Treprostinil prodrugs

A method of synthesizing a compound of formula (VII):

• the method comprising:
• reacting treprostinil NH2CH2COOR4 to form a protected acetato amide compound of the following formula:
• and
• transferring the protected acetato amide compound into the compound of formula (VII), wherein R4 is C1-C4 alkyl or benzyl.

A method of synthesizing a cyclopentyl prodrug of treprostinil, the method comprising:

• (A) converting a compound of formula (1):
• wherein P1 is a hydroxyl protecting group or a silyl protecting group, into a compound of formula (2):
• wherein P0 is a hydroxyl protecting group;
• (B) converting the compound of formula (2) into a compound of formula (3):
• wherein R2 is
• Y is OR4, NR4R5, Cl, Br or OCCl3, each of R4 and R5 is independently selected from H and C1-4 alkyl;
• and
• (C) replacing in the compound of formula (3) each of P0 and P1 with hydrogen to form the cyclopentyl prodrug of treprostinil.

A method of synthesizing a side chain prodrug of treprostinil, the method comprising:

• (A) converting a compound of formula (1):
• wherein P1 is a hydroxyl protecting group or a silyl protecting group, into a compound of formula (4):
• wherein P′0 and P2 is a hydroxyl protecting group,
• (B) converting the compound of formula (4) into a compound of formula (5):
• (C) converting the compound of formula (5) into a compound of formula (6):
• where P0 is a hydroxyl protecting group,
• (D) converting the compound of formula (6) into a compound of formula (7):
• (E) converting the compound of formula (7) into a compound of formula (8):
• wherein R3 is
• wherein Y is OR4, NR4R5, Cl, Br or OCCl3, each of R4 and R5 is independently selected from H and C1-4 alkyl;
• and
• (F) replacing each of P0 and P2 in the compound of formula (8) with hydrogen to form the side chain prodrug of treprostinil.