Method for chlorinating benzaldoxime

Abstract

The present invention relates to a novel process for the preparation of chlorobenzaldoximes of general formula (I).

Description

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

[0002] Chlorobenzaldehyde oxime of general formula (I) is an important precursor of active agrochemical 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] A variety of chlorination methods are described in the prior art; for example, WO 2004 / 29066 and Industrial Crops & Products 2019, 140, 111706 teach that chlorobenzaldehyde oxime is prepared by reacting oxime with N-chlorosuccinimide (NCS), followed by aqueous treatment (using EtOAc / water extraction). However, in the method described, only a small amount (2.45g) of the obtained chlorobenzaldehyde oxime is isolated, which is in solid form. However, in principle, it is undesirable to separate chlorobenzaldehyde oxime in solid form on an industrial scale, because chlorobenzaldehyde oxime is generally a high-energy compound with a high decomposition tendency. The method described in WO 2004 / 29066 uses dimethylformamide (DMF) as a solvent. However, it is well known that its use as a solvent on an industrial scale may be problematic. This is due to the strongly exothermic reaction between DMF and the chlorinating agent, which reaction can in turn proceed in an uncontrolled manner (OPRD 2020, 24, 1586; Bull. Chem. Soc. Jpn. 1994, 67, 156).

[0004] For example, the chlorination of oximes using chlorine is described in Journal of Organic Chemistry 1971, 36, 2146. In this case, the reaction is carried out only in highly diluted chloroform or dichloromethane, which is not suitable for large-scale industrial synthesis and provides chlorobenzaldehyde oxime in a medium to low yield of 3-80%. The chlorination is preferably carried out under alkaline conditions by adding triethylamine, which results in partial decomposition of the chlorooxime compound. In addition, Journal of Heterocyclic Chemistry; 2012, 49, 621 teaches the use of chlorine in a methanol solvent under mild alkaline reaction conditions (by adding sodium carbonate). In addition to forming a safety-related amount of gaseous carbon dioxide, the product may decompose again under alkaline conditions. The hydrogen chloride released during the chlorination process may also cause the formation of toxic compounds by reacting with the solvent. Using methanol as a solvent also prevents the direct use of the product solution without changing the solvent in many chemical reactions. In addition to the safety-related restrictions caused by the high energy of such chlorine compounds and the preferred use of a dilution system, changing the solvent also reduces the efficiency and sustainability of the method.

[0005] Journal of Enzyme Inhibition and Medicinal Chemistry; Vol. 31; No. 6; (2016); Pages 964-973 teach the chlorination of oximes using trichloroisocyanuric acid (TCCA) and using triethylamine as a base. Although DMF is not used as a solvent here, it has been observed that chlorooximes tend to degrade in alkaline media due to the formation of nitrile oxides, which may lead to yield losses (e.g., dimerization of nitrile oxides to furoxan): "Kinetics and Mechanism of 1,3-Dipolar Cycloadditions", Professor R. Huisgen, Angew. Chem. 1963, 75, 742-754, p. 751; "Fragmentation of Nitrile Oxides with Triethylamine" Tetrahedron Lett. 1983, 24, 4377-4380). Furthermore, the use of trichloroisocyanuric acid (TCCA) generates relatively large amounts of solid isocyanuric acid waste product, which is detrimental to the process in terms of sustainability and waste management.

[0006] Therefore, the object of the present invention is to provide a method for chlorinating benzaldehyde oxime, which, on the one hand, dispenses with the use of DMF or chlorinated alkane compounds as solvents, and also dispenses with the use of chlorinating agents (e.g. trichloroisocyanuric acid or N-chlorosuccinimide) with low atom economy and high waste, and, on the other hand, does not cause yield losses due to the use of relatively strong bases (e.g. triethylamine), is cost-effective, and can be used on an industrial scale. In this case, chlorobenzaldehyde oxime should be obtained in high yield and can be used as a solution in various chemical reactions by appropriately selecting a solvent without forcing a solvent change.

