阅读说明：本技术 一种制备美托洛尔琥珀酸盐的方法 (Method for preparing metoprolol succinate ) 是由 朱晓仁 向浪 朱元勋 颜峰峰 于 2020-06-20 设计创作，主要内容包括：本发明涉及一种制备高纯度美托洛尔琥珀酸盐的方法,该方法采用单一的溶剂体系,以反滴加方式制备得到美托洛尔琥珀酸盐。操作简便,工艺稳定,成盐收率和纯度均很高,工艺成本低,具有很好的实用价值；而且采用单一常规溶剂有利于后处理和溶剂回收,对环境友好。(The invention relates to a method for preparing high-purity metoprolol succinate, which adopts a single solvent system and prepares the metoprolol succinate in a reverse dropwise adding mode. The method has the advantages of simple and convenient operation, stable process, high salifying yield and purity, low process cost and good practical value; and the single conventional solvent is favorable for post-treatment and solvent recovery, and is environment-friendly.)

1. A preparation method of metoprolol succinate (II) is characterized by comprising the following steps:

(1) adding metoprolol (I) into an organic solvent, and stirring to obtain a metoprolol solution;

(2) adding succinic acid into an organic solvent, heating, stirring and dissolving to be clear, and controlling the temperature to be 20-45 ℃ to obtain a succinic acid solution;

(3) slowly dripping the metoprolol solution obtained in the step (1) into the succinic acid solution obtained in the step (2), after finishing dripping, carrying out heat preservation and crystallization at the temperature of 20-45 ℃, filtering, and drying to obtain metoprolol succinate (II);

wherein, the organic solvent in the step (1) and the organic solvent in the step (2) are the same solvent and are selected from methanol, ethanol and acetone; the mass ratio of the using amount of the metoprolol (I) in the step (1) to the total using amount of the organic solvent in the step (1) and the step (2) is 1: 1.5-4.

2. The method according to claim 1, wherein the molar ratio of metoprolol (I) in step (1) to succinic acid in step (2) is 1: 0.5-0.6.

3. The preparation method according to claim 1, wherein the mass ratio of the amount of the organic solvent in the step (1) to the amount of the metoprolol (I) in the step (1) is 1-3: 1, preferably 1-2: 1.

4. The preparation method according to claim 1, wherein the mass ratio of the amount of metoprolol (I) in the step (1) to the total amount of the organic solvent in the steps (1) and (2) is 1: 1.5-3.

5. The method according to claim 1, wherein the ethanol is absolute ethanol.

6. The preparation method according to claim 1, wherein the dropping time in the step (3) is 2 to 5 hours, and the crystallization time is 0.5 to 3 hours.

7. The method according to any one of claims 1 to 6, wherein the metoprolol (I) in step (1) is prepared by the following method:

(a) adding 4- (2-p-methoxyethyl) phenol (III) and epoxy chloropropane into a strong alkali aqueous solution, heating to 30-70 ℃, keeping the temperature and stirring for 2-10 hours, collecting an organic phase in a layering manner after the reaction is finished, washing the organic phase for 2 times, controlling the temperature to be 60-100 ℃, and distilling under reduced pressure until the organic phase is dried to obtain a phenol ether mixture (IV);

(b) putting isopropylamine into drinking water, controlling the temperature to be 0-40 ℃, adding the phenol ether mixture (IV) obtained in the step (a) into an isopropylamine aqueous solution, carrying out heat preservation reaction for 2-8 hours, carrying out reduced pressure distillation at 20-40 ℃ to remove isopropylamine after the reaction is finished, then adding an organic solvent into the residue, stirring and dissolving the residue, washing the organic phase for 2 times, collecting the organic phase, and evaporating to dryness to obtain metoprolol (I), wherein the synthetic route is as follows:

wherein the molar ratio of 4- (2-p-methoxyethyl) phenol (III) in the step (a) to epichlorohydrin in the step (a) and isopropylamine in the step (b) is 1: 1.2-3.0: 1.5-3.5;

wherein, the strong alkali in the step (a) is selected from: sodium hydroxide or strong potassium oxide, wherein the molar ratio of the sodium hydroxide or strong potassium oxide to the 4- (2-p-methoxyethyl) phenol (III) is 1-3: 1, preferably 2: 1;

wherein the mass ratio of the amount of 4- (2-p-methoxyethyl) phenol (III) in the step (a) to the amount of drinking water in the step (b) to the amount of organic solvent in the step (b) is 1: 2-10: 2-12.

