RU2024482C1 - Method of synthesis of 3-bromo-4-hydroxybenzaldehyde - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: 3-bromo-4-hydroxybenzaldehyde. Reagent 1: bromine. Reaction conditions: in the presence of hydrogen peroxide at its molar ratio to aldehyde and bromine = (0.53-0.58): 1: (0.53-0.58), in the medium of chlorohydrocarbon, at temperature 0 C. Synthesized product is used in medicine. EFFECT: improved method of synthesis. 1 tbl

Description

 The invention relates to aldehydes, in particular to 3-bromo-4-hydroxybenzaldehyde (I), which has bacteriostatic activity, and can be used as an intermediate in the synthesis of aromatic substances, for example vanillin.

Only known method for preparing 3-bromo-4-hydroxybenzaldehyde (I), consists in the fact that a suspension of 4-hydroxybenzaldehyde (II) in chloroform is treated with molecular bromine at ⁰ ° C, wherein the molar ratio of II: Br = 1.0 :( ₂ 1.0-1.1).

CHO+Br

HO

CHO+HBr^↗
Целевой продукт I выделяют путем разбавления реакционной массы петролейным эфиром, фильтрации осадка и перекристаллизации технического I из воды.The scheme of the prototype method
HO

CHO + Br

HO

CHO + HBr ^↗
The target product I is isolated by diluting the reaction mass with petroleum ether, filtering the precipitate and recrystallizing technical I from water.

In this way, compound I is obtained in a yield of 65-75%, mp. 124 ^about S.

Reproduced the method of obtaining the product 1 in the conditions of the prototype method (see table, experiment I). Received the technical target product with a yield of 60%, so pl. 118-122 ^about S.

The main disadvantages of this method are:
the need to use deficient bromine in stoichiometric (or with a slight excess) ratio to II, namely (1.0-1.1): 1.0, respectively;
loss of half the amount of bromine with unused waste of hydrobromic acid (see the scheme of the prototype method);
the need to purify the technical target product from impurities of products of deeper bromination of the benzene ring (see table, experiment I);
the duration of the process (24 hours);
relatively low and unstable yield of the target product.

 The aim of the invention is to simplify the process and increase the yield of the target product.

The goal is achieved by a method preparing 3-bromo-4-hydroxybenzaldehyde (1) using the reaction of 4-hydroxybenzaldehyde with bromine and hloruglevodopoda at ⁰ ° C, the distinguishing feature of which is that use bromine as a solution in a chlorohydrocarbon, to the 4-hydroxybenzaldehyde add water, bromine, and then sulfuric acid and hydrogen peroxide, and the process is carried out at a molar ratio of 4-hydroxybenzaldehyde, bromine and hydrogen peroxide equal to 1: (0.53-0.58); (0.53-0.58).

^H2^O2

Целевой продукт I выделяют путем фильтрации. Получают соединение I с выходом 86-88%, т.пл. 123-124^оС (лит. т.пл. 124^оС/5/), хроматографически чистый.The scheme of the proposed method

^H 2 ^O 2

Target product I is isolated by filtration. Get connection I with the release of 86-88%, so pl. 123-124 ^about C (lit. mp. 124 ^about C / 5 /), chromatographically pure.

 In the inventive method, molecular bromine is used in the form of a 23-26% solution in the corresponding chlorohydrocarbon. Hydrogen peroxide is used in the form of a 28-34% aqueous solution (GOST 177-77).

 Dichloroethane, chloroform or methylene chloride, which have good solubility with respect to bromine and limited solubility with respect to starting material II and target product I, are used as lower chlorohydrocarbon.

 To absorb hydrogen bromide and to carry out the oxidation reaction to molecular bromine with hydrogen peroxide as the second phase, immiscible with chlorohydrocarbon, water and an aqueous solution of sulfuric acid were studied.

 As can be seen from the table, the use of the two-phase chlorohydrocarbon-water system (experiments 2-5) does not allow to achieve the goal, namely, increasing the yield of the target product 1 in comparison with the prototype method. In addition, the technical target product is significantly inferior in quality to the technical target product obtained by the prototype method (compare the results of experiment I with experiments 2-5).

 The desired effect of the bromination of compound II in order to obtain product 1 (scheme of the proposed method) is achieved by using a solution of sulfuric acid instead of water (experiments 6-14). The possibility of implementing the inventive method for producing I from II in the presence of sulfuric acid was unpredictable, since this is not consistent with published data (6) on the oxidation of substituted benzaldehydes to the corresponding benzoic acids by molecular bromine in a solution of sulfuric acid.

