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 process for preparing chlorobenzaldehyde oximes of general formula (I). [Background technology]

[0002] Chlorobenzaldehyde oximes of general formula (I) are important precursors of active pesticide ingredients (see WO 2018 / 228985) and active pharmaceutical ingredients (e.g., DNA binders: 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, WO 2004 / 029066 and Industrial Crops & Products 2019, 140, 111706 describe the reaction of oximes with N-chlorosuccinimide (NCS) and subsequent aqueous work-up (EtOAc / H 2 O) to prepare chlorobenzaldehyde oxime. However, in the described method, only a small amount (2.45 g) of the obtained chlorobenzaldehyde oxime was isolated in solid form. In principle, it is not desirable to isolate chlorobenzaldehyde oxime in solid form on an industrial scale, since chlorobenzaldehyde oxime is often a high-energy compound with a high tendency to decompose. The method described in WO 2004 / 029066 uses dimethylformamide (DMF) as a solvent. However, it is known that the use of DMF as a solvent on an industrial scale can be problematic. This is due to the 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 use of chlorine gas to chlorinate oximes is described, for example, in the Journal of Organic Chemistry 1971, 36, 2146. In this case, the reaction is carried out only in chloroform or dichloromethane at high dilution, which is not suitable for large-scale industrial synthesis and gives chlorobenzaldehyde oximes in medium to low yields of 3-80%. The preferred chlorination under basic conditions by the addition of triethylamine as described leads to partial decomposition of the chlorooxime compound. Furthermore, the Journal of Heterocyclic Chemistry;2012, 49, 621 teaches the use of chlorine gas in methanol as a solvent under weakly basic reaction conditions by the addition of sodium carbonate. In addition to the formation of safety-critical amounts of gaseous carbon dioxide, the product may re-decompose under basic conditions. Hydrogen chloride released during chlorination may also lead to the formation of toxic compounds by reaction with the solvent. The use of methanol as a solvent also prevents the direct use of the product solution without replacing the solvent in many chemical reactions. In addition to the high energy of such chlorinated compounds and the significant safety limitations due to the preferred use of dilute systems, the solvent exchange also reduces the efficiency and sustainability of the process.

[0005] Journal of Enzyme Inhibition and Medicinal Chemistry; Vol. 31; No. 6; (2016); pp. 964-973 teaches the chlorination of oximes using trichloroisocyanuric acid (TCCA) and triethylamine as base. Although DMF as solvent is not used here, it has been observed that chlorooximes tend to decompose in basic media due to the formation of nitrile oxides, which can result in reduced yields (e.g., dimerization of nitrile oxides to furoxans: Prof. Dr. R. Huisgen, "Kinetics and Mechanism of 1,3-Dipolar Cycloadditions", Angew. Chem. 1963, 75, pp. 742-754, 751; "Fragmentation of Nitrile Oxides with Triethylamine", Tetrahedron Lett. 1983, 24, 4377-4380). Furthermore, the use of trichloroisocyanuric acid (TCCA) leads to increased production of solid isocyanuric acid as waste, which has negative effects on the process in terms of sustainability and waste management. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2018 / 228985 [Patent Document 2] International Publication No. 2004 / 029066 [Non-patent literature]

[0007] [Non-Patent Document 1] Woods, Craig R. et al., Bioorganic & Medicinal Chemistry Letters, 12(18), 2647~2650, 2002 [Non-Patent Document 2] Industrial Crops & Products 2019, 140, 111706 [Non-Patent Document 3] OPRD 2020, 24, 1586;Bull.Chem.Soc.Jpn.1994, 67, 156 [Non-Patent Document 4] Journal of Organic Chemistry 1971, 36, 2146 [Non-Patent Document 5] Journal of Heterocyclic Chemistry;2012, 49, 621 [Non-Patent Document 6] Journal of Enzyme Inhibition and Medicinal Chemistry; Volume 31; Issue 6; (2016); Pages 964-973 [Non-Patent Document 7] "Kinetics and Mechanism of 1,3-Dipolar Cycloadditions" by Prof. Dr. R. Huisgen, Angew. Chem. 1963, 75, 742-754, 751 [Non-Patent Document 8] "Fragmentation of Nitrile Oxides with Triethylamine" Tetrahedron Lett.1983, 24, 4377~4380) Summary of the Invention