8. The preparation method according to claim 7, wherein the weight percentage of the strong alkali aqueous solution in the step (a) is 2-12%.

9. The method according to claim 7, wherein the organic solvent in the step (b) is selected from the group consisting of: ethyl acetate, methyl tert-butyl ether, toluene.

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a method for preparing metoprolol succinate.

Background

Metoprolol (marketed under the name Betaloc) is a drug developed by astrazeneca, usa for the treatment of angina and antiarrhythmic drugs, and is a selective beta 1 receptor blocker. The chemical name of the metoprolol is 1-isopropylamino-3- [4- (2-methoxyethyl) phenoxy ] -2-propanol (I), and the metoprolol is taken in the form of salt and mainly comprises metoprolol tartrate and metoprolol succinate (II). Metoprolol succinate, the structure of which is shown below:

CN 102503843 discloses a preparation method of metoprolol succinate, which comprises the steps of dissolving metoprolol in an absolute ethyl alcohol or methanol solvent, then dropwise adding an ethanol or methanol solution of an organic acid, reacting for 4-6 hours at 40-45 ℃, cooling to 0-5 ℃, stirring for 1.5-2 hours, crystallizing, filtering, and drying to obtain a metoprolol salt crude product. And adding the obtained crude metoprolol salt into ethanol, heating until the metoprolol salt is completely dissolved, filtering, cooling the filtrate to 0-5 ℃ under stirring, continuing stirring for 2-3 hours, crystallizing, filtering, and drying to obtain the refined metoprolol salt. The method has the disadvantages of insufficient salt forming reaction, yield of only 85 percent, recrystallization and purification of the obtained metoprolol salt, complex process and increased production cost.

IN1082MU2004 discloses a method for preparing metoprolol succinate, which comprises adding acetone solution containing succinic acid into acetone solution containing metoprolol, reacting at 20-30 deg.C for 20 hr, and crystallizing at 0-10 deg.C for 2 hr. The method has long reaction period and low yield of about 51 percent.

US 20050107635A 1 discloses a method for preparing metoprolol succinate, which comprises the steps of dissolving succinic acid in acetone solution, adding the dissolved acetone solution of succinic acid into the metoprolol acetone solution, adjusting the pH value to 7.2 +/-0.1, carrying out heat preservation and reflux, cooling and crystallizing after the reflux is finished, and further recrystallizing the obtained metoprolol succinate with methanol. The method is low in yield, only 72-75% of the metoprolol salt is complicated to operate, the obtained metoprolol salt needs to be recrystallized and purified, the process is complicated, and the production cost is increased. .

CN 106083614A reports a preparation method of metoprolol salt, tartaric acid or succinic acid is heated and refluxed to be dissolved in a mixed solvent of acetone and water, under the reflux condition, metoprolol acetone solution is added into the mixed solvent of the tartaric acid or the succinic acid in the acetone and the water to form salt, and the metoprolol salt is obtained after filtration and drying; the specification of the invention also describes that an acetone/water mixed solvent system is selected in the salt forming process, the dissolving capacity of the system to organic acid is stronger than that of an acetone single system, the full dissolution of the organic acid and the full reaction are facilitated, the acetone amount used in the embodiment is large, the mass ratio of the metoprolol usage to the total acetone usage reaches 1:5.5, the reaction is carried out in a reflux state, the crystallization is carried out after cooling, the method is complicated in process, the acetone/water mixed solvent system is not beneficial to solvent recovery, the solvent usage is large, and the cost is increased.

Therefore, the development of a preparation method with simple operation, low cost and high yield is of great significance.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a preparation method of metoprolol succinate.

