A method for preparing metoprolol succinate

Abstract

The invention relates to a method for preparing high-purity metoprolol succinate, wherein the method adopts a single solvent system and prepares metoprolol succinate in a reverse dropwise manner. The method is simple to operate, has a stable process, has a high salt yield and purity, has a low process cost, and has good practical value; and the use of a single conventional solvent is conducive to post-processing and solvent recovery, and is environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a method for preparing metoprolol succinate. Background Art

[0002] Metoprolol (trade name Betaloc) is a drug developed by AstraZeneca LP in the United States for the treatment of angina pectoris and antiarrhythmics. Metoprolol is a selective β1 receptor blocker. Its chemical name is 1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]-2-propanol (Ⅰ). Metoprolol is used in the form of salts, mainly including metoprolol tartrate and metoprolol succinate (Ⅱ). Metoprolol succinate, the structure is as follows:

[0003]

[0004] CN 102503843 discloses a method for preparing metoprolol succinate, wherein metoprolol is dissolved in anhydrous ethanol or methanol solvent, and then an ethanol or methanol solution of an organic acid is added dropwise, and the mixture is kept at 40-45°C for 4-6 hours, cooled to 0-5°C, stirred for 1.5-2 hours, crystallized, filtered, and dried to obtain a crude metoprolol salt. The obtained crude metoprolol salt is added to ethanol, heated to completely dissolved, filtered, and the filtrate is cooled to 0-5°C under stirring, and stirred for 2-3 hours, and crystallized, filtered, and dried to obtain a refined metoprolol salt. The salt-forming reaction of the method is insufficient, and the yield is only 85%. Moreover, the obtained metoprolol salt needs to be recrystallized and purified, and the process is cumbersome, which increases the production cost.

[0005] IN1082MU2004 discloses a method for preparing metoprolol succinate, which comprises adding an acetone solution containing succinic acid to an acetone solution containing metoprolol, reacting at 20-30°C for 20 hours, and crystallizing at 0-10°C for 2 hours. This method has a long reaction cycle and a low yield of about 51%.

[0006] US 20050107635 A1 discloses a method for preparing metoprolol succinate, which comprises dissolving succinic acid in an acetone solution, adding the dissolved succinic acid acetone solution to the metoprolol acetone solution, adjusting the pH to 7.2±0.1, and then refluxing at a temperature, cooling after reflux, and crystallizing, and further recrystallizing the obtained metoprolol succinate with methanol. The method has a low yield of only 72-75%, and the operation is relatively cumbersome, and the obtained metoprolol salt also needs to be recrystallized and purified, which is a cumbersome process and increases the production cost.

[0007] CN 106083614A reports a method for preparing a metoprolol salt, comprising heating tartaric acid or succinic acid in a mixed solvent of acetone and water and refluxing to dissolve the tartaric acid or succinic acid, adding the metoprolol acetone solution to the tartaric acid or succinic acid in the mixed solvent of acetone and water under reflux conditions to form a salt, filtering and drying to obtain the metoprolol salt; the specification of the invention also describes that the acetone / water mixed solvent system is selected for the salt-forming process, and the solubility of the system for organic acids is stronger than that of the single acetone system, which is conducive to the full dissolution of the organic acid and the full reaction, and the amount of acetone used in the embodiment is large, and the mass ratio of the amount of metoprolol to the total amount of acetone is 1:5.5, and the reaction is carried out under reflux, and crystallization needs to be cooled. The method is complicated, and the use of the acetone / water mixed solvent system is not conducive to solvent recovery, and the amount of solvent used is large, which increases the cost.

[0008] Therefore, it is of great significance to develop a preparation method with simple operation, low cost and high yield. Summary of the invention

[0009] In order to solve the above problems in the prior art, the present invention provides a method for preparing metoprolol succinate.

