EP4323334A1

EP4323334A1 - Method for chlorinating benzaldehyde oximes

Info

Publication number: EP4323334A1
Application number: EP22722154.6A
Authority: EP
Inventors: Anton Lishchynskyi; Frank Memmel; Mark James Ford; Stefan MOCZARSKI; Heiko Schirmer
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 2021-04-13
Filing date: 2022-04-08
Publication date: 2024-02-21
Also published as: BR112023019712A2; JP2024513598A; TW202304853A; IL307487A; CN117222618A; WO2022218853A1; KR20230169208A

Abstract

The invention relates to a novel method for producing chloro-benzaldehyde oximes of the general formula (I).

Description

Process for the chlorination of benzaldehyde oximes

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

Chlorobenzaldehyde oximes of the general formula (I) are important precursors of agrochemical active ingredients (cf. WO 2018/228985) and pharmaceutical active ingredients (e.g. DNA binding agents: Woods, Craig R. et al. Bioorganic & Medicinal Chemistry Leiters, 12(18), 2647-2650; 2002).

Numerous chlorination methods are described in the prior art, for example WO 2004/29066 teaches the preparation of chlorobenzaldehyde oximes by reacting oximes with N-chlorosuccinimide (NCS) and subsequent aqueous work-up (extraction with EtOAcTFO). However, only small amounts (2.45 g) of the chlorobenzaldehyde oximes obtained were isolated as a solid in the process described. In principle, however, the isolation of chlorobenzaldehyde oximes on an industrial scale as a solid is undesirable, since chlorobenzaldehyde oximes are often high-energy compounds which have a high tendency to decompose. The method described in WO 2004/29066 uses dimethylformamide (DMF) as a solvent. However, it is known that its use as a solvent on an industrial scale can be problematic. This is due to the strongly exothermic reaction between DMF and the chlorinating agent, which may then proceed uncontrolled. (OPRD 2020, 24, 1586; Bull. Chem. Soc. Jpn. 1994, 67, 156).

The Journal of Enzyme Inhibition and Medicinal Chemistry; volume 31; nb. 6; (2016); p. 964 - 973 teaches the chlorination of oximes with trichloroisocyanuric acid (TCCA) with triethylamine as the base, DMF is not used as the solvent here, but it has been observed that the chlorooximes tend to degrade in a basic environment through the formation of nitrile oxides, which can lead to yield losses (e.g. dimerization of nitrile oxides to furoxanes: "Kinetics and mechanism of 1.3-dipolar cycloadditions" by Prof. Dr. R. Huisgen, Angew. Chem. 1963, 75, 742-754, page 751; "Fragmentation of nitrile oxides with triethylamine" Tetrahedron Lett. 1983, 24, 4377-4380).

The object of the invention was therefore to provide a process for the chlorination of benzaldehyde oximes which, on the one hand, can dispense with DMF as a solvent and, on the other hand, does not result in the yield losses caused by stronger bases, such as triethylamine, and is at the same time inexpensive and can be used on an industrial scale. The object was achieved according to the invention by a process for preparing chlorobenzaldehyde oximes of the general formula (I) where X ² is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, CN,

X ³ is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, chlorine, CN,

X ⁴ is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, CN,

X ⁵ is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, chlorine, CN,

X ⁶ is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, CN, characterized in that the compounds of the general formula (II) wherein

X ² to X ⁶ have the meanings given above, with the aid of trichloroisocyanuric acid (TCCA) and an amide base to give compounds of the general formula (I).

Preferred radical definitions for the compounds of the general formulas (I) and (II) are the following: X ² is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, methoxy, CN,

X ³ is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, chloro, methoxy, CN, X ⁴ is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, methoxy, CN,

X ⁵ is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, chloro, methoxy, CN,

X ⁶ is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, methoxy, CN.

Particularly preferred radical definitions for the compounds of the general formulas (I) and (II) are the following:

^X2 is H,

X ³ is H, methyl, trifluoromethyl, difluoromethyl, fluoro, chloro, methoxy, CN, X ⁴ is fluoro, H,

X ⁵ is H, methyl, trifluoromethyl, difluoromethyl, fluoro, chloro, methoxy, CN,

X ⁶ is H

Very particularly preferred radical definitions for the compounds of the general formulas (I), (II) are the following: X ² is H,

X ³ is H, fluorine,

X ⁴ is H, fluorine,

X ⁵ is H, fluorine,

X ⁶ is H Most preferred radical definitions for the compounds of general formulas (I) and (II) are the following:

^X2 is H,

X ³ is fluorine, X ⁴ is H,

X ⁵ is fluorine,

X ⁶ is H

The compounds of formula (I) can exist as geometric mixtures of isomers:

(£ -isomer

(ZJ isomer

The ratio between E and Z isomers varies.

