阅读说明：本技术 一种2,2,2（4-溴苯基）-2-羟基乙酸的合成方法及其应用 (Synthetic method and application of 2,2,2 (4-bromophenyl) -2-glycolic acid ) 是由 冯魏 贾利华 陈华 陈石秀 徐鹏鹏 邢燕 于 2021-08-13 设计创作，主要内容包括：本发明提供一种2,2-2(4-溴苯基)-2-羟基乙酸合成方法及其应用,本发明在碱性条件催化下2,2-2(4-溴苯基)-2-羟基乙酸溴苯与乙醛酸经加成、氧化、二次加成、酸化制得溴螨酯关键中间体2,2-2(4-溴苯基)-2-羟基乙酸。本发明制得的2,2-2(4-溴苯基)-2-羟基乙酸收率较高,乙醛酸利用率较高,本发明制得的2,2-2(4-溴苯基)-2-羟基乙酸用于制备溴螨酯。(The invention provides a synthesis method and application of 2,2-2 (4-bromophenyl) -2-hydroxyacetic acid, and bromopropylate key intermediate 2,2-2 (4-bromophenyl) -2-hydroxyacetic acid is prepared by carrying out addition, oxidation, secondary addition and acidification on 2,2-2 (4-bromophenyl) -2-hydroxyacetic acid under the catalysis of alkaline conditions. The yield of the 2,2-2 (4-bromophenyl) -2-hydroxyacetic acid prepared by the invention is higher, the utilization rate of glyoxylic acid is higher, and the 2,2-2 (4-bromophenyl) -2-hydroxyacetic acid prepared by the invention is used for preparing bromopropylate.)

1. A synthetic method of 2,2-2 (4-bromophenyl) -2-hydroxyacetic acid is characterized in that the synthetic route is as follows:

1) bromobenzene and glyoxylic acid are added to prepare an intermediate I,

2) the intermediate I is oxidized to prepare an intermediate II,

3) the intermediate II is added twice to prepare an intermediate III,

4) and acidifying the intermediate III to obtain a bromopropylate intermediate 2,2-2 (4-bromophenyl) -2-hydroxyacetic acid.

2. The synthesis method according to claim 1, which is characterized by comprising the following steps:

1) adding alkali liquor into a reaction kettle, dropwise adding glyoxylic acid under the low-temperature condition, keeping the temperature, adding bromobenzene after the reaction is finished, and heating to react until the bromobenzene is less than or equal to 1 percent and the intermediate I;

2) adjusting the pH value of the intermediate I to 7-8 by using 30% concentrated hydrochloric acid, dehydrating to 120 ℃ under negative pressure, adding toluene, refluxing to bring water to the kettle until the water content is less than or equal to 0.1%, removing toluene under negative pressure, adding dimethyl sulfoxide, N-hydroxyphthalimide and cobalt acetate with four crystal water, slowly introducing oxygen under the conditions of 0.3-0.6MPa and 80-120 ℃, maintaining the pressure in the kettle between 0.3-0.6MPa, and lowering the pressure in the kettle to be less than or equal to 0.01MPa to prepare an intermediate II;

3) cooling the intermediate II to 10-20 ℃, adding bromobenzene and strong base, heating to 60-80 ℃, and carrying out heat preservation reaction until the intermediate II is less than or equal to 1% to obtain an intermediate III;

4) removing dimethyl sulfoxide from the intermediate III under negative pressure, adding toluene, dropwise adding concentrated hydrochloric acid at 10-20 ℃, carrying out phase separation for 0.5-1h, extracting the water layer for 2 times by using toluene at 70-80 ℃, combining the toluene layers, removing part of toluene, cooling, crystallizing, and carrying out suction filtration to obtain a finished product of 2,2-2 (4-bromophenyl) -2-hydroxyacetic acid and a crystallization mother liquor.

3. The method of synthesis according to claim 2, characterized in that: also comprises the following steps of,

adding 30% alkali liquor into the crystallization mother liquor obtained in the step 4), heating to 40-60 ℃, stirring, carrying out phase separation, adding toluene into a water layer, quantifying concentrated hydrochloric acid, heating to 70-80 ℃, extracting, stirring, carrying out phase separation, and mechanically applying a toluene layer to the next batch.