[0010] The method comprises the following steps:

[0011] (1) adding metoprolol (I) into an organic solvent and stirring to obtain a metoprolol clear solution;

[0012] (2) adding succinic acid to an organic solvent, heating and stirring to dissolve, controlling the temperature at 20 to 45° C., to obtain a succinic acid solution;

[0013] (3) slowly adding the metoprolol solution obtained in step (1) to the succinic acid solution in step (2), and after the addition is completed, the solution is kept at 20 to 45° C. for crystallization, filtered, and dried to obtain metoprolol succinate (II);

[0014] Wherein, the organic solvent in step (1) and step (2) is the same solvent, selected from methanol, ethanol, and acetone; further, the ethanol is anhydrous ethanol;

[0015] Wherein, the mass ratio of the amount of metoprolol (I) used in step (1) to the total amount of the organic solvent used in step (1) and step (2) is 1:1.5-4;

[0016] Further, the mass ratio of the amount of metoprolol (I) used in step (1) to the total amount of the organic solvent used in step (1) and step (2) is 1:1.5-3;

[0017] Wherein, the molar ratio of metoprolol (I) in step (1) to succinic acid in step (2) is 1:0.5-0.6;

[0018] Wherein, the mass ratio of the amount of the organic solvent used in the step (1) to the metoprolol (I) in the step (1) is 1 to 3:1;

[0019] Furthermore, the mass ratio of the amount of the organic solvent used in step (1) to the metoprolol (I) in step (1) is preferably 1 to 2:1;

[0020] Furthermore, in step (3), the dropping time is 2 to 5 hours, and the crystallization time is 0.5 to 3 hours.

[0021] Further, in step (1), metoprolol (I) is prepared by the following method:

[0022] (a) adding 4-(2-p-methoxyethyl)phenol (III) and epichlorohydrin to a strong alkaline aqueous solution, heating to 30-70°C, stirring for 2-10 hours, and after the reaction is completed, collecting the organic phase by stratification, washing the organic phase with water twice, controlling the temperature at 60-100°C, and distilling under reduced pressure to dryness to obtain a phenol ether mixture (IV);

[0023] (b) isopropylamine is added to drinking water, the temperature is controlled at 0-40°C, the phenol ether mixture (IV) obtained in step (a) is added to the isopropylamine aqueous solution, and the reaction is carried out for 2-8 hours. After the reaction is completed, the isopropylamine is removed by distillation under reduced pressure at 20-40°C, and then an organic solvent is added to the residue and stirred to dissolve. The organic phase is washed with water twice, the organic phase is collected, and metoprolol (I) is obtained after evaporation. The synthesis route is as follows:

[0024]

[0025] Wherein, the molar ratio of 4-(2-p-methoxyethyl)phenol (III) in step (a) to epichlorohydrin in step (a) and isopropylamine in step (b) is 1:1.2-3.0:1.5-3.5;

[0026] Wherein, the strong base in step (a) is selected from: sodium hydroxide or strong potassium hydroxide, and the molar ratio of the strong base to 4-(2-p-methoxyethyl)phenol (III) is 1 to 3:1, preferably 2:1;

[0027] Wherein, the mass ratio of the amount of 4-(2-p-methoxyethyl)phenol (III) used in step (a), the amount of drinking water used in step (b), and the amount of organic solvent used in step (b) is 1:2-10:2-12.

[0028] Wherein, the mass percentage of the strong alkali aqueous solution in step (a) is 2% to 12%;

[0029] In the further step (b), the organic solvent is selected from: ethyl acetate, methyl tert-butyl ether, toluene

[0030] The technical solution of the present invention has the following advantages over the existing process:

[0031] 1) The preparation method has good salt-forming effect and high yield, and the amount of organic solvent used in the process is small. The single solvent used in the reaction system is conducive to post-treatment and solvent recovery, low cost, and environmentally friendly;

[0032] 2) The reaction temperature is low, and crystallization can be carried out without further cooling after the reaction, which simplifies the operation. When the crystallization temperature is high, some impurities are not easy to precipitate. Under the condition of ensuring the yield, the quality of the product is greatly improved, the yield is about 95%, and the purity is greater than 99.50%;

[0033] 3) There is no need to add excessive succinate, there is no need to adjust the pH value of the reaction system, and the generated metoprolol succinate does not need to be further purified, thereby reducing production costs, being simple to operate, and having a stable process.

[0034] 4) The present invention also provides a method for preparing metoprolol, which is simple and easy to operate. The yield and purity of the obtained metoprolol are both high. The total yield of the two steps of phenol etherification and amination is 86% to 92%, and the purity of metoprolol is greater than 96%. The method has good practical value, and the reaction system is carried out in water, which is environmentally friendly. DETAILED DESCRIPTION

[0035] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0036] Example 1: Preparation of Metoprolol (I)

[0037] Add 200 g of 2% aqueous caustic soda solution, 11.1 g of epichlorohydrin and 15.2 g of 4-(2-p-methoxyethyl)phenol into a four-necked bottle, control the temperature at 30-40°C, and keep the reaction for 10 hours. After the reaction is completed, separate the aqueous phase, wash the organic phase with water twice, and distill under reduced pressure at 60-70°C to dryness to obtain a phenol ether mixture (IV).