The method comprises the following steps:

(1) adding metoprolol (I) into an organic solvent, and stirring to obtain a metoprolol solution;

(2) adding succinic acid into an organic solvent, heating, stirring and dissolving to be clear, and controlling the temperature to be 20-45 ℃ to obtain a succinic acid solution;

(3) slowly dripping the metoprolol solution obtained in the step (1) into the succinic acid solution obtained in the step (2), after finishing dripping, carrying out heat preservation and crystallization at the temperature of 20-45 ℃, filtering, and drying to obtain metoprolol succinate (II);

wherein, the organic solvent in the step (1) and the organic solvent in the step (2) are the same solvent and are selected from methanol, ethanol and acetone; further, the ethanol is absolute ethanol;

wherein the mass ratio of the using amount of the metoprolol (I) in the step (1) to the total using amount of the organic solvent in the step (1) and the step (2) is 1: 1.5-4;

further, the mass ratio of the using amount of the metoprolol (I) in the step (1) to the total using amount of the organic solvent in the step (1) and the step (2) is 1: 1.5-3;

wherein the molar ratio of the metoprolol (I) in the step (1) to the succinic acid in the step (2) is 1: 0.5-0.6;

wherein the mass ratio of the amount of the organic solvent in the step (1) to the metoprolol (I) in the step (1) is 1-3: 1;

further, the mass ratio of the dosage of the organic solvent in the step (1) to the metoprolol (I) in the step (1) is preferably 1-2: 1;

and (3) further, the dripping time is 2-5 hours, and the crystallization time is 0.5-3 hours.

Further, in the step (1), the metoprolol (I) is prepared by the following method:

(a) adding 4- (2-p-methoxyethyl) phenol (III) and epoxy chloropropane into a strong alkali aqueous solution, heating to 30-70 ℃, keeping the temperature and stirring for 2-10 hours, collecting an organic phase in a layering manner after the reaction is finished, washing the organic phase for 2 times, controlling the temperature to be 60-100 ℃, and distilling under reduced pressure until the organic phase is dried to obtain a phenol ether mixture (IV);

(b) putting isopropylamine into drinking water, controlling the temperature to be 0-40 ℃, adding the phenol ether mixture (IV) obtained in the step (a) into an isopropylamine aqueous solution, carrying out heat preservation reaction for 2-8 hours, carrying out reduced pressure distillation at 20-40 ℃ to remove isopropylamine after the reaction is finished, then adding an organic solvent into the residue, stirring and dissolving the residue, washing the organic phase for 2 times, collecting the organic phase, and evaporating to dryness to obtain metoprolol (I), wherein the synthetic route is as follows:

wherein the molar ratio of 4- (2-p-methoxyethyl) phenol (III) in the step (a) to epichlorohydrin in the step (a) and isopropylamine in the step (b) is 1: 1.2-3.0: 1.5-3.5;

wherein, the strong alkali in the step (a) is selected from: sodium hydroxide or strong potassium oxide, wherein the molar ratio of the sodium hydroxide or strong potassium oxide to the 4- (2-p-methoxyethyl) phenol (III) is 1-3: 1, preferably 2: 1;

wherein the mass ratio of the amount of 4- (2-p-methoxyethyl) phenol (III) in the step (a) to the amount of drinking water in the step (b) to the amount of organic solvent in the step (b) is 1: 2-10: 2-12.

Wherein, the weight percentage of the strong alkaline aqueous solution in the step (a) is 2-12 percent;

further in step (b) the organic solvent is selected from: ethyl acetate, methyl tert-butyl ether, toluene

Compared with the prior art, the technical scheme of the invention has the following advantages:

1) the preparation method has the advantages of good salifying effect, high yield, less organic solvent consumption in the process, low cost and environmental friendliness, and the single solvent adopted by the reaction system is favorable for post-treatment and solvent recovery;

2) the reaction temperature is low, crystallization can be carried out without further cooling after the reaction is finished, the operation is simplified, and when the crystallization temperature is high, some impurities are not easy to separate out, the quality of the product is greatly improved under the condition of ensuring the yield, the yield is about 95%, and the purity is more than 99.50%;

3) excessive succinate is not required to be added, the pH value of a reaction system is not required to be adjusted, and the generated metoprolol succinate is not required to be further purified, so that the production cost is reduced, the operation is simple and convenient, and the process is stable.

4) The invention also provides a preparation method of metoprolol, which is simple and easy to operate, the yield and the purity of the obtained metoprolol are high, the total yield of phenol etherification and amination is 86-92%, the purity of the metoprolol is more than 96%, the method has good practical value, and reaction systems are carried out in water and are environment-friendly.

Detailed Description

For a further understanding of the invention, reference will now be made to the preferred embodiments of the present invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the present invention, and not to limit the scope of the claims.

