Process for preparing p-bromophenoxyacetaldehyde dialkylacetal derivatives

Abstract: There is disclosed a process for preparing a p-bromo­ phenoxyacetaldehyde dialkylacetal derivative represented by the formula: wherein R¹ and R² each represent a hydrogen atom or a lower alkyl group and R³ represents an alkyl group having 1 to 6 carbon atoms, which comprises reacting a bromine to a phenoxyacetalde­ hyde dialkylacetal represented by the formula: wherein R¹, R² and R³ have the same meanings as defined above, and then the reaction mixture is treated with an alkali metal hydroxide or alcoholate dissolved in an alcohol represented by the formula: R³OH wherein R³ has the same meaning as defined above.

Description: This invention relates to an improved process for preparing p-bromophenoxyacetaldehyde dialkylacetal derivatives. The acetals are useful for synthetic intermediate of a substituted phenoxyalkylaminopyrimidine derivative (for example, Japanese Provisional Patent Publications No. 36667/1984 and No. 67/1987) which shows potent activity as an acaricide. p-Bromophenoxyacetaldehyde dialkylacetal derivatives have heretofore been prepared by reacting p-bromophenols and chloroacetaldehyde dialkylacetals in the presence of a base (J. Agric. Food Chem., vol 36, p. 378 (1988), French Patent No. 1,537,206 and Japanese Provisional Patent Publication No. 313743/1988). However, this method has disadvantages that (1) ortho-isomer and dibromo compound are formed with amounts of 20 to 30 % when phenols being brominated and (2) the reaction rate is extremely slow. The former disadvantage can be overcome only by recrystallization to obtain the pure para-isomer. Besides, in order to overcome the latter disadvantage of reaction rate, bromoacetaldehyde dialkylacetals which are expensive and hardly obtainable in industry must be used in place of cheap chloroacetaldehyde dialkylacetal, and also as a solvent, amides such as dimethylformamide, which are easily decomposable should be used. The acetal substituent is generally extremely weak to acid, and it is decomposed in the condition of forming hydrogen bromide, so that a novel method which is to be replaced with the conventional method has been desired. SUMMARY OF THE INVENTION The present inventors have found that after reacting bromine with phenoxyacetaldehyde dialkylacetals, a specific treatment is effected to the reaction mixture whereby bromination reaction proceeds smoothly and surprisingly the desired compound can be obtained with extremely high yield and selectively without forming by-products such as ortho-isomer and dibromo compound to accomplish the present invention. That is, the present invention is a process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative represented by the formula: wherein R¹ and R² each represent hydrogen, methyl or ethyl, and R³ represents an alkyl group having 1 to 6 carbon atoms, which comprises reacting bromine with a phenoxyacetaldehyde dialkylacetal represented by the formula: wherein R¹, R² and R³ have the same meanings as defined above, and then the reaction mixture is treated with an alkali metal hydroxide or alcoholate (or alkoxide) dissolved in an alcohol represented by the formula: R³OH wherein R³ has the same meaning as defined above. DESCRIPTION OF THE PREFERRED EMBODIMENTS The starting compound of the formula (I) can be obtained by a similar method as disclosed in Japanese Patent Publication No. 50466/1987 by reacting phenols and chloroacetaldehyde dialkylacetal in the presence of a base without using a specific solvent. The reaction solvent to be used in the present invention is preferably an alcohol (R³OH) which is the same as the alcohol which constitutes the alkylacetal, or an alkane chloride selected from the group consisting of methylene chloride, dichloroethane and trichloroethane. The amount of bromine is preferably 1.0 to 1.3 mole based on the starting compound of the formula (I). The reaction can be carried out at a reaction temperature in the range of - 10 to 50 °C, but preferably in the range of 0 to 10 °C. The reaction can be carried out with a solution containing the compound of the formula (I) in a reaction concentration of 1 to 50 % by weight, but generally preferably 5 to 30 % by weight. The time required for dropwise addition of bromine is 1 to 5 hours, and the reaction is completed within one hour after dropwise addition of bromine. After completion of the reaction, the reaction mixture as it were or after partial or complete removal of the reaction solvent under reduced pressure e.g. 2.67 to 26.7 kPa (200 to 20 mmHg) and at 40 °C or lower) is added dropwise to an alcoholic solution of an alkali metal hydroxide dissolved in an alcohol of the formula R³OH while maintaining