阅读说明：本技术 一种苯基丙二酸二乙酯的提纯方法 (Method for purifying diethyl phenylmalonate ) 是由 张朋 牛磊磊 杨文兵 郭云山 于 2021-08-27 设计创作，主要内容包括：本申请公开了一种苯基丙二酸二乙酯的提纯方法,包括以下步骤：(S1)将苯基丙二酸二乙酯粗品溶液通入到熔融结晶器中,进行初次结晶；(S2)将初次结晶后的苯基丙二酸二乙酯粗品溶液再次通入到熔融结晶器中,进行再次结晶；重复结晶4～10次；(S3)将熔融结晶器升温至-9～-2℃,析出部分杂质；(S4)将熔融结晶器升温至25～35℃,得到苯基丙二酸二乙酯纯品。该提纯方法能耗低,产品纯度更高,适用于大规模生产苯基丙二酸二乙酯。(The application discloses a method for purifying diethyl phenylmalonate, which comprises the following steps: (S1) introducing the crude diethyl phenylmalonate solution into a melt crystallizer for primary crystallization; (S2) introducing the crude diethyl phenylmalonate solution after primary crystallization into the melt crystallizer again for recrystallization; repeating the crystallization for 4-10 times; (S3) heating the melt crystallizer to-9-2 ℃, and separating out partial impurities; (S4) heating the melt crystallizer to 25-35 ℃ to obtain a pure product of the diethyl phenylmalonate. The purification method has low energy consumption and higher product purity, and is suitable for large-scale production of the diethyl phenylmalonate.)

1. The method for purifying diethyl phenylmalonate is characterized by comprising the following steps:

(S1) introducing the crude diethyl phenylmalonate solution into a melt crystallizer for primary crystallization;

(S2) introducing the crude diethyl phenylmalonate solution after primary crystallization into the melt crystallizer again for recrystallization;

the repeated crystallization times are 4-10 times;

(S3) heating the melt crystallizer to-9-2 ℃, and separating out partial impurities;

(S4) heating the melt crystallizer to 25-35 ℃ to obtain a diethyl phenylmalonate product;

wherein, in the steps (S1) and (S2),

the temperature of the melting crystallizer is controlled to be-30 to-20 ℃;

the introduction rate of the crude phenylmalonic acid diethyl ester solution is 4-20 mL/min.

2. The purification method according to claim 1, wherein the content of the diethyl phenylmalonate in the crude solution of diethyl phenylmalonate is 60-95 wt%;

preferably, the content of the diethyl phenylmalonate is 75-90 wt%.

3. The purification method as claimed in claim 2, wherein the crude solution of diethyl phenylmalonate comprises diethyl phenylmalonate, ethanol, diethyl carbonate, diethyl ethylphenylmalonate and ethyl phenylacetate.

4. The purification method according to claim 1, wherein the temperature of the melt crystallizer is controlled to be-26 to-22 ℃.

5. The purification method according to claim 1, wherein the flow rate of the crude solution of diethyl phenylmalonate is 4-15 mL/min.

6. The purification method according to claim 1, wherein the number of the repeated crystallization is 5 to 7;

preferably, the content of the diethyl phenylmalonate in the crude solution of the diethyl phenylmalonate after repeated crystallization is less than or equal to 40 wt%.

7. The purification method according to claim 1, wherein in the step (S3), the temperature of the melt crystallizer is raised to-8 to-5 ℃.

8. The purification method according to claim 1, wherein in the step (S4), the temperature of the melt crystallizer is raised to 28-32 ℃.

9. The purification method according to claim 1, wherein the purity of the diethyl phenylmalonate product is greater than or equal to 98%.

10. The purification method according to claim 1, wherein the yield of the diethyl phenylmalonate product is 65% or more.

Technical Field

The application relates to a method for purifying diethyl phenylmalonate, and belongs to the field of pharmaceutical chemicals.

