Process to prepare treprostinil, the active ingredient in remodulin

A process for the preparation of a compound of formula I

• comprising
• (a) alkylating a compound of structure II with an alkylating agent to produce a compound of formula III,
• wherein
• w=1, 2, or 3;
• Y1 is trans-CH═CH—, cis-CH═CH—, —CH2(CH2)m—, or —C≡C—;
• m is 1, 2, or 3;
• R7 is
• (1) —CpH2p—CH3, wherein p is an integer from 1 to 5, inclusive,
• (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3) alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy, only when R3 and R4 are hydrogen or methyl, being the same or different,
• (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl,
• (4) cis-CH═CH—CH2—CH3,
• (5) —(CH2)2—CH(OH)—CH3, or
• (6) —(CH2)3—CH═C(CH3)2;
• —C(L1)-R7 taken together is
• (1) (C4-C7)cycloalkyl optionally substituted by 1 to 3 (C1-C5)alkyl;
• (2) 2-(2-furyl)ethyl,
• (3) 2-(3-thienyl)ethoxy, or
• (4) 3-thienyloxymethyl;
• M1 is α-OH:β-R5 or α-R5:β-OH or α-OR1:β-R5 or α-R5:β-OR2, wherein R5 is hydrogen or methyl, R2 is an alcohol protecting group, and
• L1 is α-R3:β-R4, α-R4:β-R3, or a mixture of α-R3:β-R4 and α-R4:β-R3, wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and
• R4 is fluoro only when the other is hydrogen or fluoro,
• (b) hydrolyzing the product of formula III of step (a) with a base,
• (c) contacting the product of step (b) with a base B to form a salt of formula Is,
• (d) reacting the salt formed in step (c) with an acid to form the compound of formula I.