Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-10-03
2001-10-23
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S106000, C562S493000, C562S494000
Reexamination Certificate
active
06307091
ABSTRACT:
Trifluoro-substituted benzoic acid, esters thereof and processes for preparing the same
1. Technical Field
This invention relates to a trifluoro-substituted benzoic acid, esters thereof and the processes for preparing the same, more specifically, to a 2,3,4-trifluoro-5-substituted benzoic acid, esters thereof and the novel processes for preparing the same and 2,4,5-trifluoro-3-substituted benzoic acid esters.
2. Background Art
The above-mentioned trifluoro-substituted benzoic acid and esters thereof are useful as a starting material for preparing 2,3,4-trifluoro-5-trifluoromethylbenzoic acid or 2,4,5-trifluoro-3-trifluoromethylbenzoic acid which is an important intermediate for synthesis of quinolone carboxylic acids useful as, for example, a medicine, particularly as an anti-bacterial or antiviral agent. Trifluoro-trifluoromethylbenzoic acids can be converted into quinolone carboxylic acids having a 6-trifluoromethyl group according to the method as disclosed in, for example, WO 96/02512 publication or Japanese Provisional Patent Publication No. 66180/1989.
As methods for preparing 2,4,5-trifluoro-3-iodobenzoic acid derivatives which are starting materials for producing 2,4,5-trifluoro-3-trifluoromethylbenzoic acid, it has been known the method for preparing 2,4,5-trifluoro-3-iodobenzoic acid from 3-amino-2,4,5-trifluorobenzoic acid by the Sandmeyer's reaction. More specifically, the methods shown below may be mentioned.
(1) In Japanese Provisional Patent Publication No. 95176/1991, there is disclosed a method for obtaining 2,4,5-trifluoro-3-iodobenzoic acid by reacting cuprous iodide, tert-butyl nitrite and 3-amino-2,4,5-trifluorobenzoic acid in acetonitrile.
(2) In Japanese Provisional Patent Publication No. 88157/1988 and Japanese Provisional Patent Publication No. 25125/1994, there are disclosed a method for obtaining 2,4-dichloro-5-fluoro-3-iodobenzoic acid by reacting 3-amino-2,4-dichloro-5-fluorobenzoic acid with hydrochloric acid and sodium nitrite to once forma diazonium salt, and then, reacting it with potassium iodide.
However, in the above-mentioned method (1), many side reactions proceed and the yield is 50% or less, and thus, it is not an industrially satisfied method. Also, the above-mentioned method (2) is not an industrially satisfied method in the point that the yield is less than 60%.
Accordingly, neither of the known method (1) or (2) is satisfactory as a method for obtaining 2,4,5-trifluoro-3-iodobenzoic acid.
Also, in Japanese Provisional Patent Publication No. 66180/1989 and WO 96/02512 publication, there is disclosed a method for preparing 2,4,5-trifluoro-3-trifluoromethylbenzoic acid by lithiating 1-bromo-2,4,5-trifluoro-3-trifluoromethylbenzene with n-butyl lithium, etc., and incorporating the carboxyl group by carbon dioxide.
However, the above-mentioned method has the following disadvantageous points. That is,
(1) It has been reported that lithium compounds having a trifluoromethyl group at the benzene ring, such as m-trifluoromethylphenyl lithium even without fluorine substituent has an explosive property, and still more polyfluorophenyl lithium also has an explosive property (see Chemistry and Industry, p. 1017 (1971), Chem. Eng. News, 1961, vol. 39, No. 16, p. 43).
(2) It has been reported that a trifluoromethylphenyl magnesiumcompoundobtainedfromatrifluoromethylhalobenzene by the Grignard reaction shows the similar reactivity as that of the above-mentioned lithium compound and a carboxyl group can be introduced by carbon dioxide, but the compound also has an explosive property. (see Chemistry and Industry, p. 120 (1971)).
Accordingly, it can be expected as a matter of course that 2,4,5-trifluoro-3-trifluoromethylphenyl lithium which is obtained by lithiating 1-bromo-2,4,5-trifluoro-3-trifluoromethylbenzene also has an explosive property. In the conventionally known methods, it is expected to cause an explosion during the process which is a significant problem in industrial production, so that it is not quite satisfactory as a method for producing 2,4,5-trifluoro-3-trifluoromethylbenzoic acid esters.