4. The method of synthesis according to claim 2, characterized in that: in the step 1), the feeding molar ratio of bromobenzene to glyoxylic acid is 0.95-0.97: 1.

5. The method of synthesis according to claim 2, characterized in that: the intermediate I in the step 2): n-hydroxyphthalimide: the feeding molar ratio of the four crystal water cobalt acetate is 1:0.005-0.01: 0.005-0.01.

6. The method of synthesis according to claim 2, characterized in that: the feeding molar ratio of the intermediate II to bromobenzene in the step 3) is 1: 1.05-1.2.

7. The method of synthesis according to claim 2, characterized in that: the feeding molar ratio of the intermediate II to the strong base in the step 3) is 1: 1.4-1.6.

8. The method of synthesis according to claim 2, characterized in that: and 3) the strong base is one of sodium methoxide, sodium tert-butoxide and sodium amide.

9. The method of synthesis according to claim 8, characterized in that: and 3) the strong base is sodium methoxide.

10. The method of synthesis according to claim 2, characterized in that: the application of the prepared 2,2-2 (4-bromophenyl) -2-hydroxyacetic acid is to prepare the fenisobromolate.

Technical Field

The invention relates to a synthetic method and application of a fenisobromolate intermediate

Background

2,2,2 (4-bromophenyl) -2-hydroxyacetic acid is esterified with isopropanol to prepare the fenisobromolate, 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid is an intermediate for synthesizing the fenisobromolate, and two routes are generally used for synthesizing the fenisobromolate in industrial production:

1. p-bromobenzaldehyde is used as a raw material, and the fenisobromolate is prepared by benzoin condensation, oxidation, rearrangement and esterification.

The raw material p-bromobenzaldehyde required by the route is difficult to obtain, the yield in the preparation process is low, solid waste of manganese dioxide is generated, and the industrial production cost is high.

2. The propargite is prepared by condensation, esterification and oxidation of glyoxylic acid and bromobenzene.

In addition, because the strong water absorbent is added, the water in the system is reduced, the glyoxylic acid is self-polymerized at a higher temperature, and the utilization rate is lower.

Disclosure of Invention

The invention aims to provide a novel method for synthesizing 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid, which solves the problems of low product yield and low utilization rate of glyoxylic acid.

In order to achieve the purpose, the invention adopts the following technical scheme:

a method for synthesizing 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid is characterized in that bromobenzene and glyoxylic acid are subjected to addition, oxidation, secondary addition and acidification under the catalysis of alkaline conditions to prepare a key intermediate 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid of fenisobromolate.

The synthetic route of the invention is as follows:

1) bromobenzene and glyoxylic acid are added to prepare an intermediate I,

2) the intermediate I is oxidized to prepare an intermediate II,

3) the intermediate II is added twice to prepare an intermediate III,

4) and acidifying the intermediate III to obtain a key intermediate 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid of the bromopropylate.

Further, the method for synthesizing 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid comprises the following steps:

1) adding alkali liquor into a reaction kettle, dropwise adding glyoxylic acid under the low-temperature condition, keeping the temperature, adding bromobenzene after the reaction is finished, and heating to react until the bromobenzene is less than or equal to 1% to obtain an intermediate I;

2) adjusting the pH value of the intermediate I to 7-8 by using 30% concentrated hydrochloric acid, dehydrating to 120 ℃ under negative pressure, adding toluene, refluxing to bring water to the kettle until the water content is less than or equal to 0.1%, removing toluene under negative pressure, adding dimethyl sulfoxide, N-hydroxyphthalimide and cobalt acetate with four crystal water, slowly introducing oxygen under the conditions of 0.3-0.6MPa and 80-120 ℃, maintaining the pressure in the kettle between 0.3-0.6MPa, and lowering the pressure in the kettle to be less than or equal to 0.01MPa to prepare an intermediate II;

3) cooling the intermediate II to 10-20 ℃, adding bromobenzene and strong base, heating to 60-80 ℃, and carrying out heat preservation reaction until the intermediate II is less than or equal to 1% to obtain an intermediate III;

4) removing dimethyl sulfoxide from the intermediate III under negative pressure, adding toluene, dropwise adding concentrated hydrochloric acid at 10-20 ℃ until the pH value is 2-3, carrying out phase separation, extracting the water layer for 2 times by using toluene at 70-80 ℃, combining the toluene layers, removing part of toluene, cooling, crystallizing, and filtering to obtain a finished product of 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid and a crystallization mother liquor;

preferably, the method also comprises the step 5) of adding 30 percent alkali liquor into the crystallization mother liquor obtained in the step 4) until the pH value is 11-12, heating to 40-60 ℃, stirring, carrying out phase separation, adding toluene into a water layer, adding concentrated hydrochloric acid until the pH value is 2-3, heating to 70-80 ℃ for extraction, stirring, carrying out phase separation, and mechanically applying a toluene layer to the next batch.

