阅读说明：本技术 一种联苯乙酸及其制备方法 (Biphenylacetic acid and preparation method thereof ) 是由 孙学喜 杨会来 毛杰 于 2020-06-18 设计创作，主要内容包括：本发明公开了一种联苯乙酸及其制备方法,通过将溴苯溶解在二甲基甲酰胺中,在钯粉的作用下,制得联苯,将联苯溶解在环己烷中,由联苯在盐酸溶液和饱和甲醛水溶液的作用下,进行氯甲基化反应制得中间体1,将氰化钠溶解在去离子水中,将中间体1与氰化钠水溶液在催化剂正丁基溴化铵的作用下,进行氰化反应,制得中间体2,中间体2在碱性水溶液的条件下,进一步水解,在盐酸作用下酸化制得联苯乙酸,该方法制备的联苯乙酸的产率比传统工艺制备出的联苯乙酸的产率要高,且反应物价格较低,大大降低了联苯乙酸的制备成本,有利于市场推广。(The invention discloses biphenylacetic acid and a preparation method thereof, bromobenzene is dissolved in dimethylformamide to prepare biphenyl under the action of palladium powder, the biphenyl is dissolved in cyclohexane, the biphenyl is subjected to chloromethylation reaction under the action of hydrochloric acid solution and saturated formaldehyde water solution to prepare an intermediate 1, sodium cyanide is dissolved in deionized water, the intermediate 1 and sodium cyanide water solution are subjected to cyanidation reaction under the action of a catalyst n-butyl ammonium bromide to prepare an intermediate 2, the intermediate 2 is further hydrolyzed under the condition of alkaline water solution, and the biphenylacetic acid is prepared by acidification under the action of hydrochloric acid.)

1. A biphenylacetic acid characterized by: the method comprises the following steps:

step S1: adding bromobenzene and dimethylformamide into a reaction kettle, stirring at the rotation speed of 300-;

step S2: adding the biphenyl prepared in the step S1 into cyclohexane, stirring until the biphenyl is completely dissolved to prepare a mixed solution, adding a hydrochloric acid solution into a reaction kettle, slowly adding a saturated formaldehyde aqueous solution under the conditions that the rotation speed is 300-500r/min and the temperature is 65-70 ℃, adding the mixed solution, and reacting for 4-5h to prepare an intermediate 1;

step S3: adding sodium cyanide and deionized water into a reaction kettle, stirring until the sodium cyanide is completely dissolved, adding n-butyl ammonium bromide and the intermediate 1 prepared in the step S2, and reacting for 4-5h at the rotation speed of 500-800r/min and the temperature of 60-70 ℃ to prepare an intermediate 2;

step S4: adding sodium hydroxide, n-butanol and deionized water into a reaction kettle, stirring for 3-5min at the rotation speed of 300-500r/min, adding the intermediate 2 prepared in the step S3, performing reflux reaction for 8-10h at the temperature of 100-110 ℃, cooling to the temperature of 60-70 ℃, adding a hydrochloric acid solution, and stirring for 2-3h at the rotation speed of 200-300r/min to prepare the felbinac.

2. A biphenylacetic acid according to claim 1, wherein: and step S1, wherein the mass ratio of bromobenzene to dimethylformamide to palladium powder is 1: 2: 5.

3. a biphenylacetic acid according to claim 1, wherein: the usage mass ratio of the biphenyl to the cyclohexane in the step S2 is 1: 5, the dosage mass ratio of the hydrochloric acid solution to the saturated formaldehyde solution to the mixed solution is 60: 20: 1, the mass fraction of the hydrochloric acid solution is 35-40%.

4. A biphenylacetic acid according to claim 1, wherein: the mass ratio of the sodium cyanide, the deionized water, the n-butyl ammonium bromide and the intermediate 1 in the step S3 is 2: 2: 0.1: 10.

5. a biphenylacetic acid according to claim 1, wherein: the dosage ratio of the sodium hydroxide, the n-butanol, the deionized water, the intermediate 2 and the hydrochloric acid solution in the step S4 is 4g to 10mL to 3mL to 6g to 10mL, and the mass fraction of the hydrochloric acid solution is 40-45%.

6. The method for preparing biphenylacetic acid according to claim 1, wherein: the method specifically comprises the following steps:

step S1: adding bromobenzene and dimethylformamide into a reaction kettle, stirring at the rotation speed of 300-;

step S2: adding the biphenyl prepared in the step S1 into cyclohexane, stirring until the biphenyl is completely dissolved to prepare a mixed solution, adding a hydrochloric acid solution into a reaction kettle, slowly adding a saturated formaldehyde aqueous solution under the conditions that the rotation speed is 300-500r/min and the temperature is 65-70 ℃, adding the mixed solution, and reacting for 4-5h to prepare an intermediate 1;

step S3: adding sodium cyanide and deionized water into a reaction kettle, stirring until the sodium cyanide is completely dissolved, adding n-butyl ammonium bromide and the intermediate 1 prepared in the step S2, and reacting for 4-5h at the rotation speed of 500-800r/min and the temperature of 60-70 ℃ to prepare an intermediate 2;

step S4: adding sodium hydroxide, n-butanol and deionized water into a reaction kettle, stirring for 3-5min at the rotation speed of 300-500r/min, adding the intermediate 2 prepared in the step S3, performing reflux reaction for 8-10h at the temperature of 100-110 ℃, cooling to the temperature of 60-70 ℃, adding a hydrochloric acid solution, and stirring for 2-3h at the rotation speed of 200-300r/min to prepare the felbinac.

Technical Field

The invention belongs to the technical field of chemical medicine synthesis, and particularly relates to biphenylacetic acid and a preparation method thereof.

