Treprostinil production
The present invention is directed to a novel method for preparing a synthetic intermediate for treprostinil via a stereoselective alkyne addition reaction. Also described are methods of preparing treprostinil comprising the alkyne addition reaction described herein as well as novel intermediates useful for synthesis prostacyclin derivatives, such as treprostinil.
1. A method of preparing a compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, comprising:
reacting a compound represented by structural formula (I):
with a compound represented by structural formula (a):
to form a compound represented by structural formula (A):
wherein:
P 1 is an alcohol protecting group;
R is —(CH 2 ) m X;
X is COOR 1 ;
R 1 is an alkyl group; and
m is 1, 2 or 3, wherein the process further comprises:
(a) reacting the compound of structural formula (A) with a second alcohol protecting group to form a compound represented by structural formula (4):
and
(b) converting the compound of structural formula (4) to a tricyclic compound represented by structural formula (5):
(c) hydrogenating the tricyclic compound of structural formula (5) to form a hydrogenated tricyclic compound represented by structural formula (6):
and
(d) converting the hydrogenated tricyclic compound represented by structural formula (6) to a compound represented by structural formula (IX):
wherein said converting (d) accomplishes cleaving of the protective group P 1 and ester hydrolysis of R 1 in a single pot.
2. The method of claim 1 , wherein P2 is tert-butyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl (TBDPS), triethylsilyl (TES) or triphenylmethyl (trityl group).
3. The method of claim 2 , wherein P2 is tert-butyldimethylsilyl (TBDMS).
4. The method of claim 1 , wherein P1 is tetrahydrofuranyl (THP), benzyl, 2,4-dinitrobenzyl, methoxymethyl (MOM), tertiarybutyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl (TBDPS) or triethylsilyl (TES).
5. The method of claim 4 , wherein P1 is THP.
6. The method of claim 1 , wherein for the converting step (b), the compound of structural formula (4) is converted to the compound of structural formula (5) through a cobalt-mediated cyclization reaction.
7. The method of claim 6 , wherein the cobalt-mediated cyclization reaction is carried out in the presence of Co2(CO)8.
8. The method of claim 1 , wherein the hydrogenation reaction of step (c) is carried out in the presence of a base.
9. The method of claim 8 , wherein the base is K2CO3.
10. The method of claim 1 , wherein R1 is straight or branched C1-C5 alkyl.
11. The method of claim 10 , wherein R1 is methyl.
12. The method of claim 1 , further comprising
reacting the compound represented by formula (I):
to form the compound represented by the structural formula
13. The method of claim 1 , wherein m=1.
14. A method of preparing a compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, comprising:
reacting a compound represented by structural formula (I):
with a compound represented by structural formula (a):
to form a compound represented by structural formula (A):
wherein:
P 1 is an alcohol protecting group;
R is —(CH 2 ) m X;
X is COOR 1 ;
R 1 is a substituted or unsubstituted benzyl group; and
m is 1, 2 or 3, wherein the process further comprises:
(a) reacting the compound of structural formula (A) with a second alcohol protecting group to form a compound represented by structural formula (4):
and
(b) converting the compound of structural formula (4) to a tricyclic compound represented by structural formula (5):
(c) hydrogenating the tricyclic compound of structural formula (5) to form a hydrogenated tricyclic compound represented by structural formula (6′):
and
(d) converting the hydrogenated tricyclic compound represented by structural formula (6′) to a compound represented by structural formula (IX):
15. The method of claim 14 , wherein the hydrogenation reaction of step (c) is carried out in the presence of a base.
16. The method of claim 15 , wherein the base is K2CO3.
17. The method of claim 14 , wherein R1 is an unsubstituted benzyl group.
18. The method of claim 14 , wherein P2 is tert-butyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl (TBDPS), triethylsilyl (TES) or triphenylmethyl (trityl group).
19. The method of claim 18 , wherein P2 is tert-butyldimethylsilyl (TBDMS).
20. The method of claim 14 , wherein P1 is tetrahydrofuranyl (THP), benzyl, 2,4-dinitrobenzyl, methoxymethyl (MOM), tertiarybutyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl (TBDPS) or triethylsilyl (TES).
21. The method of claim 20 , wherein P1 is THP.
22. The method of claim 14 , wherein for the converting step (b), the compound of structural formula (4) is converted to the compound of structural formula (5) through a cobalt-mediated cyclization reaction.
23. The method of claim 22 , wherein the cobalt-mediated cyclization reaction is carried out in the presence of Co2(CO)8.