Further, the feeding molar ratio of bromobenzene to glyoxylic acid in the step 1) is 0.95-0.97: 1;

step 1) the feeding molar ratio of 30 percent liquid caustic soda to glyoxylic acid is 1.25-1.4:1

The toluene is used in excess relative to the water in the step 2), and is removed from the reaction system after the reaction is finished;

the dimethyl sulfoxide is used in an excessive amount in the step 2), and is removed from the reaction system after the reaction is finished.

The feeding molar ratio of the intermediate I, the N-hydroxyphthalimide and the cobalt acetate with four crystal water in the step 2) is 1:0.005-0.01: 0.005-0.01;

the feeding molar ratio of the intermediate II to bromobenzene in the step 3) is 1: 1.05-1.2;

the feeding molar ratio of the intermediate II to the strong base in the step 3) is 1: 1.4-1.6;

in the step 4), the toluene is used in an excessive amount relative to the intermediate III, and is removed from the reaction system after the reaction is finished;

in the step 4)5), the dosage of the concentrated hydrochloric acid is relatively excessive, so that the pH value of the system is ensured to be between 2 and 3;

the toluene dosage in the step 5) is excessive relative to the crystallization mother liquor;

in the step 1) and the step 5), the alkali is common alkali, such as sodium hydroxide, potassium hydroxide and the like, the concentration is 30%, the alkali is added to enable the reaction to be carried out in an alkaline environment, the reaction temperature is kept at a relatively low temperature, such as-5-0 ℃, the reaction condition is mild, and the reaction at a low temperature avoids the self-polymerization of the glyoxylic acid under a strong acid condition, so that the utilization rate of the glyoxylic acid is greatly improved.

Removing excessive moisture before oxidation, and controlling the moisture in the reaction system to be less than or equal to 0.1% before oxidation in the step 2);

step 2), in the oxidation step, oxygen is slowly introduced, and the pressure in the kettle is maintained between 0.3 and 0.6MPa, so that the reaction process is safe and controllable;

step 2) reaction in an aprotic strong polar solvent, mild conditions and high yield of the intermediate II.

Step 3), catalyzing by using strong base in the secondary addition step, wherein the strong base is one of sodium methoxide, sodium tert-butoxide and sodium amide, and preferably sodium methoxide is selected;

the application of the prepared fenisobromolate intermediate 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid in preparing fenisobromolate is to prepare the fenisobromolate by further esterifying the fenisobromolate with isopropanol.

Compared with the prior art, the invention has the following beneficial effects;

1) the reaction is carried out at low temperature, and the reaction condition is mild;

2) the utilization rate of the glyoxylic acid is greatly improved

3) The whole reaction system is safe and controllable.

4) The 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid prepared by the method has the advantages that the average yield is up to 95% or more, and the purity of a finished product is up to 97%;

5) the invention adopts conventional process equipment, has low equipment investment and is simple to operate.

Detailed Description

The present invention will be described in further detail with reference to specific examples

Example 1:

1) adding 167g of 30% NaOH into a reaction kettle, dropwise adding 247g of 30% glyoxylic acid at the temperature of-5-0 ℃, keeping the temperature for 1-2h after dropwise adding is finished, adding 149g of bromobenzene after the reaction is finished, and heating for reacting for 6-8h until the bromobenzene is less than or equal to 1% to obtain an intermediate I;

2) adjusting the pH value of the intermediate I to 7-8 by using concentrated hydrochloric acid, dehydrating to 120 ℃ under negative pressure, adding 100g of toluene, refluxing to bring water to the kettle until the water content is less than or equal to 0.1%, removing the toluene under negative pressure, adding 200g of dimethyl sulfoxide, 0.82g N hydroxyphthalimide and 1.25g of cobalt acetate with four crystal water, slowly introducing oxygen under the conditions of 0.3-0.6MPa and 80-120 ℃, keeping the pressure in the kettle between 0.3-0.6MPa until the pressure is within 4-6h, and reducing the pressure in the kettle to less than or equal to 0.01MPa to prepare an intermediate II;