Explanation of the processes and intermediates

Process for preparing chlorobenzaldehyde oximes of the formula (I), characterized in that the compounds of the general formula (II) are converted into compounds of the general formula (I) using trichloroisocyanuric acid (TCCA) and an amide base. The method according to the invention has the advantage that DMF is avoided as a solvent. This minimizes the risk that the reaction will be highly exothermic and uncontrolled. Consequently, the reaction is suitable for large-scale operation.

Other suitable amide bases are, for example, dibutylformamide (DBF), diethylformamide (DEF), or dimethylacetamide (DMAc), with dibutylformamide being preferred.

In the process according to the invention, preference is given to using 0.5-2 equivalents of amide base, based on the benzaldehyde oxime (II), particularly preferably 1-1.5 equivalents. Preference is given to using 0.3-0.4 equivalents of TCCA, based on the benzaldehyde oxime (II) (0.9-1.3 equivalents “CI”). In addition, the reaction mixture can be worked up anhydrous and the cyanuric acid which has precipitated can be separated off by filtration.

The chlorination is usually carried out in a temperature range of -10°C to 40°C, preferably -5°C to 10°C, particularly preferably 0 to 5°C.

Furthermore, the chlorination is carried out in the presence of a solvent or diluent, the solvents preferably being tetrahydrofuran, Me-THF, acetonitrile, N,N-dimethylacetamide, toluene, ethyl acetate, isopropyl acetate, methyl tert-butyl ether.

The trichloroisocyanuric acid (TCCA) is added to the benzaldehyde oxime of the formula (II) as a solid or as a freshly prepared solution in ethyl acetate, isopropyl acetate or acetonitrile. The concentration of the solution depends on the solubility of TCCA in the respective solvent. For example, up to approx. 25 w/w% dissolves in ethyl acetate and up to approx. 20 w/w% in isopropyl ester.

examples

The present invention is explained in more detail using the following examples, without restricting the invention to these.

Method of measurement The products were characterized by means of Ή- and/or ¹⁹ F-NMR spectroscopy and/or HPLC and/or LC/MS (Liquid Chromatography Mass Spectrometry). The NMR spectra were determined with a Bruker Avance 400 equipped with a flow-through probe (60 μl volume). In individual cases, the NMR spectra were measured with a Bruker Avance II 600.

Example 1 (Adding the TCCA as a solid)

In a 2 L four-neck flask with KPG stirrer and dropping funnel, under an argon protective gas atmosphere, at 23 °C, 313.50 g of an N-(3,5-difluorobenzylidene)hydroxylamine solution (31.9 w/w% in toluene/THF) submitted. Thereafter, 151.66 g of N,N-dibutylformamide were added via the dropping funnel within 15 minutes while stirring. After the solution had been cooled to 0° C. in an ice bath, 50.06 g of TCCA were added in portions of approx. 0.46 g each with the aid of a solids feeder over a period of 2 hours while stirring (210 rpm). The temperature during the addition was kept below 5°C. After the addition of TCCA was complete, the reaction mixture was stirred at 0° C. for a further 30 minutes. HPLC analysis showed 92.8% content of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride and no remaining N-(3,5-difluorobenzylidene)hydroxylamine. The reaction mixture was then heated to 23° C. with stirring and stirred for a further hour. The cyanuric acid formed was filtered off as a white solid and washed twice with 25 ml of toluene each time, with 460.00 g of a 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride solution being obtained. Analysis by ¹⁹ F Q-NMR gave a yield of 84% at a concentration of 22.4 w/w%. In addition, after drying in air, 26.09 g of cyanuric acid (95%) could be recovered.

Tf NMR (401MHz, CDC1 ₃ ): d (ppm) = 6.84-6.89 (m, 1H), 7.37-7.45 (m, 2H), 10.86 (bs, 1H).

¹⁹ F NMR (377MHZ, CDCL): d (ppm) = -109.3 (m, 2F).

