Method of producing beraprost
An improved method is described for making single isomers of synthetic benzoprostacyclin analogue compounds, in particular the pharmacologically active 314-d isomer of beraprost. In contrast to the prior art, the method is stereoselective and requires fewer steps than the known methods for making these compounds.
1. A process for preparing a stereoselectively produced isomeric compound of the following formula:
wherein in R 2a and R 6 independently represent hydroxy protecting groups and R 7 represents C 1-6 alkoxy or C 1-12 alkyl-COOR 9 , where R 9 represents C 1-3 alkyl comprising the steps of:
(1) performing a cycloaddition reaction on a compound of the following formula:
wherein in R 2a and R 6 independently represent hydroxy protecting groups to form a cyclodiene compound of the following formula:
wherein R 2a , R 6 and R 7 are each defined above;
(2) aromatizing of the cyclodiene compound of formula (IV) to form an aromatic product of the following formula:
wherein R 2a , R 6 and R 7 are each defined above.
2. The process of claim 1 , wherein R 2a and R 6 each independently represent trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, phenyldimethylsilyl, or tetrahydropyranyl.
3. The process of claim 1 , wherein the cycloaddition of step (1) is an inverse electron demand Diels Alder reaction followed by thermal decarboxylation.
4. The process of claim 1 , wherein the aromatization step (2) is treatment of the compound of formula (IV) with palladium on carbon.