Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-10-22
2004-03-16
Rotman, Alan L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06706918
ABSTRACT:
The present invention relates to 3-cyano-2,4,5-trifluoro-benzoyl fluoride, to a process for its preparation, and to other novel halogenobenzene derivatives as intermediates.
3-Cyano-2,4,5-trifluoro-benzoyl chloride can be used for the preparation of antiinfective quinolonecarboxylic acids (cf. DE-A 1 963 805 No.19 606 762.6=WO 97/31001). The preparation starts from 2,4-dichloro-5-fluoro-3-cyanobenzoic acid and leads by a known method (cf. DE 3702393 A1) to 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride, which is then fluorinated. A disadvantage of this process is, in particular, the Sandmeyer reaction, which proceeds with poorly reproducible yield, using a molar amount of copper cyanide and an additional three-fold excess of sodium cyanide to give 2,4-dichloro-3-cyano-5-fluoro-benzoic acid. The use of such large amounts of cyanide also harbours a considerable hazard potential when the reaction is carried out industrially.
The present invention relates to novel 3-cyano-2,4,5-trifluoro-benzoyl fluoride of the formula (I)
The invention also relates to a process for the preparation of 3-cyano-2,4,5-trifluoro-benzoyl chloride by chlorination of 3-cyano-2,4,5-trifluoro-benzoyl fluoride.
In addition, the invention also relates to the use of 3-cyano-2,4,5-trifluoro-benzoyl fluoride for the synthesis of quinolones.
The invention further relates to a multistage process for the preparation of 3-cyano-2,4,5-trifluoro-benzoyl fluoride, which starts from 5-fluoro-1,3-xylene (VIII), characterized in that 5-fluoro-1,3-xylene (VIII) is bichlorinated in the ring in the presence of a catalyst under ionic conditions to give 2,4-dichloro-5-fluoro-1,3-dimethylbenzene (VII), which is then chlorinated in the side chains under free-radical conditions to give 2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene (VI), which is hydrolysed via 2,4-dichloro-5-fluoro-3-dichloromethylbenzoic acid (V), which can be isolated if necessary, to give 2,4-dichloro-5-fluoro-3-formyl-benzoic acid (IV), the aldehyde group of which is reacted to give 2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic acid (III), from which, with simultaneous conversion of the carboxyl group into the chlorocarbonyl group, water is eliminated using an acid chloride to give the nitrile 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride (II), which, finally, is subjected to fluorine/chlorine exchange.
Alternatively, 2,4-dichloro-5-fluoro-3-formyl-benzoic acid (IV) can also be reacted to give 2,4-dichloro-5-fluoro-3-cyano-benzoic acid (IX), which can then be converted into the acid chloride (II).
The intermediates of the formulae (III) to (VII) are novel without exception and are likewise provided by the invention.
3-Cyano-2,4,5-trifluoro-benzoyl fluoride is an intermediate, readily obtainable by the process described here, for the preparation of 3-cyano-2,4,5-trifluoro-benzoyl chloride.
The process according to the invention is described in more detail below.
The ring chlorination of commercially available 5-fluoro-1,3-xylene (VIII) to give 2,4-dichloro-5-fluoro-1,3-dimethylbenzene (VII) is carried out using chlorine gas.
2,4-Dichloro-5-fluoro-1,3-dimethylbenzene (VII) is novel.
The catalyst used is one or more Friedel-Crafts catalysts, preferably a Lewis acid, such as, for example, iron (III) chloride or aluminium chloride. For example, from 0.1 to 10 mol %, preferably from 0.2 to 2 mol %, based on 5-fluoro-1,3-xylene, are used.
The reaction can be carried out at temperatures below room temperature or at slightly elevated temperature. Preference is given to temperatures between 0 and 40° C.
