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US 4,380,645 AGranted
Process for preparing Benzoxepino- or Benzthiapino[4,3-b]pyrrole-2-acetic acids
AssigneeMerck & Co., Inc.
InventorsBruce E. Witzel, Paul E. Finke, Debra L. Allison
Life of this patent
Estimating the term…
Abstract
Improved yields of Benzoxepino- or Benzthiapino[4,3-b]pyrrole-2-acetic acids have been achieved from processes based on modifications performed on a pyrrole carboxylic ester rather than on a pyrrole-.alpha.-oxoacetate.
Claims10
A process for preparing a compound of formula (II) ##STR13## wherein:
- Y is 0 or S;
- n is an integer from 1 to 4;
- R is
- (a) hydrogen;
- (b) lower alkyl;
- (c) halo-loweralkyl;
- (d) hydroxy or loweralkoxy;
- (e) --OCH.sub.2 O-- when n is 2 and the two Rs join together to form the methylenedioxy group;
- (f) halo;
- (g) lower alkylthio;
- (h) lower alkylsulfinyl;
- (i) lower alkylsulfonyl;
- or
- (j) lower alkenyl;
- R.sup.1 is
- (a) hydrogen;
- (b) lower alkyl;
- (c) lower alkenyl;
- (d) aralkyl;
- and
- R.sup.2 is
- (a) hydrogen;
- (b) lower alkyl;
- (c) halo;
- or
- (d) loweralkoxy;
- comprising:
- (1) Halogenating a compound of formula (III) ##STR14## wherein:
- R.sup.1 is as previously defined;
- and
- R.sup.3 is lower alkyl;
- (2) Treating the resultant 4-halomethyl derivative from Step (1) with a compound of formula ##STR15## wherein R, n, and Y are as previously defined;
- and M is an alkali metal cation;
- (3) Hydrolyzing the resultant 4--(R).sub.n C.sub.6 H.sub.5-n --Y-CH.sub.2 -derivative from Step (2) to a diacid of formula (V) ##STR16## (4) Inducing intramolecular ring closure of the diacid (V) by treatment with a condensing agent to form a tricyclic carboxylic acid of formula (VI) ##STR17## (5) Extending the carboxylic acid side chain of the tricyclic compound (VI) by the Arndt Eistert procedure which further comprises:
- (a) converting the tricyclic carboxylic acid (VI) to its corresponding acid chloride;
- (b) treating the acid chloride with a diazoalkane to form the corresponding diazoketone of compound (VI);
- (c) causing the diazoketone to rearrange to a homologous acid of formula (II) in the presence of a metal salt and a solvent.
34 more elements
A process for preparing a compound of formula (II) ##STR18## wherein:
- Y is 0 or S;
- n is an integer from 1 to 2;
- R is
- (a) hydrogen;
- (b) lower alkyl;
- (c) halo-loweralkyl;
- (d) hydroxy or loweralkoxy;
- (e) --OCH.sub.2 O-- when n is 2 and the two Rs join together to form the methylenedioxy group;
- (f) halo;
- (g) lower alkylthio;
- (h) lower alkylsulfinyl;
- (i) lower alkylsulfonyl;
- or
- (j) lower alkenyl;
- R.sup.1 is lower alkyl;
- R.sup.2 is
- (a) hydrogen;
- (b) lower alkyl;
- (c) halo;
- or
- (d) loweralkoxy;
- comprising:
- (1) Treating a 1,4-dialkylpyrrole-2-carboxylic acid ester with a compound of formula ##STR19## in the presence of a Lewis acid;
- (2) Converting the product from Step (1) to a compound of formula IX ##STR20## wherein X is halo;
- by halogenation and subsequent ether cleavage catalyzed by a Lewis acid;
- (3) Inducing intramolecular ring closure by treating compound IX with a strong base to form the tricyclic compound of formula (X);
- and ##STR21## (4) Converting the tricyclic compound (X) to its corresponding acid by hydrolysis;
- and
- (5) Extending the carboxylic acid side chain of the tricyclic compound of step (4) by the Arndt Eistert procedure which further comprises:
- (a) converting the tricyclic carboxylic acid of step (4) to its corresponding acid chloride;
- (b) treating the acid chloride with a diazoalkane to form the corresponding diazoketone of the compound of step (4);
- (c) causing the diazoketone to rearrange to a homologous acid of formula (II) in the presence of a metal salt and a solvent.
29 more elements
Dependencies are inferred from the claim text.