Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-08-09
2002-05-28
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S083000, C560S105000
Reexamination Certificate
active
06395921
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing [bis-(trifluoromethyl)-phenyl]-acetic acids and alkyl esters thereof from bromo-bis-(trifluoromethyl)- benzenes and dialkyl malonates and to dialkyl [bis-(trifluoromethyl)-phenyl]-malonates which can be obtained as intermediates in this process.
Bis-(trifluoromethyl)-substituted phenylacetic acids and derivatives thereof are important intermediates for pharmaceutically active compounds (see, for example, U.S. Pat. No. 5,817,658, WO 98/00405, WO 98/07722, WO 95/21819 and U.S. Pat. No. 5,696,267).
WO 96/05827 describes the preparation of 2,4-bis-(trifluoromethyl)-phenylacetic acid by acid hydrolysis of the corresponding phenylacetonitrile. The yield of 68.5% is unsatisfactory. The nitrile was prepared from 2,4-bis(-trifluoromethyl)-benzyl bromide, which is difficult to obtain, by reaction with a large excess of sodium cyanide. Owing to its toxicity, the handling and disposal of the sodium cyanide requires considerable expense with respect to industrial hygiene.
Methyl 3,5-bis(trifluoromethyl)-phenylacetate can be prepared by esterification of the corresponding acid with thionyl chloride in the presence of methanol (WO 95/21819). No details are given here with respect to the synthesis of the bis-(trifluoromethyl)-phenylacetic acid structure.
The same ester can also be obtained in a yield of about 75% of theory by base hydrolysis and acid work-up from 1-&bgr;,&bgr;,&bgr;-trichloroethyl-3,5-bis-(trifluoromethyl)-benzene. This, in turn, was obtained by reaction of 3,5-bis-(trifluoromethyl)-aniline, which has been diazotized in hydrochloric acid, with vinylidene chloride in a yield of 73% (DE 33 14 249). It is generally known that the yields in this type of reaction are not reproducible and vary considerably. When this process was repeated, yields of barely 10 to barely 50% of theory were achieved. In addition, vinylidene chloride (1,1-dichloroethene) is a carcinogenic substance which can only be handled with considerable expense.
Accordingly, there continues to be a demand for a simple process for preparing [bis-(trifluoromethyl)-phenyl]-acetic acids and alkyl esters thereof in high yields requiring the handling of less toxic and noncarcinogenic substances which employs starting materials which are readily obtainable.
SUMMARY OF THE INVENTION
This invention accordingly provides a process for preparing [bis-(trifluoromethyl)-phenyl]-acetic acids, characterized in that an appropriate bromo- or iodo-bis-(trifluoromethyl)-benzene is reacted with a di-C
1
-C
4
-alkyl malonate in the presence of a deprotonating agent and a copper salt and the reaction product is, in basic medium, hydrolysed and decarboxylated.
REFERENCES:
patent: 5665883 (1997-09-01), Baker et al.
patent: 5696297 (1997-12-01), Kneuper et al.
patent: 5776930 (1998-07-01), Lynch, Jr. et al.
patent: 5817658 (1998-10-01), Siegl et al.
patent: 5817663 (1998-10-01), Pees et al.
patent: 5922906 (1999-07-01), Lynch et al.
patent: 33 14 249 (1984-10-01), None
patent: 96/05827 (1996-02-01), None
patent: 98/07722 (1998-02-01), None
Jerry March, Advanced Organic Chemistry, 4th edition, 1992.*
Lindley, James, Copper Assisted Nucleophilic Substitution of Aryl Halogen, Tetrahedron, vol. 40, No. 9, pp1456-1456, 1984.*
Aldrich , Handbook of Fine Chemicals, 1996-1997.*
Lindley, James Copper Assited Nucleophilic Substitutionv of Aryl Halogen, Tetrahedron , vol. 40, No. 9, pp1433-1456.
Marhold Albrecht
Stölting Jörn
Bayer Aktiengesellschaft
Gil Joseph C.
Henderson Richard E. L.
Killos Paul J.
Reyes Hector M
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