Example 1: preparation of metoprolol (I)

Adding 200g of 2% aqueous alkali solution, 11.1g of epoxy chloropropane and 15.2g of 4- (2-p-methoxyethyl) phenol into a four-mouth bottle, controlling the temperature to be 30-40 ℃, carrying out heat preservation reaction for 10 hours, separating out a water phase after the reaction is finished, washing an organic phase for 2 times, and carrying out reduced pressure distillation at the temperature of 60-70 ℃ until the organic phase is dried to obtain a phenol ether mixture (IV).

Adding 11.8g of isopropylamine into 41.6g of drinking water, controlling the temperature to be 30-40 ℃, slowly adding the phenol ether mixture (IV) obtained in the previous step, finishing feeding, carrying out heat preservation reaction at 0-10 ℃ for 8 hours, finishing the reaction, evaporating isopropylamine to dryness at 30-40 ℃ under reduced pressure, adding 41.6g of methyl tert-butyl ether into a reaction bottle, stirring and dissolving, washing an organic phase for 2 times by using drinking water, evaporating an organic phase to dryness under reduced pressure, finishing distillation, weighing, calculating the yield, sampling and detecting the yield to be 86.1% and the purity to be 97.5%.

Example 2: preparation of metoprolol (I)

600g of 2% aqueous alkali solution, 27.7g of epichlorohydrin and 15.2g of 4- (2-p-methoxyethyl) phenol are added into a four-mouth bottle, and the mixture is reacted for 2 hours at the temperature of 60-70 ℃. And (3) after the reaction is finished, removing the water phase, washing the organic phase for 2 times, and distilling the organic phase under reduced pressure at 90-100 ℃ to obtain a phenol ether mixture (IV).

Adding 20.8g of isopropylamine into 124.8g of drinking water, controlling the temperature to be 30-40 ℃, slowly adding the phenol ether mixture (IV) obtained in the previous step, finishing feeding, carrying out heat preservation reaction at 30-40 ℃ for 2 hours, finishing the reaction, evaporating isopropylamine to dryness at 30-40 ℃ under reduced pressure, adding 166.4g of ethyl acetate into a reaction bottle, stirring and dissolving, washing an organic phase for 2 times by using drinking water, evaporating the organic phase to dryness under reduced pressure, finishing distillation, weighing, calculating the yield, sampling and detecting, wherein the yield is 88.4%, and the purity is 96.8%.

Example 3: preparation of metoprolol (I)

Adding 67g of 12% aqueous alkali solution, 18.5g of epoxy chloropropane and 15.2g of 4- (2-p-methoxyethyl) phenol into a four-mouth bottle, carrying out heat preservation reaction at 30-40 ℃ for 5 hours, separating out a water phase after the reaction is finished, washing an organic phase for 2 times, and carrying out reduced pressure distillation at 90-100 ℃ to dry the organic phase to obtain a phenol ether mixture (IV).

Adding 20.8g of isopropylamine into 83.2g of drinking water, controlling the temperature to be 20-30 ℃, slowly adding the phenol ether mixture (IV) obtained in the previous step, finishing feeding, carrying out heat preservation reaction at 20-30 ℃ for 5 hours, finishing the reaction, controlling the temperature to be 20-30 ℃, and evaporating the isopropylamine under reduced pressure. 166.4g of methyl tert-butyl ether is added into a reaction bottle, stirred and dissolved, an organic phase is washed for 2 times by drinking water, the organic phase is evaporated to dryness under reduced pressure, the distillation is finished, the yield is calculated by weighing, and the sampling detection is carried out, so that the yield is 91.9 percent, and the purity is 97.1 percent.

Example 4: preparation of metoprolol (I)

Adding 67g of 12% aqueous alkali solution, 18.5g of epoxy chloropropane and 15.2g of 4- (2-p-methoxyethyl) phenol into a four-mouth bottle, carrying out heat preservation reaction for 4 hours at 40-50 ℃, separating out a water phase after the reaction is finished, washing an organic phase for 2 times, and carrying out reduced pressure distillation at 90-100 ℃ to dry the organic phase to obtain a phenol ether mixture (IV).