[0007] According to the present invention, this object is achieved by a method for preparing chlorobenzaldehyde oxime of general formula (I)

[0008]

[0009] in

[0010] X 2 is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine, CN,

[0011] X 3 is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine, chlorine, CN,

[0012] X 4 is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine, CN,

[0013] X 5 is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine, chlorine, CN,

[0014] X 6 is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine, CN,

[0015] It is characterized in that the compound of general formula (II)

[0016]

[0017] in

[0018] X 2 To X 6 has the meaning as stated above,

[0019] With the aid of chlorine (Cl2) conversion into compounds of the general formula (I).

[0020] In one Preferred In an embodiment, in addition to chlorine, an amide base is added to the reaction mixture to convert the compound of formula (II) to the compound of general formula (I).

[0021] In one Particularly preferred In an embodiment, in addition to chlorine, a catalytic amount of an amide base is added to the reaction mixture to convert the compound of formula (II) to the compound of general formula (I).

[0022] The radicals of the compounds of formula (I) and (II) Best The definition is as follows:

[0023] X 2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN,

[0024] X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN,

[0025] X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN,

[0026] X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN,

[0027] X 6 It is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, or CN.

[0028] The radicals of the compounds of formula (I) and (II) Especially preferred is defined as follows:

[0029] X 2 For H,

[0030] X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN,

[0031] X 4 For fluorine, H,

[0032] X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN,

[0033] X 6 For H.

[0034] The group of the compound of formula (I) and (II) Very Special is defined as follows:

[0035] X 2 For H,

[0036] X 3 is H, fluorine,

[0037] X 4 is H, fluorine,

[0038] X 5 is H, fluorine,

[0039] X 6 For H.

[0040] The radicals of the compounds of formula (I) and (II) Best choice is defined as follows:

[0041] X 2 For H,

[0042] X 3 For fluorine,

[0043] X 4 For H,

[0044] X 5 For fluorine,

[0045] X 6 For H.

[0046] The compounds of formula (I) may exist as mixtures of geometric isomers:

[0047]

[0048] The ratio between the E and Z isomers can vary.

[0049] Description of Methods and Intermediates

[0050]

[0051] A process for preparing chlorobenzaldehyde oxime of formula (I), characterized in that a compound of general formula (II) is converted into a compound of general formula (I) by means of chlorine (Cl2).

[0052] Preferably In addition to chlorine, an amide base is added to the reaction mixture to convert the compound of formula (II) into the compound of general formula (I).

[0053] Particularly preferably In addition to chlorine, a catalytic amount of an amide base is added to the reaction mixture to convert the compound of formula (II) into the compound of general formula (I).

[0054] The method of the present invention has the advantages of avoiding the use of stoichiometric amounts of DMF or chlorinated alkane compounds as Solvents This minimizes the risk of the reaction proceeding in a highly exothermic and uncontrollable manner and eliminates the need for solvents with poor sustainability. In addition, the use of chlorine eliminates the need to use N-chlorosuccinimide (NCS) or trichloroisocyanuric acid (TCCA), thereby reducing waste and significantly improving the sustainability of the process. Therefore, the reaction is suitable for large-scale operation.

[0055] Amide bases suitable as catalysts are, for example, dimethylformamide (DMF), dibutylformamide (DBF), diethylformamide (DEF) or dimethylacetamide (DMAc), Best Dimethylformamide or dibutylformamide.

[0056] In the process of the present invention, based on benzaldehyde oxime (II), Best No amide base is used or 0.05 to 0.3 equivalents of amide base is used, Especially preferred Use 0.1 to 0.3 equivalents of amide base. Based on benzaldehyde oxime (II), Best 0.95 to 2.0 equivalents of Cl2 are used, particularly preferably 1.0 to 1.5 equivalents.

