Method for making 2-(N-phenylamino)benzoic acids

Details Method for making 2-(N-phenylamino)benzoic acids Method for making 2-(N-phenylamino)benzoic acids

2001-08-20

2004-02-03

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S457000

Reexamination Certificate

active

06686499

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method for making 2-(N-phenylamino)benzoic acids by coupling a benzoic acid and an aniline.
BACKGROUND OF THE INVENTION
The compound 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamine is being developed as a selective MEK-1 inhibitor for the treatment of proliferative diseases, including cancer, restenosis, psoriasis, and atherosclerosis. See, for example, U.S. Patent Application No. 60/051,440, filed Jul. 1, 1997, or PCT Published patent Application Number WO 99/01426, published Jan. 14, 1999, which are hereby incorporated by reference. To make 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamine, one of the intermediates that is needed is a 2-(N-phenylamino)benzoic acid. The present invention provides a method for making 2-(N-phenylamino)benzoic acids.
SUMMARY OF THE INVENTION
The present invention provides a method for making 2-(N-phenylamino)benzoic acids, the method comprising the step of reacting a benzoic acid having the Formula I
and an aniline having the Formula II
with an alkaline metal hexamethyldisilazide to form a 2-(N-phenylamino)benzoic acid having the Formula III
wherein
each R is independently hydrogen, halogen, C
1
-C
6
alkyl, —OC
1
-C
6
alkyl, CN, or NO
2
.
In a preferred embodiment of the invention, the alkaline metal hexamethyldisilazide is lithium hexamethyldisilazide (LiHMDS).
In another preferred embodiment of the invention, the alkaline metal hexamethyldisilazide is about 3 equivalents or more with respect to the benzoic acid.
In another preferred embodiment of the invention, the halo substituent in the 2 position of the benzoic acid is fluorine.
In another preferred embodiment of the invention, the reaction is carried out at about −78° C. to about 25° C. in a polar, aprotic solvent.
In a more preferred embodiment, the solvent is tetrahydrofuran.
In another preferred embodiment of the invention, the benzoic acid is 2,3,4,-trifluorobenzoic acid and the aniline is 2-chloro-4-iodoaniline.
In another preferred embodiment of the invention, the benzoic acid and the aniline are present in about a 1:1 molar ratio.
In another preferred embodiment of the invention, one or more of the substituents R on the aniline is an electron donating group.
In another preferred embodiment of the invention, the electron donating group on the aniline is —OCH
3
.


REFERENCES:
patent: 5166441 (1992-11-01), Moldt
patent: 5612483 (1997-03-01), Jautelat
patent: WO 98/37881 (1998-09-01), None
patent: WO 98/37881 (1998-09-01), None
patent: WO 99/01426 (1999-01-01), None
International Search Report PCT/US00/03982, May 2001.

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