Background

Diethyl phenylmalonate is an important medical intermediate and can be used for synthesizing diethyl phenylethylmalonate. Besides, the diethyl phenylmalonate is also applied to other fields, such as the synthesis of antiepileptic drugs and sedative drugs phenobarbital. The diethyl phenylmalonate is colorless transparent liquid at normal temperature and has no special odor, the boiling point of the diethyl phenylmalonate is 340 ℃ at normal pressure, and the common synthesis mode is to mix ethyl phenylacetate and diethyl carbonate, perform claisen ester condensation under the action of sodium ethoxide to obtain sodium salt of the diethyl phenylmalonate, neutralize the sodium salt with acid to obtain an organic phase containing a product, and obtain a pure product of the diethyl phenylmalonate by rectification or crystallization. The synthesis equation of the diethyl phenylmalonate is as follows:

the main synthesis principle is that ethyl phenylacetate loses alpha-H under the action of sodium ethoxide to form carbanions, the carbanions attack diethyl carbonate carbonyl carbon in a nucleophilic mode, ethoxy leaves in an ethanol form to generate diethyl phenylmalonate sodium salt, and finally diethyl phenylmalonate is generated in an acid-adding neutralization mode. Ethyl phenylacetate itself contains not only active α -H but also carbonyl groups, so that ethyl phenylacetate is likely to undergo self-condensation, and its self-condensation product structure is shown in the following figure (i) by chromatography and mass spectrometry. And the self-condensation product (I) of the ethyl phenylacetate is easy to decompose under the condition of high temperature (more than 200 ℃) to generate the 1, 3-diphenyl acetone (IV). Since the reaction is a reversible reaction, ethyl phenylacetate itself hardly reacts completely, and thus a small amount of ethyl phenylacetate remains in the organic phase.

The separation method commonly used in the past separates diethyl phenylmalonate, other byproducts and raw materials by a high-temperature rectification mode, and the method has the defects that: firstly, the product diethyl phenylmalonate can be decomposed under the high-temperature condition to generate benzene and diethyl malonate (free radical reaction), secondly, the boiling point of the product is close to that of a byproduct such as diethyl phenylmalonate, the purity of the product is difficult to be improved to more than 99 percent, and thirdly, the high-temperature rectification energy consumption is high, and the product does not meet the national call for energy conservation and emission reduction. In addition, static crystallization is also a good purification mode (Chinese patent CN 101633619B), but the static crystallization treatment process is complex, has certain requirements on the purity of the solution, needs activated carbon for decolorization, increases the treatment difficulty, and has a long way to use on a large scale.

Disclosure of Invention

The invention separates the diethyl phenylmalonate from impurities by a melt crystallization method, and separates products from other components by utilizing different freezing points of different substances. Compared with static crystallization, the method has the advantages that the purity requirement of the crude diethyl phenylmalonate solution is lower, the crude diethyl phenylmalonate solution does not need to be subjected to decoloration treatment, and the intermediate loss of the product is less. Moreover, the purity of the diethyl phenylmalonate obtained by the method is higher, and the product purity is over 99.8 percent, so that the method is an ideal purification mode and is very suitable for large-scale production of diethyl phenylmalonate.

According to a first aspect of the present application, there is provided a method for purifying diethyl phenylmalonate. The method provides a simple and low-cost method for purifying the diethyl phenylmalonate on the premise of ensuring the purity of the diethyl phenylmalonate product.

A method for purifying diethyl phenylmalonate comprises the following steps:

(S1) introducing the crude diethyl phenylmalonate solution into a melt crystallizer for primary crystallization;

(S2) introducing the crude diethyl phenylmalonate solution after primary crystallization into the melt crystallizer again for recrystallization;

repeating the crystallization for 4-10 times;

(S3) heating the melt crystallizer to-9-2 ℃, and separating out partial impurities;

(S4) heating the melt crystallizer to 25-35 ℃ to obtain a diethyl phenylmalonate product;

wherein, in the steps (S1) and (S2),

the temperature of the melting crystallizer is controlled to be-30 to-20 ℃;

the introduction rate of the crude phenylmalonic acid diethyl ester solution is 4-20 mL/min.