[0057] Chlorination is usually carried out at -10℃ to 40℃. Best -5℃ to 10℃, Especially preferred The temperature is between 0 and 10°C.

[0058] The chlorination is further carried out in the presence of a solvent or diluent, Preferred The solvent is 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 solvents.

[0059] The chlorine is introduced in gaseous form into the benzaldehyde oxime of the general formula (II).

[0060] It is preferred to operate under anhydrous conditions. Example

[0061] The present invention is described in more detail by the following examples, but the present invention is not limited thereto.

[0062] Measurement method

[0063] Product by 1 H- and / or 19 Characterize by F-NMR spectroscopy and / or quantitative HPLC.

[0064] The NMR spectra were measured using a Bruker Avance 400 equipped with a flow probe (volume 60 μl). In individual cases, the NMR spectra were measured using a Bruker Avance II 600.

[0065] Quantitative HPLC determinations were measured on a HPLC Agilent HP1260 series. The technique is based on HPLC with UV detection, an Agilent XDB C18 column and evaluation using the external standard method (using external standards with reference factors). Samples, reference standards and internal standards were dissolved in acetonitrile.

[0066] Example 1 (in isopropyl acetate, without adding catalyst)

[0067] At 23 ° C, under a protective nitrogen atmosphere, 25.0 g of N-(3,5-difluorobenzylidene)hydroxylamine (1.0 equivalent) in 225 g of isopropyl acetate was first added to a 0.5 L reactor equipped with a KPG stirrer and a gas inlet tube. After the solution was cooled to 15 ° C, 14.0 g of Cl2 (1.36 equivalents) were introduced within 1 hour under stirring (300 rpm). The temperature was maintained below 14-16 ° C during the addition. After the metered addition of Cl2 was completed, the reaction mixture was stirred for another 30 minutes at 15 ° C. HPLC analysis showed that the proportion of 3,5-difluoro-N-hydroxybenzencarboximidoylchlorid was 100%. Subsequently, the reaction mixture was cooled to 10 ° C and degassed at 300 mbar for 1 hour under stirring. Then 257.3 g of a yellow solution of 3,5-difluoro-N-hydroxybenzoimidoyl chloride in isopropyl acetate were obtained (10.1 w / w%, yield according to QHPLC: 92.9%). 1 The product was characterized by H-NMR and the solvent was completely removed from the analytical sample in vacuo.

[0068] 1 H-NMR (401MHz, CDCl3): δ (ppm) = 6.84-6.89 (m, 1H), 7.37-7.45 (m, 2H), 10.86 (bs, 1H).

[0069] 19 F-NMR (377MHz, CDCl3): δ (ppm) = -109.3 (m, 2F).

[0070] Example 2 (in a mixture of toluene and THF, without addition of catalyst)

[0071] At 23 ° C, under a protective nitrogen atmosphere, a solution of 89.2 g of N-(3,5-difluorobenzylidene)hydroxylamine (1.0 equivalent) in a mixture of toluene and THF (25.5 w / w%, QHPLC) was first added to a 0.5 L reactor equipped with a KPG stirrer and a gas inlet tube, and then further diluted with 138 g of toluene. After the solution was cooled to 10 ° C, 18.0 g of Cl2 was introduced within 3 hours under stirring (300 rpm). The temperature was kept below 9-12 ° C during the addition. After the metered addition of Cl2 was completed, the reaction mixture was stirred for another 30 minutes at 10 ° C. HPLC analysis showed that the proportion of 3,5-difluoro-N-hydroxybenzoyl chloride was 100%. Subsequently, the reaction mixture was cooled to 0 ° C with stirring and degassed at 100 mbar for 2 hours. 229.7 g of a yellow solution of 3,5-difluoro-N-hydroxybenzoimidoyl chloride in a mixture of toluene and THF were then obtained (9.7 w / w%, 80.5% yield according to QHPLC).

