Process for isomerization of oxime ethers

Abstract: Isomerization of an unsymmetrical ketoxime ether is effected using at least one Lewis acid selected from titanium chloride, titanium bromide, aluminium chloride, aluminium bromide, boron chloride, and boron bromide as isomerizing agents. Examples of the Lewis acid are titanium tetrachloride, titanium trichloride, aluminium trichloride, aluminium tribromide, boron trichloride, and boron tribromide. The ketoxime ether is preferably an anti-isomer or a syn-isomer of a compound represented by the formula (I) or a mixture of the anti-isomer and the syn-isomer: wherein R¹ represents an aryl group, an aralkyl group or an alkyl group and R² and R³ each represents an aralkyl group or an alkyl group, with a proviso that R¹ and R² are not identical.

Description: The present invention relates to a process for isomerization of unsymmetrical ketoxime ethers using a specific Lewis acid as an isomerizing agent. Unsymmetrical ketoxime ethers are compounds important as medicines, agricultural chemicals or intermediates thereof and starting materials for optically active amines. It is well known that they are produced as a mixture of anti-isomer and syn-isomer. (Japanese Patent Kokai No. 62-215558). However, in many cases, only either one or the other of the anti-isomer or syn-isomer is effective as medicines, agricultural chemicals or intermediates thereof and starting materials for optically active amines. And in such case, these two isomers must be separated from each other. Furthermore, in such case, the other isomer is useless. Therefore, it is an important technique to isomerize unsymmetrical ketoxime ether to increase the content of the effective isomer or to isomerize the useless isomer to convert it to effective isomer. As one such isomerization process, irradiation with light is known [e.g., J. Chem. Soc., Perkin Trans. 1,9,1691 (1986)]. However, this process suffers from the industrial problem that it requires a specific reaction equipment provided with medium pressure vapour mercury lamp. Another known process is to isomerize unsymmetrical aldoximes with boron trifluoride [e.g., J. Org. Chem . 20 , 1491 (1955)]. However, when this process is applied to isomerization of unsymmetrical ketoxime ethers, the reaction rate is extremely low and isomerization efficiency is poor. EP-A-009865 discloses isomerizing ketoximes with an anhydrous protic acid such as hydrogen chloride or a Lewis acid such as boron trifluoride or aluminium chloride used at least in a stoichiometric amount and in practice at saturation excess in relation to the ketoxime, following which the ketoxime is converted to a ketoxime ether. The inventors have conducted intensive research in an attempt to solve these problems. They have found that the isomerization reaction proceeds very efficiently in the presence of a specific Lewis acid as an isomerizing agent and further research has been conducted. Thus, the present invention has been accomplished. That is, the present invention provides an industrially excellent process for isomerization of unsymmetrical ketoxime ethers, characterised in that at least one Lewis acid selected from titanium chlorides, titanium bromides, aluminium chloride, aluminium bromide, boron chloride and boron bromide is used as an isomerizing agent, and in that the amount of the Lewis acid is less than 1 mol and at least 0.05 mol per mol of the ketoxime ether. The present invention will be explained in detail. The unsymmetrical ketoxime ethers used in the present invention include, for example, anti-isomer and syn-isomer of the compound represented by the following formula (I) or a mixture of them: wherein R¹ represents an optionally substituted aryl group, an optionally substituted aralkyl group or an alkyl group and R² and R³ each represents an optionally substituted aralkyl group or an alkyl group, with a proviso that R¹ and R² are not identical. As the substituent R¹, mention may be made of, for example, a phenyl group; halogen-substituted phenyl groups such as o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, and 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl; alkyl-substituted phenyl groups such as o-, m- or p-methylphenyl, o-, m- or p- ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-butylphenyl, and 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-dimethylphenyl; alkoxy-substituted phenyl groups such as o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl and o-, m- or p-propoxyphenyl; benzyloxy-substituted phenyl groups such as o-, m- or p-benzyloxyphenyl, 