Example 2 (Addition of the TCCA as a 20% by weight solution in isopropyl acetate)

20.00 g of an N-(3,5-difluorobenzylidene)hydroxylamine solution (31.9 w/w% in toluene/THF) and 9. 68 g of N,N-dibutylformamide was added dropwise with a syringe over 15 min with stirring. After the resulting solution was cooled to 0°C in an ice bath, 15.81 g of TCCA dissolved in isopropyl acetate (20 w/w%) was added to the reaction mixture over 2 h with a syringe pump while stirring continuously. The temperature was kept below 5 °C. After the TCCA addition was complete, the reaction mixture was stirred at 0° C. for 30 minutes, warmed to 23° C. and stirred for a further hour, and finally 7.81 g of fluorobenzene were added as an 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% ( ¹⁹ F Q-NMR).

Example 3 (19 kg solution (19.7 w/w% in toluene/THF) batch on an industrial scale)

In a 50 L steel/enamel reactor, 19.2 kg of N-(3,5-difluorobenzylidene)hydroxylamine solution (19.7 w/w% in toluene/THF) and 5.7 kg of N,N- Dibutylformamide 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 within 90 min at 0-5°C, for 30 minutes at 0° C stirred, heated to 20 ° C and stirred. The reaction solution was filtered through a layer of kieselguhr and washed with 5 L of isopropyl acetate. The resulting product solution (33.7 kg) showed complete conversion of the N-(3,5-difluorobenzylidene)hydroxylamine via HPLC, with a yield of 89% (19F Q-NMR).

Example 4 (5 kg batch on an industrial scale)

In a 50 L steel/enamel reactor, 5.0 kg of N-(3,5-difluorobenzylidene)hydroxylamine (94.0 w/w%) were placed under a protective nitrogen atmosphere and at 20° C. in 3.8 L of toluene and 9 Dissolved 3 L THF and added 7.05 kg N,N-dibutylformamide 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 within 90 min at 0-5° C. for 30 minutes 0° C., tempered to 20° C. and stirred. The reaction solution was filtered through a layer of kieselguhr and washed with 2 L of isopropyl acetate. The resulting product solution (33.3 kg) showed complete conversion of the N-(3,5-difluorobenzylidene)hydroxylamine via HPLC, with a yield of 86% ( ¹⁹ F Q-NMR).

Claims

Patent Claims:

1. Process for preparing chlorobenzaldehyde oximes of the general formula (I) where X ² is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, CN,

2. The method according to claim 1, wherein the radical definitions of the general formulas (I) and (II) are as follows: X ² is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, methoxy, CN,

X ³ is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, chloro, methoxy, CN,

X ⁴ is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, methoxy, CN,

3. The method according to claim 1, wherein the radical definitions of the general formulas (I) and (II) are as follows:

^X2 is H,

X ³ is H, methyl, trifluoromethyl, difluoromethyl, fluoro, chloro, methoxy, CN,

X ⁴ is fluorine, H,

X ⁶ is H

4. The method according to claim 1, wherein the radical definitions of the general formulas (I) and (II) are as follows:

^X2 is H,

X ³ is H, fluorine,

X ⁴ is H, fluorine,

X ⁵ is H, fluorine,

X ⁶ is H

5. The method according to claim 1, wherein the radical definitions of the general formulas (I) and (II) are as follows:

^X2 is H,

X ³ is fluorine,

^X4 is H,

X ⁵ is fluorine, X ⁶ is H

6. The method according to any one of claims 1 to 5, characterized in that the reaction is carried out at -10 ° C to 40 ° C.

7. The method according to any one of claims 1 to 5, characterized in that the reaction is carried out at -5 ° C to 10 ° C.

8. The method according to any one of claims 1 to 7, characterized in that 0.5-2 equivalents of amide base are used, based on the benzaldehyde oxime (II).

9. The method according to any one of claims 1 to 8, characterized in that 0.3 - 0.4 equivalents of TCCA are used, based on the benzaldehyde oxime (II).

10. The method according to any one of claims 1 to 9, characterized in that the base

dimethylformamide (DMF), dibutylformamide (DBF), diethylformamide (DEF) or dimethylacetamide (DMAc).

11. The method according to any one of claims 1 to 9, characterized in that the base is dibutylformamide (DBF).