Optionally, in the crude solution of the phenylmalonic acid diethyl ester, the content of the phenylmalonic acid diethyl ester is 60-95 wt%.

Optionally, the content of diethyl phenylmalonate is 75-90 wt%.

Alternatively, the diethyl phenylmalonate content is independently selected from any of 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, 90 wt%, 95 wt%, or a range between any two.

Alternatively, the crude solution of the diethyl phenylmalonate comprises diethyl phenylmalonate, ethanol, diethyl carbonate, diethyl ethylphenylmalonate and ethyl phenylacetate.

Alternatively, the crude solution of diethyl phenylmalonate comes from the following process: mixing ethyl phenylacetate and diethyl carbonate, performing claisen ester condensation under the action of sodium ethoxide to obtain sodium salt of diethyl phenylmalonate, neutralizing with acid to obtain an organic phase containing a product, and removing part of solvent by reduced pressure distillation to obtain a crude solution of diethyl phenylmalonate.

In the present application, the source of the crude solution of diethyl phenylmalonate is not strictly limited, and the crude solution of diethyl phenylmalonate is generally prepared by ester condensation reaction of ethyl phenylacetate, diethyl carbonate and sodium ethoxide. A crude solution of diethyl phenylmalonate obtained by the method disclosed in "research on the synthesis of phenobarbital" (Anhui chemical, Han Jian, 2007 4 months, volume 33, phase 2) and "research on the greening of phenobarbital synthesis method" (published by Gansu university, Zhangufu, 2007 year, volume 12, phase 2), patent GB559306A (preparation of phenyl or phenethyl malonate).

Alternatively, the crude solution of diethyl phenylmalonate may be subjected to distillation under reduced pressure to remove part of the ethanol and diethyl carbonate.

Optionally, the temperature of the melt crystallizer is controlled to be-26 to-22 ℃.

Optionally, the temperature of the melt crystallizer is controlled to-25 ℃.

Optionally, the temperature of the melt crystallizer is independently controlled to any value of-30 ℃, -29 ℃, -28 ℃, -27 ℃, -26 ℃, -25 ℃, -24 ℃, -23 ℃, -22 ℃, -21 ℃, -20 ℃, or a range of values between any two.

Under the condition of the temperature, diethyl phenylmalonate can be crystallized and separated out firstly, colored impurities can be continuously dissolved in a solution containing ethanol and diethyl carbonate, the separated diethyl phenylmalonate is colorless, the precipitation amount of the product diethyl phenylmalonate accounts for more than 65% of the total amount, and the rest solution can be continuously separated out in a concentration mode.

Optionally, the flow rate of the crude solution of diethyl phenylmalonate is 4-20 mL/min. An introduction rate of less than 4mL/min leads to an increase in energy consumption and a decrease in the rate of collection per unit time. The introduction rate of more than 20mL/min can cause incomplete crystallization of the product, increase of coating impurities and substandard product content.

Optionally, the number of repeated crystallization is 5-7.

Optionally, the number of repeated crystallizations is 4, 5, 6, 7, 8, 9, or 10.

Optionally, the flow rate of the crude solution of diethyl phenylmalonate is 4-15 mL/min.

Optionally, the flow rate of the crude solution of diethyl phenylmalonate is 4-6 mL/min.

Alternatively, the crude solution of diethyl phenylmalonate is passed at a rate independently selected from any of 4mL/min, 5mL/min, 6mL/min, 7mL/min, 10mL/min, 12mL/min, 15mL/min, 17mL/min, 20mL/min, or a range between any two.

Optionally, the content of the diethyl phenylmalonate in the crude solution of the diethyl phenylmalonate after repeated crystallization is less than or equal to 40 wt%.

Optionally, the content of the diethyl phenylmalonate in the crude solution of the diethyl phenylmalonate after repeated crystallization is 30-40 wt%.

Alternatively, the content of the diethyl phenylmalonate in the crude solution of diethyl phenylmalonate after repeated crystallization is independently selected from any value of 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt% or a range between any two.