2-benzyloxy-3-methylphenyl, 2-benzyloxy-4-methylphenyl, 2-benzyloxy-5-methylphenyl, 2-benzyloxy-5-t-butylphenyl, 2-benzyloxy-3-methoxyphenyl, 2-benzyloxy-4-methoxyphenyl, 2-benzyloxy-5-methoxyphenyl, 2-benzyloxy-3, 5-dichlorophenyl; aryl groups such as o-, m- or p-cyanophenyl and α- or β -naphthyl; a benzyl group; alkyl-substituted benzyl groups such as o-, m- or p-tolylmethyl, o-, m- or p-ethylbenzyl, and 2,3-, 2,4-, 2,5-,2,6-, 3,4-, or 3,5-dimethylbenzyl; alkoxy-substituted benzyl groups such as o-, m- or p-methoxybenzyl, o-, m- or p-ethoxybenzyl, and 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl; alkyl-substituted phenylethyl groups such as 2-phenylethyl, 2-(o-, m- or p-tolyl) ethyl, and (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-dimethylphenyl)ethyl; alkoxy - substituted phenylethyl groups such as o-, m- or p-methoxyphenylethyl, o-, m- or p-ethoxyphenylethyl, and 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5- dimethoxyphenylethyl; aralkyl groups such as 3-phenylpropyl and naphthylmethyl; and alkyl groups such as methyl, ethyl, propyl, butyl, pentyl and hexyl. Substituents R² and R³ include, for example, the same aralkyl groups and alkyl groups as R¹. As representative examples of unsymmetrical ketoxime ethers, mention may be made of o-methyl, o-octyl, o-cyclohexyl, and o-benzyl oximes of acetophenone, propiophenone, butyrophenone, isobutyrophenone, chloromethyl(phenyl) ketone, bromomethyl(phenyl) ketone, o-methoxyacetophenone, o-ethoxyacetphenone, o-propoxyacetophenone, o-benzyloxyacetophenone, o-chloroacetophenone, m-chloroacetophenone, p-chloroacetophenone, o-bromoacetophenone, m-bromoacetophenone, p-bromoacetophenone, 2′, 3′-, 2′, 4′-, 2′, 5′-, 2′, 6′-, 3′,4′- or 3′, 5′-dichloroacetophenone, 2′,3′-, 2′,4′-, 2′, 5′-, 2′, 6′-, 3′, 4′- or 3′, 5′-dibromoacetophenone, α-acetonaphthone, β-acetonaphthone, p-cyanoacetophenone, phenylbenzyl ketone, phenyl(o-tolymethyl) ketone, phenyl(m-tolylmethyl) ketone, phenyl(p-tolylmethyl) ketone, phenyl (2-phenylethyl) ketone, 2-pentanone, 2-hexanone, 2-heptanone, 2-octanone, 3-heptanone, 3-octanone, cyclohexyl methyl ketone, cylcohexyl ethyl ketone, cyclohexyl benzyl ketone, α-phenylacetone, (2-phenylethyl)methyl ketone, (2-phenylethyl)ethyl ketone, and (3-phenylpropyl)methyl ketone. Syn-isomers, anti-isomers thereof and mixtures of them are used. These ketoxime ethers can be easily produced from the corresponding ketones in accordance with known processes. The feature of the present invention is to use at least one Lewis acid selected from the group consisting of titanium chloride, titanium bromide, aluminium chloride, aluminium bromide, boron chloride, and boron bromide. Specific examples are titanium tetrachloride, titanium trichloride, titanium tetrabromide, aluminium trichloride, aluminium tribromide, boron trichloride, and boron tribromide. Mixtures of these compounds may also be used. The amount of the Lewis acid is less than 1 mol and at least 0.05 mol per 1 mol of the ketoxime ether. The isomerization reaction is usually carried out in the presence of a solvent. Suitable solvents include, for example, ethers such as dioxane, tetrahydrofuran, and diglyme, hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chlorobenzene, chloroform, and 1,2-dichloroethane, and mixed solvents thereof. The amount of the solvent is usually about 2-50 times the weight of the ketoxime ether. The reaction temperature is usually not more than 150°, preferably -20 -60°C. The progress of the reaction can be confirmed by means of analysis such as gas chromatography. After completion of the reaction, for example, an aqueous solution of sodium hydrogencarbonate (bicarbonate) or the like is added to the reaction mixture to inactivate the isomerizing agent and then the reaction mass is subjected to extraction with an organic solvent such as ether to obtain the desired product from the organic layer. Thus, isomerized unsymmetrical ketoxime ethers are obtained. According to the present invention, isomerization can be allowed to proceed very efficiently even under mild conditions without using special apparatus. That is, the process of the present invention is advantageous as a process for industrial isomerization of ketoxime ethers. The present invention will be explained in more detail by the following nonlimiting examples. Example 1 Titanium tetrachloride (0.1 mmol, 19 mg) was added to a solution of syn-phenyl (p-tolylmethyl) ketone (o-methyloxime) (anti/syn=0.7/99.3) (1 mmol, 0.24 g) in tetrahydrofuran (1 ml) at 25°C under a nitrogen atmosphere, followed by stirring for 38 hours at 