Synthesis of intermediates for producing prostacyclin derivatives

Patent metadata

Field	Value
Publication number	US-9593061-B2
Application number	US-201514887298-A
Country	US
Kind code	B2
Filing date	Oct 19, 2015
Priority date	Oct 20, 2014
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

The present disclosure provides regioselective methods for synthesizing intermediates useful in making prostacyclin derivatives, such as treprostinil.

First claim

What is claimed is:

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.

Assignees

• United Therapeutics Corp

Inventors

• Batra Hitesh
• Tuladhar Sudersan M
• Walsh David A

Classifications

• C07C67/31 Primary

  by introduction of functional groups containing oxygen only in singly bound form · CPC title

• C07C45/67 Primary

  by isomerisation; by change of size of the carbon skeleton · CPC title

• C07C47/575

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C67/333

  by isomerisation; by change of size of the carbon skeleton (introduction or elimination of carboxyl groups C07C67/313, C07C67/32) · CPC title

• C07C2603/14

  Benz[f]indenes; Hydrogenated benz[f]indenes · CPC title