[0072] Example 3 (adding catalyst to a mixture of toluene and THF)

[0073] At 23 ° C, under a protective nitrogen atmosphere, a solution of 695 g of N-(3,5-difluorobenzylidene)hydroxylamine (1.0 equivalent) in a mixture of toluene and THF (21.2 w / w%, QHPLC) was first added to a 1 L reactor equipped with a KPG stirrer and a gas inlet tube, then further diluted with 41.7 g of THF and 13.7 g (0.2 equivalent) of dimethylformamide (DMF) were added. After the solution was cooled to 0 ° C, 77.7 g (1.17 equivalent) of Cl2 were introduced within 1.5 hours under stirring (300 rpm). The temperature was kept below 10 ° C during the addition. After the metered addition of Cl2 was completed, the reaction mixture was stirred for another 30 minutes at 10 ° C. HPLC analysis showed that the proportion of 3,5-difluoro-N-hydroxybenzoyl chloride was 100%. Subsequently, the reaction mixture was cooled to 0 ° C with stirring and degassed at 50 mbar for 1 hour. The product solution was subsequently washed with 130 g of 5% aqueous sodium chloride solution at 0° C. and phase separated at 20° C. The phase containing the organic product, which still contained water, was then azeotropically dried at 45° C. and 85 mbar. After adding 258 g of toluene, 740.0 g of a pale yellow, transparent solution of 3,5-difluoro-N-hydroxybenzoimidoyl chloride in a mixture of toluene and THF were obtained (22.3 w / w%, yield according to QHPLC 91.9%).

[0074] Example 4 (adding a catalyst to a mixture of chlorobenzene and THF)

[0075] At 23 ° C, under a protective nitrogen atmosphere, 46.1 g of N-(3,5-difluorobenzylidene)hydroxylamine (1.0 equivalent) in 145 g of chlorobenzene and 36.0 g of tetrahydrofuran was first added to a 0.5 L reactor equipped with a KPG stirrer and a gas inlet tube, followed by 5.0 g of dibutylformamide (DBF, 0.1 equivalent). After the solution was cooled to 0 ° C, 23.0 g of Cl2 (1.2 equivalent) was introduced within 40 minutes under stirring (300 rpm). The temperature was kept below 17 ° C during the addition. After the metered addition of Cl2 was completed, the reaction mixture was stirred for another 30 minutes at 10 ° C. HPLC analysis showed that the proportion of 3,5-difluoro-N-hydroxybenzoyl chloride was 100%. Subsequently, the reaction mixture was cooled to 0 ° C under stirring and degassed at 50 mbar for 1 hour. Then, 242.2 g of a light yellow transparent solution of 3,5-difluoro-N-hydroxybenzoimidoyl chloride in a mixture of chlorobenzene and THF were obtained (21.3 w / w%, yield according to QHPLC: 91.7%).

Claims

1. Method for preparing chlorobenzaldehyde oxime of general formula (I) in 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, It is characterized in that The compound of general formula (II) in X 2 To X 6 has the meanings given above, With the help of chlorine (Cl 2 ) is converted into a compound of formula (I).

2. The method according to claim 1, wherein the groups of general formula (I) and (II) are defined 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 It is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN.

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

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

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

6. The method according to any one of claims 1 to 5, It is characterized in that The amide base is added to the reaction mixture during the reaction.

7. The method according to any one of claims 1 to 6, It is characterized in that A catalytic amount of an amide base is added to the reaction mixture during the reaction.

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

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

10. The method according to any one of claims 1 to 9, It is characterized in that The reaction is carried out at -10°C to 40°C.

11. The method according to any one of claims 1 to 9, It is characterized in that The reaction is carried out at -5°C to 10°C.

12. The method according to any one of claims 1 to 11, It is characterized in that Based on benzaldehyde oxime (II), 0.1 to 0.3 equivalents of the amide base are used.

13. The method according to any one of claims 1 to 11, It is characterized in that Based on benzaldehyde oxime (II), 1.0-1.5 equivalents of Cl 2 .

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