EP4222140A1

EP4222140A1 - Benzaldehyde oximes and method for producing same

Info

Publication number: EP4222140A1
Application number: EP21778513.8A
Authority: EP
Inventors: Andreas REMBIAK
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 2020-10-01
Filing date: 2021-09-29
Publication date: 2023-08-09
Also published as: TW202229231A; BR112023005190A2; WO2022069553A1; CN116438159A; US20230348366A1; JP2023545399A; KR20230074569A; IL301695A; MX2023003873A

Abstract

The invention relates to a method for producing benzaldehyde oximes of the general formula (I) and to the use thereof as important precursors for the synthesis of agrochemical and pharmaceutical active substances.

Description

Benzaldehyde oximes and process for their preparation

The present invention relates to a process for preparing benzaldehyde oximes of the general formula (I) and their use as important precursors for the synthesis of agrochemical and pharmaceutical active ingredients.

Benzaldehyde oximes are an important precursor of agrochemical (e.g.: WO 2014/048827A1 or WO 2019/145245A1) and pharmaceutical (e.g. J. Med. Chem. 2003, 46, 284) active ingredients containing phenylisoxazoline.

The preparation of benzaldehyde oximes starting from the corresponding benzaldehydes is widely described in the literature, for example in Org. Lett. 2001, 3, 4209 (reaction in an organic solvent with the addition of a base), JP2016166153A (two-phase system), US 20090062342A1 (aqueous system with the addition of a phase transfer catalyst and an inorganic base) or in Molecules 2018, 23, 2545 (aqueous system with addition of an organic base). WO 2012/130798 A1 and WO 2014/048827 A1 describe the preparation of the oxime from 3,5-difluorobenzaldehyde.

The preparation of 3,5-difluorobenzaldehyde is described, for example, in US Pat. No. 4,424,229A, US Pat. Alternatively, the use of Turbo-Grignard has already been described in EP 1582523 A1 and sec-butyllithium in J. Org. Chem. 2011, 76, 9391. Furthermore, its production by means of metal-catalyzed cyanation and subsequent reduction was described in EP 1389608A1 and the oxidation of the corresponding benzyl alcohol in WO 2019/224774A1 and CN 101565344A.

There is a wealth of literature for the two-step preparation of benzaldehyde oximes from halogenated benzene via benzaldehyde to the corresponding oxime. However, to date no process has been described in which these two reaction steps are carried out without isolating the intermediate product. The isolation of the aldehyde is a critical step due to its volatility and its sensitivity to oxidation by atmospheric oxygen and leads to the formation of unwanted by-products and a reduction in yield. Therefore, bypassing the isolation would be desirable.

In the light of the prior art described above, the object of the present invention is to find a process for preparing the compounds of the general formula (I) so that they are obtained in higher yield, in high purity and in an environmentally friendly manner so that important intermediates for the production of active substances can be produced on an industrial scale.

The object described above is achieved by a process for preparing compounds of the general formula (I) (I), wherein

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 is,

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, and where the compounds of the general formula (II) in which the radicals are as defined above, are reacted in a first reaction step in the presence of Ao-propylmagnesium chloride and DMF to form the corresponding adducts (III), which are converted in a second reaction step with the addition of acid and hydroxylamine to form aldehydes of the general formula (IV) in which the radicals are as defined above, react further and the compounds of the general formula (I) are then formed.

Preferred radical definitions for the compounds of the general formulas (I), (II), (III) and

(IV) 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), (II),

(III) and (IV) are the following:

^X2 is H,

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

X ⁴ is fluorine, 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), (III) and (IV) are the following:

^X2 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), (II),

(III) and (IV) are the following: X ² is H,

X ³ is fluorine,

^X4 is H,

X ⁵ is fluorine,

X ⁶ is H

Explanation of the processes and intermediates

Scheme 1

The compounds of the general formula (II) are in the first step with constant cooling with Ao-propylmagnesium chloride, which can be used directly as a commercially available solution, for example as a 2 molar solution in THF, or from magnesium and 2-propyl chloride in a suitable solvent , e.g. THF, is preformed. The reaction mixture is then treated with DMF (V,A-dimethylformamide). The corresponding DMF adduct (III) is obtained without working up with continuous cooling with aqueous

Acid and hydroxylamine (as a salt or as an aqueous solution) is added and the corresponding aldehyde (IV) reacts continuously to give compounds of the general formula (I).

