Method of producing beraprost
AssigneeLung Biotechnology Inc.
InventorsVijay Sharma, Hitesh Batra, Sudersan Tuladhar
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Abstract
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.
Claims15
-6. (canceled)
The process of for preparing the stereoselectively produced isomeric compound of the following formula:
- wherein in R2a and R6 independently represent hydroxy protecting groups and R7 represents C1-6 alkoxy or C1-12 alkyl-COOR9, where R9 represents C1-3 alkyl comprising the steps of:
- (1) performing a cycloaddition reaction on the compound of the following formula:
- wherein in R2a and R6 independently represent hydroxy protecting groups to form a compound of the following formula:
- wherein R2a, R6 and Rare each defined above;
- (2) aromatization of the cyclodiene of formula (IV) to form the aromatic product of the following formula:
- wherein R2a, R6 and R7 are each defined above.
A process for preparing a compound of the following formula:
- wherein R1a represents a cation, H, or C1-12 alkyl, comprising the steps of:
- (1) performing a cycloaddition reaction on the compound of the following formula:
- wherein in R2a and R6 independently represent hydroxy protecting groups, with a compound of the following formula:
- wherein R7 represents C1-6 alkoxy or C1-12 alkyl-COOR9, where R9 represents C1-3 alkyl and R8 represents halide or H to form a compound of the following formula:
- wherein R2a, R6, R7, and R8 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 N2CH2CO2R1a, wherein R1a represents a C1-12 alkyl followed by hydrogenation of the alkyne to its corresponding alkane followed by deprotection of the hydroxyl protective groups to form a compound of the following formula:
- wherein R1a represents a cation, H, or C1-12 alkyl.
A compound represented by the formula:
- wherein x is
- R4 represents H or C1-3 alkyl, and
- R5 represents H or C1-6 alkyl, and the compound has a chiral purity of at least 95%.
A process for preparing a substantially pure compound of the following formula:
- R2 represents H or a hydroxy protective group,
- R4 represents H or C1-3 alkyl,
- R5 represents H or C1-6 alkyl, and
- Z represents C1-12 alkyl-COOR12, R12 is a cation, H, or C1-12 alkyl, comprising the steps of:
- (1) reacting an aldehyde of the formula
- with a substantially pure compound of the formula:
- wherein Z′ is C1-12 alkyl-COOR12′, R12′ is a C1-6 alkyl or a protecting group, R2a is a hydroxy protecting group, R4 and R5 are each defined above to form a compound of the following formula:
- (2) selectively reducing the carbonyl and deprotecting secondary alcohol to form a substantially pure compound of the following formula:
- and
- (3) optionally deprotecting the ester of protected acid of Z′ to form an acid or salt thereof.
Dependencies are inferred from the claim text.