Adding 20.8g of isopropylamine into 83.2g of drinking water, controlling the temperature to be 20-30 ℃, slowly adding the phenol-ether mixture (IV) obtained in the previous step, finishing feeding, carrying out heat preservation reaction at 20-30 ℃ for 5 hours, finishing the reaction, controlling the temperature to be 20-30 ℃, evaporating isopropylamine under reduced pressure, adding 124.8g of toluene into a reaction bottle, stirring and dissolving, washing an organic phase for 2 times by using drinking water, evaporating an organic phase under reduced pressure, finishing distillation, weighing, calculating the yield, sampling and detecting, wherein the yield is 91.3%, and the purity is 97.5%.

The metoprolol (I) used below was prepared by the above method.

Example 5: preparation of metoprolol succinate (II)

26.7g of acetone and 26.7g of metoprolol are added into a reaction bottle, and stirred to be dissolved and clear for later use. And adding 23.6g of acetone and 5.9g of succinic acid into the other reaction bottle, heating to 20-35 ℃, and stirring to dissolve. And controlling the temperature to be 20-35 ℃, dropwise adding the prepared metoprolol acetone solution into the succinic acid solution, and controlling the dropwise adding time to be 2-5 hours. And after the dropwise addition, controlling the temperature to be 20-35 ℃, and carrying out heat preservation and crystallization for 0.5-1.5 hours. After crystallization, filtration and drying are carried out to obtain the metoprolol succinate with the yield of 97.8 percent and the purity of 99.65 percent.

Example 6: preparation of metoprolol succinate (II)

Adding 26.7g of methanol and 26.7g of metoprolol into a reaction bottle, and stirring to dissolve the mixture to be clear for later use. And adding 23.6g of methanol and 5.9g of succinic acid into the other reaction bottle, heating to 25-35 ℃, and stirring to dissolve. And controlling the temperature to be 25-35 ℃, dropwise adding the prepared metoprolol methanol solution into the succinic acid solution, and controlling the dropwise adding time to be 2-5 hours. And after the dropwise addition, controlling the temperature to be 25-35 ℃, and carrying out heat preservation and crystallization for 1.5-2.5 hours. After crystallization, filtration and drying are carried out to obtain the metoprolol succinate with the yield of 95.4 percent and the purity of 99.75 percent.

Example 7: preparation of metoprolol succinate (II)

Adding 53.4g of absolute ethyl alcohol and 26.7g of metoprolol into a reaction bottle, and stirring to dissolve the mixture to be clear for later use. Adding 23.6g of absolute ethyl alcohol and 5.9g of succinic acid into another reaction bottle, heating to 25-35 ℃, stirring to dissolve, controlling the temperature to 25-35 ℃, dropwise adding the prepared metoprolol absolute ethyl alcohol solution into the succinic acid solution, controlling the dropwise adding time to 2-5 hours, controlling the temperature to 25-35 ℃, carrying out heat preservation and crystallization for 1.5-2.5 hours, finishing crystallization, filtering, and drying to obtain the metoprolol succinate, wherein the yield is 95.3%, and the purity is 99.80%.

Example 8: preparation of metoprolol succinate (II)

Adding 53.4g of acetone and 26.7g of metoprolol into a reaction bottle, and stirring to dissolve the mixture to be clear for later use. And adding 23.6g of acetone and 5.9g of succinic acid into the other reaction bottle, heating to 35-45 ℃, and stirring to dissolve. And controlling the temperature to be 35-45 ℃, dropwise adding the prepared metoprolol acetone solution into the succinic acid solution, and controlling the dropwise adding time to be 2-5 hours. And after the dropwise addition is finished, cooling, controlling the temperature to be 25-35 ℃, and carrying out heat preservation and crystallization for 1.5-2.5 hours. After crystallization, filtration and drying are carried out to obtain the metoprolol succinate with the yield of 96.4 percent and the purity of 99.80 percent.

Example 9: preparation of metoprolol succinate (II)

Adding 53.4g of 95% ethanol solution and 26.7g of metoprolol into a reaction bottle, and stirring to dissolve the mixture clear for later use. Adding 26.7g of 95% ethanol solution and 7.1g of succinic acid into another reaction bottle, stirring for dissolving, controlling the temperature to be 20-30 ℃, slowly dropwise adding the prepared metoprolol 95% ethanol solution into the succinic acid solution, controlling the dropwise adding time to be 2-5 hours, finishing dropwise adding, carrying out heat preservation and crystallization at the temperature of 20-30 ℃ for 1.5-2.5 hours, finishing crystallization, filtering, and drying to obtain the metoprolol succinate, wherein the yield is 93.7%, and the purity is 99.75%.