3) cooling the intermediate II to 10-20 ℃, adding 165g of bromobenzene and 75.6g of sodium methoxide, heating to 60-80 ℃, and reacting for 8-12 hours in a heat preservation manner until the intermediate II is less than or equal to 1% to obtain an intermediate III;

4) removing dimethyl sulfoxide from the intermediate III under negative pressure, adding 300g of toluene, dropwise adding concentrated hydrochloric acid at 10-20 ℃ until the pH value is 2-3, carrying out phase separation for 0.5-1h, extracting the water layer for 2 times by using 100g of toluene at 70-80 ℃, combining the toluene layers, removing 250g of toluene, cooling, crystallizing, carrying out suction filtration and drying to obtain 309.5g of a finished product of 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid, wherein the purity is 97.3%, and the yield is 78.0% and a crystallization mother liquor;

5) 30g of 30 percent sodium hydroxide and 100g of water are added into the crystallization mother liquor, the temperature is raised to 40-60 ℃, the pH value is measured to be 11-12 after stirring for 0.5-1h, the phases are separated, 100g of toluene and 30g of concentrated hydrochloric acid are added into a water layer, the temperature is raised to 70-80 ℃, the pH value is measured to be 2-3 after stirring for 0.5-1h, the phases are separated, and 320g of toluene layer is applied to the next batch.

Example 2:

1) adding 187g of 30% NaOH into a reaction kettle, dropwise adding 247g of 30% glyoxylic acid at the temperature of-5-0 ℃, keeping the temperature for 1-2h after dropwise adding is finished, adding 152g of bromobenzene after the reaction is finished, and heating for reacting for 6-8h until the bromobenzene is less than or equal to 1% to obtain an intermediate I;

2) adjusting the pH value of the intermediate I to 7-8 by using concentrated hydrochloric acid, dehydrating to 120 ℃ under negative pressure, adding 100g of toluene, refluxing to bring water to the kettle until the water content is less than or equal to 0.1%, removing the toluene under negative pressure, adding 200g of dimethyl sulfoxide, 1.63g N hydroxyphthalimide and 2.5g of cobalt acetate with four crystal water in a certain amount, slowly introducing oxygen under the conditions of 0.3-0.6MPa and 80-120 ℃, keeping the pressure in the kettle between 0.3-0.6MPa and within 4-6h, and reducing the pressure in the kettle to be less than or equal to 0.01MPa to prepare an intermediate II;

3) cooling the intermediate II to 10-20 ℃, adding 188.5g of bromobenzene and 86.4g of sodium methoxide, heating to 60-80 ℃, and reacting for 8-12 hours in a heat preservation manner until the intermediate II is less than or equal to 1% to obtain an intermediate III;

4) removing dimethyl sulfoxide from the intermediate III under negative pressure, adding 320g of toluene layer and 100g of toluene used in the example 1, dropwise adding concentrated hydrochloric acid at 10-20 ℃ until the pH value is 2-3, carrying out phase separation for 0.5-1h, extracting a water layer for 2 times by using 100g of toluene at 70-80 ℃, combining the toluene layers, removing 250g of toluene, cooling, crystallizing, carrying out suction filtration, and drying to obtain 403.1g of 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid finished product with the purity of 97.2 percent, the average yield of two batches is 89.8 percent, and crystallization mother liquor;

5) adding 32.6g of 30% sodium hydroxide and 100g of water into the crystallization mother liquor, heating to 40-60 ℃, stirring for 0.5-1h, measuring the pH value to be 11-12, carrying out phase separation, adding 100g of toluene and 30g of concentrated hydrochloric acid into a water layer, heating to 70-80 ℃, stirring for 0.5-1h, measuring the pH value to be 2-3, carrying out phase separation, and mechanically applying 330g of toluene layer to the next batch.

