryl or when taken together with N form a heterocyclic moiety which optionally can contain other hetero atoms, or acyloxy, and Z is a protected hydroxy group or a sulfonyloxy group of the formula:
- ##STR55## wherein R.sub.2 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl or arylalkyl.
A process for producing an .alpha.-arylalkanoic acid of the formula:
- ##STR57## which comprises:
- contacting an organometallic compound of the formula:
- ArMX, (Ar).sub.2 M or ArM'
- with an acyl halide, an acyl amine or an acid anhydride of the formula:
- ##STR58## wherein Ar is aryl, M is cadmium, copper(II), manganese, magnesium or zinc, M' is copper(I) or lithium, R.sub.1 is alkyl or cycloalkyl, X is halogen, Y is halogen, the group of the formula:
- ##STR59## wherein R' and R" are alkyl or aryl or when taken together with N form a heterocyclic moiety which optionally can contain other hetero atoms, or acyloxy, and Z is a protected hydroxy group or a sulfonyloxy group of the formula:
- ##STR60## wherein R.sup.2 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl or arylalkyl to form a ketone of the formula:
- ##STR61## reducing said ketone to the corresponding alcohol;
- contacting said alcohol so formed with a protic or dipolar, aprotic solvent for a time sufficient to form the aldehyde of the formula:
- ##STR62## oxidizing said aldehyde to said acid, and if Z is a protected hydroxy group, converting said group to said sulfonyloxy group either before or after said reducing step but before said contacting step.
Dependencies are inferred from the claim text.