[0008] The present invention was therefore based on the object of providing a process for the chlorination of benzaldehyde oxime which, on the one hand, dispenses with the use of DMF or chlorinated alkane compounds as solvents or of chlorinating agents with low atom efficiency and high waste, such as trichloroisocyanuric acid or N-chlorosuccinimide, and, on the other hand, is free of the yield reduction caused by relatively strong bases such as triethylamine, and which is at the same time cost-effective and can be used on an industrial scale. The chlorobenzaldehyde oxime should in this case be obtained in high yield and, by suitable selection of the solvent, can be used as a solution in various chemical reactions without the need for solvent exchange.

[0009] This object is achieved according to the present invention by providing a compound of general formula (I) [ka] (In the formula, X 2 , H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 Alkoxy, fluorine, CN; X 3 , H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 Alkoxy, fluorine, chlorine, CN; X 4 , H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 Alkoxy, fluorine, CN; X 5 , H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 Alkoxy, fluorine, chlorine, CN; X 6 , H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C1 ~C 4 Alkoxy, fluorine, CN) 1. A process for preparing a chlorobenzaldehyde oxime of the formula General formula (II) [ka] (In the formula, X 2 ~X 6 have the meaning given above) The compound is chlorine gas (Cl 2 ) to a compound of general formula (I), This was achieved by the method.

[0010] In a preferred embodiment, an amide base is added to the reaction mixture in addition to chlorine gas to convert the compound of formula (II) to a compound of general formula (I).

[0011] In a particularly preferred embodiment, a catalytic amount of an amide base is added to the reaction mixture in addition to chlorine gas to convert the compound of formula (II) to a compound of general formula (I).

[0012] Preferred definitions of the groups for the compounds of general formulae (I) and (II) are as follows: X 2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN; X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN; X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN; X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN; X6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN.

[0013] Particularly preferred definitions of the groups for the compounds of general formulae (I) and (II) are as follows: X 2 is H, X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN, X 4 is fluorine, H, X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN, X 6 is H.

[0014] Very particularly preferred definitions of the radicals for the compounds of general formulae (I), (II) are as follows: X 2 is H, X 3 is H, fluorine, X 4 is H, fluorine, X 5 is H, fluorine, X 6 is H.

[0015] The most preferred definitions of the groups for the compounds of general formulae (I) and (II) are as follows: X 2 is H, X 3 is fluorine, X 4 is H, X 5 is fluorine, X 6 is H.

[0016] Compounds of formula (I) may exist as mixtures of geometric isomers. [ka]

[0017] The ratio of E to Z isomers varies.

[0018] Description of Methods and Intermediates [ka] The compound of formula (II) is reacted with chlorine gas (Cl 2 ) to convert the chlorobenzaldehyde oxime of formula (I) into a compound of general formula (I).

[0019] Preferably, an amide base is added to the reaction mixture in addition to chlorine gas to convert the compound of formula (II) to a compound of general formula (I).

[0020] Particularly preferably, a catalytic amount of an amide base is added to the reaction mixture in addition to chlorine gas to convert the compound of formula (II) to a compound of general formula (I).

[0021] The method according to the present invention has the advantage that it avoids the use of stoichiometric amounts of DMF or chlorinated alkane compounds as solvents. This minimizes the risk of the reaction proceeding in an uncontrolled manner with high exothermicity, and eliminates the need for less sustainable solvents. Furthermore, the use of chlorine gas eliminates the need to use N-chlorosuccinimide (NCS) or trichloroisocyanuric acid (TCCA), thus reducing waste and significantly increasing the sustainability of the method. Therefore, the reaction is suitable for carrying out on a large scale.

