Process for the preparation of treprostinil

Method for the preparation of treprostinil of formula I and its amorph salt forms, salt anhydrates, and monohydrates and polyhydrates of salts given with bases,

• characterized in that,
• a compound of the general formula XVII
• wherein R1 is a protective group containing a silicon atom, or a tetrahydropyranyl-, trityl-, methoxymethyl, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group, with the proviso that the R1 protective group must be selectively removable in the presence of R2 and R4, x is 0 or 2, is reacted with a compound of the general formula XVI
• wherein R2 is —(CH2)nY, where Y stands for a hydrogen atom, halogen atom, phenyl, nitrile, —OR5 or —COOR5 group, wherein R5 means C1-4 alkyl-, or a tetrahydropyranyl-, tri(C1-4 )alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl- group and n stands for 1,2,3, or 4,
• a1.) in the presence of Grignard reagent, and the resulting compound of the general formula XV
• wherein x, R1 and R2 have the meanings as defined above, is oxidized, the resulting compound of the general formula XIV
• wherein x, R1 and R2 have the meanings as defined above, is selectively reduced, or
• a2.) in the presence of chiral base and zinc salt, and the compound of the general formula XIII. obtained in step a1.) or a2.)
• wherein x, R1 and R2 have the meanings as defined above, is reacted with a compound which introduces the group R3 where R3 is a protective group containing a silicon atom, or a tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group,
• b.) the resulting compound of the general formula XII
• wherein x, R1, R2 and R3 have the meanings as defined above, is subjected to intramolecular cyclisation,
• c.) the resulting compound of the general formula XI
• wherein x, R1, R2 and R3 have the meanings as defined above, is catalytically hydrogenated, and in the case where x═0, isomerized,
• d.) the resulting compound of the general formula Xa. or Xb.
• wherein R1, R2 have the meanings as defined above, and in compound of formula Xa. x═0, in compound of formula Xb. x═2 is reduced,
• e.) the resulting compound of the general formula IX
• wherein x, R1 and R2 have the meanings as defined above, is reacted with a compound which introduces the group R4 where R4 is a protective group containing a silicon atom, or a trityl-, methoxytrityl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group, with the proviso that the R4 protective group must be selectively removable in the presence of R2 and R1 must be selectively removable in the presence of R4,
• f.) from the resulting compound of the general formula VIII
• wherein x, R1, R2 and R4 have the meanings as defined above, the R1 protective group is cleaved in acidic medium,
• g.) the resulting compound of the general formula VII
• wherein x, R2 and R4 have the meanings as defined above, is oxidized,
• h.) the resulting compound of the general formula VI
• wherein x, R2 and R4 have the meanings as defined above,
• h1.) in the case where x means 0, is reacted in Wittig reaction with the compound of the general formula
• CH3—(CH2)4—CO—CH2—PO(OR6)2
• wherein R6 stands for C1-4 alkyl- or phenyl-group and the resulting compound of the general formula V
• wherein R2 and R4 have the meanings as defined above, is selectively reduced, and the R4 protective group of the resulting compound of the general formula IVa.
• wherein R2 and R4 have the meanings as defined above, R4 is removed, and the resulting compound of the general formula III
• wherein R2 has the meaning as defined above, is hydrogenated, or
• h2.) in the case where x means 2, is reacted in the presence of chiral catalyst with an organic metal reagent, and the protective group R4 of the resulting compound of the general formula IVb.
• wherein R2 and R4 have the meanings as defined above, R4 is removed,
• i) the compound of the general formula II obtained in steps h1.) or h2.)
• wherein R2 has the meaning as defined above is transformed into treprostinil of formula I and if desired, into its salts given with bases.