METHOD FOR CHLORINATING BENZALDEHYDE OXIMES

Abstract

The present invention relates to a novel process for preparing chlorobenzaldehyde oximes of the general formula (I).

Claims

1. A process for preparing chlorobenzaldehyde oximes of general formula (I) ##STR00005## in which X.sup.2 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.4 fluoroalkoxy, C.sub.1-C.sub.4 alkoxy, fluorine, or CN, X.sup.3 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.4 fluoroalkoxy, C.sub.1-C.sub.4 alkoxy, fluorine, chlorine, or CN, X.sup.4 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.4 fluoroalkoxy, C.sub.1-C.sub.4 alkoxy, fluorine, or CN, X.sup.5 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.4 fluoroalkoxy, C.sub.1-C.sub.4 alkoxy, fluorine, chlorine, or CN, X.sup.6 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.4 fluoroalkoxy, C.sub.1-C.sub.4 alkoxy, fluorine, or CN, characterized in that benzaldehyde oxime compounds of general formula (II) ##STR00006## in which X.sup.2 to X.sup.6 have the meanings stated above, are converted in a reaction into compounds of the general formula (I) in the presence of trichloroisocyanuric acid (TCCA) and an amide base.

2. The process according to claim 1, wherein the definitions of the radicals of the general formulae (I) and (II) are as follows: X.sup.2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, or CN, X.sup.3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, or CN, X.sup.4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, or CN, X.sup.5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, or CN, X.sup.6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, or CN.

3. The process according to claim 2, wherein the definitions of the radicals of the general formulae (I) and (II) are as follows: X.sup.2 is H, X.sup.3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, or CN, X.sup.4 is fluorine or H, X.sup.5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, or CN, X.sup.6 is H.

4. The process according to claim 3, wherein the definitions of the radicals of the general formulae (I) and (II) are as follows: X.sup.2 is H, X.sup.3 is H or fluorine, X.sup.4 is H or fluorine, X.sup.5 is H or fluorine, X.sup.6 is H.

5. The process according to claim 4, wherein the definitions of the radicals of the general formulae (I) and (II) are as follows: X.sup.2 is H, X.sup.3 is fluorine, X.sup.4 is H, X.sup.5 is fluorine, X.sup.6 is H.

6. The process according to claim 1, characterized in that the reaction is carried out at ?10? C. to 40? C.

7. The process according to claim 6, characterized in that the reaction is carried out at ?5? C. to 10? C.

8. The process according to claim 1, characterized in that 0.5-2 equivalents of amide base are used, based on the benzaldehyde oxime (II).

9. The process according to claim 1, characterized in that 0.3-0.4 equivalents of TCCA are used, based on the benzaldehyde oxime (II).

10. The process according to claim 1, characterized in that the amide base is dimethylformamide (DMF), dibutylformamide (DBF), diethylformamide (DEF) or dimethylacetamide (DMAc).

11. The process according to claim 10, characterized in that the amide base is dibutylformamide (DBF).

Description

EXAMPLES

[0052] The present invention is elucidated in more detail by the examples that follow, without restriction of the invention thereto.

Measurement Methods

[0053] The products were characterized by .sup.1H and/or .sup.19F NMR spectroscopy and/or HPLC and/or LC-MS (Liquid Chromatography Mass Spectrometry).

[0054] The NMR spectra were determined using a Bruker Avance 400 fitted with a flow probe head (volume 60 ?l). In individual cases, the NMR spectra were measured with a Bruker Avance II 600.

Example 1 (Addition of TCCA in Solid Form)

[0055] 313.50 g of an N-(3,5-difluorobenzylidene)hydroxylamine solution (31.9 w/w % in toluene/THF) were initially charged into a 2 l four-necked flask with precision glass stirrer and dropping funnel, under a protective argon gas atmosphere, at 23? C. 151.66 g of N,N-dibutylformamide were then added via the dropping funnel over the course of 15 min, with stirring. After the solution had been cooled to 0? C. in an ice bath, 50.06 g of TCCA were added in portions of in each case approx. 0.46 g by means of a solids metering system, with stirring (210 rpm) over the course of 2 h. The temperature during the addition was kept below 5? C. here. After the addition of TCCA had been concluded, stirring of the reaction mixture was continued for a further 30 minutes at 0? C. The HPLC analysis showed a proportion of 92.8% of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride and no remaining N-(3,5-difluorobenzylidene)hydroxylamine. Subsequently, the reaction mixture was heated to 23? C. with stirring and stirring was continued for 1 h. The cyanuric acid formed was filtered off as a white solid and washed twice with 25 ml of toluene in each case, with 460.00 g of a 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride solution being obtained. The analysis by .sup.19F Q-NMR gave a yield of 84% at a concentration of 22.4 w/w %. After drying in air, 26.09 g of cyanuric acid (95%) could also be recovered.