[0022] Amide bases suitable as catalysts are, for example, dimethylformamide (DMF), dibutylformamide (DBF), diethylformamide (DEF) or dimethylacetamide (DMAc), preferably dimethylformamide or dibutylformamide.

[0023] In the process according to the present invention, preferably, no amide base is used or 0.05 to 0.3 equivalents of an amide base relative to the benzaldehyde oxime (II) are used, particularly preferably 0.1 to 0.3 equivalents of an amide base. Preferably, 0.95 to 2.0 equivalents of Cl relative to the benzaldehyde oxime (II) are used. 2 is used, and particularly preferably 1.0 to 1.5 equivalents of Cl 2 is used.

[0024] The chlorination is usually carried out at a temperature range of -10°C to 40°C, preferably -5°C to 10°C, and particularly preferably 0 to 10°C.

[0025] The chlorination is further carried out in the presence of a solvent or diluent, preferred solvents being tetrahydrofuran, Me-THF, acetonitrile, N,N-dimethylacetamide, toluene, xylene, chlorobenzene, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, cyclopentyl methyl ether, tert-amyl methyl ether, or a mixture of the above mentioned solvents.

[0026] Chlorine is introduced as a gas into the benzaldehyde oxime of formula (II).

[0027] Working under anhydrous conditions is preferred, as this increases the yield. EXAMPLES

[0028] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

[0029] Measurement method The product 1 H-spectroscopy and / or 19 The compounds were characterized by F-NMR spectroscopy and / or quantitative HPLC.

[0030] NMR spectra were recorded using a Bruker Avance 400 equipped with a flow probe head (volume 60 μL). In each case, NMR spectra were recorded using a Bruker Avance II 600.

[0031] Quantitative HPLC measurements were performed on an HPLC Agilent HP1260 series. The technique is based on HPLC with UV detection, an Agilent XDB C18 column, and external standard evaluation (use of an external standard with a reference factor). Samples, reference standards, and internal standards are dissolved in acetonitrile.

[0032] Example 1 (in isopropyl acetate without added catalyst) 25.0 g of N-(3,5-difluorobenzylidene)hydroxylamine (1.0 equiv.) in 225 g of isopropyl acetate was initially charged into a 0.5 L reactor equipped with a KPG stirrer and gas inlet tube under a protective nitrogen gas atmosphere at 23° C. After the solution was cooled to 15° C., Cl 2 14.0 g (1.36 eq.) was introduced with stirring (300 rpm) over 1 hour. The temperature during the addition was kept below 14-16°C. 2 After the metered addition was complete, stirring of the reaction mixture was continued for a further 30 min at 15° C. HPLC analysis showed that the proportion of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride was 100%. The reaction mixture was then 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 was then obtained (10.1 w / w%, 92.9% yield by QHPLC). The solvent was completely removed from the analytical sample in vacuum in order to characterize the product by 1H-NMR. 1 H-NMR (401 MHz, CDCl 3 ): δ (ppm) = 6.84-6.89 (m, 1H), 7.37-7.45 (m, 2H), 10.86 (bs, 1H). 19F-NMR (377 MHz, CDCl 3 ): δ (ppm) = -109.3 (m, 2F)

[0033] Example 2 (in a mixture of toluene and THF without added catalyst) 89.2 g of a solution of N-(3,5-difluorobenzylidene)hydroxylamine (1.0 equiv.) in a mixture of toluene and THF (25.5 w / w%, QHPLC) was initially charged into a 0.5 L reactor equipped with a KPG stirrer and gas inlet tube under a protective nitrogen gas atmosphere at 23° C. and further diluted with 138 g of toluene. After cooling the solution to 10° C., Cl was added. 2 18.0 g were added over 3 hours with stirring (300 rpm). The temperature during the addition was kept below 9-12°C. 2 After the metered addition was complete, stirring of the reaction mixture was continued for a further 30 min at 10° C. HPLC analysis showed that the proportion of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride was 100%. The reaction mixture was then 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 was then obtained (9.7 w / w%, 80.5% yield by QHPLC).