Background

Felbinac is a non-steroidal anti-inflammatory drug, and esterification, nitration, hydrogenation reduction products and the like of felbinac are intermediates of various fine chemical products such as synthetic medicines and the like. Ethyl felbinate, for example, produced by esterification, is an anti-inflammatory analgesic, for example, the japanese "Napageln" ointment is a nonsteroidal anti-inflammatory drug with anti-inflammatory activity similar to fenbufen, with indications: the fat emulsion injection has the functions of metabolizing to felbinac in vivo after administration, has stronger inflammation diminishing and fever relieving effects than lysine pilin, has stronger analgesic effect than the analgesic effect, has good effects on treating rheumatic arthritis, lumbago, scapulohumeral periarthritis, traumatic pain and postoperative pain, and particularly has good effect on treating cancer pain.

The traditional felbinac preparation process is carried out by taking biphenyl as a raw material or boracic acid and acetophenone as raw materials, the yield of felbinac preparation by the two methods is low, the price of most of the used raw materials is high, so that the production cost of felbinac is increased, and the low yield makes the existing felbinac preparation process not suitable for popularization.

Disclosure of Invention

The invention aims to provide biphenyl acetic acid and a preparation method thereof.

The technical problems to be solved by the invention are as follows:

the traditional felbinac preparation process is carried out by taking biphenyl as a raw material or boracic acid and acetophenone as raw materials, the yield of felbinac preparation by the two methods is low, the price of most of the used raw materials is high, so that the production cost of felbinac is increased, and the low yield makes the existing felbinac preparation process not suitable for popularization.

The purpose of the invention can be realized by the following technical scheme:

a biphenylacetic acid is prepared by the following steps:

step S1: adding bromobenzene and dimethylformamide into a reaction kettle, stirring at the rotation speed of 300-;

step S2: adding the biphenyl prepared in the step S1 into cyclohexane, stirring until the biphenyl is completely dissolved to prepare a mixed solution, adding a hydrochloric acid solution into a reaction kettle, slowly adding a saturated formaldehyde aqueous solution under the conditions that the rotation speed is 300-500r/min and the temperature is 65-70 ℃, adding the mixed solution, and reacting for 4-5h to prepare an intermediate 1;

the reaction process is as follows:

step S3: adding sodium cyanide and deionized water into a reaction kettle, stirring until the sodium cyanide is completely dissolved, adding n-butyl ammonium bromide and the intermediate 1 prepared in the step S2, and reacting for 4-5h at the rotation speed of 500-800r/min and the temperature of 60-70 ℃ to prepare an intermediate 2;

the reaction process is as follows:

step S4: adding sodium hydroxide, n-butanol and deionized water into a reaction kettle, stirring for 3-5min at the rotation speed of 300-500r/min, adding the intermediate 2 prepared in the step S3, performing reflux reaction for 8-10h at the temperature of 100-110 ℃, cooling to the temperature of 60-70 ℃, adding a hydrochloric acid solution, and stirring for 2-3h at the rotation speed of 200-300r/min to prepare the felbinac.

The reaction process is as follows:

further, in the step S1, the mass ratio of the bromobenzene to the dimethylformamide to the palladium powder is 1: 2: 5.

further, the usage mass ratio of biphenyl to cyclohexane in step S2 is 1: 5, the dosage mass ratio of the hydrochloric acid solution to the saturated formaldehyde solution to the mixed solution is 60: 20: 1, the mass fraction of the hydrochloric acid solution is 35-40%.

Further, the mass ratio of the sodium cyanide, the deionized water, the n-butylammonium bromide and the intermediate 1 in the step S3 is 2: 2: 0.1: 10.

further, the dosage ratio of the sodium hydroxide, the n-butanol, the deionized water, the intermediate 2 and the hydrochloric acid solution in the step S4 is 4g:10mL:3mL:6g:10mL, and the mass fraction of the hydrochloric acid solution is 40-45%.

Further, the preparation method of the biphenyl acetic acid specifically comprises the following steps:

step S1: adding bromobenzene and dimethylformamide into a reaction kettle, stirring at the rotation speed of 300-;

step S2: adding the biphenyl prepared in the step S1 into cyclohexane, stirring until the biphenyl is completely dissolved to prepare a mixed solution, adding a hydrochloric acid solution into a reaction kettle, slowly adding a saturated formaldehyde aqueous solution under the conditions that the rotation speed is 300-500r/min and the temperature is 65-70 ℃, adding the mixed solution, and reacting for 4-5h to prepare an intermediate 1;

step S3: adding sodium cyanide and deionized water into a reaction kettle, stirring until the sodium cyanide is completely dissolved, adding n-butyl ammonium bromide and the intermediate 1 prepared in the step S2, and reacting for 4-5h at the rotation speed of 500-800r/min and the temperature of 60-70 ℃ to prepare an intermediate 2;

step S4: adding sodium hydroxide, n-butanol and deionized water into a reaction kettle, stirring for 3-5min at the rotation speed of 300-500r/min, adding the intermediate 2 prepared in the step S3, performing reflux reaction for 8-10h at the temperature of 100-110 ℃, cooling to the temperature of 60-70 ℃, adding a hydrochloric acid solution, and stirring for 2-3h at the rotation speed of 200-300r/min to prepare the felbinac.

The invention has the beneficial effects that: according to the felbinac prepared by the method, the bromobenzene is used for preparing the biphenyl under the action of the palladium powder, the biphenyl is subjected to chloromethylation reaction under the action of a hydrochloric acid solution and a saturated formaldehyde solution to prepare the intermediate 1, the intermediate 1 and sodium cyanide are subjected to cyanidation reaction under the action of a catalyst n-butyl ammonium bromide to prepare the intermediate 2, and the intermediate 2 is further subjected to hydrolysis and acidification to prepare the felbinac.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.