[0056] .sup.1H NMR (401 MHz, CDCl.sub.3): ? (ppm)=6.84-6.89 (m, 1H), 7.37-7.45 (m, 2H), 10.86 (bs, 1H).

[0057] .sup.19F NMR (377 MHz, CDCl.sub.3): ? (ppm)=?109.3 (m, 2F).

Example 2 (Addition of TCCA as a 20 wt % Solution in Isopropyl Acetate)

[0058] 20.00 g of an N-(3,5-difluorobenzylidene)hydroxylamine solution (31.9 w/w % in toluene/THF) were initially charged into a 250 ml three-necked flask with magnetic stirrer and septum under a protective argon gas atmosphere at 23? C. and 9.68 g of N,N-dibutylformamide were added dropwise using a syringe over the course of 15 min with stirring. After the resulting solution had been cooled to 0? C. in an ice bath, 15.81 g of TCCA dissolved in isopropyl acetate (20 w/w %) were added to the reaction mixture over the course of 2 h using a syringe pump with continued stirring. The temperature was kept below 5? C. here. After the addition of TCCA had been completed, the reaction mixture was stirred for a further 30 minutes at 0? C., heated to 23? C. and stirred for a further hour, and then 7.81 g of fluorobenzene were added as internal standard (19F Q-NMR). The resulting reaction mixture showed, via HPLC, a complete conversion of the N-(3,5-difluorobenzylidene)hydroxylamine, with a yield of 87% (.sup.19F Q-NMR).

Example 3 (19 kg Solution (19.7 w/w % in Toluene/THF) Industrial-Scale Batch)

[0059] 19.2 kg of N-(3,5-difluorobenzylidene)hydroxylamine solution (19.7 w/w % in toluene/THF) were initially charged into a 50 l steel/enamel reactor under a protective nitrogen gas atmosphere and 5.7 kg of N,N-dibutylformamide were added at 15-20? C. After the resulting solution had been cooled to 0? C., 1.9 kg of TCCA dissolved in 10 l of isopropyl acetate (20 w/w %) were metered into the reaction mixture over the course of 90 min at 0-5? C., the mixture was stirred for a further 30 minutes at 0? C., the temperature of the mixture was adjusted to 20? C. and stirring was continued. The reaction solution was filtered off via a layer of kieselguhr and washed with 5 l of isopropyl acetate. The resulting product solution (33.7 kg) showed, via HPLC, a complete conversion of the N-(3,5-difluorobenzylidene)hydroxylamine, with a yield of 89% (19F Q-NMR).

Example 4 (5 kg Industrial-Scale Batch)

[0060] 5.0 kg of N-(3,5-difluorobenzylidene)hydroxylamine (94.0 w/w %) were initially charged into a 50 l steel/enamel reactor under a protective nitrogen gas atmosphere and dissolved in 3.8 l of toluene and 9.3 l of THF at 20? C., and 7.05 kg of N,N-dibutylformamide were added at 15-20? C. After the resulting solution had been cooled to 0? C., 2.5 kg of TCCA dissolved in 11.3 l of isopropyl acetate (20 w/w %) were metered into the reaction mixture over the course of 90 min at 0-5? C., the mixture was stirred for a further 30 minutes at 0? C., the temperature of the mixture was adjusted to 20? C. and stirring was continued. The reaction solution was filtered off via a layer of kieselguhr and washed with 2 l of isopropyl acetate. The resulting product solution (33.3 kg) showed, via HPLC, a complete conversion of the N-(3,5-difluorobenzylidene)hydroxylamine, with a yield of 86% (.sup.19F Q-NMR).