[0034] Example 3 (in a mixture of toluene and THF with a catalyst) 695 g of a solution of N-(3,5-difluorobenzylidene)hydroxylamine (1.0 equiv.) in a mixture of toluene and THF (21.2 w / w%, QHPLC) was initially charged into a 1 L reactor equipped with a 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 13.7 g (0.2 equiv.) of dimethylformamide (DMF) was also added. After cooling the solution to 0° C., Cl was added. 2 77.7 g (1.17 eq.) were introduced with stirring (300 rpm) over 1.5 hours. The temperature during the addition was kept below 10° C. 2After the metered addition of was completed, stirring of the reaction mixture was continued for a further 30 min at 10° C. HPLC analysis showed that the proportion of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride was 100%. The reaction mixture was then cooled to 0° C. with stirring and degassed at 50 mbar for 1 h. The product solution was then washed with 130 g of 5% aqueous sodium chloride solution at 0° C. and the phases were separated at 20° C. The organic product-containing phase, which still contained water, was then azeotropically dried at 45° C. and 85 mbar. After the 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 was obtained (22.3 w / w%, 91.9% yield by QHPLC).

[0035] Example 4 (in a mixture of chlorobenzene and THF with a catalyst) 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 into a 0.5 L reactor equipped with a KPG stirrer and a gas inlet tube under a protective nitrogen gas atmosphere at 23° C., followed by the addition of 5.0 g of dibutylformamide (DBF, 0.1 eq.). After cooling the solution to 0° C., Cl was added. 2 23.0 g (1.2 eq.) were introduced with stirring (300 rpm) over 40 min. The temperature during the addition was kept below 17° C. 2 After the metered addition was complete, stirring of the reaction mixture was continued for a further 30 min at 10° C. HPLC analysis showed that the proportion of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride was 100%. The reaction mixture was then cooled to 0° C. with stirring and degassed at 50 mbar for 1 h. 242.2 g of a clear yellowish solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in a mixture of chlorobenzene and THF was then obtained (21.3 w / w%, 91.7% yield by QHPLC).

Claims

1. General formula (I) 【Chemistry 1】 (In the formula, X 2 , H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 Alkoxy, fluorine, CN; X 3 , H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 Alkoxy, fluorine, chlorine, CN; X 4 , H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 Alkoxy, fluorine, CN; X 5 , H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 Alkoxy, fluorine, chlorine, CN; X 6 , H, C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 1 ~C 4 Fluoroalkoxy, C 1 ~C 4 Alkoxy, fluorine, CN) 1. A process for preparing a chlorobenzaldehyde oxime of the formula General formula (II) 【Chemistry 2】 (In the formula, X 2 ~X 6 have the meaning given above) The compound is chlorine gas (Cl 2 ) to the compound of general formula (I), method.

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

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

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

6. 6. The process according to claim 1, wherein an amide base is added to the reaction mixture during the reaction.

7. 7. The process according to claim 1, characterized in that a catalytic amount of an amide base is added to the reaction mixture during the reaction.

8. 8. The method according to claim 6 or 7, characterized in that the amide base is dimethylformamide (DMF), dibutylformamide (DBF), diethylformamide (DEF) or dimethylacetamide (DMAc).

9. 8. The method according to claim 6 or 7, characterized in that the amide base is dimethylformamide (DMF) or dibutylformamide (DBF).

10. The process according to any one of claims 1 to 9, characterized in that the reaction is carried out at a temperature between -10°C and 40°C.

11. The process according to any one of claims 1 to 9, characterized in that the reaction is carried out at a temperature between -5°C and 10°C.

12. 12. The process according to claim 1, wherein 0.1 to 0.3 equivalents of amide base relative to benzaldehyde oxime (II) are used.

13. 1.0 to 1.5 equivalents of Cl per benzaldehyde oxime (II) 2 12. The method according to claim 1, wherein

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