Example 3:

1) 233.5g of 30% KOH is added into a reaction kettle, 247g of 30% glyoxylic acid is dropwise added at the temperature of-5-0 ℃, the temperature is kept for 1-2h after the dropwise addition is finished, 150g of bromobenzene is added after the reaction is finished, the temperature is increased for reaction for 6-8h until the bromobenzene is less than or equal to 1%, and an intermediate I is prepared;

2) adjusting the pH value of the intermediate I to 7-8 by using concentrated hydrochloric acid, dehydrating to 120 ℃ under negative pressure, adding 100g of toluene, refluxing to bring water to the kettle until the water content is less than or equal to 0.1%, removing the toluene under negative pressure, adding 200g of dimethyl sulfoxide, 1.1g N hydroxyphthalimide and 1.5g of cobalt acetate with four crystal water, slowly introducing oxygen under the conditions of 0.3-0.6MPa and 80-120 ℃, keeping the pressure in the kettle between 0.3-0.6MPa and within 4-6h, and reducing the pressure in the kettle to be less than or equal to 0.01MPa to obtain an intermediate II;

3) cooling the intermediate II to 10-20 ℃, adding 170.5g of bromobenzene and 82.6g of sodium methoxide, heating to 60-80 ℃, and reacting for 8-12 hours in a heat preservation manner until the intermediate II is less than or equal to 1% to obtain an intermediate III;

4) removing dimethyl sulfoxide from the intermediate III under negative pressure, adding 330g of toluene layer used in the example 2 and 100g of toluene, dropwise adding concentrated hydrochloric acid at 10-20 ℃ until the pH value is 2-3, carrying out phase separation for 0.5-1h, extracting a water layer for 2 times by using 100g of toluene at 70-80 ℃, combining the toluene layers, removing 250g of toluene, cooling, crystallizing, carrying out suction filtration and drying to obtain 403.0g of a finished 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid product with the purity of 97.4 percent and the average yield of three batches of 93.7 percent and a crystallization mother liquor;

5) adding 35.7g of 30% sodium hydroxide and 100g of water into the crystallization mother liquor, heating to 40-60 ℃, stirring for 0.5-1h, measuring the pH value to be 11-12, carrying out phase separation, adding 100g of toluene and 30g of concentrated hydrochloric acid into a water layer, heating to 70-80 ℃, stirring for 0.5-1h, measuring the pH value to be 2-3, carrying out phase separation, and mechanically applying 330g of toluene layer to the next batch.

Example 4:

1) 361.5g of 30% KOH is added into a reaction kettle, 247g of 30% glyoxylic acid is dropwise added at the temperature of-5-0 ℃, the dropwise addition is finished within 1-2h, the temperature is kept for 1-2h, 152g of bromobenzene is added after the reaction is finished, the temperature is increased for reaction for 6-8h until the bromobenzene is less than or equal to 1%, and an intermediate I is prepared;

2) adjusting the pH value of the intermediate I to 7-8 by using concentrated hydrochloric acid, dehydrating to 120 ℃ under negative pressure, adding 100g of toluene, refluxing to bring water to the kettle until the water content is less than or equal to 0.1%, removing the toluene under negative pressure, adding 200g of dimethyl sulfoxide, 1.55g N hydroxyphthalimide and 2.5g of cobalt acetate with four crystal water in a certain amount, slowly introducing oxygen under the conditions of 0.3-0.6MPa and 80-120 ℃, keeping the pressure in the kettle between 0.3-0.6MPa and within 4-6h, and reducing the pressure in the kettle to be less than or equal to 0.01MPa to prepare an intermediate II;

3) cooling the intermediate II to 10-20 ℃, adding 188.5g of bromobenzene and 85.5g of sodium methoxide, heating to 60-80 ℃, and reacting for 8-12 hours in a heat preservation manner until the intermediate II is less than or equal to 1% to obtain an intermediate III;

4) removing dimethyl sulfoxide from the intermediate III under negative pressure, adding 330g of toluene layer used in the example 3, dropwise adding concentrated hydrochloric acid at 10-20 ℃ until the pH value is 2-3, carrying out phase separation for 0.5-1h, extracting the water layer for 2 times by using 100g of toluene at 70-80 ℃, combining the toluene layers, removing 250g of toluene, cooling, crystallizing, carrying out suction filtration and drying to obtain 404.8g of a finished product of 2,2,2 (4-bromophenyl) -2-hydroxyacetic acid, the purity of 97.5 percent, the average yield of four batches of 95.9 percent and a crystallization mother liquor;

5) the crystallization mother liquor is repeatedly used and has more impurities without being used again.