7-oxabicycloheptane carboxylic acid prostaglandin analog intermediates useful in the preparation of anti-thrombotic and anti-vasospastic compounds and method for preparing same

Abstract

A method is provided for preparing intermediates for 7-oxabicycloheptane carboxylic acid intermediates of the structures ##STR1## wherein R is alkyl, aryl, arylalkyl or cycloalkyl; R.sup.1 is alkyl, arylalkyl or cycloalkyl; R.sup.2 is aryl or arylalkyl; and of the structure ##STR2## where R and R.sup.1 are as defined above, which may be used in making the final anti-thrombotic--anti-vasospastic compounds.

Claims

1. A method for preparing a compound of the structure ##STR36## wherein R is alkyl, aryl, arylalkyl or cycloalkyl and R.sup.1 is alkyl, arylalkyl or cycloalkyl, which comprises providing a compound of the structure ##STR37## wherein R.sup.2 is aryl or arylalkyl, and subjecting the above compound to hydrogenolysis to form a compound of the structure ##STR38##

2. The method as defined in claim 1 wherein R.sup.1 is CH.sub.3 and R is n-pentyl.

3. The method as defined in claim 1 wherein the hydrogenolysis is carried out by treatent with hydrogen in the presence of hydrogenolysis catalyst.

4. The method as defined in claim 1 wherein the starting compound ##STR39## is prepared by subjecting a compound of the structure ##STR40## to an amination reaction by reacting with an amine of the structure

5. The method as defined in claim 4 wherein R.sup.1 is alkyl, R.sup.2 is arylalkyl, R is alkyl, and Hal is Br.

6. The method as defined in claim 4 wherein the compound of the structure ##STR41## is prepared by subjecting a compound of the structure ##STR42## to an amidation reaction by reacting with an amine of the structure

7. The method as defined in claim 6 wherein the compound of the structure ##STR43## wherein R.sup.1 is alkyl, is prepared by subjecting a compound of the structure ##STR44## to a halohydrin reaction by reacting with a halogenating agent and an alcohol R.sup.1 OH.

8. The method as defined in claim 6 wherein the halohydrin reaction is carried out by reacting the compound of the structure ##STR45## with N-bromosuccinimide and methanol, wherein R.sup.1 is alkyl.

9. A method for preparing a compound of the structure ##STR46## wherein R is alkyl, aryl, arylalkyl or cycloalkyl and R.sup.1 is alkyl, arylalkyl or cycloalkyl; which comprises reacting an acid chloride of the structure ##STR47## and a compound of the structure ##STR48## wherein R is alkyl, aryl, arylalkyl of cycloalkyl and R.sup.1 is alkyl, arylalkyl or cycloalkyl; in acoupling reaction to form a compound of the structure ##STR49##

10. The method as defined in claim 9 wherein the coupling reaction is a Schotten-Baumann coupling carried out in the presence of a base at a temperature within the range from about -15.degree. to about 20.degree. C.

11. A method for preparing a compound of the structure ##STR50## which comprises providing a starting compound of the structure ##STR51## wherein R is alkyl, aryl, arylalkyl or cycloalkyl and R.sup.1 is alkyl, aryl, arylalkyl or cycloalkyl, treating the above compound with a cyclizing agent to form a mixture of isomers of the structure ##STR52## and subjecting the above isomers to an elimination reaction to form the thromboxane receptor antagonist.

12. The method as defined in claim 11 wherein cyclization is achieved by reacting the starting compound with trimethylsilyl trifluoromethane sulfonate.

13. The method as defined in claim 11 wherein the elimination reaction is achieved by reacting the mixture of isomers with an organic base which is an alkali metal alkoxide.

14. The method as defined in claim 12 wherein the cyclization is carried out at a temperature within the range from about 15.degree. to about 50.degree. C.

15. The method as defined in claim 11 wherein R is n-pentyl and alkyl is CH.sub.3.

16. The method as defined in claim 11 wherein cyclization is achieved by reacting the starting material with a halosulfonic acid.

17. The method as defined in claim 16 wherein the halosulfonic acid is chlorosulfonic acid, bromosulfonic acid or fluorosulfonic acid.

18. The method as defined in claim 16 wherein the halosulfonic acid is chlorosulfonic acid.

19. The method as defined in claim 16 wherein the elimination reaction is achieved by reacting the mixture of isomers with potassium t-butoxide/butanol.

20. A compound having the structure ##STR53## wherein R is alkyl, aryl, arylalkyl or cycloalkyl; R.sup.1 is alkyl, arylalkyl or cycloalkyl;

R.sup.2 is aryl or arylalkyl;

R.sup.5 is amino, halogen, R.sup.2 NH, alkyl, aryl, arylalkyl or cycloalkyl.

21. The compound as defined in claim 20 having the structure ##STR54##

22. A compound as defined in claim 20 having the structure ##STR55##