U.S. Pat. No. 5,100,889 to Misra et al discloses 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs which are thromboxane A.sub.2 (TXA.sub.2) receptor antagonists or combined thromboxane A.sub.2 receptor antagonist/thromboxane synthetase inhibitors useful, for example, in the treatment of thrombotic and/or vasospastic diseases, and have good duration of action. Examples of compounds disclosed in Misra et al have the structural formula I ##STR1## and including all stereoisomers thereof, wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;
R.sup.1 is hydrogen, lower alkyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl, or amide ##STR2## wherein t is 1 to 12 and R.sub.a is lower alkyl, aryl, cycloalkyl, or cycloalkylalkyl); PA1 R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl; or R.sup.1 and R.sup.2 together with the nitrogen to which they are linked may form a 5- to 8-membered ring. PA1 R.sup.9 is H, OH or lower alkyl, preferably OH or H. PA1 R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl; or R.sup.1 and R.sup.2 together with the nitrogen to which they are linked may form a 5- to 8-membered ring. PA1 R.sup.1 is preferably lower alkyl such as n-pentyl, aryl such as phenyl, halophenyl such as 4-chlorophenyl, or cyclohexylalkyl, such as cyclohexylbutyl. PA1 R.sup.2 is preferably H or phenyl. PA1 R.sup.8 is H, aryl or lower alkyl, preferably H and PA1 R.sup.9 is H, OH or lower alkyl, preferably OH or H.
Misra et al disclose that these compounds may be prepared by transmetallating bromophenylalkyl B ##STR3## by treatment with t-C.sub.4 H.sub.9 Li or n-C.sub.4 H.sub.9 Li or subjecting B to a Grignard reaction by treatment with Mg, and then condensing with the perhydro benzopyran-3-ol derivative or the perhydro benzofuran-1-ol derivative C ##STR4## to form the condensed 7-oxabicycloheptane alcohol compound of the structure Z ##STR5## and then subjecting the condensed compound to hydrogenolysis to form the following alcohol D ##STR6## Where Pro is thexyldimethylsilyl or t-butyldimethylsilyl, the alcohol is acetylated and the silyl protecting group of the so-formed acetate is removed to form the following acetate: ##STR7## which is treated with a protecting compound and the acetate is removed by treatment with aqueous hydroxide or excess methyllithium to form the following alcohol: ##STR8## (where Pro is t-butyldiphenylsilyl). The protected alcohol is subjected to a Jones oxidation to form the following acid: ##STR9##
The so-formed carboxylic acid intermediate is then employed to make the final compound.
In a more preferred procedure, Misra et al disclose protecting the alcohol function of alcohol Z to form the protected alcohol ##STR10## subjecting the protected alcohol to a Jones oxidation and esterification to form the ester ##STR11## which is made to undergo hydrogenolysis and subsequent removal of the acetate protecting group by transesterification to afford the alcohol ##STR12## which is subjected to a Jones oxidation to form the carboxylic acid intermediate II ##STR13##
In an alternative procedure where n is 1, the above carboxylic acid intermediate II is formed by treating D' with acetic anhydride and removing the protecting group to form the acetate alcohol ##STR14## which is made to undergo a Dess-Martin oxidation to form the aldehyde ##STR15## The above aldehyde is oxidized and esterified to the corresponding acetate ester, deprotected, and subjected to a Jones oxidation to form carboxylic acid II where n is 1.