Method of producing beraprost
An improved method is described for making single isomers of synthetic benzoprostacyclin analog 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 substantially pure compound of the following formula:
R 2 represents H or a hydroxy protective group,
R 4 represents H or C 1-3 alkyl,
R 5 represents H or C 1-6 alkyl, and
Z represents C 1-12 alkyl-COOR 12 , R 12 is a cation, H, or C 1-12 alkyl, comprising the steps of:
(1) reacting an aldehyde of the formula
with a substantially pure compound of the formula:
wherein Z′ is C 1-12 alkyl-COOR 12′ , R 12′ is a C 1-6 alkyl or a protecting group, R 2a is a hydroxy protecting group, R 4 and R 5 are each defined above to form a compound of the following formula:
and
(2) selectively reducing the carbonyl and deprotecting secondary alcohol to form a substantially pure compound of the following formula:
2. The method of claim 1 , wherein selective reduction of the carbonyl includes an asymmetric catalyst.
3. The method of claim 1 , further comprising deprotecting the ester of protected acid of Z′ to form an acid or salt thereof.
4. The method of claim 3 , wherein R 4 and R 5 are each CH 3 , Z is (CH 2 ) 3 COO R 12 and R 12 is a cation or H.
5. The method of claim 4 , wherein R 12 is a cation and the cation is K + .
6. The method of claim 5 , wherein the resulting substantially pure compound comprises greater than 99% of the isomer represented by the following formula:
7. The method of claim 3 , wherein Z′ is C 1-12 alkyl-COOR 12′ , and R 12′ is a C 1-6 alkyl.
8. The method of claim 1 , wherein R 2a is a silyl protecting group.
9. The method of claim 8 , wherein R 2a is trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or phenyldimethylsilyl.
10. The method of claim 1 , wherein said selective reducing uses a selective reducing agent selected from the group consisting of (R)-(+)-2-Butyl-CBS-oxazaborolidine and catecholborane, (R)-(+)-2-Methyl-CBS-oxazaborolidine and catecholborane, (+) DIP-chloride, NaBH 4 and 2-(3-Nitrophenyl)-1,3,2-dioxaborolane-4S,5S-dicarboxylic acid (D-TarB-NO 2 ), modified DIBAL reagents, and modified LAH agents.
11. The method of claim 1 , wherein R 2a is a silyl protecting group and wherein said selective reducing uses a selective reducing agent selected from the group consisting of (R)-(+)-2-Butyl-CBS-oxazaborolidine and catecholborane, (R)-(+)-2-Methyl-CBS-oxazaborolidine and catecholborane, (+) DIP-chloride, NaBH 4 and 2-(3-Nitrophenyl)-1,3,2-dioxaborolane-4S,5S-dicarboxylic acid (D-TarB-NO 2 ), modified DIBAL reagents, and modified LAH agents.
12. The method of claim 11 , wherein R 2a is trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or phenyldimethylsilyl.