Synthesis and use of omega-hydroxylated polyunsaturated fatty acids

Patent metadata

Field	Value
Publication number	US-10689595-B2
Application number	US-201716275293-A
Country	US
Kind code	B2
Filing date	Aug 16, 2017
Priority date	Aug 16, 2016
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

The present invention provides a synthetic chemical method for preparing ω-hydroxylated polyunsaturated fatty acids (PUFAs) including 20-hydroxyeicosatetraenoic acid (20-HETE), 20-hydroxyeicosapentaenoic acid (20-HEPE), and 22-hydroxydocosahexaenoic acid (22-HDoHE) and a method of use thereof for treating cancer and macular degeneration.

First claim

What is claimed is:

1. A method for preparing a compound of Formula II:

the method comprising:
forming a coupling reaction mixture comprising a transition-metal coupling agent, a base, a compound of Formula III:

 and
a compound of Formula IV:

under conditions suitable to form the compound of Formula II;

wherein:
the transition-metal coupling agent comprises a metal selected from the group consisting of copper, iron, nickel, palladium, zinc, and combinations thereof;
R is C 1 -C 4 alkyl;
X is selected from the group consisting of Cl, Br, I, —OTs, and —OTf;
subscript m is 2 or 3;
subscript n is 0 or 1; and
bond a is a single bond or a triple bond.

2. The method of claim 1 , wherein the transition-metal coupling agent comprises a copper ion.

3. The method of claim 2 , wherein the copper ion is a copper (I) ion.

4. The method of claim 3 , wherein the copper (I) ion is a copper (I) salt selected from the group consisting of CuI, CuBr, CuCl, and Cu(OAc).

5. The method of claim 1 , wherein the base is selected from the group consisting of a di-(C 1 -C 4 alkyl)amine, a tri-(C 1 -C 4 alkyl)amine, and an alkali carbonate.

6. The method of claim 5 , wherein the alkali carbonate is potassium carbonate or cesium carbonate.

7. The method of claim 1 , wherein the coupling reaction mixture further comprises an iodide salt selected from the group consisting of sodium iodide or potassium iodide.

8. The method of claim 1 , wherein the coupling reaction mixture further comprises an aprotic solvent.

9. The method of claim 8 , wherein the aprotic solvent is dimethylformamide.

10. The method of claim 1 , wherein the compound of Formula III is a compound of Formula III-1:

or
a compound of Formula III-2:

11. The method of claim 1 , wherein the compound of Formula IV is a compound of Formula IV-1:

or
a compound of Formula IV-2:

12. The method of claim 1 , wherein the compound of Formula II is selected from the group consisting of:

13. A method for preparing a compound of Formula I:

the method comprising:
i) forming a coupling reaction mixture comprising a transition-metal coupling agent, a base, a compound of Formula III:

 and
a compound of Formula IV:

under conditions suitable to form a compound of Formula II:

 and

ii) forming a hydrogenation reaction mixture comprising the compound of Formula II, a deactivated palladium catalyst, a deactivating agent, and hydrogen, under conditions suitable for hydrogenation to form the compound of Formula I;

wherein:
the transition-metal coupling agent comprises a metal selected from the group consisting of copper, iron, nickel, palladium, zinc, and combinations thereof;
R is C 1 -C 4 alkyl;
X is selected from the group consisting of Cl, Br, I, —OTs, and —OTf;
subscript m is 2 or 3;
subscript n is 0 or 1; and
bond a and bond b are each a single bond or bond a is a triple bond and bond b is a double bond.

14. The method of claim 13 , wherein the deactivated palladium catalyst is Lindlar catalyst.

15. The method of claim 13 , wherein the deactivating agent is selected from the group consisting of quinoline, pyridine, and ethylenediamine.

16. The method of claim 13 , wherein the hydrogenation reaction mixture further comprises a C 2 -C 6 alkene.

17. The method of claim 16 , wherein the C 2 -C 6 alkene is 2-methyl-2-butene.

18. A method of preparing a ω-hydroxylated polyunsaturated fatty acid having a structure of:

or a salt thereof,
the method comprising:
i) forming a coupling reaction mixture comprising a copper ion, an iodide salt, an alkali carbonate, an aprotic solvent, a compound of Formula III-1a:

 and
a compound of Formula Iv-1 or Iv-2:

under conditions suitable to form a compound of Formula II-1a or II-2a:

ii) forming a hydrogenation reaction mixture comprising the compound of Formula II-1a or II-2a, Lindlar catalyst, a N-containing 5- to 10-membered heteroaryl compound, a C 2 -C 6 alkene, and hydrogen, under conditions suitable for hydrogenation to form a corresponding compound of Formula I-1a or I-2a:

iii) forming a hydrolysis reaction mixture comprising the compound of Formula I-1a or I-2a and an alkali hydroxide under conditions suitable for saponification to form the corresponding 20-HETE or 20-HEPE;

wherein:
the copper ion is a copper (I) ion salt selected from the group consisting of CuI, CuBr, CuCl, and Cu(OAc), and
X is selected from the group consisting of Cl, Br, I, and —OTs.

19. A method of preparing a w-hydroxylated polyunsaturated fatty acid having a structure of:

or a salt thereof,
the method comprising:
i) forming a coupling reaction mixture comprising a copper ion, an iodide salt, an alkali carbonate, an aprotic solvent, a compound of Formula III-2a:

 and
a compound of Formula IV-2:

under conditions suitable to form the compound of Formula II-3a:

Assignees

• Univ California
• Univ Massachusetts

Inventors

• Zhang Guodong
• Hammock Bruce
• Hwang Sung Hee
• Wang Weicang

Classifications

• C07C67/303

  by hydrogenation of unsaturated carbon-to-carbon bonds · CPC title

• C07C67/343

  by increase in the number of carbon atoms · CPC title

• C07C51/09 Primary

  from carboxylic acid esters or lactones · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C11C3/126 Primary

  using catalysts based principally on other metals or derivates · CPC title