Process for the synthesis of pirfenidone

• US 10,472,325 B2
• Filed: 10/27/2016
• Issued: 11/12/2019
• Est. Priority Date: 10/29/2015
• Status: Active Grant

• Current Assignee: Procos S.P.A. (CBC Company Limited), Proco S.p.A.
• Original Assignee: Procos S.P.A. (CBC Company Limited)
• Inventors: Mossotti, Matteo, Barozza, Alessandro, Roletto, Jacopo, Paissoni, Paolo
• Primary Examiner(s): Davis, Zinna Northington
• Application Number:
  US15/771,050
• Publication Number:
  US 20180319747A1
• Time in Patent Office: 1,111 Days
• Field of Search: None
• CPC Class Codes: C07D 213/64 attached in position 2 or 6

Abstract

Disclosed is a process for the synthesis of Pirfenidone (1) from 5-methyl-2(1H)-pyridinone and chlorobenzene in the presence of a catalytic system consisting of a copper salt and an organic ligand, in the presence of a base.

The process exploits the high efficiency of the catalytic system consisting of copper(I) salt and an organic ligand in the presence of an inorganic base in the N-amidation reaction of chlorobenzene, a cheap reagent also usable as solvent in this case; reaction conditions at high temperatures, at atmosphere pressure or higher, produce a reaction with good yields.

Claims

1. A process for the synthesis of Pirfenidone (1)

2. The process of claim 1, wherein said arylation is carried out at atmospheric pressure at a temperature ranging between 100 and 170°

C.

3. The process of claim 1, wherein said arylation is carried out at a pressure higher than atmospheric pressure at a temperature ranging between 120 and 190°

C.

4. The process of claim 3, which is performed at a temperature ranging between 160 and 180°

C.

5. The process according to claim 1, wherein said arylation is carried out in the absence of solvent.

6. The process according to claim 1, wherein said arylation is carried out in a solvent selected from dimethylformamide, dimethylsulfoxide, toluene, dioxane or chlorobenzene.

7. The process according to claim 1, wherein the inorganic base is selected from alkali metal hydroxides, carbonates and phosphates.

8. The process according to claim 1, wherein the copper salt is selected from copper(I) chloride, copper(I) bromide and copper(I) iodide.

9. The process according to claim 1, wherein the organic ligand of formula (4) is selected from N,N′

-dimethylethylene-1,2-diamine, cyclohexane-1,2-diamine, N,N′

-dimethylcyclohexane-1,2-diamine, ethylene-1,2-diamine, and N,N,N′

,N′

-tetramethylethylene-1,2-diamine.

10. The process according to claim 1, wherein, for 1 molar equivalent of 5-methyl-2(1H)-pyridinone (3), the copper salt is used in an amount ranging between 0.005 and 1 molar equivalent and the organic ligand is used in an amount ranging between 0.01 and 2 molar equivalents.

11. The process according to claim 7, wherein the inorganic base is potassium carbonate.

12. The process according to claim 8, wherein the copper salt is copper (I) iodide.

13. The process according to claim 10, wherein the copper salt is used in an amount ranging between 0.01 and 0.5 molar equivalent and the organic ligand is used in an amount ranging between 0.02 and 1 molar equivalent.