Process for the preparation of treprostinil and derivatives thereof
A method for the preparation of treprostinil and its derivatives is described. In contrast to prior art, this method utilizes an easily scalable enzymatic resolution of a key intermediate for making these compounds. Another significant improvement of the described method over prior methods is the regioselective Claisen rearrangement of a 5-allyloxy-benzaldehyde precursor, which is facilitated by a bromo substituent in 2-position.
1. A compound of the following formula I or formula II:
wherein:
X is Br and Y is H;
PG 1 is selected from the group consisting of methyl, methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, benzyl, 4-methoxybenzyl, 2,6-dichlorobenzyl, 3,4-dichlorobenzyl, —CH 2 COOH, —CH 2 COOR x , and —CH 2 CH 2 OPG 2 ;
PG 2 is tert-butyl-dimethylsilyl (TBDMS), tetrahydropyran (THP), SiR1R2R3, or —CH2ORx;
R a is hydrogen, hydroxy —OR x , —OCOOR x , —OSO 2 R x , Cl, Br, F, I, —SR x , or —SO 2 R x ; and
R x is C 1-4 alkyl or aryl.
2. The compound of claim 1 , wherein PG 2 is TBDMS.
3. The compound of claim 1 , wherein PG 2 is THP.
4. The compound of claim 1 , wherein PG 1 is benzyl.
5. The compound of claim 1 , wherein R a is hydrogen.
6. The compound of claim 1 , wherein R a is hydroxy.
7. The compound of claim 1 , wherein the compound is of formula I:
8. The compound of claim 7 , wherein PG 2 is TBDMS.
9. The compound of claim 7 , wherein PG 2 is THP.
10. The compound of claim 7 , wherein PG 1 is benzyl.
11. The compound of claim 7 , wherein R a is hydrogen.
12. The compound of claim 7 , wherein R a is hydroxy.
13. The compound of claim 1 , wherein the compound is of formula II:
14. The compound of claim 13 , wherein PG 2 is TBDMS.
15. The compound of claim 13 , wherein PG 2 is THP.
16. The compound of claim 13 , wherein R a is hydrogen.
17. The compound of claim 13 , wherein R a is hydroxy.