Method for chlorinating benzaldehyde oxime

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to a novel method for preparing chlorobenzaldehyde oxime of general formula (I). [Background technology]

[0002] Chlorobenzaldehyde oxime of general formula (I) is an important precursor of active pesticide components (see International Publication No. 2018 / 228985) and active pharmaceutical components (e.g., DNA binding agents: Woods, Craig R. et al., Bioorganic & Medicinal Chemistry Letters, 12(18), 2647-2650; 2002).

[0003] Numerous chlorination methods are described in the prior art. For example, International Publication No. 2004 / 029066 teaches the preparation of chlorobenzaldehyde oxime by reaction of oxime with N-chlorosuccinimide (NCS) and subsequent aqueous work-up (extraction with siRNA / H2O). However, in the described method, only a small amount (2.45 g) of the resulting chlorobenzaldehyde oxime was isolated in solid form. However, in principle, it is desirable to isolate chlorobenzaldehyde oxime in solid form on an industrial scale, because chlorobenzaldehyde oxime is often a high-energy compound that tends to decompose. The method described in International Publication No. 2004 / 029066 uses dimethylformamide (DMF) as a solvent. However, the industrial-scale use of DMF as a solvent is known to be problematic. This is due to a strong exothermic reaction between DMF and the chlorinating agent, which can proceed uncontrolled. (OPRD 2020, 24, 1586; Bull.Chem.Soc.Jpn.1994, 67, 156).

[0004] The Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 31, 6th edition (2016), pp. 964-973, describes the chlorination of oximes using trichloroisocyanuric acid (TCCA) with triethylamine as the base. In this case, DMF is not used as the solvent, but it has been observed that chlorooximes tend to decompose in a basic environment by forming nitrile oxides, which can reduce the yield (e.g., formation of phloxanes by dimerization of nitrile oxides: "Kinetics and Mechanism of 1,3-Dipolar Cycloadditions", Prof. Dr. R. Huisgen, Angew. Chem. 1963, 75, pp. 742-754, 751; "Fragmentation of Nitrile Oxides with Triethylamine", Tetrahedron Lett. 1983, 24, 4377-4380). [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2018 / 228985 [Patent Document 2] International Publication No. 2004 / 029066 [Non-patent literature]

[0006] [Non-Patent Document 1] Woods, Craig R. et al., Bioorganic & Medicinal Chemistry Letters, 12(18), 2647~2650;2002 [Non-Patent Document 2] OPRD 2020, 24, 1586;Bull.Chem.Soc.Jpn.1994, 67, 156 [Non-Patent Document 3] Journal of Enzyme Inhibition and Medicinal Chemistry; Volume 31; Issue 6; (2016); pages 964-973 [Non-Patent Document 4] "Kinetics and Mechanism of 1,3-Dipolar Cycloadditions", Prof. Dr. R. Huisgen, Angew. Chem. 1963, 75, 742-754, page 751 [Non-Patent Document 5] "Fragmentation of Nitrile Oxides with Triethylamine" Tetrahedron Lett. 1983, 24, 4377-4380) [Summary of the Invention]

[0007] Accordingly, the present invention is based on the object of providing a process for chlorinating benzaldehyde oxime which, on the one hand, allows the elimination of DMF as a solvent, and on the other hand, does not result in a yield reduction caused by relatively strong bases such as triethylamine, and is therefore cost-effective and at the same time can be used on an industrial scale.

[0008] According to the present invention, this object is achieved by the general formula (I) [Chemical Formula] (wherein, X 2 is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine or CN, X 3 is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine, chlorine or CN, X 4 is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine or CN, X 5represents H, C1~C4 alkyl, C1~C4 fluoroalkyl, C1~C4 fluoroalkoxy, C1~C4 alkoxy, fluorine, chlorine or CN, X 6 represents H, C1~C4 alkyl, C1~C4 fluoroalkyl, C1~C4 fluoroalkoxy, C1~C4 alkoxy, fluorine or CN) A method for preparing chlorobenzaldehyde oxime, general formula (II)

Chemical Formula

[0009] Preferred definitions of groups for compounds of general formula (I) and (II) are as follows: X 2 represents H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN, X 3 represents H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN, X 4 represents H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN, X 5 represents H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN, X 6 represents H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN.

[0010] The particularly preferred definitions of the group for compounds of general formulas (I) and (II) are as follows: X 2 H is, X 3 These are H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, and CN. X 4 These are fluorine and H, X 5 These are H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, and CN. X 6 H is H.

[0011] A very particular preferred definition of a group for compounds of general formulas (I) and (II) is as follows: X 2 H is, X 3 These are H and fluorine, X 4 These are H and fluorine, X 5 These are H and fluorine, X 6 H is H.

