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 method for preparing chlorobenzaldehyde oximes of general formula (I) ##STR00005## in which X.sup.2 is one of 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, and CN, X.sup.3 is one of 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, and CN, X.sup.4 is one of 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, and CN, X.sup.5 is one of 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, and CN, X.sup.6 is one of 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, and CN, the method comprising: preparing a reaction mixture comprising chloring gas (Cl.sub.2) and compounds of [[the]] general formula (II) in which ##STR00006## X.sup.2 to X.sup.6 have the meanings stated above; and converting, in a chemical reaction, the compounds of general formula (II) to compounds of the general formula (I) with [[the]] aid of the chlorine gas (Cl.sub.2).

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

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

4. The method 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 method 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 method according to claim 1, further comprising adding an amide base to the reaction mixture during the reaction.

7. The method according to claim 1, further comprising adding catalytic amounts of an amide base to the reaction mixture during the reaction.

8. The method according to claim 6, characterized in that the amide base is dimethylformamide (DMF), dibutylformamide (DBF), diethylformamide (DEF) or dimethylacetamide (DMAc).

9. The method according to claim 6, characterized in that the amide base is dimethylformamide (DMF) or dibutylformamide (DBF).

10. The method according to claim 1, characterized in that the reaction is conducted at 10 C. to 40 C.

11. The method according to claim 10, characterized in that the reaction is conducted at 5 C. to 10 C.

12. Precess The method according to claim 6, characterized in that 0.1-0.3 equivalents of the amide base is added, based on the benzaldehyde oxime (II).

13. The method according to claim 1, characterized in that the reaction mixture comprises 1.0-1.5 equivalents of Cl.sub.2, based on the benzaldehyde oxime (II).

Description

Example 1

Without Addition of a Catalyst in Isopropyl Acetate

[0057] 25.0 g of N-(3,5-difluorobenzylidene) hydroxylamine (1.0 eq.) in 225 g of isopropyl acetate were initially charged in a 0.5L reactor equipped with KPG stirrer and gas inlet tube under a protective nitrogen gas atmosphere at 23 C. After the solution had been cooled to 15 C., 14.0 g of Cl.sub.2 (1.36 eq.) were introduced over 1 hour with stirring (300 rpm). The temperature during the addition was kept below 14-16 C. After the metered addition of Cl.sub.2 was complete, stirring of the reaction mixture was continued for a further 30 minutes at 15 C. The HPLC analysis showed a proportion of 100% of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride. Subsequently, the reaction mixture was cooled to 10 C. with stirring and degassed at 300 mbar for 1 h. 257.3 g of a yellow solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in isopropyl acetate were then obtained (10.1 w/w %, 92.9% yield according to QHPLC). To characterize the product by 1H-NMR, an analytical sample was completely freed of solvent in vacuo.

[0058] .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).

[0059] .sup.19F-NMR (377 MHz, CDCl.sub.3): (ppm)=109.3 (m, 2F).

Example 2

Without Addition of a Catalyst in a Mixture of Toluene and THF

[0060] 89.2 g of a solution of N-(3,5-difluorobenzylidene) hydroxylamine (1.0 eq.) in a mixture of toluene and THF (25.5 w/w %, QHPLC) were initially charged in a 0.5L reactor equipped with KPG stirrer and gas inlet tube under a protective nitrogen gas atmosphere at 23 C. and further diluted with 138 g of toluene. After the solution had been cooled to 10 C., 18.0 g of Cl.sub.2 were introduced over 3 hours with stirring (300 rpm). The temperature during the addition was kept below 9-12 C. After the metered addition of Ch was complete, stirring of the reaction mixture was continued for a further 30 minutes at 10 C. The HPLC analysis showed a proportion of 100% of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride. Subsequently, the reaction mixture was cooled to 0 C. with stirring and degassed at 100 mbar for 2 h. 229.7 g of a yellow solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in a mixture of toluene and THF were then obtained (9.7 w/w %, 80.5% yield according to QHPLC).

Example 3

With Catalyst in a Mixture of Toluene and THF

[0061] 695 g of a solution of N-(3,5-difluorobenzylidene) hydroxylamine (1.0 eq.) in a mixture of toluene and THF (21.2 w/w %, QHPLC) were initially charged in a 1L reactor equipped with KPG stirrer and gas inlet tube under a protective nitrogen gas atmosphere at 23 C. and further diluted with 41.7 g of THF and also 13.7 g (0.2 eq.) of dimethylformamide (DMF) were added. After the solution had been cooled to 0 C., 77.7 g (1.17 eq.) of Cl.sub.2 were introduced over 1.5 hours with stirring (300 rpm). The temperature during the addition was kept below 10 C. After the metered addition of Cl.sub.2 was complete, stirring of the reaction mixture was continued for a further 30 minutes at 10 C. The HPLC analysis showed a proportion of 100% of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride. Subsequently, the reaction mixture was cooled to 0 C. with stirring and degassed at 50 mbar for 1 h. The product solution was subsequently washed with 130 g of a 5% aqueous sodium chloride solution at 0 C. and the phases separated at 20 C. The organic product-containing phase, still containing water, was then azeotropically dried at 45 C. and 85 mbar. After addition of 258 g of toluene, 740.0 g of a pale yellow clear solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in a mixture of toluene and THF were obtained (22.3 w/w %, 91.9% yield according to QHPLC).

Example 4

With Catalyst in a Mixture of Chlorobenzene and THF

[0062] 46.1 g of N-(3,5-difluorobenzylidene) hydroxylamine (1.0 eq.) in 145 g of chlorobenzene and 36.0 g of tetrahydrofuran were initially charged in a 0.5L reactor equipped with KPG stirrer and gas inlet tube under a protective nitrogen gas atmosphere at 23 C. and then 5.0 g of dibutylformamide (DBF, 0.1 eq.) were added. After the solution had been cooled to 0 C., 23.0 g of Cl.sub.2 (1.2 eq.) were introduced over 40 minutes with stirring (300 rpm). The temperature during the addition was kept below 17 C. After the metered addition of Cl.sub.2 was complete, stirring of the reaction mixture was continued for a further 30 minutes at 10 C. The HPLC analysis showed a proportion of 100% of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride. Subsequently, the reaction mixture was cooled to 0 C. with stirring and degassed at 50 mbar for 1 h. 242.2 g of a yellowish clear solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in a mixture of chlorobenzene and THF were then obtained (21.3 w/w %, 91.7% yield according to QHPLC).