Process for making piloloctam and derivatives thereof
AssigneeAllergan, Inc.
InventorsLloyd J. Dolby, Nestor A. Fedoruk, Shervin Esfandiari, Michael E. Garst
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Abstract
A process of preparing lactam derivatives of pilocarpine is disclosed. The process involves condensation of a dihydroxybutene and alkyl orthoester to form a lactone intermediate which is oxidized to trans-pilopic acid. This lactone ring is reacted with a benzylamine and the benzyl group removed with a novel dissolving metal reduction mixture to yield the key intermediate IV ##STR1## which can be elaborated to pilolactam through a known sequence of steps.
Claims19
A process of making ##STR10## which is useful in the synthesis of isopilolactam, pilolactam and derivatives thereof, comprising the steps of:
- (1) reacting trans-1,4-dihydroxy-2-butene with an ortho ester, R'C(OR.sub.1).sub.3, wherein R' is hydrogen or C.sub.1 to C.sub.6 alkyl, and R.sub.1 is methyl or ethyl, in the presence of hydroquinone to form a compound of formula I ##STR11## wherein R is hydrogen, methyl or ethyl;
- (2) cyclizing, with further heating, to a compound of formula II wherein the wavy line represents either the .alpha. or .beta. configuration;
- ##STR12## (3) treating the lactone intermediate of formula II in sequence with diborane, hydrogen peroxide and oxidation with chromium trioxide (Jones reagent) to yield trans-pilopic acid or analog of formula III;
- ##STR13## (4) condensing the trans-pilopic acid or analog with a benzylamine by heating;
- and
- (5) reducing the resulting N-benzylated lactam to a secondary lactam of formula IV ##STR14## by treatment with lithium in a mixture of R.sub.2 -NH.sub.2, wherein R.sub.2 is C.sub.1 to C.sub.6 alkyl, and ethylenediamine.
A process of reducing an N-benzyl-lactam to a secondary lactam comprising exposing the N-benzyl-lactam to a solution of lithium in R.sub.2 -NH.sub.2 wherein R.sub.2 is chosen from the group consisting of ethyl, propyl, and butyl, including all straight and branched chain isomers thereof, and ethylenediamine, for a time sufficient to effect reduction.
A process of converting a lactone ring of pilocarpine or a derivative thereof or a pilopic acid or a derivative thereof to a secondary lactam analog comprising condensing the lactone with a benzylamine to form a tertiary lactam and reducing said lactam in a solution of lithium in R.sub.2 -NH.sub.2 wherein R.sub.2 is chosen from the group consisting of ethyl, propyl, and butyl, including all straight and branched chain isomers thereof, and ethylenediamine, for a time sufficient to effect reduction.
A process of preparing the lactam of formula VI comprising ##STR15## reacting trans-1,4-dihydroxy-2-butene and ##STR16## wherein R' is or C.sub.1 to C.sub.3 alkyl, R is hydrogen, methyl or ethyl and R.sub.1 is methyl or ethyl, and Bz is benzyl or .alpha.-methylbenzyl, in the presence of hydroquinone to effect condensation, rearrangement and cyclization to the compound of formula VI.
Dependencies are inferred from the claim text.