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

(E) isomer Z) isomer The ratio between E and Z isomers varies, generally the E isomer is in excess.

reaction step 1

The first reaction step is carried out in a suitable solvent. Suitable solvents are basically all organic solvents that are inert under the specific reaction conditions, such as aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane and technical hydrocarbons, cyclohexane, methylcyclohexane , petroleum ether, ligroin, benzene, toluene, xylene, mesitylene), aliphatic, cycloaliphatic or aromatic ethers (e.g. 1,2-dimethoxyethane (DME), diglyme, tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, methyl tert-butyl ether (MTBE), cyclopentyl methyl ether, anisole) or mixtures of the solvents mentioned. The first reaction step is preferably carried out in toluene, xylene, mesitylene, anisole, THF, methylcyclohexane, 2-methyl-THF or methyl tert-butyl ether or from a mixture of the solvents mentioned. Toluene, THF or a mixture of toluene and THF is particularly preferably used. Anhydrous solvents are particularly preferred.

Furthermore, the reaction mixture is cooled during the addition of z.s -propylmagnesium chloride. The reaction is preferably carried out at temperatures between -10.degree. C. and 20.degree. C., particularly preferably at temperatures between 0.degree. C. and 15.degree. DMF is preferably added at temperatures between -10.degree. C. and 60.degree. C., particularly preferably at temperatures between 0.degree. C. and 30.degree. Very particularly preferably, the addition of DMF to the reaction mixture takes place at the same temperature as the addition of z.s-propylmagnesium chloride. Reaction step 1 is carried out by metering in the compounds of the general formula (II), as a pure substance or as a solution in a suitable solvent, to a solution of z.s - propylmagnesium chloride. Reaction step 1 is preferably carried out by metering z.s-propylmagnesium chloride into a solution of the compounds of the general formula (II). The reaction mixture is then metered into a solution of DMF; DMF is particularly preferably metered into the reaction mixture.

/.s -Propylmagnesiumchlorid is used in equimolar amounts or in excess, preferably 5.0 to 1.05 equivalents, particularly preferably 2.0 to 1.05 equivalents.

DMF is used in equimolar amounts or in excess, preferably 5.0 to 1.05 equivalents, particularly preferably 2.0 to 1.05 equivalents. The /.s -propylmagnesium chloride can be used in the form of the purchased solution as a 2 molar solution in THF or be prepared in situ. Here, metallic magnesium is placed in a suitable organic solvent which is inert under the reaction conditions, diethyl ether or tetrahydrofuran being particularly preferred, and 2-chloropropane is added. Activation of the magnesium using methods well known to those skilled in the art, for example activation by iodine, dibromoethane or by the addition of active iodine-propylmagnesium chloride, can optionally be carried out. This is followed by reaction step 1, preferably by metering the compounds of the general formula (II) into the solution of isopropyl magnesium chloride described according to the invention.

reaction step 2

The second reaction step is carried out in aqueous solution.

Furthermore, upon hydrolysis of the reaction mixture, addition of aqueous acid and hydroxylamine as an aqueous solution of a salt or the free base, the reaction mixture is cooled. The reaction is preferably carried out at temperatures in a range between 0°C and 40°C, particularly preferably at temperatures between 0°C and 30°C.

The hydrolysis of the reaction mixture from reaction step 1 can be carried out by adding an aqueous acid or water; the hydrolysis is preferably carried out by metering the reaction mixture into aqueous acid or water, particularly preferably by metering the reaction mixture into water.

