Process for preparing synthetic prostacyclins

1. A method for preparing a synthetic prostacyclin or a synthetic intermediate thereof, wherein the method comprises contacting an aldehyde with an enantiomerically pure phosphonate in a Horner-Emmons reaction to provide an alkene,

wherein the enantiomerically pure phosphonate has a structure:

wherein R″ and R′″ are alkyl; and

wherein the synthetic prostacyclin or synthetic intermediate thereof is produced as a single isomer.

2. The method of claim 1 , wherein the aldehyde is a product of the ozonolysis of a compound of formula (V), (V′) or (V″):

wherein:

R is a directly attached carboxylic acid or ester group or is a carboxylic acid or ester group attached via an aliphatic linker, optionally wherein the aliphatic linker is branched or substituted;

X 1 and X 2 are independently H or an aryl group substituent;

X 3 is H or an alkyl group substituent;

A is —O—, —S—, or —CH 2 —; and

Y and Z are hydroxyl protecting groups, which can be the same or different;

or a stereoisomer thereof.

3. The method of claim 2 , wherein R is —CO 2 R′, —(CH 2 ) n —CO 2 R′, —O—(CH 2 ) n —CO 2 R′, or —CH 2 ═CH 2 —(CH 2 ) n —CO 2 R′, wherein n is an integer between 1 and 8 and R′ is H, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl.

4. The method of claim 2 , wherein Y and Z are each —C(═O)CH 3 .

5. The method of claim 2 , wherein the aldehyde is the product of the ozonolysis of a compound of formula (V):

wherein:

R is a directly attached carboxylic acid or ester group or is a carboxylic acid or ester group attached via an aliphatic linker, optionally wherein the aliphatic linker is branched or substituted;

X 1 and X 2 are independently H or an aryl group substituent; and

Y and Z are hydroxyl protecting groups, which can be the same or different;

or a stereoisomer thereof.

6. The method of claim 5 , wherein the compound of formula (V) is the compound:

or a stereoisomer thereof.

7. The method of claim 1 , further comprising stereoselectively reducing a ketone in the alkene compound formed during the Horner-Emmons reaction.

8. The method of claim 7 , wherein the stereoselective reduction is performed using a Corey-Bakshi-Shibata (CBS) catalyst.

9. The method of claim 1 , further comprising deprotecting protected hydroxyl groups.

10. The method of claim 1 , wherein the synthetic prostacyclin is Beraprost.

11. A synthetic prostacyclin or synthetic intermediate thereof, prepared according to the method of claim 1 .

12. A synthetic prostacyclin prepared according to the method of claim 1 , wherein the synthetic prostacyclin is a single isomer of Beraprost.

13. A method for preparing a synthetic prostacyclin or synthetic intermediate thereof, wherein the method comprises:

(a) providing a compound of formula (V), (V′) or (V″):

wherein:

R is a directly attached carboxylic acid or ester group or is a carboxylic acid or ester group attached via an aliphatic linker, optionally wherein the aliphatic linker is branched or substituted;

X 1 and X 2 are independently H or an aryl group substituent;

X 3 is H or an alkyl group substituent;

A is —O—, —S—, or —CH 2 —; and

Y and Z are hydroxyl protecting groups, which can be the same or different;

or a stereoisomer thereof;

(b) deprotecting the compound of formula (V), (V′) or (V″) to provide a diol comprising a primary alcohol and a secondary alcohol; and

(c) selectively oxidizing the primary alcohol of the diol to provide an aldehyde-containing compound of one of formulas (XIII), (XIII′) or (XIII″):

or a stereoisomer thereof, wherein R, X 1 , X 2 , X 3 , and A are as defined for the compounds of formulas (V), (V′), and (V″).

14. A method for producing a compound of formula (V), wherein the method comprises:

(a) coupling compound A:

or a stereoisomer thereof, and

a compound of formula (B):

wherein:

X is halo,

R is a directly attached carboxylic acid or ester group or is a carboxylic acid or ester group attached via an aliphatic linker, optionally wherein the aliphatic linker is branched or substituted; and

X 1 and X 2 are independently H or an aryl group substituent;

(b) cyclizing the product of step (a) to form a cyclized compound;

(c) reducing a ketone group in the cyclized compound to form a compound comprising a secondary alcohol; and

(d) performing an oxidative rearrangement of the compound prepared in step (c) or a compound prepared by protecting the secondary alcohol group of the compound prepared in step (c).

15. A method for preparing a synthetic prostacyclin or synthetic intermediate thereof, wherein the method comprises the use of a synthetic intermediate of formula (V), (V′), or (V″) or a hydroxyl group deprotected derivative thereof, wherein formulas (V), (V′), and (V″) are:

wherein:

R is a directly attached carboxylic acid or ester group or is a carboxylic acid or ester group attached via an aliphatic linker, optionally wherein the aliphatic linker is branched or substituted;

X 1 and X 2 are independently H or an aryl group substituent;

X 3 is H or an alkyl group substituent;

A is —O—, —S—, or —CH 2 —; and

Y and Z are hydroxyl protecting groups, which can be the same or different; or a stereoisomer thereof, and

wherein the hydroxyl group deprotected derivative thereof is a compound of one of formulas (V), (V′), and (V″) wherein one or both of Z and Y are replaced by a hydrogen atom.

16. A compound of formula (V), (V′), or (V″) or a hydroxyl group deprotected derivative thereof, wherein formulas (V), (V′), and (V″) are:

wherein:

R is a directly attached carboxylic acid or ester group or is a carboxylic acid or ester group attached via an aliphatic linker, optionally wherein the aliphatic linker is branched or substituted;

X 1 and X 2 are independently H or an aryl group substituent;

X 3 is H or an alkyl group substituent;

A is —O—, —S—, or —CH 2 —; and

Y and Z are hydroxyl protecting groups, which can be the same or different; or a stereoisomer thereof, and

wherein the hydroxyl group deprotected derivative thereof is a compound of one of formulas (V), (V′), and (V″) wherein one or both of Z and Y are replaced by a hydrogen atom.

17. A method for preparing an intermediate for a synthetic prostacyclin, wherein the method comprises contacting compound A:

or a stereoisomer and/or analog thereof with a halogenated coupling precursor molecule in a coupling reaction to provide a coupled halogenated molecule.

18. A compound of formula (XIV), (XIV′), or (XIV″):

wherein:

R is a directly attached carboxylic acid or ester group or is a carboxylic acid or ester group attached via an aliphatic linker, optionally wherein the aliphatic linker is branched or substituted;

X 1 and X 2 are independently H or an aryl group substituent;

X 3 is H or an alkyl group substituent; and

A is —O—, —S—, or —CH 2 —;

or a stereoisomer thereof.

19. A method of preparing a synthetic prostacyclin, wherein the method comprises alkylating a compound of formula (XIV), (XIV′), or (XIV″).