Alternatively, in step (S3), the melt crystallizer is warmed to-8 to-5 ℃.

Alternatively, in step (S3), the temperature at which the melt crystallizer is warmed is independently selected from any one of-9 ℃, -8 ℃, -7 ℃, -6 ℃, -5 ℃, -4 ℃, -3 ℃, or a range between any two of them.

The impurities in the separated crystals are mainly trace diethyl ethylphenylmalonate, and after the crystals are separated out to a certain amount, the temperature of the condensate is raised to-8 to-5 ℃, and the diethyl ethylphenylmalonate is melted and flows out.

Optionally, in the step (S4), the temperature of the melt crystallizer is raised to 28-32 ℃.

Alternatively, in step (S4), the melt crystallizer is warmed to 30 ℃.

Alternatively, in the step (S4), the temperature at which the melt crystallizer is warmed is independently selected from any value of 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, 31 ℃, 32 ℃, 33 ℃, 34 ℃, 35 ℃ or a range value between any two thereof.

Optionally, the purity of the diethyl phenylmalonate product is greater than or equal to 98%.

Optionally, the purity of the diethyl phenylmalonate product is greater than or equal to 99%.

Alternatively, the yield of the diethyl phenylmalonate product is greater than or equal to 65%.

Alternatively, the yield of the diethyl phenylmalonate product is greater than or equal to 70%.

Alternatively, the yield of the diethyl phenylmalonate product is greater than or equal to 83%.

As a preferred embodiment, the method for purifying diethyl phenylmalonate comprises the following steps:

(1) adding a crude product (> 60%) of the phenyl diethyl malonate into a melting crystallizer at a constant speed, controlling the temperature of the crystallizer between minus 25 ℃ and minus 20 ℃, wherein the phenyl diethyl malonate is firstly crystallized and separated out under the temperature condition, colored impurities are continuously dissolved in a solution containing ethanol and diethyl malonate, the separated phenyl diethyl malonate is colorless and transparent, the precipitation amount of the product phenyl diethyl malonate accounts for more than 65% of the total amount, and the rest product can be continuously crystallized and separated out after being concentrated;

(2) the impurities in the separated crystals are mainly trace diethyl ethylphenylmalonate, and after the crystals are separated out to a certain amount, the temperature of the condensate is raised to-8 to-5 ℃, and the diethyl ethylphenylmalonate is melted and flows out. Finally, the temperature is integrally raised to 30 ℃ to obtain a pure product of the phenyl diethyl malonate, and the purity of the phenyl diethyl malonate is over 99 percent.

(3) And concentrating and crystallizing the residual solution for multiple times, wherein the final yield of the obtained product is over 96 percent.

Optionally, the crystallizer comprises a crystallization kettle, a crystallization pipe, a cooling and heating circulation all-in-one machine, a circulating pump, a residual liquid tank, a product tank and a pipeline.

Optionally, the crystallization tube is placed inside a crystallization kettle; the cold and hot circulation all-in-one machine is arranged outside the crystallization kettle and is respectively communicated with the upper part and the lower part of the crystallization kettle through pipelines; the residual liquid tank and the product tank are respectively connected to the lower part of the crystallization kettle through pipelines; and the circulating pump is respectively communicated with the top of the crystallization kettle and a pipeline of the residual liquid tank.

Optionally, the conduit is provided with a valve.

As a preferred embodiment, the method for purifying diethyl phenylmalonate comprises the following steps:

1. opening a switch of the cold and hot circulation all-in-one machine, and setting the temperature of the cooling liquid to be-25 ℃;

2. opening a raw material inlet valve, adjusting a flow valve, and conveying the crude product liquid of the diethyl phenylmalonate to a melting crystallizer at a constant speed;

3. separating out a part of product on the surface of the crystallizer, allowing the part which is not crystallized to flow out from the bottom of the crystallizer, circulating for 5-7 times, detecting the content of the product in an effluent liquid, collecting the effluent liquid into a residue tank if the content of the product is lower than or equal to 40%, evaporating the solvent under reduced pressure, and then continuously crystallizing, and if the content of the product is higher than 40%, continuously circulating;

4. setting the temperature of the cold and hot circulation all-in-one machine to-8 ℃, discharging the effluent liquid, and collecting the effluent liquid into a residual liquid tank;

5. and (4) heating the cold-hot circulation all-in-one machine to 30 ℃, melting and flowing out the product, and collecting the product to a product tank.

