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 compound of the following formula:
wherein R 1 represents a cation, H, or C 1-12 alkyl,
R 2 and R 3 each represent H or a hydroxy protective group,
R 4 represents H or C 1-3 alkyl, and
R 5 represents H or C 1-6 alkyl, comprising the steps of:
(1) performing a cycloaddition reaction on the compound of the following formula:
wherein in R 2a and R 6 independently represent hydroxy protecting groups,
with a compound of the following formula:
wherein R 7 represents C 1-6 alkoxy or C 1-12 alkyl-COOR 9 , where R 9 represents C 1-3 alkyl and R 8 represents halide or H to form a compound of the following formula:
wherein R 2a , R 6 , R 7 , and R 8 are each defined above;
(2) aromatizing the cyclodiene of formula (IV) to form the aromatic product of the following formula:
(3) Reducing the ester of the compound of formula (V) to a benzyl alcohol and oxidation of benzyl alcohol to an aldehyde followed by addition of a carbon to said aldehyde to form an alkyne resulting in a compound of the following formula:
(4) coupling the terminal alkyne with N 2 CH 2 CO 2 R 1a , wherein R 1a represents a C 1-12 alkyl followed by hydrogenation of the alkyne to its corresponding alkane to form a compound of the following formula:
(5) selectively deprotecting the primary hydroxyl protective group, followed by oxidation of the primary hydroxyl group to the corresponding aldehyde, followed by coupling with a side-chain of the formula:
wherein R 4 and R 5 are each defined above to form a compound of the following formula:
(6) reduction of the ketone, deprotection of any remaining hydroxy protective group and optionally converting the R 1a into a cation or H to form a compound of the following formula:
2. The process of claim 1 , wherein the compound of formula (I) is produced as a substantially pure single isomer.
3. The process of claim 1 , wherein R 1 is a cation or H, R 2 and R 3 are H, R 4 and R 5 are CH 3 .
4. The process of claim 1 , wherein R 2 , R 3 , R 2a and R 6 each independently represent trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, phenyldimethylsilyl, or tetrahydropyranyl.
5. The process of claim 1 , wherein the cycloaddition of step (1) is an inverse electron demand Diels Alder reaction followed by thermal decarboxylation.
6. The process of claim 1 , wherein the aromatization step (2) is treatment of the compound of formula (IV) with palladium on carbon.