Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-2pyrimidinyl]amino]benzonitrile

• US 7,399,856 B2
• Filed: 08/07/2003
• Issued: 07/15/2008
• Est. Priority Date: 08/09/2002
• Status: Expired due to Term

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Guillemont, Jérôme Emile Georges, Pasquier, Elisabeth Therese Jeanne, Heeres, Jan, Janssen, Paul Adriaan Jan, Leenders, Ruben Gerardus George, Schils, Didier Philippe Robert, Medaer, Bart Petrus Anna Maria Jozef, Willems, Joannes Josephus Maria
• Primary Examiner(s): Balasubramanian; Venkataraman
• Application Number:
  US10/523,753
• Publication Number:
  US 20060167253A1
• Time in Patent Office: 1,804 Days
• Field of Search: 544/323, 544/330
• US Class Current: 544/323
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07C 253/20 by dehydration of carboxylic acid amides
• CPC Class Codes: C07C 253/30 by reactions not involving the formation of cyano groups
• CPC Class Codes: C07C 255/42 the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
• CPC Class Codes: C07D 239/48 Two nitrogen atoms

Abstract

Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]amino]benzonitrile of formula (I), a N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof are provided, said processes comprise:

• • a) reacting 4-(2-cyanoethenyl)-2,6-dimethylbenzenamine with an intermediate of formula (III)

• •  in the presence of a suitable solvent;
  • b) reacting an intermediate of formula (IV)

• •  with acrylonitrile in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent;
  • c) dehydrating the corresponding amide of the compound of formula (I).

Claims

1. A process for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile of formula (I), a N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof,

2. A process according to claim 1 wherein the solvent is acetonitrile.

3. A process according to claim 1 wherein 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E) or a N-oxide, a pharmaceutically acceptable acid addition salt, or a quaternary amine thereof is prepared.

4. A process according to claim 1 wherein the solvent is 1-methyl-2-pyrrolidinone.

5. A process for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2, 6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E) or a pharmaceutically acceptable acid addition salt thereof, wherein

6. The process of claim 5, wherein the pharmaceutically acceptable acid addition salt is hydrochloric acid salt.

7. The process of claim 5, wherein W₁ is halo.

8. The process of claim 7, wherein W₁ is chloro.

9. A process for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2, 6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E) or a pharmaceutically acceptable acid addition salt thereof, wherein an acid addition salt of

10. The process of claim 9, wherein the pharmaceutically acceptable acid addition salt is hydrochloric acid salt.

11. The process of claim 9, wherein W₁ is halo.

12. The process of claim 10, wherein W₁ is chloro.