Preparation of chalcone derivatives

• US 8,765,992 B2
• Filed: 05/16/2011
• Issued: 07/01/2014
• Est. Priority Date: 05/17/2010
• Status: Active Grant

• Current Assignee: Genfit SA
• Original Assignee: Genfit SA
• Inventors: Bertrand, Karine, Roudot, Alice, Rool, Patrice
• Primary Examiner(s): Fetterolf, Brandon
• Assistant Examiner(s): Doletski, Blaine G
• Application Number:
  US13/698,832
• Publication Number:
  US 20130131372A1
• Time in Patent Office: 1,142 Days
• Field of Search: 560/53, 560/9, 568/315, 568/43
• US Class Current: 560/9
• CPC Class Codes: C07C 319/12 by reactions not involving the formation of mercapto groups
• CPC Class Codes: C07C 319/20 by reactions not involving the formation of sulfide groups
• CPC Class Codes: C07C 323/22 containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 45/45 by condensation
• CPC Class Codes: C07C 67/08 by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
• CPC Class Codes: C07C 67/31 by introduction of functional groups containing oxygen only in singly bound form
• CPC Class Codes: C07C 69/738 Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to methods for producing chalcone (1,3-diphenylprop-2-en-1-one) derivatives that have multiple substitutions on a phenyl ring. Intermediate chalcone derivatives are modified by Phase Transfer Catalysis (PTC) for introducing a substituted alkyl group that is provided by a sulfonic acid derivative on a phenyl ring already containing substituent groups on one or two carbon atoms adjacent to the carbon atom where a substituent group is being introduced. The methods of the invention allow producing efficiently, by either S-alkylation or O-alkylation, chalcones derivatives that are characterized for their biological activities that are intermediate compounds for producing molecules having such activities, or that can be used for generating libraries of compounds to be screened by means of in vitro and/or in vivo assays and establishing structure-activity relationships.

Claims

1. A method for preparing a compound of following General Formula (I_b):

2. The method of claim 1, wherein R_L group is an unsubstituted alkyl or alkenyl group having from two to seven carbon atoms.

3. The method of claim 1, wherein L group is CO—

CH═

CH, CO—

CH₂—

CH₂, CH═

CH—

CO or CH₂—

CH₂—

CO.

4. The method of claim 1, wherein one of the substituent groups among X_a1, X_a2, X_a3, X_a4, and X_a5 of General Formula (I_a) and (I_b) is a halogen, a Ra or Ga—

Ra group and the other four substituent groups among X_a1, X_a2, X_a3, X_a4, and X_a5 groups are hydrogen atoms.

5. The method of claim 1, wherein X_a3 of General Formula (I_a) and (I_b) is a halogen, a R_a or G_a-R_a group and the other four substituent groups among X_a1, X_a2, X_a4, and X_a5 groups are hydrogen atoms.

6. The method of claim 1, wherein the X_b substituent group of General Formula (I_a) that, after step (b) becomes a G_b-R_c group, is a G_b-H group.

7. The method of claim 1, wherein G_b is an oxygen atom.

8. The method of claim 1, wherein the compounds of General Formula (I_a) and (I_b) present a single R_a or G_a-R_a group.

9. The method of claim 1, wherein the X_b substituent group of General Formula (I_a) that is a R′

_b-G_b-H or a G_b-H group is X_b1 or X_b3.

10. The method of claim 1, wherein at least two among the X_b1, X_b2, X_b3, X_b4, and X_b5 of General Formula (I_a) and (I_b) that are not the R′

_b-G_b-H or G_b-H group, are a halogen or a R″

_b group, one being an X_b adjacent to the X_b that is a R′

_b-G_b-H or G_b-H group, and the remaining substituent group(s) being hydrogen atom(s).

11. The method of claim 1, wherein the X_b groups that are neither the R′

_b-G_b-H or G_b-H group nor an hydrogen atom, are identical or different R″

_b groups being unsubstituted alkyl groups or alkyloxy groups.

12. The method of claim 1, wherein the X_b groups that are neither the R′

_b-G_b-H or G_b-H group nor an hydrogen atom, are identical or different R″

_b groups being unsubstituted alkyl groups or alkyloxy groups and wherein said X_b groups are X_b2 and X_b4.

13. The method of claim 1, wherein the compounds of General Formula (I_b) comprise R_c and R_d that are identical or different alkyl groups having from one to seven carbon atoms.

14. The method of claim 1, wherein the sulfonic acid derivative of General Formula (II) is the mesylate of the R_c group.

15. The method of claim 1, wherein the compound of General Formula (III) is of formula (III) wherein A is a nitrogen atom.

16. The method of claim 1, wherein the compound of General Formula (Ib) is further modified using hydrolysis, reduction, or epoxydation reactions.

17. The method according to claim 16, wherein the compound to be modified is of General Formula (Ib), wherein L is a CO—

CH═

CH group;

X_a1, X_a2, X_a4, X_a5, X_b1, and X_b5 are H;

X_a3 is a halogen, a R_a, or G_a-R_a group;

X_b2 and X_b4, identical or different, are a halogen or a R″

_b group;

X_b3 is a G_b-R_c, group.