The beneficial effects that this application can produce include:

according to the purification method of the diethyl phenylmalonate, the requirement on the purity of the crude solution of the diethyl phenylmalonate is lower, the crude solution of the diethyl phenylmalonate does not need to be subjected to decoloration treatment, and fewer products are consumed in the middle. The diethyl phenylmalonate obtained by the method has higher purity, the product purity is over 98 percent, the energy consumption is low, and the method is an ideal purification mode and is very suitable for large-scale production of diethyl phenylmalonate.

Drawings

FIG. 1 is a flow chart of a melt crystallization process.

Detailed Description

The present application will be described in detail with reference to examples, but the present application is not limited to these examples.

The crude diethyl phenylmalonate solution used in the embodiment is synthesized by the company, the synthesis method is to synthesize diethyl phenylmalonate sodium salt by taking diethyl carbonate and ethyl phenylacetate as raw materials and sodium ethoxide as an alkali source, obtain diethyl phenylmalonate by adding acid for neutralization, and finally obtain the crude diethyl phenylmalonate solution by reduced pressure distillation.

In the present application, the content and purity are the same.

In the examples, the contents of diethyl phenylmalonate, raw materials and byproducts were analyzed by Gas Chromatography (GC) using Shimadzu GC-2014C, FID, and HP-5 as the chromatographic column.

The content of diethyl phenylmalonate was calculated by GC analysis as follows:

the yield of diethyl phenylmalonate was calculated as follows:

the contents of impurities diethyl ethylphenylmalonate and ethyl phenylacetate were analyzed by GC and calculated as follows:

FIG. 1 is a flow chart of a melt crystallization process.

1. The crystallizer mainly comprises six parts, including a crystallization kettle, a crystallization pipe, a cold and hot circulation integrated machine, a circulating pump, a residual liquid tank, a product tank and a plurality of pipelines.

2. The crude product liquid of the diethyl phenylmalonate enters a crystallization kettle from a raw material pipeline, crystallization and separation are started at the temperature of minus 25 ℃, the solidification point of the raw material is higher, and the raw material does not crystallize under the temperature condition.

3. Detecting the product content in the effluent liquid at the bottom of the kettle, if the product content is higher than 40%, continuing to circularly crystallize, otherwise, collecting the effluent liquid into a residue tank for next treatment;

4. continuously heating to-8 ℃, and allowing a small amount of impurities to flow out of the bottom of the crystallizer;

5. heating to 30 ℃, melting and flowing out the product, and collecting the product in a product tank;

6. the next batch of material was added and crystallization continued.

Example 1

100.00g of crude diethyl phenylmalonate solution with the content of 61.15 wt% is uniformly added into a melt crystallizer, the introduction rate is 5mL/min, the temperature of a cooling medium of the melt crystallizer is set to be-25 ℃, colorless transparent crystals are slowly separated out on the surface of the crystallizer, after 5 times of circulation, the content of diethyl phenylmalonate in the solution is reduced to 35.52 wt%, the temperature is increased to be-8 ℃, a small amount of colorless impurities flow out, and most of the impurities are diethyl carbonate and diethyl ethylphenylmalonate. The temperature was further raised to 30 ℃ to obtain 39.75g of a colorless transparent liquid having a purity of 98.24%. The content of impurity diethyl ethylphenylmalonate was 0.0483%, the content of ethyl phenylacetate was 0.0427%, and the product yield was 63.86%.