The chlorination can be carried out without a diluent or in a suitable inert diluent. Particularly suitable diluents are halogenated hydrocarbons such as dichloro-, trichloro-, tetrachloromethane, 1,2-dichloroethane or 1,2,4-trichlorobenzene. The chlorination can be carried out continuously or batchwise. In a continuous process, it is wise to proceed only to a low conversion because the chlorination does not take place with complete selectivity. In the batchwise procedure, chlorine is introduced in an amount up to approximately 0.8-1.1 times, preferably 0.8-0.95 times, the theoretical amount, the reaction mixture achieving a solid consistency in the chlorination without diluent. It is also advantageous in this connection to proceed only up to this not-too-high conversion because then the losses as a result of superchlorination on the one hand and the space-time yield on the other are in an optimum range.
The mixture is worked up, for example, by fractional distillation. It is advantageous to return recovered starting material and monochlorinated compounds to the process.
The side-chain chlorination of 2,4-dichloro-5-fluoro-1,3-dimethylbenzene (VII) to give 2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene (VI) is preferably carried out without a diluent using chlorine gas.
2,4-Dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene (VI) is novel.
The conditions for the free-radical reaction are achieved by elevated temperature and optional irradiation with a light source or addition of a customary free-radical initiator. Suitable light sources are incandescent lamps such as, preferably, halogen lamps or medium- or high-pressure mercury vapour lamps. Suitable free-radical initiators are, for example, benzoyl peroxide, di-tert-butyl peroxide or 2,2-azobis(isobutteronitrile) (AIBN). The reaction temperature can be between 80 and 200° C., preferably 100 and 180° C., particularly preferably between 120 and 170° C.
The chlorination can be carried out continuously or batchwise. In a continuous process, it is wise to proceed only up to a low conversion because the chlorination does not take place with complete selectivity. In the batchwise procedure, chlorine is introduced in an amount up to approximately 0.8-1.2 times, preferably 0.95-1.15 times the theoretical amount, corresponding to from 40 to 75%, preferably from 65 to 75%, conversion to the desired product.
The reaction mixture can be worked up, for example, by fractional distillation or recrystallization from a suitable solvent such as, for example, methanol. Preference is given to distillation. Insufficiently chlorinated compounds can be introduced again into the chlorination.
The chlorinated side chains are hydrolysed using a protic acid, optionally in the presence of water. Suitable protic acids are mineral acids such as, for example, sulphuric acid, hydrochloric acid or phosphoric acid, and organic acids such as, for example, formic acid, acetic acid or oxalic acid, and mixtures thereof and with a protic solvent such as, for example, water.
Depending on the type, concentration and amount of acid and reaction temperature, it is possible to carry out the hydrolysis of 2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene (VI) to give 2,4-dichloro-5-fluoro-3-formyl-benzoic acid (IV) in one or two steps. Because the trichloromethyl group is hydrolysed significantly more quickly, 2,4-dichloro-5-fluoro-3-dichloromethylbenzoic acid (V) can, if the reaction conditions are suitable, be isolated directly and converted to (IV) in a further hydrolysis step. As far as the overall process of the preparation of 3-cyano-2,4,5-trifluoro-benzoyl fluoride according to the invention is concerned, it is advantageous to carry out the hydrolysis in one step.
2,4-Dichloro-5-fluoro-3-formyl-benzoic acid (IV) and 2,4-dichloro-5-fluoro-3-dichloromethylbenzoic acid (V) are novel.
The amount of protic acid is unimportant. The acid, for example, is initially introduced and the molten aromatic compound (VI) or (V) is added. Preference is given to using sufficient acid (mixture) for the reaction mixture to remain stirrable.
The temperature for the hydrolysis can be varied within a wide range depending on the desired product, acid and reaction time. The temperature is generally from 0 to 100° C.
The product can be isolated, for example, by precipitation with water and removal by filtration or extraction.
The oxime (III) is prepared from 2,4-dichloro-5-fluoro-3-formyl-benzoic acid (
Marhold Albrecht
Wolfrum Peter
Bayer Aktiengesellschaft
Pellegrino Susan M.
Rotman Alan L.
Sackey Ebenezer
LandOfFree
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