 In the inventive method, sulfuric acid is used in the form of a 20-30% aqueous solution (experiments 7,8,9,12,13). The use of acid with a concentration below 20 and above 30% does not allow to achieve a significant increase in the yield of the target product compared with the upper limit of the prototype method (experiments 6,10,11,14).

 The table shows that the use of a small excess of bromine, as well as hydrogen peroxide, namely 3-8% over stoichiometry according to equation 2 is sufficient to obtain a stable yield (86-88%) of the technical target product (experiments 7-9 and 12-13 )

Using the combination of the above differences allows, in comparison with the prototype:
- utilize the released hydrobromic acid by in situ oxidation to molecular bromine with hydrogen peroxide, which allows the process to be carried out without waste on bromine;
halve the consumption of molecular bromine per reaction;
to obtain the target product with a stable and increased by 13-23% yield (in the prototype method, the output of I is unstable and ranges from 65-75%, in the claimed method the yield of the target product is 86-88%);
reduce the duration of the process by 18 hours (in the prototype process takes 24 hours, in the present method - 6 hours).

 The following example illustrates the inventive method.

PRI me R 1. To a mixture of 12.21 g (0.1 mol) II, 42 ml of dichloroethane and 16 ml of a 25% aqueous solution of sulfuric acid, cooled to 0 ^about With stirring for 2.0 h, a solution of 8.8 g (0.055 mol) of bromine in 20 ml of dichloroethane is added. Then, 6.0 ml of 28% hydrogen peroxide (0.055 mol) are added to the reaction mass at the same temperature over 1.0 h. After 2 hours at 0 ° ^C the precipitate was filtered off, washed with ice water and dried in air or at ⁶⁰ ° C until constant weight.

Receive 17.7 g of technical 3-bromo-4-hydroxybenzaldehyde (88.0%, counting on II) with so pl. 123-124 ^{° C,} chromatographically pure.

 EXAMPLES 2-12,14 are given in the table.

EXAMPLE EXAMPLE 13 To a mixture of 12.21 g (0.1 mol.) Of 4-hydroxybenzaldehyde (II), 42 ml of dichloroethane and 12.7 ml of water, cooled ^to 0 ° C with stirring for 2 hours a solution of 9.3 g (0.058 mol.) of bromine in 20 ml of dichloroethane is added. Then, thereto was dropwise added with stirring 3.3 ml of a cold sulfuric acid (92.1%), maintaining the temperature at weight 0 C. To ^the resulting mixture for 1 h, added 6.3 ml of 28% hydrogen peroxide ( 0.058 mol) at the same temperature. After 2 hours at 0 ° ^C the precipitate was filtered off, washed with ice water and dried in air or at ⁶⁰ ° C until constant weight.

Obtain 17.71 g of technical 3-bromo-4-hydroxybenzaldehyde (88.1%, counting on II) with so pl. 123-124 ^{° C,} chromatographically pure.

EXAMPLE EXAMPLE 15. To a mixture of 91.58 g (0.75 mol.) Of 4-hydroxybenzaldehyde (II), 315 ml of dichloroethane and 99.7 ml of water, cooled ^to 0 ° C with stirring for 2 hours 66.0 g (0.413 mol.) of bromine are added in 150 ml of dichloroethane. Then, thereto was slowly added with stirring 20.3 ml of a cold sulfuric acid (92.1%) at such a rate that the reaction temperature did not exceed 0 ° ^C.

 To the resulting mixture, 45 ml of 28% hydrogen peroxide (0.413 mol) are added over 1 hour with stirring at the same temperature. Then proceed analogously to example 13.

Get 135.85 g of technical 3-bromo-4-hydroxybenzaldehyde (90.1%, counting on II) with so pl. 123-124 ^{° C,} chromatographically pure.

Claims (1)

METHOD FOR PRODUCING 3-BROMO-4-HYDROXYBENZALDEHYDE using interaction of 4-hydroxybenzaldehyde with bromine and chlorohydrocarbon at 0 ^o С, characterized in that, in order to simplify the process, increase the yield of the target product, bromine is used as a solution in chlorohydrocarbon, to 4- hydroxybenzaldehyde is added with water, bromine, and then sulfuric acid and hydrogen peroxide, and the process is carried out at a molar ratio of 4-hydroxybenzaldehyde, bromine and hydrogen peroxide 1: 0.53 - 0.58: 0.53 - 0.58.

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