Process for the production of beraprost and its salts

1. A compound of formula (VI):

wherein R 2 is a straight or branched alkyl group containing 1–4 carbon atoms—and R 1 is a methyl or an ethyl group.

2. A compound of the general formula (VI):

wherein R 1 stands for ethyl group and R 2 stands for methyl group.

3. A compound of formula (V):

wherein R 2 is a straight or branched alkyl group containing 1–4 carbon atoms—and R 1 is a methyl or an ethyl group.

4. A compound of formula (V):

wherein R 1 stands for ethyl group and R 2 stands for methyl group.

5. A compound of formula (IV):

wherein R 2 is a straight or branched alkyl group containing 1–4 carbon atoms—and R 1 is a methyl or an ethyl group.

6. A compound of the general formula (IV):

wherein R 1 stands for ethyl group and R 2 stands for methyl group.

7. A process for the preparation of the compound of formula (I):

and salts thereof, which comprises:

(A) reacting a compound of formula (VII):

wherein R 2 is a straight or branched alkyl group containing 1–4 carbon atoms, with a compound of formula (VIII):

(R 1 ) 3 Si—X  (VIII)

wherein R 1 is a methyl or an ethyl group, X is a chlorine, bromine or iodine atom,

CF 3 SO 2 —O-group, azido-, cyano-, or

group or acetamido or acetyloxy, to obtain a compound of formula (VI):

wherein the meaning of R 1 and R 2 are as defined above;

(B) oxidizing the compound of Formula (VI) into the aldehyde of the formula (V):

wherein the meaning of R 1 and R 2 are as defined above;

(C) reacting the aldehyde of formula (V), with or without isolation, with a phosphonate of formula (IX)

wherein R 3 is a straight or branched alkyl group containing 1–4 carbon atoms to obtain the compound of formula (IV):

wherein the meaning of R 1 and R 2 are as defined above;

(D) deprotecting the compound of formula (IV) by splitting off the protecting group at the position 11 to obtain the compound of formula (III):

wherein the meaning of R 2 is as defined above;

(E) reducing the compound of formula (III) to obtain the compound of formula (II):

wherein the meaning of R 2 is as defined above;

(F) hydrolyzing the compound of formula (II) to obtain an acid of the formula (I); and either:

(G) (i) isolating the acid of the compound of formula (I);

(ii) reacting the isolated acid of the compound of formula (I) with a base to form a salt of the compound of formula (I); and

(ii) isolating the salt of the compound of formula (I); or

(H) (i) reacting the acid of the compound of formula (I) with a base to form a salt of the compound of formula (I); and

(ii) isolating the salt of the compound of formula (I) thus obtained.

8. The process according to claim 7 , wherein in the compound of formula (VIII), R 1 is ethyl and X is chlorine, bromine or iodine atom, cyano-, azido-, CF 3 SO 2 —O— or

9. The process according to claim 1 , wherein the compound of formula (VI) is oxidized into a compound of formula (V) by using a mixture of dimethyl sulfoxide, oxalyl chloride and triethylamine.

10. The process according to claim 1 , wherein an aldehyde of formula (V) and a phosphonate of formula (IX) are reacted in a Wittig-HornerEmmon's reaction.

11. The process according to claim 1 , wherein the protecting group of the hydroxyl group at position 11 of the compound of formula (IV) is split off in the acidic medium.

12. The process according to claim 1 , wherein the reduction of a compound of formula (III) is carried out with diisobutylaluminium-2,6-di-tert.butyl-4-methylphenoxide.

13. The process according to claim 1 , wherein the compound of formula (II) is hydrolized in basic medium.

14. The process according to claim 1 , wherein the acid of formula (I) is transformed into its sodium salt and that salt is isolated.

15. The process of claim 7 , wherein the salt is a sodium salt of a compound of formula (I).