The acid used is preferably aqueous hydrochloric acid or aqueous sulfuric acid, particularly preferably aqueous sulfuric acid. The sulfuric acid can be present before the hydrolysis of the reaction mixture, but the sulfuric acid is preferably metered in after the hydrolysis of the reaction mixture to water has taken place under the preferred conditions. The aqueous sulfuric acid is preferably used in concentrations of between 1 and 80% by weight, particularly preferably in concentrations of between 10 and 50% by weight. Preference is given to using 0.2 to 5.0 equivalents of the sulfuric acid, particularly preferably 0.3 to 2 equivalents.

Hydroxylamine is preferably used as the chloride (NH2OH*HC1) or sulphate salt ((NH2OH)2*H2SO4), as a pure substance or as an aqueous solution, or as an aqueous solution of the free base (NH2OH), use as an aqueous is particularly preferred solution of the sulphate salt. This solution is preferably used in concentrations of between 5 and 40% by weight, particularly preferably between 15 and 35% by weight. Preference is given to using 0.5 to 0.7 equivalents of (NH2OH)2*H2SO4, particularly preferably 0.55 to 0.6 equivalents. The compounds of the general formula (I) can be worked up and isolated after the reaction is complete, for example by separating the phases, extracting the aqueous phase with a suitable organic solvent, washing the organic phase with water and removing the solvent completely or partially. The compounds of general formula (I) can be isolated as a solid or as a solution in a suitable solvent.

This yield is 92 to 97 percent over two stages compared to 55 to 79 percent over two stages compared to the prior art.

examples

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

measurement method

The products were characterized by ^^F NMR.

Example 1: (IE)-3,5-difluorobenzaldehyde oximes (1-1)

100.0 g (1.0 eq) 1-bromo-3,5-difluorobenzene in 100 mL toluene were placed in an IL four-neck flask with mechanical stirrer under an argon atmosphere and 279.3 mL (275.3 g, 2M in THF, 1.1 eq) at <10 °C. After the addition was complete, the mixture was stirred at <5° C. for a further 3 h and then 40.8 g (1.1 eq) of N,N-dimethylformamide were metered in at <10° C. over 60 min. After stirring at this temperature for a further 15-20 min, the reaction mixture was slowly added to 500 mL of water over 30 min, which had previously been cooled to <5°C. The internal temperature was kept at < 10 °C. After the addition was complete, 29.9 g (0.3 eq) of 50% by weight sulfuric acid were metered in at <10° C. over 30 minutes. A solution of 45.8 g (0.55 eq) of hydroxylamine sulphate in 120 mL of water was then metered in at <5 °C over 45 min and the reaction mixture was stirred for a further 3 h after the addition was complete, during which time the temperature was increased to 20-25 °C. After the addition of a further 100 mL toluene, the phases were separated and the organic phase was washed with 200 mL water. Partial removal of the solvent from the organic phase at 100-150 mbar and 40 °C gave the product as a solution in toluene/THF: 240.0 g (31.5 wt.%, 95% yield)

'H NMR (600MHz, CDCh): δ 6.83 ppm (m, 1H), 7.09 (m, 2H), 7.64 (br s, 1H), 8.06 (s, 1H) ppm.

¹⁹ F NMR (600MHz, CDCh): 5 -109.0 (2F) ppm. Example 2: (IE)-3,5-difluorobenzaldehyde oximes (1-1)

In a 500 mL reactor, 6.8 g (1.1 eq) of magnesium in 10 mL of THF were placed under argon and activated with 2 mL (0.01 eq, 2M in THF) of commercial isopropyl magnesium chloride. 21.9 g (1.1 eq) of 2-propyl chloride and, in parallel, 65 mL of THF were then metered in at 30° C. over 1 hour. The reaction mixture was stirred at this temperature for a further hour, then cooled to <5° C. and a solution of 50.0 g (1.0 eq) of l-bromo-3,5-difluorobromobenzene in 50 mL of toluene was metered in at this temperature over 1 hour, after complete metering, the mixture was stirred at this temperature for a further 3 h and then 20.4 g (1.1 eq) of A,A-dimethylformamide were metered in at <10° C. over 30 min. After 15-20 min further stirring at this temperature, the reaction mixture was poured over 30 min into 250 mL of water, cooled to <5°C and the internal temperature was maintained at <10°C. After the metering was complete, 14.9 g (0.3 eq) of 50% by weight sulfuric acid were metered in over 30 minutes at <10°C. A solution of 22.9 g (0.55 eq) of hydroxylamine sulphate in 50 mL of water was then metered in at <5°C over 45 minutes and the reaction mixture was stirred for a further 3 hours after metering was complete, during which time the temperature was increased to 20-25°C. After the addition of a further 50 ml of toluene, the phases were separated and the organic phase was washed with 100 ml of water. Partial removal of the solvent from the organic phase at 100-150 mbar and 40°C gave the product as a solution in toluene/THF: 150.0 g (24.9% by weight, 94% yield).