the temperature of the reaction mixture at 30 °C or lower. As the alkali metal hydroxide, it may preferably include sodium hydroxide, potassium hydroxide, etc. The amount of the alkali metal hydroxide or alcoholate (alkoxide) is 0.5 to 2.0-fold moles of the used bromine. The alkali metal alcoholate is also used as an alcoholic solution of the formula R³OH. As the alkali metal alkoxide, it may preferably include lithium alkoxide, sodium alkoxide, potassium alkoxide, etc. After completion of the above treatment, the solvent was removed under reduced pressure and after removing the inorganic salt formed with filtration, washing, etc., the compound of the formula (II) can be obtained by distillation under reduced pressure, recrystallization, etc. As the p-bromophenoxyacetaldehyde dialkylacetals (II), there may be mentioned 1-bromo-4-(2,2-diethoxyethoxy)benzene, 1-bromo-4-(2,2-dimethoxyethoxy)benzene, 1-bromo-4-(2,2-diethoxyethoxy)-3-methylbenzene, 1-bromo-4-(2,2-dimethoxyethoxy)-3-methylbenzene, 1-bromo-4-(2,2-diethoxyethoxy)-3-ethylbenzene, 1-bromo-4-(2,2-dimethoxyethoxy)-3-ethylbenzene, 1-bromo-4-(2,2-diethoxyethoxy)-2,3-dimethylbenzene, 1-bromo-4-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene, 1-bromo-4-(2,2-diethoxyethoxy)-2,5-dimethylbenzene, 1-bromo-4-(2,2-dimethoxyethoxy)-2,5-dimethylbenzene, 1-bromo-4-(2,2-diethoxyethoxy)-3,5-dimethylbenzene, 1-bromo-4-(2,2-dimethoxyethoxy)-3,5-dimethylbenzene, etc. EXAMPLES In the following, the present invention will be explained in more detail by referring to Examples. Example 1 Bromine (140 g) was added dropwise to a 760 ml of dichloroethane solution containing 180 g of 1-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene while stirring and cooling (ice bath) and maintaining the temperature of the reaction mixture not exceeding 10 °C. After stirring for 30 minutes after completion of the addition, the reaction mixture was condensed under reduced pressure (a temperature of 40 °C or lower). The condensate was added dropwise in a solution comprising 37 g of sodium hydroxide dissolved in 185 g of methanol while stirring. Stirring was continued for one hour after completion of the addition, methanol was removed under reduced pressure, and 30 ml of dichloroethane and 570 ml of water were added to the residue and then the mixture was separated with each other. The organic layer was condensed under reduced pressure, a resulting brownish oil was distilled under reduced pressure to give 228 g of 1-bromo-4-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene. Boiling point: 128 to 131 °C/0.5 mmHg; Melting point: 40 to 41 °C; and Yield: 92 %. Example 2 In the same manner as in Example 1 except for replacing a methanol solution of sodium hydroxide with 180 ml of methanol solution containing 28 % of sodium methylate, the reaction was carried out as in Example 1. As the result, 1-bromo-4-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene was obtained with a yield of 93 %. Example 3 In the same manner as in Example 1 except for replacing a reaction solvent for bromination of dichloroethane with methanol, the reaction was carried out as in Example 1. Yield: 93 %. Example 4 In the same manner as in Example 1 except for replacing 1-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene with 2,2-diethoxyethoxybenzene, the reaction was carried out as in Example 1 (with 1/50 scale of Example 1) to give 1-bromo-4-(2,2-diethoxyethoxy)benzene (Boiling point: 123 to 127 °C/2 mmHg) with a yield of 89 %. Example 5 In the same manner as in Example 1 except for replacing 1-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene with 1-(2,2-diethoxyethoxy)-2-ethylbenzene, the reaction was carried out as in Example 1 (with 1/50 scale of Example 1) to give 1-bromo-4-(2,2-diethoxyethoxy)-3-ethylbenzene (Boiling point: 180 to 185 °C/7 mmHg) with a yield of 90 %. Example 6 In the same manner as in Example 1 except for replacing 1-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene with 1-(2,2-dimethoxyethoxy)-2,5-dimethylbenzene, the reaction was carried out as in Example 1 to give 1-bromo-4-(2,2-dimethoxyethoxy)-2,5-dimethylbenzene (Boiling point: 118 to 120 °C/2.5 mmHg) with a yield of 91 %. Example 7 In the same manner as in Example 1 except for replacing 1-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene with 1-(2,2-diethoxyethoxy)-2,6-dimethylbenzene, the reaction was carried out as in Example 1 to give 1-bromo-4-(2,2-diethoxyethoxy)-3,5-dimethylbenzene (Boiling point: 138 to 145 °C/4 mmHg) with a yield of 96 %. According to the present invention, the aimed p-bromophenoxyacetaldehyde dialkylacetal can be obtained with high yield and high purity and forming substantially no by-products such as ortho-isomer and dibromo compounds.

