Synthesis of intermediates for producing prostacyclin derivatives

Patent metadata

Field	Value
Publication number	US-11225452-B2
Application number	US-202016991460-A
Country	US
Kind code	B2
Filing date	Aug 12, 2020
Priority date	Oct 20, 2014
Publication date	Jan 18, 2022
Grant date	Jan 18, 2022

Abstract

The present disclosure provides regioselective methods for synthesizing intermediates useful in making prostacyclin. The methods include heating the compound of Formula 2 at a temperature of 180° C. to 185° C. Wherein the heatingcomprises irradiating the compound of formula 2 with microwave radiation.

First claim

What is claimed is:

1. A method of producing a compound of formula 3:

comprising heating a compound of formula 2:

at a temperature ranging from 180° C. to 182° C., wherein said heating comprises irradiating the compound with microwave radiation,
wherein X is hydrogen, alkoxy, OR 2 , unsubstituted or substituted aryl, or unsubstituted or substituted benzyl, and
wherein R 2 is C 1-4 alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted benzyl,
wherein said heating results in separating the compound of formula 3 from a compound of formula 4:

2. The method of claim 1 , 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.

3. The method of claim 2 , further comprising forming from the compound of formula 5 treprostinil using a process comprising Pauson-Khand cyclization.

4. The method of claim 2 , wherein R 1 is benzyl or substituted benzyl.

5. The method of claim 2 , wherein R 1 is CH 2 COOR 4 , wherein R 4 is C 1-4 alkyl.

6. The method of claim 1 , wherein X is OR 2 .

7. The method of claim 6 , wherein R 2 is methyl.

8. The method of claim 6 , wherein R 2 is ethyl.

9. The method of claim 6 , 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.

10. The method of claim 9 , further comprising forming from the compound of formula 5 treprostinil using a process comprising Pauson-Khand cyclization.

11. The method of claim 9 , wherein R 1 is benzyl or substituted benzyl.

12. The method of claim 9 , wherein R 1 is CH 2 COOR 4 .

13. The method of claim 1 , further comprising allylating a compound of formula 1:

to produce the compound of formula 2.

14. The method of claim 1 , wherein the compound of formula 2 is heated without a solvent.

15. The method of claim 1 , wherein the compound of formula 2 is heated in a solution comprising carbitol.

16. A method of producing a compound of formula 3:

comprising heating a solution comprising a solvent and a compound of formula 2:

at a temperature ranging from 182° C. to 185° C., wherein said heating comprises irradiating the solution with microwave radiation,
wherein X is hydrogen, alkoxy, OR 2 , unsubstituted or substituted aryl, or unsubstituted or substituted benzyl, and
wherein R 2 is C 1-4 alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted benzyl,
wherein the solvent comprises at least one of tetrahydronaphthalene, N-methylpyrrolidone, and 1,2 dichlorobenzene.

17. The method of claim 16 wherein the solvent comprises at least one of tetrahydronaphthalene and 1,2 dichlorobenzene.

18. A method of producing a compound of formula 3:

comprising heating a compound of formula 2:

at a temperature ranging from 180° C. to 182° C., wherein said heating comprises irradiating the compound with microwave radiation,
wherein X is hydrogen, alkoxy, OR 2 , unsubstituted or substituted aryl, or unsubstituted or substituted benzyl, and
wherein R 2 is C 1-4 alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted benzyl and wherein the compound of formula 2 is heated without a solvent.

19. The method of claim 18 , 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.

20. The method of claim 19 , further comprising forming from the treprostinil compound of formula 5 using a process comprising Pauson-Khand cyclization.

21. The method of claim 19 , wherein R 1 is benzyl or substituted benzyl.

22. The method of claim 19 , wherein R 1 is CH 2 COOR 4 , wherein R 4 is C 1-4 alkyl.

23. The method of claim 18 , wherein X is OR 2 .

24. The method of claim 23 , wherein R 2 is methyl.

25. The method of claim 23 , wherein R 2 is ethyl.

26. The method of claim 23 , 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.

27. The method of claim 26 , further comprising forming from the compound of formula 5 treprostinil using a process comprising Pauson-Khand cyclization.

28. The method of claim 26 , wherein R 1 is benzyl or substituted benzyl.

29. The method of claim 26 , wherein R 1 is CH 2 COOR 4 .

30. The method of claim 18 , further comprising allylating a compound of formula 1:

to produce the compound of formula 2.

31. A method of producing a compound of formula 3:

comprising heating a compound of formula 2:

at a temperature ranging from 180° C. to 182° C., wherein said heating comprises irradiating the compound with microwave radiation,
wherein X is hydrogen, alkoxy, OR 2 , unsubstituted or substituted aryl, or unsubstituted or substituted benzyl, and
wherein R 2 is C 1-4 alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted benzyl and wherein the compound of formula 2 is heated in a solution comprising carbitol.

32. The method of claim 31 , 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.

33. The method of claim 32 ,

Assignees

• United Therapeutics Corp

Inventors

• Batra Hitesh
• Tuladhar Sudersan M
• Walsh David A

Classifications

• C07C67/333

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

• C07C67/31 Primary

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

• C07C67/343 Primary

  by increase in the number of carbon atoms · CPC title

• C07C69/84

  of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring · CPC title

• C07C2603/14

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