Process for the preparation of 2-trifluoromethyl isonicotinic acid and esters

Patent metadata

Field	Value
Publication number	US-9481650-B2
Application number	US-201314442971-A
Country	US
Kind code	B2
Filing date	Nov 13, 2013
Priority date	Nov 16, 2012
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

Abstract

The invention relates to a novel process for the preparation of 2-trifluoromethyl isonicotinic acid and esters of the formula I which involves a palladium catalyzed carbonylation or cyanation step wherein R 1 is hydrogen or Q 1-6 -alkyl. The 2-trifluoromethyl isonicotinic acid and esters of the formula I are versatile intermediates for the preparation of active pharmaceutical and agrochemical agents such as for instance TAAR 1 agonists of the formula III.

First claim

The invention claimed is:

1. A process for the preparation of 2-trifluoromethyl isonicotinic acid and esters of the formula

wherein R 1 is hydrogen or C 1-6 -alkyl, comprising the conversion of a 2-trifluoromethyl pyridine derivative of the formula

wherein X is halogen or —OSO 2 CY 3 , wherein Y is halogen, by either palladium-catalyzed: (i) cyanation of II and subsequent hydrolysis of the nitrile to afford I, or, (ii) carbonylation of II in the presence of R 1 OH to afford I.

2. The process of claim 1 , wherein the conversion comprises the palladium-catalyzed reaction of II with carbon monoxide (CO) in the presence of the reactant R 1 OH, wherein R 1 is hydrogen or C 1-6 -alkyl.

3. The process of claim 1 , wherein the conversion comprises the palladium-catalyzed reaction of II with a metal cyanide MCN, wherein M stands for a metal ion to form a nitrile of formula IV

and the further hydrolysis or esterification of IV to form the 2-trifluoromethyl isonicotinic acid and esters of the formula I.

4. The process of claim 1 , wherein the palladium-complex catalyst is selected from bis(benzonitrile)palladium(II)-chloride, tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate, or palladium(II)chloride with the ligands selected from 1,1-bis(diphenylphosphino)ethane (dppe), 1,1′ bis-(diphenylphosphino)ferrocen (dppf), bis(diphenylphosphino)methane (dppm), 1,3-bis(diphenylphosphino)propane (dppp), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or triphenylphosphine.

5. The process of claim 2 , wherein the palladium complex catalyst is selected from palladium(II)chloride with the ligands 1,1′-bis(diphenylphosphino)ferrocen (dppf) or 1,3-bis(diphenylphosphino)propane (dppp).

6. The process of claim 2 , wherein the conversion is performed under a CO pressure of 5 bar to 100 bar.

7. The process of claim 2 , wherein the conversion is performed in the presence of a base.

8. The process of claim 2 , wherein the conversion is performed at a reaction temperature between 50° C. and 170° C.

9. The process of claim 2 , wherein the conversion to I wherein R 1 is C 1-6 alkyl is carried out in the presence of hydrogen chloride.

10. The process of claim 9 , wherein the hydrogen chloride is produced by adding thionyl chloride or acetyl chloride.

11. The process of claim 10 , wherein the hydrogen chloride is produced under reflux conditions of the reaction mixture.

12. The process of claim 3 , wherein the palladium complex catalyst is selected from Pd(PPh 3 ) 4 (0), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct, Pd(P-tert-Bu 3 ) 2 , tris(dibenzylideneacetone)dipalladium(0) or Pd(TFA) 2 with the ligands 1,1′-bis(diphenylphosphino)ferrocen (dppf) or rac-2-(di-tert-butylphosphino)-1,1-binaphthyl.

13. The process of claim 3 , wherein the metal cyanide MCN is zinc cyanide, or zinc cyanide with a mixture with sodium cyanide or potassium cyanide.

14. The process of claim 3 , wherein the conversion is performed at a reaction temperature between 50° C. and 120° C.

15. The process of claim 3 , wherein the hydrolysis of the nitrile of formula IV to the 2-trifluoromethyl isonicotinic acid of formula I with R 1 =hydrogen is performed with a base.

16. The process of claim 15 , wherein the base is an alkali hydroxide.

17. The process of claim 3 , wherein the esterification of the nitrile of formula IV to afford the 2-trifluoromethyl isonicotinic acid ester of formula I with R 1 ═C 1-6 -alkyl is performed with an alcohol R 1 OH, wherein R 1 is C 1-6 -alkyl in the presence of hydrogen chloride.

18. The process of claim 17 , wherein the hydrogen chloride is produced by adding thionyl chloride or acetyl chloride.

19. The process of claim 1 , wherein R 1 is hydrogen, methyl, ethyl or i-propyl.

20. The process of claim 1 , wherein R 1 is hydrogen or methyl.

21. The process of claim 1 , wherein X is fluorine, chlorine, bromine, iodine or trifluoromethanesulfonyl.

22. The process of claim 1 , wherein X is chlorine.

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• TRUSSARDI RENé

Classifications

• C07D213/803 Primary

  Processes of preparation · CPC title

• C07D213/81

  Amides; Imides · CPC title

• C07D213/79

  Acids; Esters · CPC title

• C07D213/84 Primary

  Nitriles · CPC title