The reactions (Examples 1 and 2) can also be carried out analogously in the following solvents:

Furthermore, the following compounds were produced using the process according to the invention:

3,5-dichlorobenzaldehyde oxime

'H NMR (400MHz, CDCh): 5 7.37 (t, J=1.9 Hz, 1H), 7.45 (br s, 1H), 7.46 (d, J=7.5 Hz, 2H), 8.03 (s, 1H) ppm . 3-Fluoro-5-methoxy-benzaldehyde oxime

'H NMR (400MHz, CDCh): δ 3.79 (s, 3H), 6.85 (dt, J=2.3/11.0 Hz, 1H), 6.97-7.01 (m, 2H), 8.11 (s, 1H) ppm.

3-Fluoro-5-methyl-benzaldehyde oxime 'H-NMR (400MHz, CDCh): 5 2.37 ppm (s, 3H), 7.09 (m, 2H), 6.89 (d, J= 9.4 Hz, lH), 7.10-7.14 (m, 2H), 7.46 (br s, 1H), 8.07 (s, 1H) ppm.

Claims

patent claims

1. Process for preparing compounds of 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 ⁶ is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, CN, and where the compounds of the general formula (II)

(II), in which the radicals are as defined above, are reacted in a first reaction step in the presence of Ao-propylmagnesium chloride and DMF to form the corresponding adducts (III), which are converted in a second reaction step with the addition of acid and hydroxylamine to form aldehydes of the general formula ( IV) in which the radicals are as defined above, react further and the compounds of the general formula (I) are then formed.

2. The method according to claim 1, wherein the radical definitions are as follows:

fluoro, methoxy, CN,

fluoro, chloro, methoxy, CN,

fluoro, methoxy, CN.

3. The method of claim 1, wherein the radical definitions are as follows:

^X2 is H,

X ⁴ is fluorine, H,

X ⁶ is H

4. The method of claim 1, wherein the radical definitions 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 of claim 1, wherein the radical definitions 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 first reaction step is carried out in an anhydrous solvent.

7. The method according to any one of claims 1 to 6, characterized in that the first reaction step is carried out in toluene or THF or a mixture of these two solvents.

8. The method according to any one of claims 1 to 7, characterized in that the first reaction step is carried out at temperatures between 0 ° C and 30 ° C and the addition of DMF to the reaction mixture in the second step at the same temperature as the addition of Ao propylmagnesium chloride.

9. The method according to any one of claims 1 to 8, characterized in that 2.0 to 1.05 equivalents of Ao-propyl magnesium chloride are used based on the compounds of general formula (II).

10. Process according to one of Claims 1 to 9, characterized in that 2.0 to 1.05 equivalents of DMF, based on the compounds of the general formula (II), are used.

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

Reaction step sulfuric acid is used as the acid.

12. The method according to any one of claims 1 to 11, characterized in that in the second reaction step the hydroxylamine is used as (NH2OH)2*H2SO4.

13. Process according to one of Claims 1 to 12, characterized in that 0.3 to 2 equivalents of sulfuric acid, based on the compounds of the general formula (II), are used in the second reaction step.

14. Process according to one of Claims 1 to 13, characterized in that 0.5 to 0.7 equivalents of (NH2OH)2*H2SO4, based on the compounds of the general formula (II), are used in the second reaction step.