Example 10: preparation of metoprolol succinate (II)

62.4g of absolute ethyl alcohol and 26.7g of metoprolol are added into a reaction bottle, and stirred to be dissolved and clear for later use. 26.7g of absolute ethyl alcohol and 7.1g of succinic acid were put into another reaction flask, and the mixture was stirred to be clear. Controlling the temperature to be 30-40 ℃, slowly dripping the prepared metoprolol absolute ethyl alcohol solution into the succinic acid solution, controlling the dripping time to be 2-5 hours, controlling the temperature to be 30-40 ℃ after finishing dripping, and carrying out heat preservation and crystallization for 2-3 hours. After crystallization, filtration and drying are carried out to obtain the metoprolol succinate with the yield of 95.6 percent and the purity of 99.70 percent.

Example 11: preparation of metoprolol succinate (II)

Adding 62.4g of methanol and 26.7g of metoprolol into a reaction bottle, and stirring to dissolve the mixture to be clear for later use. Into another reaction flask, 23.6g of methanol was charged, 5.9g of succinic acid was added, and the mixture was stirred to dissolve. And controlling the temperature to be 20-30 ℃, dropwise adding the prepared metoprolol methanol solution into the succinic acid solution, controlling the temperature to be 20-30 ℃ after the dropwise adding is finished, and carrying out heat preservation and crystallization for 2-3 hours. After crystallization, filtration and drying are carried out to obtain the metoprolol succinate with the yield of 93.8 percent and the purity of 99.85 percent.

Example 12: preparation of metoprolol succinate (II)

26.7g of 95% ethanol and 26.7g of metoprolol are added into a reaction bottle, and stirred to be dissolved and clear for later use. And adding 13.4g of 95% ethanol and 5.9g of succinic acid into the other reaction bottle, heating to 35-45 ℃, and stirring to dissolve. Controlling the temperature to be 35-45 ℃, dropwise adding the prepared metoprolol 95% ethanol solution into the succinic acid solution, controlling the temperature to be 20-30 ℃ after the dropwise adding is finished, and carrying out heat preservation and crystallization for 2-3 hours. After crystallization, filtration and drying are carried out to obtain the metoprolol succinate with the yield of 95.8 percent and the purity of 99.70 percent.

Comparative example 1: just dropwise adding salifying to prepare metoprolol succinate (II)

23.6g of acetone and 5.9g of succinic acid are put into a reaction bottle, and stirred to be dissolved and clear for later use. Adding 26.7g of acetone and 26.7g of metoprolol into another reaction bottle, stirring for dissolving, controlling the temperature to be 25-35 ℃, dropwise adding the prepared succinic acid acetone solution into the metoprolol acetone solution, controlling the dropwise adding time to be 2-5 hours, finishing the dropwise adding, controlling the temperature to be 25-35 ℃, carrying out heat preservation and crystallization for 0.5-1.5 hours, finishing the crystallization, filtering, and drying to obtain the metoprolol succinate, wherein the yield is 83.5%, and the purity is 99.50%.

Comparative example 2: preparation of metoprolol succinate in Mixed solvent (II)

Adding 38.1g of acetone and 26.7g of metoprolol into a reaction bottle, and stirring to dissolve the mixture to be clear for later use. Into another reaction flask were charged 108.8g of acetone, 7.5g of water and 9.44g of succinic acid, and the mixture was stirred and heated to reflux until the succinic acid was dissolved. Under the reflux condition, the prepared metoprolol acetone solution is dropwise added into a succinic acid solution, the dropwise adding time is controlled to be 2-5 hours, the dropwise adding is finished, the temperature is controlled to be 50-65 ℃, the temperature is kept for 0.5 hour, the solution is cooled to be 0-5 ℃, the solution is stirred for crystallization for 2 hours, the crystallization is finished, and the solution is filtered and dried to obtain metoprolol succinate, wherein the yield is 85.1%, the purity is 99.75%, the yield is low, and when the crystallization mother solution is analyzed, the crystallization mother solution contains 4.5g of metoprolol succinate. Because the metoprolol succinate is very soluble in water, the solubility of the metoprolol succinate in a mixed solvent of acetone and water is greatly enhanced and the crystallization efficiency is greatly reduced due to the existence of water in the mixed solvent, so that the yield is low.