Process for preparation of optically pure and optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives and their use in preparing pharmaceuticals

Patent metadata

Field	Value
Publication number	US-10130635-B2
Application number	US-201615073324-A
Country	US
Kind code	B2
Filing date	Mar 17, 2016
Priority date	May 4, 2012
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives represented by formula (IA) and (IB), processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals.

First claim

The invention claimed is:

1. A compound of formula (IA) or (IB)

or a salt thereof, wherein
each occurrence of R is independently selected from hydrogen, halogen, and unsubstituted alkyl;
R 1 is unsubstituted C 1-6 alkyl;
Cy 1 is substituted or unsubstituted phenyl; and
n is an integer selected from 0, 1, 2, 3 or 4,

wherein the compound is not selected from

or a salt thereof.

2. The compound of claim 1 , wherein R is unsubstituted alkyl or halogen and n is 1.

3. A compound of claim 1 , wherein
R is fluoro or methyl;
Cy 1 is

and
R 1 is methyl or ethyl.

4. A compound of claim 1 , wherein R 1 is methyl or ethyl.

5. A compound of claim 1 , wherein n is 1.

6. A compound of claim 1 , wherein the compound has an enantiomeric excess of at least 75%.

7. A compound selected from
(R)-6-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one;
(R)-2-(1-hydroxyethyl)-5-methyl-3-phenyl-4H-chromen-4-one;
(R)-6-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one;
(R)-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one;
(R)-3-(3-fluorophenyl)-2-(1-hydroxypropyl)-4H-chromen-4-one;
(R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one;
(S)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one;

and salts thereof.

8. A compound of claim 1 , wherein the compound has an enantiomeric excess of at least 90%.

9. A compound of claim 1 , wherein the compound has an enantiomeric excess of at least 95%.

10. A compound of claim 1 , wherein the compound has an enantiomeric excess of at least 97%.

11. A compound of claim 1 , wherein the compound has an enantiomeric excess of at least 98%.

12. A compound of claim 1 , wherein Cy 1 is unsubstituted phenyl.

13. A compound of claim 1 , wherein Cy 1 is 3-fluorophenyl.

14. A compound of claim 1 , wherein
R is fluoro or methyl;
n is 0 or 1;
Cy 1 is

and
R 1 is methyl or ethyl.

15. A compound of claim 1 , wherein Cy 1 is unsubstituted phenyl or fluoro-substituted phenyl.

Assignees

• Rhizen Pharmaceuticals Sa

Inventors

• Raman Jayaraman V
• Vakkalanka Swaroop K

Classifications

• C07B55/00

  Racemisation; Complete or partial inversion · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D311/58

  other than with oxygen or sulphur atoms in position 2 or 4 · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title