Also, the method for producing an aromatic trifluoromethyl compound by reacting an aromatic iodine compound with 2,2-difluoro-(fluorosulfonyl)acetic acid ester in the presence of a copper catalyst has been known (see the following literature).
However, there is no report about a compound having an ester group as an aromatic substituent. As a reaction mechanism of this reaction, it has been proposed that the ester group of the 2,2-difluoro-(fluorosulfonyl)acetic acid ester initially reacts with the copper catalyst. (For example, see J. Chem. Soc., Chem. Commun., 1989, p. 705, J. Chem. Soc., Perkin Trans. I, 1989, p.2385, J. Fluorine Chem., 45 (1989) p. 435, J. Fluorine Chem., 66 (1994) p.167, J. Fluorine Chem., 72 (1995) p. 241).
Thus, when a compound having an ester group as the aromatic substituent is applied to the present reaction, it is expected that the aromatic ester substituent reacts with the copper catalyst and that the desired compound cannot be obtained. In the reaction of chloroformic acid ethyl ester which is an aliphatic ester, an yield of trifluoromethylation is extremely low, as low as 5% (see Tetrahedron Letters, 32 (1991) p. 7689).
The present inventors have earnestly studied the cause of the low yield by the method disclosed in Japanese Provisional Patent Publication No. 95176/1991 for the purpose of producing 2,4,5-trifluoro-3-iodobenzoic acid. The present inventors have investigated the reaction conditions of the above-mentioned Sandmeyer's reaction to overcome the low yield but the yield did not improve under any of these conditions. As a result of the intensive investigations into the causes, they have judged that there is a limit to improve the yield by the method of using a usual iodine source or the method of reacting with an iodine source after the formation of the diazonium salt since a diazonium salt of 2,4,5-trifluorobenzoic acid which is formed during the reaction is extremely unstable, whereby they have earnestly investigated into the iodine source and the reaction method.
As a result, they have found that by using hydriodic acid as an acid and iodine sources, and adding an alkali metal nitrite to a mixed heterogeneous solution of hydriodic acid, a cuprous halide and 3-amino-2,4,5-trifluorobenzoic acid, an iodizing reaction proceeds simultaneously with the formation and decomposition of an unstable diazonium salt whereby a side reactioncanbecontrolledandtheyieldcanbeimproved. Thus, they have accomplished the present invention. According to the present invention, the yield which had never conventionally exceeded 60% is markedly improved and the yield of nearly 90% can be accomplished.
The present inventors have also earnestly investigated to overcome the problems involved in the above-mentioned conventionally known process for producing 2,4,5-trifluoro-3-trifluoromethylbenzoic acid. As a result, when an ester of the above-mentioned 2,4,5-trifluoro-3-iodobenzoic acid and a 2,2-difluoro-(fluorosulfonyl)acetic acid ester are reacted in the presence of a copper catalyst in an organic solvent, a 2,4,5-trifluoro-3-trifluoromethylbenzoic acid ester can be obtained with a good yield without no explosive property as mentioned above to accomplish the present invention.
On the other hand, 2,3,4-trifluoro-5-trifluoromethylbenzoic acid and an ester thereof, and 2,3,4-trifluoro-5-iodobenzoic acid and an ester thereof which are starting materials of the present invention are compounds not yet described in any literature.
The present inventors have found that, for the purpose of producing 2,3,4-trifluoro-5-trifluoromethylbenzoic acid as a starting material for synthesizing a novel quinolonecarboxylic acid series compound having a trifluoromethyl group at the 6-position, when a 2,3,4-trifluoro-5-iodobenzoic acid ester and a 2,2-difluoro-(fluorosulfonyl)acetic acid ester are reacted in the presence of a copper catalyst in an organic solvent, a novel 2,3,4-trifluoro-5-trifluoromethylbenzoic acid ester can be obtained with a go
Ataka Kikuo
Yamamoto Yasuhito
Yokota Naoyuki
Yoneda Yasuhiro
Jordan and Hamburg LLP
Solola T. A.
Ube Industries Ltd.
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