Synthesis of intermediates for producing prostacyclin derivatives
The present disclosure provides regioselective methods for synthesizing intermediates useful in making prostacyclin derivatives, such as treprostinil.
1. A method of producing a compound of formula 3:
comprising heating a solution comprising a compound of formula 2:
and an organic solvent, wherein said heating comprises irradiating said solution with microwave radiation and wherein X is hydrogen, an alkoxy group, or OR 2 , unsubstituted or substituted aryl, or unsubstituted or substituted benzyl, wherein R 2 is C 1-4 alkyl; unsubstituted or substituted aryl; or unsubstituted or substituted benzyl, and wherein the organic solvent comprises at least one of triglyme, N-methylpyrrolidinone, tetradecane, tetrahydronaphthalene, p-chlorophenol, 1,2-dichlorobenzene, diphenyl ether, and a mixture of 26.5% diphenyl and 73.5% diphenyl oxide.
2. The method of claim 1 , wherein said solution is heated at a temperature ranging from 175° C. to 195° C.
3. The method of claim 1 , wherein X is hydrogen or an alkoxy group.
4. The method of claim 3 , wherein said heating results in separating the compound of formula 3 from a compound of formula 4:
5. The method of claim 3 , further comprising O-alkylating the compound of formula 3 to form a compound of formula 5
wherein R 1 is selected from (a) unsubstituted or substituted benzyl and (b) CH 2 COOR 4 , wherein R 4 is C 1-4 alkyl.
6. The method of claim 5 , further comprising forming from the compound of formula 5 treprostinil using a process comprising Pauson-Khand cyclization.
7. The method of claim 5 , wherein R 1 is benzyl or substituted benzyl.
8. The method of claim 5 , wherein R 1 is CH 2 COOR 4 , wherein R 4 is C 1-4 alkyl.
9. The method of claim 1 , wherein X is OR 2 , where R 2 is C 1-4 alkyl; unsubstituted or substituted aryl; or unsubstituted or substituted benzyl.
10. The method of claim 9 , wherein R 2 is methyl.
11. The method of claim 9 , wherein R 2 is ethyl.
12. The method of claim 9 , further comprising separating the compound of formula 3 from a compound of formula 4:
by a selective base hydrolysis.
13. The method of claim 9 , further comprising O-alkylating the compound of formula 3 to form a compound of formula 5
wherein R 1 is selected from a) benzyl or substituted benzyl; and b) CH 2 COOR 4 , wherein R 4 is C 1-4 alkyl.
14. The method of claim 13 , further comprising forming from the compound of formula 5 treprostinil using a process comprising Pauson-Khand cyclization.
15. The method of claim 13 , wherein R 1 is benzyl or substituted benzyl.
16. The method of claim 13 , wherein R 1 is CH 2 COOR 4 .
17. The method of claim 9 , further comprising O-alkylating and hydrolyzing the compound of formula 3 to form a compound of formula 11
wherein R 3 is C 1-4 alkyl or a phenolic protecting group.
18. The method of claim 17 , further comprising forming from the compound of formula 11 treprostinil using a process comprising Pauson-Khand cyclization.
19. The method of claim 17 , wherein R 3 is C 1-4 alkyl.
20. The method of claim 17 , wherein R 3 is a phenolic protecting group.
21. The method of claim 20 , wherein R 3 is benzyl.
22. The method of claim 1 , further comprising allylating a compound of formula 1
to produce the compound of formula 2.