3-Chloro-4-fluorobenzoyl chloride and its derivatives are important precursors for the preparation of pharmaceuticals and crop-protection compositions (J. Med. Chem. 1997, Vol. 40, 35-43, DE 29 14 915 A1).
3-Chloro-4-fluorobenzoyl chloride is available via a multi-stage synthesis. According to Diep et al., J. Chem. Soc. [1963], 2784-2787, ortho-chlorofluorobenzene is initially reacted with acetyl chloride in the presence of large amounts of aluminum chloride in the presence of carbon disulfide, methylene chloride or tetrachloroethylene, the reaction mixture is decomposed with dilute hydrochloric acid, the organic phase is washed with aqueous sodium hydroxide, then with water, and dried over sodium sulfate, the solvent is evaporated, and the residue is subjected to fractional distillation at reduced pressure. This method gives 3-chloro-4-fluoroacetophenone in a yield of about 80%.
The 3-chloro-4-fluoroacetophenone is then reacted with an aqueous solution of sodium hypobromite, the aqeuous phase is treated with sodium hydrogensulfite and acidified with hydrochloric acid, and the precipitated product is recrystallized from benzene. 3-Chloro-4-fluorobenzoic acid obtained in a yield of 74%.
The 3-chloro-4-fluorobenzoic acid can be reacted with thionyl chloride in the presence of small amounts of pyridine, as in DE 29 14 915, page 20, lines 28 to 35, to prepare the 3-chloro-4-fluorobenzoyl chloride.
This process, which starts from ortho-chlorofluorobenzene, has a number of disadvantages. Firstly, it requires a relatively large number of individual process steps and, secondly, uses a starting material which has relatively poor availability and is expensive, namely ortho-fluorochlorobenzene. Moreover, the Friedel-Crafts acetylation requires the use of large amounts of aluminum chloride and long reaction times (50 hours). In addition, it is carried out in the presence of solvents which create problems, for example carbon disulfide. In the 3-chloro-4-fluorobenzoyl chloride preparation stage, the yield is only 57%. Based on orthofluorochlorobenzene, 3-chloro-4-fluorobenzoyl chloride is obtained in a yield of only 33.7%.
It is known from the publication by E. Hope and G. C. Riley, J. Chem. Soc. [1922] 121, pages 2510-2527 that benzoyl chloride can be reacted with chlorine in the presence of iron(III) chloride to give 3-chlorobenzoyl chloride. As the analysis results on page 2525 show, as well as 76% of monochlorinated compounds, significant amounts of dichlorinated compounds, namely 5%, are formed. The amount of unreacted benzoyl chloride is 13.5%. The 3-chlorobenzoyl chloride is however contaminated with considerable amounts of undesired isomers. Their content is not less than 16.5% (14.5% of 2-chlorobenzoyl chloride and 2% of 4-chlorobenzoyl chloride).
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