Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic halides
Reexamination Certificate
1998-12-10
2001-02-13
Wilson, James O. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic halides
C562S864000
Reexamination Certificate
active
06187952
ABSTRACT:
CROSS-REFERENCES TO RELATED APPLICATIONS
The present invention is described in the German priority application No. 197 55 298.6, filed Dec. 12, 1997, which is fully disclosed herein.
The present invention relates to an advantageous process for the preparation of 3-chloro-4-fluorobenzoyl chloride.
BACKGROUND OF THE INVENTION
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).
SUMMARY OF THE INVENTION
In view of the situation described above, the object was therefore to provide a process for the preparation of 3-chloro-4-fluorobenzoyl chloride which avoids the disadvantages described above and which is also easy to carry out industrially. In addition, it should make available the desired product in good yields and very good purity.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
This object is achieved by a process for the preparation of 3-chloro-4-fluorobenzoyl chloride. It comprises reacting 4-fluorobenzaldehyde with a chlorinating agent in the presence of a free-radical initiator in the presence or absence of a solvent at from −20 to 200° C. to give 4-fluorobenzoyl chloride, and reacting the 4-fluorobenzoyl chloride with a chlorinating agent in the presence of a chlorination catalyst in the presence or absence of a solvent at from −20 to 200° C. to give 3-chloro-4-fluorobenzoyl chloride.
The advantages of the novel process include the fact that it is possible, firstly, to react a starting material which is available in industrial amounts, and, secondly, it is possible to dispense with the use of a Friedel-Crafts catalyst such as aluminum chloride, which must normally be used in very large amounts. Moreover, the reaction can be carried out with comparatively few working steps having comparatively short reaction times.
It is also very surprising that the novel reaction of 4-fluorobenzoyl chloride with a chlorinating agent to give 3-chloro-4-fluorobenzoyl chloride takes place not only with good yield but also with very high selectivity. In view of the results of the chlorination of benzoyl chloride, not only would a formation of dichlorinated products have been expected, but also appreciable amounts of monochlorinated isomeric 4-fluorobenzoyl chlorides. However, entirely unexpectedly this is not the case. Isomeric 2-chloro-4-fluorobenzoyl chloride is formed only in an amount of about 1% and dichlorofluorobenzoyl chlorides are produced in an amount below 0.5%.
4-Fluorobenzaldehyde and the chlorinating agent are normally used in the molar ratio 1:(0.2 to 1.5), in particular 1:(0.25 to 1), preferably 1:(0.5 to 1).
The chlorinating agent used can be chlorine or a chlorine-releasing agent. Suitable chlorinating agents are chlorine, sulfuryl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, antimony pentachloride, iodine trichloride, sulfur dichloride, disulfur dichloride, manganese tetrachloride or a mixture thereof.
In particular, 4-fluorobenzaldehyde is reacted with chlorine, sulfuryl chloride, thionyl chloride or a mixture thereof as chlorinating agent.
It has proven particularly favorable to react 4-fluorobenzaldehyde with chlorine as chlorinating agent.
The reaction of 4-fluorobenzaldehyde with the chlorinating agent takes place according to a type of free-radical chlorination, where the presence of a free-radical initiator is beneficial. The free-radical initiator normally used is a peroxide, an azo compound, light having a wavelength of from 200 to 400 nm individually or in combination with one another. It is known that organic peroxides and organic azo compounds dissociate, under the influence of heat and/or light, into free-radicals which initiate the free radical chlorination.
Examples of suitable peroxides or azo compounds are ethyl methyl ketone peroxide, 4,4′-azobis(4-cyanopentanoic acid), 1,1′-azobis-(cyclohexanecarbonitrile), &agr;,&agr;′-azo(isobutyronitrile), &agr;,&agr;′-azodiisobutyroamidine dihydrochloride, tert-butyl hydroperoxide, tert-butyl trimethylsilyl peroxide, cumene hydroperoxide, dibenzoyl peroxide, di-tert-butyl peroxide, lauroyl peroxide and/or tert-butyl perbenzoate, in particular &agr;,&agr;′-azo(isobutyronitrile), tert-butyl hydroperoxide, dibenzoyl peroxide and/or lauroyl peroxide.
Light having a wavelength of from 200 to 400, in particular from 250 to 300 nm, has proven particularly suitable.
In a particularly preferred variant, azobisisobutyronitrile (&agr;,&agr;′-azo(isobutyronitrile)) is used as free-radical initiator.
The free-radical initiator (peroxide and/or azo compound) is normally used in an amount of from 0.1 to 10 mol %, in particular from 0.5 to 5 mol %, preferably from 0.7 to 2 mol %, based on 4-fluorobenzaldehyde.
The reaction of 4-fluorobenzaldehyde with the chlorinating agent takes place in the presence or absence of a solvent. The solvent used may be a chlorinated aliphatic or aromatic hydrocarbon or an aliphatic carboxylic acid having from 1 to 6 carbon atoms. Examples of suitable solvents are 1,2-dichloroethane, methyl chloride, methylene chloride, chloroform, carbon tetrachloride, trichlorobenzene, glacial acetic acid, acetic anhydride, in particular 1,2,4-trichlorobenzene, methyl chloride, glacial acetic acid and acetic anhydride.
In a large number of cases it has proven sufficient to react 4-fluorobenzaldehyde with the chlorinating agent at from 0 t
Pfirmann Ralf
Wessel Thomas
Clariant GmbH
Deemie Robert W.
Hanf Scott E.
Wilson James O.
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