阅读说明：本技术 一种高纯度4-氯-4’-羟基二苯甲酮的合成方法 (Synthesis method of high-purity 4-chloro-4' -hydroxybenzophenone ) 是由 李建平 徐寿军 吴卫清 于 2019-10-25 设计创作，主要内容包括：本发明是一种高纯度4-氯-4’-羟基二苯甲酮的合成方法,将氯苯和苯甲醚,冷却至5摄氏度以下；分三批投入无水三氯化铝,控制温度,滴加对氯苯甲酰氯和氯苯的混合液,控制反应温度；加毕,维持低温,升温至常温,再维持常温反应；一次性添加无水三氯化铝,再分两阶段升温反应；降温水解；离心水洗得到粗品,再经过碳酸钠和氢氧化钠溶液的洗涤,盐酸调节pH值后离心析出成精品。本发明的温度控制精细,结合反应时间的控制,可以减少副产物,纯度达到99.9%以上。(The invention relates to a method for synthesizing high-purity 4-chloro-4' -hydroxybenzophenone, which comprises the steps of cooling chlorobenzene and anisole to below 5 ℃; adding anhydrous aluminum trichloride in three batches, controlling the temperature, dropwise adding a mixed solution of p-chlorobenzoyl chloride and chlorobenzene, and controlling the reaction temperature; after the addition, maintaining the low temperature, heating to the normal temperature, and then maintaining the normal temperature for reaction; adding anhydrous aluminum trichloride at one time, and then heating to react in two stages; cooling and hydrolyzing; and (4) centrifugally washing to obtain a crude product, washing by using sodium carbonate and sodium hydroxide solution, regulating the pH value by using hydrochloric acid, and centrifugally separating to obtain a fine product. The invention has fine temperature control, can reduce by-products by combining the control of reaction time, and has the purity of more than 99.9 percent.)

1. A method for synthesizing high-purity 4-chloro-4' -hydroxybenzophenone is characterized by comprising the following steps: the following parts are all parts by weight;

putting 735 parts of chlorobenzene and 150 parts of anisole into a reaction kettle, and cooling to below 5 ℃;

a total of 120 ~ 200 parts of anhydrous aluminum trichloride was charged in three portions, and the mixture was stirred at a temperature of 5 ℃ or lower for 2 ~ 4 hours.

2. Dropwise adding a mixed solution of 245 parts of p-chlorobenzoyl chloride and 120 parts of chlorobenzene, controlling the reaction temperature to be 0 ~ 5 ℃, and finishing the addition within 10 hours;

after the addition, the temperature is maintained at 0 ~ 5 ℃, and the reaction is carried out for 1 ~ 3 hours;

heating to normal temperature, and maintaining the normal temperature for reaction for 1 ~ 3 hours;

adding 150 parts of anhydrous aluminum trichloride at one time, and stirring for 0.5 ~ 2 hours;

heating to 80 ℃, and reacting for 0.5 ~ 1 hours at constant temperature;

then heating to 125 ~ 130 ℃ and reacting for 2 ~ 4 hours at constant temperature;

cooling to below 40 ℃ to prepare for hydrolysis;

adding 2000 parts of water into a hydrolysis kettle, cooling to below 30 ℃, and dropwise adding the reaction liquid, wherein the reaction temperature is not higher than 40 ℃;

after the addition, the reaction is carried out for 0.5 ~ 2 hours under the condition of heat preservation;

cooling to below 10 ℃, centrifuging and washing with water to obtain the 4-chloro-4' -hydroxybenzophenone.

3. The method for synthesizing 4-chloro-4 '-hydroxybenzophenone according to claim 1, further comprising a purification step of dispersing, beating and washing the obtained 4-chloro-4' -hydroxybenzophenone with 1000 parts by weight of a 2% sodium carbonate solution, followed by centrifugation;

the method for synthesizing high-purity 4-chloro-4 '-hydroxybenzophenone according to claim 2, wherein the purification step further comprises, after pulping, washing and centrifuging a sodium carbonate solution, dissolving 4-chloro-4' -hydroxybenzophenone with 3000 parts by weight of a 2% sodium hydroxide solution, adding 200 parts by weight of chlorobenzene for extraction, adding 5 parts by weight of activated carbon into an aqueous phase, heating for decolorization, press-filtering, adjusting the pH value of the filtrate to be less than 2 with concentrated hydrochloric acid at 60 ~ 70 ℃, cooling to below 20 ℃ for precipitation, and centrifuging to separate out a refined product with a purity of more than 99%.

4. The method for synthesizing 4-chloro-4' -hydroxybenzophenone according to claim 3, wherein in the purification step, chlorobenzene is used for 5 times after being extracted and layered, and then the chlorobenzene is rectified and reused.

5. The method for synthesizing 4-chloro-4' -hydroxybenzophenone according to claim 3, wherein the purification step is carried out by absorbing hydrochloric acid tail gas with water.

6. The method for synthesizing 4-chloro-4' -hydroxybenzophenone according to claim 1, wherein the anhydrous aluminum trichloride in the step (2) is 160 parts by weight in total, and is added in three times and evenly distributed.

7. The method for synthesizing 4-chloro-4' -hydroxybenzophenone according to claim 1, wherein the room temperature in the step (2) is 25 ℃.