[0012] The most preferred definitions of the group for compounds of general formulas (I) and (II) are as follows: X 2 H is, X 3 It is fluorine, X 4 H is, X 5 It is fluorine, X 6 H is H.

[0013] The compound of formula (I) may exist as a mixture of geometric isomers. [ka]

[0014] The ratio of E isomers to Z isomers varies.

[0015] Description of method and intermediates [ka] A method for preparing a chlorobenzaldehyde oxime of formula (I), characterized in that a compound of general formula (II) is converted to a compound of general formula (I) using trichloroisocyanuric acid (TCCA) and an amide base.

[0016] The method according to the present invention has the advantage of avoiding the use of DMF as a solvent. This minimizes the risk of the reaction proceeding uncontrolledly with strong exothermic reactions. Therefore, this reaction is suitable for large-scale implementation.

[0017] Further preferred amide bases include, for example, dibutylformamide (DBF), diethylformamide (DEF), or dimethylacetamide (DMAc), with dibutylformamide being preferred.

[0018] In the method according to the present invention, preferably 0.5 to 2 equivalents, particularly preferably 1 to 1.5 equivalents, of an amide base relative to benzaldehyde oxime(II) are used. Preferably, 0.3 to 0.4 equivalents of TCCA (0.9 to 1.3 equivalents of "Cl") are used relative to benzaldehyde oxime(II).

[0019] Furthermore, the reaction mixture can be post-treated without water, and the precipitated cyanuric acid can be removed by filtration.

[0020] Chlorination is usually carried out in a temperature range of -10°C to 40°C, preferably -5°C to 10°C, and particularly preferably 0 to 5°C.

[0021] Chlorination is further carried out in the presence of a solvent or diluent, preferred solvents being tetrahydrofuran, Me-THF, acetonitrile, N,N-dimethylacetamide, toluene, ethyl acetate, isopropyl acetate, and methyl-tert-butyl ether.

[0022] Trichloroisocyanuric acid (TCCA) is added to the benzaldehyde oxime of formula (II) in solid form or as a freshly prepared solution dissolved in ethyl acetate, isopropyl acetate, or acetonitrile. The concentration of the solution here is determined by the solubility of TCCA in each solvent. For example, up to approximately 25 w / w% dissolves in ethyl acetate, and up to approximately 20 w / w% dissolves in isopropyl ester.

[0023] Examples The present invention will be described in more detail by the following embodiments, but the present invention is not limited to these embodiments.

[0024] Measurement method The product is, 1 H and / or 19 The samples were characterized by 1F NMR spectroscopy and / or HPLC and / or LC-MS (liquid chromatography-mass spectrometry).

[0025] NMR spectra were measured using a Bruker Avance 400 equipped with a flow probe head (60 μl capacity). In individual cases, NMR spectra were measured using a Bruker Avance II 600.

[0026] Example 1 (Addition of TCCA in solid form) 313.50 g of N-(3,5-difluorobenzylidene)hydroxylamine solution (31.9 w / w%) in toluene / THF was first placed in a 2 L four-necked flask equipped with a precision glass stirrer and dropping funnel at 23°C under a protective argon gas atmosphere. Then, while stirring, 151.66 g of N,N-dibutylformamide was added over 15 minutes via the dropping funnel. After cooling the solution to 0°C in an ice bath, 50.06 g of TCCA was added over 2 hours with stirring (210 rpm) using a solid weighing system, in portions of approximately 0.46 g each. The temperature during the addition was maintained below 5°C. After the addition of TCCA was complete, the reaction mixture was stirred for a further 30 minutes at 0°C. HPLC analysis revealed that the proportion of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride was 92.8%, and that there was no residual N-(3,5-difluorobenzylidene)hydroxylamine. The reaction mixture was then heated to 23°C with stirring, and stirring was continued for 1 hour. The formed cyanuric acid was filtered off as a white solid, and each filter was washed twice with 25 ml of toluene to obtain 460.00 g of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride solution. 19 Analysis by F Q-NMR revealed an 84% yield at a concentration of 22.4 w / w%. After drying in air, 26.09 g (95%) of cyanuric acid was also recovered. 1 H NMR(401MHz,CDCl3):δ(ppm)=6.84-6.89(m,1H),7.37-7.45(m,2H),10.86(bs,1H) 19 F NMR(377MHz,CDCl3):δ(ppm)=-109.3(m,2F)