Claims: A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative represented by the formula: wherein R¹ and R² each represent hydrogen, methyl or ethyl, and R³ represents an alkyl group having 1 to 6 carbon atoms, which comprises reacting bromine with a phenoxyacetaldehyde dialkylacetal represented by the formula: wherein R¹, R² and R³ have the same meanings as defined above, and then the reaction mixture is treated with an alkali metal hydroxide or alcoholate dissolved in an alcohol represented by the formula: R³OH wherein R³ has the same meaning as defined above. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, wherein the reaction is carried out in the presence of a solvent. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 2, wherein the solvent is an alcohol represented by the formula R³OH wherein R³ has the same meaning as defined in Claim 1; or alkane chloride selected from the group consisting of methylene chloride, dichloroethane and trichloroethane. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, wherein the amount of bromine is 1.0 to 1.3 mole based on the amount of the phenoxyacetaldehyde dialkylacetal of the formula (I). A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 4, wherein bromine is added dropwise to a solution of phenoxyacetaldehyde dialkylacetal of the formula (I). A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 5, wherein dropwise addition is carried out within 1 to 5 hours. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, wherein the reaction is carried out at a temperature of - 10 to 50 °C. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 7, wherein the reaction is carried out at a temperature of 0 to 10 °C. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, wherein the concentration of the phenoxyacetaldehyde dialkylacetal of the formula (I) in the reaction mixture is 1 to 50 % by weight. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 9, wherein the concentration of the phenoxyacetaldehyde dialkylacetal of the formula (I) is 5 to 30 % by weight. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, wherein treatment with the alkali metal hydroxide or the alcoholate dissolved in the alcohol is carried out by adding the reaction mixture dropwise to the alcoholic solution. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 11, wherein the dropwise addition of the reaction mixture is carried out while maintaining the temperature of the mixture at 30°C or lower. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, wherein the alcoholate is lithium alkoxide, sodium alkoxide or potassium alkoxide. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, wherein the amount of the alkali metal hydroxide or alcoholate is 0.5 to 2.0-fold mole of the used bromine. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, wherein the process further comprises removing the inorganic salt formed and then purifying the desired compound by distillation under reduced pressure or by recrystallization. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, which comprises adding 1.0 to 1.3 moles of bromine dropwise to a solution of the phenoxyacetaldehyde dialkylacetal in a solvent having a concentration of 1 to 50 % by weight, at a temperature of - 10 to 50 °C; and then adding the reaction mixture dropwise to 0.5 to 2.0-fold moles (based on used bromine) of the alkali metal hydroxide or alcoholate dissolved in the alcohol at a temperature of 30 °C or lower. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, which comprises adding 1.0 to 1.3 moles of bromine dropwise to a solution of the phenoxyacetaldehyde dialkylacetal in a solvent, having a concentration of 5 to 30 % by weight, at a temperature of 0 to 10 °C; and then adding the reaction mixture dropwise to 0.5 to 2.0-fold moles (based on used bromine) of the alkali metal hydroxide or alcoholate dissolved in the alcohol at a temperature of 30 °C or lower. A process for preparing a p-bromophenoxyacetaldehyde dialkylacetal derivative according to Claim 1, wherein the p-bromophenoxyacetaldehyde dialkylacetal of the formula (II) is selected from 1-bromo-4-(2,2-diethoxyethoxy)benzene, 1-bromo-4-(2,2-dimethoxyethoxy)benzene, 1-bromo-4-(2,2-diethoxyethoxy)-3-methylbenzene, 1-bromo-4-(2,2-dimethoxyethoxy)-3-methylbenzene, 1-bromo-4-(2,2-diethoxyethoxy)-3-ethylbenzene, 1-bromo-4-(2,2-dimethoxyethoxy)-3-ethylbenzene, 1-bromo-4-(2,2-diethoxyethoxy)-2,3-dimethylbenzene, 1-bromo-4-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene, 1-bromo-4-(2,2-diethoxyethoxy)-2,5-dimethylbenzene, 1-bromo-4-(2,2-dimethoxyethoxy)-2,5-dimethylbenzene, 1-bromo-4-(2,2-diethoxyethoxy)-3,5-dimethylbenzene and 1-bromo-4-(2,2-dimethoxyethoxy)-3,5-dimethylbenzene.

Inventors: ATAKA KIKUO UBE RESEARCH LABOR, KOHNO MASAHIKO UBE RESEARCH LA, ATAKA, KIKUO UBE RESEARCH LABORATORY, KOHNO, MASAHIKO UBE RESEARCH LABORATORY
Applicants: SANKYO CO, UBE INDUSTRIES, SANKYO COMPANY LIMITED, UBE INDUSTRIES, LTD.
Application year: 1989
Main classification: C07C43
IPC codes: C07C43, C07C67, C07C41