25°C. Then, a saturated aqueous sodium bicarbonate (NaHCO₃) solution was added to the reaction mixture and thereafter, the reaction mixture was subjected to extraction with ethyl ether. The resulting organic layer was concentrated to obtain 0.24 g of anti-phenyl(p-tolylmethyl) ketone (o- methyloxime). Anti/syn ratio was measured by gas chromatograpy. Anti-syn was 97.5/2.5 and yield was 100%. Examples 2 and 3 Example 1 was repeated except that toluene or 1,2-dichloroethane was used in place of the tetrahydrofuran as solvent, thereby to obtain anti-phenyl(p-tolylmethyl) ketone (o-methyloxime). The results are shown in Table 1. Examples 4-9 and Comparative Example 1 Example 1 was repeated except that anti-syn mixed phenyl(p-tolylmethyl) ketone (o-methyloxime) (anti/syn=63.6/36.4) was used in place of the syn-phenyl (p-tolylmethyl) ketone (o-methyloxime) and 0.1 mmol of titanium trichloride, titanium tetrabromide, boron trichloride, boron tribromide, aluminium trichloride, aluminium tribromide, or boron trifluoride etherate was used in place of the titanium tetrachloride. As a result, the desired products were quantitatively obtained without producing by-products. The results are shown in Table 2. Examples 10-21 Example 1 was repeated except that phenyl (p-tolylmethyl) ketone (o-butyloxime), phenyl(p-tolylmethyl) ketone (o-benzyloxime), 2-octanone (o-benzyloxime), syn-p-bromoacetophenone (o-methyloxime), syn-2′,4′-dichloroacetophenone (o-methyloxime), anti-2′,4′-dichloroacetophenone (o-methyloxime), syn-3′,4′-dichloroacetophenone (o-methyloxime), syn-p-chloroacetophenone (o-methyloxime), syn-o-chloroacetophenone (o-methyloxime), anti-o-chloroacetophenone (o-methyloxime), syn-o-methylacetophenone (o-methyloxime), or anti-o-methylacetophenone (o-methyloxime) was used in place of the syn-phenyl(p-tolylmethyl) ketone (o-methyloxime). In all cases, no by-product was produced and the desired product was able to be obtained quantitatively. The results are shown in Table 3.

Claims: A process for isomerization of an unsymmetric ketoxime ether characterised in that at least one Lewis acid selected from the group consisting of titanium chlorides, titanium bromides, aluminium chloride, aluminium bromide, boron chloride and boron bromide is used as an isomerizing agent, and in that the amount of the Lewis acid is less than 1 mol and at least 0.05 mol per mol of the ketoxime ether. A process as claimed in claim 1 characterised in that the amount of Lewis acid is 0.05-0.5 mol per mole of the ketoxime ether. A process as claimed in claim 1 or claim 2 characterised in that the Lewis acid is titanium tetrachloride, titanium trichloride, aluminium trichloride, aluminium tribromide, boron trichloride, or boron tribromide. A process as claimed in claim 1, 2 or 3 characterised in that the ketoxime ether is an anti-isomer or a syn-isomer of a compound represented by the following formula (I) or a mixture of the anti-isomer and the syn-isomer: wherein R¹ represent an optionally substituted aryl group, an optionally substituted aralkyl group or an alkyl group and R² and R³ each represents an optionally substituted aralkyl group or an alkyl group, with a proviso that R¹ and R² cannot be identical. A process as claimed in Claim 4 characterised in that R¹ in the formula (I) is phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, alkoxy-substituted phenyl, benzyloxy-substituted phenyl, cyano-substituted phenyl, naphthyl, benzyl, alkyl-substituted benzyl, alkoxy-substituted benzyl, phenylethyl, alkyl-substituted phenylethyl, phenylpropyl, naphthylmethyl, methyl, ethyl, propyl, butyl, pentyl or hexyl. A process as claimed in Claim 4 or Claim 5 characterised in that R² in the formula (I) is benzyl, alkyl-substituted benzyl, alkoxy-substituted benzyl, phenylethyl, alkyl-substituted phenylethyl, phenylpropyl, naphthylmethyl, methyl, ethyl, propyl, butyl, pentyl or hexyl. A process as claimed in Claim 4, 5 or 6 characterised in that R³ in the formula (I) is benzyl, alkyl-substituted benzyl, alkoxy-substituted benzyl, phenylethyl, alkyl-substituted phenylethyl, phenylpropyl, naphthylmethyl, methyl, ethyl, propyl, butyl, pentyl or hexyl. A process as claimed in any one of Claims 1 to 7 characterised in that the isomerization temperature is not more than 150°C.

Inventors: KONYA NAOTO, SUZUKAMO GOHFU, YONEYOSHI YUKIO HIGASHI APT NO, KONYA, NAOTO, SUZUKAMO, GOHFU, YONEYOSHI, YUKIO, HIGASHI APT. NO. 232
Applicants: SUMITOMO CHEMICAL CO, SUMITOMO CHEMICAL COMPANY, LIMITED
Application year: 1990
Main classification: C07C249
IPC codes: B01J27, C07C251, C07B61, C07C249