Metal-catalyzed asymmetric 1,4-conjugate addition of vinylboron compounds to 2-substituted-4-oxy-cyclopent-2-en-1-ones yielding prostaglandins and prostaglandin analogs

Patent metadata

Field	Value
Publication number	US-9670234-B2
Application number	US-201514795506-A
Country	US
Kind code	B2
Filing date	Jul 9, 2015
Priority date	Jul 10, 2014
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

This invention provides a novel method for the preparation of 2,3-disubstituted -4-oxy-cyclopentan1-one compounds that are useful for the synthesis of prostaglandins and prostaglandin analogs of industrial relevance. The method comprises the metal-catalyzed asymmetric 1,4-conjugate addition of vinylboron compounds to 2-substituted -4-oxy-cyclopent-2-en-1-ones. This method relies on the use of less toxic, easily-handled reagents, and can be performed under milder conditions than offered by some conventional methods, affording 2,3-disubstituted-4-oxy-cyclopentan-1-one compounds enantio- and diastereoselectively, which are precursors to the said prostaglandin and prostaglandin analogs, in high yield.

First claim

What is claimed is:

1. A process for preparing a 2,3-disubstituted-4-oxy-cyclopentan -1-one compound of formula I

the process comprises contacting a 2-substituted-4-oxy-cyclopent-2-en-1-one compound of formula II

with a compound of formula III

in a solvent with a metal additive, optionally in the presence of a basic additive, wherein the metal additive is used in substoichiometric amounts,
to give the compound of formula I;
wherein
R 1 , R 3 , R 4 and R 5 independently represent hydrogen, aryl, heteroaryl, alkyl, arylalkyl, aryloxyalkyl, alkenyl, or alkynyl; or R 3 and R 5 are taken together to form a 5- to 7- membered carbocyclic ring, optionally having one or two heteroatoms as ring vertices, wherein the heteroatoms are selected from the group consisting of O, N and S; or R 3 and R 4 are taken together to form a 5- to 7-membered carbocyclic ring, optionally having one or two heteroatoms as ring vertices, wherein the heteroatoms are selected from the group consisting of O, N and S, and wherein each of R 1 , R 3 , R 4 and R 5 are optionally substituted with from one to three members selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, silyloxy, aryloxy, acyloxy, a 5- to 7-membered heterocyclic ring, oxo, COOH, CONH 2 , CONHC 1-4 alkyl, C(O)OCH 2 C 6-10 aryl, C(O)OC 6-10 aryl and C(O)OC 1-4 alkyl;
R 2 represents hydrogen or a hydroxyl-protecting group;
X represents a boron-containing group.

2. The process of claim 1 , wherein the compound of formula I is

3. The process of claim 1 , wherein R 3 is alkyl, aryl, arylalkyl or aryloxyalkyl, each of which is optionally substituted with from one to three members selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, silyloxy, aryloxy, acyloxy, tetrahydropyranyl (THP), trifluoromethyl and fluoro.

4. The process of claim 1 , wherein the solvent is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, isobutyl alcohol, 1,4-dioxane, toluene, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-Me-THF), diglyme, acetonitrile, N-methylpyrrolidone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), ethylene glycol and combinations thereof.

5. The process of claim 4 , wherein the solvent is methanol.

6. The process of claim 1 , wherein the metal additive is selected from the group consisting of rhodium compounds, cobalt compounds, nickel compounds and combinations thereof.

7. The process of claim 6 , wherein the rhodium compound is a rhodium(I) compound selected from the group consisting of [RhCl(1,5-cyclooctadiene)] 2 , [RhCl(C 2 H 4 ) 2 ] 2 , [RhCl(C 2 H 4 ) 2 ] 2 with a diene ligand additive, [RhCl(norbornadiene)] 2 , [RhOH(1,5-cyclooctadiene)] 2 and combinations thereof.

8. The process of claim 7 , wherein the rhodium(I) compound is selected from the group consisting of [RhCl(1,5-cyclooctadiene)] 2 and [RhOH(1,5-cyclooctadiene)] 2 .

9. The process of claim 1 , wherein the basic additive is selected from the group consisting of KHF 2 , t-BuOLi, t-BuONa, t-BuOK, K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , LiOH, NaOH, KOH, CsOH, KF, CsF, NaHCO 3 , KH 2 PO 4 , 1,3-diaminopropane, t-BuNH 2 , i-Pr 2 NH, piperidine, Et 3 N, 2,6-lutidine and combinations thereof.

10. The process of claim 9 , wherein the basic additive is potassium hydroxide.

11. The process of claim 1 , wherein the hydroxyl-protecting group is selected from the group consisting of tetrahydropyranyl (THP), methoxymethyl (MOM), [2-(trimethylsilyl) ethoxy]methyl (SEM), trialkylsilyl, triarylsilyl, diarylalkylsilyl, benzyl, 4-methoxybenzyl (PMB), alkylcarbonyl, arylcarbonyl and allyl.

12. The process of claim 11 , wherein the trialkylsilyl is tert-butyldimethylsilyl (TBS).

13. The process of claim 1 , wherein the boron-containing group X is selected from the group consisting of B(OH) 2 , B(OR) 2 where R is an alkyl group or an aryl group, BR 2 where R is an alkyl group, BR 2 where R is a vinyl group, BR 2 where R is a carboxylate group, BR where R is a bidentate carboxylate group, BR 2 where R is an aryloxy group, BR where R is a bidentate aryloxy group, a 9-borabicyclo(3.3.1)nonane (9-BBN) group, BF 3 M where M is a metal ion, BF 3 M where M is an ammonium or phosphonium ion, and BR 3 M where R is a vinyl group and where M is a metal ion or is an ammonium or phosphonium ion.

14. The process of claim 13 , wherein the boron-containing group X is selected from the group consisting of B(OH) 2 and BF 3 M where M is a metal ion.

15. The process of claim 1 is conducted at a temperature from 0 to 80° C.

16. The process of claim 1 , wherein the basic additive is used in substoichiometric amounts.

17. The process of claim 1 , further comprising converting the 2,3-disubstituted -4-oxy-cyclopentan-l-one compound of formula I to travoprost, bimatoprost, lubiprostone, dinoprost, dinoprostone, tafluprost, carboprost, alprostadil, latanoprost or unoprostone isopropyl.

18. The process of claim 1 , wherein the 2,3-disubstituted-4-oxy-cyclopentan -1-one compound of formula I is the compound of formula 10.9a,

19. The process of claim 1 , wherein the 2,3-disubstituted-4-oxy-cyclopentan -1-one compound of formula I is the compound of formula 10.17,

20. The process of claim 1 , wherein the 2,3-disubstituted-4-oxy-cyclopentan -1-one compound of formula I is the compound of formula 10.18,

21. The process of claim 1 , wherein the 2,3-disubstituted-4-oxy-cyclopentan -1-one compound of formula I is the compound of formula 10.7,

22. The process of claim 1 , wherein the 2,3-disubstituted-4-oxy-cyclopentan -1-one compound of formula I is the compound of formula 10.19,

Assignees

• Scinopharm Taiwan Ltd

Inventors

• Henschke Julian Paul
• Wu Ping-Yu
• Wu Hsyueh-Liang
• Wen Wen-Hsien

Classifications

• C07C69/738

  Esters of keto-carboxylic acids {or aldehydo-carboxylic acids} · CPC title

• C07F7/0834 Primary

  Compounds having one or more O-Si linkage (for compounds with C-O-Si linkages see C07F7/18) · CPC title

• C07C67/343

  by increase in the number of carbon atoms · CPC title

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07F5/025

  Boronic and borinic acid compounds · CPC title