Example 2

100.00g of crude diethyl phenylmalonate solution with the content of 70.74 wt% is uniformly added into a melt crystallizer, the introduction rate is 5mL/min, the temperature of a cooling medium of the melt crystallizer is set to be-25 ℃, colorless transparent crystals are slowly separated out on the surface of the crystallizer, after 6 times of circulation, the content of diethyl phenylmalonate in the solution is reduced to 35.55 wt%, the temperature is increased to be-8 ℃, a small amount of colorless impurities flows out, and most of the impurities are diethyl carbonate and diethyl ethylphenylmalonate. The temperature was further raised to 30 ℃ to obtain 54.62g of a colorless transparent liquid with a purity of 99.15%. The content of impurity diethyl ethylphenylmalonate was 0.0271%, the content of ethyl phenylacetate was 0.0311%, and the product yield was 76.55%.

Example 3

100.00g of crude diethyl phenylmalonate solution with the content of 75.53 wt% is uniformly added into a melt crystallizer, the introduction rate is 5mL/min, the temperature of a cooling medium of the melt crystallizer is set to be-25 ℃, colorless transparent crystals are slowly separated out on the surface of the crystallizer, after 6 times of circulation, the content of diethyl phenylmalonate in the solution is reduced to 32.61 wt%, the temperature is increased to-8 ℃, a small amount of colorless impurities flows out, and most of the impurities are diethyl carbonate and diethyl ethylphenylmalonate. The temperature was further raised to 30 ℃ to obtain 63.69g of a colorless transparent liquid with a purity of 99.36%. The content of impurity diethyl ethylphenylmalonate is 0.0165%, the content of ethyl phenylacetate is 0.0249%, and the product yield is 83.78%.

Example 4

100.00g of crude diethyl phenylmalonate solution with the content of 81.45 wt% is uniformly added into a melt crystallizer, the introduction rate is 5mL/min, the temperature of a cooling medium of the melt crystallizer is set to be-25 ℃, colorless transparent crystals are slowly separated out on the surface of the crystallizer, after 6 times of circulation, the content of diethyl phenylmalonate in the solution is reduced to 33.51 wt%, the temperature is increased to be-8 ℃, a small amount of colorless impurities flow out, and most of the impurities are diethyl carbonate and diethyl ethylphenylmalonate. The temperature was further raised to 30 ℃ to obtain 72.37g of a colorless transparent liquid with a purity of 99.74%. The content of impurity diethyl ethylphenylmalonate was 0.0147%, the content of ethyl phenylacetate was 0.0134%, and the product yield was 88.62%.

Example 5

100.00g of a crude solution of 87.36 wt% of diethyl phenylmalonate is uniformly added into a melt crystallizer, the introduction rate is 5mL/min, the temperature of a cooling medium of the melt crystallizer is set to-25 ℃, colorless transparent crystals are slowly separated out on the surface of the crystallizer, after 5 times of circulation, the content of diethyl phenylmalonate in the solution is reduced to 38.90 wt%, the temperature is raised to-8 ℃, a small amount of colorless impurities flows out, and most of the impurities are diethyl carbonate and diethyl ethylphenylmalonate. The temperature was further raised to 30 ℃ to obtain 79.59g of a colorless transparent liquid with a purity of 99.78%. The content of impurity diethyl ethylphenylmalonate is 0.0115%, the content of ethyl phenylacetate is 0.0011%, and the product yield is 90.90%.

Example 6

100.00g of crude diethyl phenylmalonate solution with the content of 93.59 wt% is uniformly added into a melt crystallizer, the introduction rate is 5mL/min, the temperature of a cooling medium of the melt crystallizer is set to be-25 ℃, colorless transparent crystals are slowly separated out on the surface of the crystallizer, after 5 times of circulation, the content of diethyl phenylmalonate in the solution is reduced to 35.79 wt%, the temperature is increased to-8 ℃, a small amount of colorless impurities flows out, and most of the impurities are diethyl carbonate and diethyl ethylphenylmalonate. The temperature is continuously increased to 30 ℃, and 90.12g of colorless transparent liquid with the purity of 99.86 percent is obtained. The content of impurity diethyl ethylphenylmalonate is 0.0079%, the content of ethyl phenylacetate is 0.0011%, and the product yield is 96.15%.

Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.