Technical Field

The invention relates to a synthetic method of a drug intermediate, in particular to a synthetic method of high-purity 4-chloro-4' -hydroxybenzophenone.

Background

The purity of the drug, i.e., the reduction and control of by-products, has a great influence on the therapeutic effects and side effects of the drug. The difference of the purity of the product as a pharmaceutical intermediate, which is a few tenths of a percent, affects the sale and price of the product.

4-chloro-4' -hydroxybenzophenone, 4-CBP for short, is an important intermediate of fenofibrate drugs, and after the effect is found, the research on the synthesis of the fenofibrate drugs is not stopped. Although a plurality of catalysts and synthesis routes appear after years of development, the classical traditional synthesis route still has a place in production, and the root cause is that the aluminum trichloride is cheap and has better cost control. However, it should be formally understood that the conventional synthesis route and the use of aluminum trichloride have many byproducts and low overall purity, and the fundamental reasons are that the temperature is not precisely controlled, the reaction time and the temperature are not matched, that is, the effective reaction time is not well controlled, and the reaction conditions are rough, and the invention carries out detailed optimization work in order to further optimize the conventional synthesis route.

In addition, for the improvement and optimization of the purification process, fine adjustment is also needed to be performed in a matching manner, so that the purity of the whole synthesis process is improved to a greater extent.

Disclosure of Invention

In order to improve the synthesis method, reduce by-products and improve purity, the invention provides an optimized synthesis method of high-purity 4-chloro-4' -hydroxybenzophenone, wherein the purity is over 99.9 percent, and the technical scheme is as follows:

a method for synthesizing high-purity 4-chloro-4' -hydroxybenzophenone is characterized by comprising the following steps: the following parts are all parts by weight;

(1) putting 735 parts of chlorobenzene and 150 parts of anisole into a reaction kettle, and cooling to below 5 ℃;

(2) adding total 120 ~ 200 parts of anhydrous aluminum trichloride in three batches, controlling the temperature to be below 5 ℃, and stirring for 2 ~ 4 hours;

(3) dropwise adding a mixed solution of 245 parts of p-chlorobenzoyl chloride and 120 parts of chlorobenzene, controlling the reaction temperature to be 0 ~ 5 ℃, and finishing the addition within 10 hours;

(4) after the addition, the temperature is maintained at 0 ~ 5 ℃, and the reaction is carried out for 1 ~ 3 hours;

(5) heating to normal temperature, and maintaining the normal temperature for reaction for 1 ~ 3 hours;

(6) adding 150 parts of anhydrous aluminum trichloride at one time, and stirring for 0.5 ~ 2 hours;

(7) heating to 80 ℃, and reacting for 0.5 ~ 1 hours at constant temperature;

(8) then heating to 125 ~ 130 ℃ and reacting for 2 ~ 4 hours at constant temperature;

(9) cooling to below 40 ℃ to prepare for hydrolysis;

(10) adding 2000 parts of water into a hydrolysis kettle, cooling to below 30 ℃, and dropwise adding the reaction liquid, wherein the reaction temperature is not higher than 40 ℃;

(11) after the addition, the reaction is carried out for 0.5 ~ 2 hours under the condition of heat preservation;

(12) cooling to below 10 ℃, centrifuging and washing with water to obtain the 4-chloro-4' -hydroxybenzophenone.

Further comprises a purification step of dispersing, pulping and washing the prepared 4-chloro-4' -hydroxybenzophenone by 1000 parts by weight of a 2% sodium carbonate solution, and then centrifuging and separating.

Preferably, the purification step further comprises the steps of pulping, washing and centrifuging the sodium carbonate solution, dissolving 4-chloro-4' -hydroxybenzophenone by 3000 parts by weight of a 2% sodium hydroxide aqueous solution, adding 200 parts by weight of chlorobenzene for extraction, continuously adding 5 parts by weight of activated carbon into the water phase, heating for decolorization, press-filtering, adjusting the pH value of the filtrate to be less than 2 by using concentrated hydrochloric acid at 60 ~ 70 ℃, cooling to below 20 ℃ for precipitation, and centrifuging to separate out a fine product with the purity of more than 99%.

Preferably, in the purification step, chlorobenzene is mechanically used for 5 times after extraction and layering, and then is repeatedly used after rectification.

Further, in the purification step, the hydrochloric acid tail gas is treated by water absorption.

Further, the anhydrous aluminum trichloride in the step (2) accounts for 160 parts by weight in total, and is added and evenly distributed for three times.

Further, the normal temperature in the step (2) is 25 ℃.

Further optimization in reaction time was performed as: the reaction time in the step (2) is 3 hours; the reaction time in the step (4) is 2 hours; the reaction time in the step (5) is 3 hours; the reaction time in the step (6) is 1 hour, the reaction time in the step (7) is 0.5 hour, the reaction time in the step (8) is 3 hours, and the reaction time in the step (11) is 1 hour.

Advantageous effects

1. According to the technical scheme, the temperature control is more accurate, the connection conversion of the optimal synthesis temperature of each step is further optimized, byproducts can be reduced, and the purity is improved.

2. The technical scheme of the invention has good purification process effect, and can ensure that the purity of the final product exceeds 99 percent.

The specific implementation mode is as follows:

in order to better express the technical scheme of the invention, the invention is explained by combining the embodiment.