[0027] Example 2 (Addition of TCCA as a 20% by weight solution in isopropyl acetate) 20.00 g of N-(3,5-difluorobenzylidene)hydroxylamine solution (31.9 w / w%) in toluene / THF was first placed in a 250 ml three-necked flask equipped with a magnetic stirrer and septum at 23°C under a protective argon gas atmosphere. While stirring, 9.68 g of N,N-dibutylformamide was added dropwise over 15 minutes using a syringe. After cooling the resulting solution to 0°C in an ice bath, 15.81 g of TCCA (20 w / w%) dissolved in isopropyl acetate was added to the reaction mixture over 2 hours using a syringe pump while continuing to stir. The temperature was maintained below 5°C. After the addition of TCCA was complete, the reaction mixture was stirred at 0°C for a further 30 minutes, heated to 23°C, stirred for a further 1 hour, and then an internal standard was added ( 19 7.81 g of fluorobenzene was added (as measured by F Q-NMR). The resulting reaction mixture showed complete conversion of N-(3,5-difluorobenzylidene)hydroxylamine by HPLC, with a yield of 87%. 19 F Q-NMR).

[0028] Example 3 (Industrial-scale batch of 19 kg of solution (19.7 w / w%) in toluene / THF) 19.2 kg of N-(3,5-difluorobenzylidene)hydroxylamine solution (19.7 w / w%) in toluene / THF was initially placed in a 50 L steel / enamel reactor under a protective nitrogen gas atmosphere, and 5.7 kg of N,N-dibutylformamide was added at 15-20°C. After cooling the resulting solution to 0°C, 1.9 kg of TCCA (20 w / w%) dissolved in 10 L of isopropyl acetate was weighed into the reaction mixture over 90 minutes 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 through a diatomaceous earth layer and washed with 5 L of isopropyl acetate. The resulting product solution (33.7 kg) showed complete conversion of N-(3,5-difluorobenzylidene)hydroxylamine by HPLC, with a yield of 89%. 19 F Q-NMR).

[0029] Example 4 (5kg industrial-scale batch) 5.0 kg (94.0 w / w%) of N-(3,5-difluorobenzylidene)hydroxylamine was initially placed in 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. 7.05 kg of N,N-dibutylformamide was added at 15-20°C. After cooling the resulting solution to 0°C, 2.5 kg of TCCA (20 w / w%) dissolved in 11.3 L of isopropyl acetate was weighed into the reaction mixture over 90 minutes 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 through a diatomaceous earth layer and washed with 2 L of isopropyl acetate. The resulting product solution (33.3 kg) showed complete conversion of N-(3,5-difluorobenzylidene)hydroxylamine by HPLC, with a yield of 86%. 19 F Q-NMR).

Claims

1. General formula (I) 【Chemistry 1】 (In the formula, X 2 represents H, C 1 to C 4 alkyl, C 1 to C 4 fluoroalkyl, C 1 to C 4 fluoroalkoxy, C 1 to C 4 alkoxy, fluorine, or CN, X 3 H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 It is alkoxy, fluorine, chlorine, and CN. X 4 H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 It is an alkoxy, fluorine, and CN. X 5 H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 It is alkoxy, fluorine, chlorine, and CN. X 6 H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 (It is alkoxy, fluorine, and CN.) A method for preparing chlorobenzaldehyde oxime, General formula (II) 【Chemistry 2】 (In the formula, X 2 ~X 6 (This has the meaning described above.) A method characterized in that a compound is converted to a compound of general formula (I) using trichloroisocyanuric acid (TCCA) and an amide base, wherein the amide base is dibutylformamide (DBF).

2. The method according to claim 1, wherein the definitions of the bases in the above general formulas (I) and (II) are as follows: X 2 These are H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, and CN. X 3 These are H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, and CN. X 4 These are H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, and CN. X 5 These are H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, and CN. X 6 These are H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, and CN.

3. The method according to claim 1, wherein the definitions of the bases in the above general formulas (I) and (II) are as follows: X 2 H is, X 3 These are H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, and CN. X 4 These are fluorine and H, X 5 These are H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, and CN. X 6 H is H.

4. The method according to claim 1, wherein the definitions of the bases in the above general formulas (I) and (II) are as follows: X 2 H is, X 3 These are H and fluorine, X 4 These are H and fluorine, X 5 These are H and fluorine, X 6 H is H.

5. The method according to claim 1, wherein the definitions of the bases in the above general formulas (I) and (II) are as follows: X 2 H is, X 3 It is fluorine, X 4 H is, X 5 It is fluorine, X 6 H is H.

6. The method according to any one of claims 1 to 5, characterized in that the reaction is carried out at a temperature of -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 5, characterized in that 0.5 to 2 equivalents of an amide base are used relative to benzaldehyde oxime (II).

9. The method according to any one of claims 1 to 5, characterized in that 0.3 to 0.4 equivalents of TCCA are used relative to benzaldehyde oxime (II).

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