[0038] Add 11.8 g of isopropylamine to 41.6 g of drinking water, control the temperature at 30-40° C., slowly add the phenol ether mixture (IV) obtained in the previous step, and after the feeding is completed, keep the reaction at 0-10° C. for 8 hours. After the reaction is completed, evaporate the isopropylamine under reduced pressure at 30-40° C., add 41.6 g of methyl tert-butyl ether to the reaction bottle, stir to dissolve, wash the organic phase twice with drinking water, evaporate the organic phase under reduced pressure, and complete the distillation. The yield is calculated by weighing and the yield is 86.1% for sampling and detection, and the purity is 97.5%.

[0039] Example 2: Preparation of Metoprolol (I)

[0040] Add 600 g of 2% aqueous caustic soda solution, 27.7 g of epichlorohydrin, and 15.2 g of 4-(2-p-methoxyethyl)phenol to a four-necked bottle and keep the temperature at 60-70°C for 2 hours. After the reaction is completed, separate the water phase, wash the organic phase with water twice, and distill the organic phase under reduced pressure at 90-100°C to obtain a phenol ether mixture (IV).

[0041] Add 20.8 g of isopropylamine to 124.8 g of drinking water, control the temperature at 30-40° C., slowly add the phenol ether mixture (IV) obtained in the previous step, and after the feeding is completed, keep the reaction at 30-40° C. for 2 hours. After the reaction is completed, evaporate the isopropylamine under reduced pressure at 30-40° C., add 166.4 g of ethyl acetate to the reaction bottle, stir to dissolve, wash the organic phase twice with drinking water, evaporate the organic phase under reduced pressure, and after the distillation is completed, weigh to calculate the yield, take samples for detection, and the yield is 88.4% and the purity is 96.8%.

[0042] Example 3: Preparation of Metoprolol (I)

[0043] Add 67 g of 12% aqueous alkali solution, 18.5 g of epichlorohydrin and 15.2 g of 4-(2-p-methoxyethyl)phenol into a four-necked bottle and react at 30-40°C for 5 hours. After the reaction is completed, the aqueous phase is separated and the organic phase is washed with water twice. The organic phase is distilled under reduced pressure at 90-100°C to obtain a phenol ether mixture (IV).

[0044] Add 20.8g of isopropylamine to 83.2g of drinking water, control the temperature at 20-30°C, slowly add the phenol ether mixture (IV) obtained in the previous step, and react at 20-30°C for 5 hours. After the reaction is completed, control the temperature at 20-30°C, and evaporate the isopropylamine under reduced pressure. Add 166.4g of methyl tert-butyl ether to the reaction bottle, stir to dissolve, wash the organic phase with drinking water twice, evaporate the organic phase under reduced pressure, and after the distillation is completed, weigh and calculate the yield, take samples for testing, and the yield is 91.9% and the purity is 97.1%.

[0045] Example 4: Preparation of Metoprolol (I)

[0046] Add 67 g of 12% aqueous alkali solution, 18.5 g of epichlorohydrin and 15.2 g of 4-(2-p-methoxyethyl)phenol into a four-necked bottle and react at 40-50°C for 4 hours. After the reaction is completed, the aqueous phase is separated and the organic phase is washed with water twice. The organic phase is dried by vacuum distillation at 90-100°C to obtain a phenol ether mixture (IV).

[0047] Add 20.8 g of isopropylamine to 83.2 g of drinking water, control the temperature at 20-30° C., slowly add the phenol ether mixture (IV) obtained in the previous step, and after the feeding is completed, keep the reaction at 20-30° C. for 5 hours. After the reaction is completed, control the temperature at 20-30° C., evaporate the isopropylamine under reduced pressure, add 124.8 g of toluene to the reaction bottle, stir to dissolve, wash the organic phase twice with drinking water, evaporate the organic phase under reduced pressure, complete the distillation, weigh to calculate the yield, take samples for detection, the yield is 91.3%, and the purity is 97.5%.

[0048] The metoprolol (I) used below was prepared by the above method.

[0049] Example 5: Preparation of Metoprolol Succinate (II)

[0050] Add 26.7g acetone and 26.7g metoprolol to the reaction bottle, stir to dissolve, and set aside. Add 23.6g acetone and 5.9g succinic acid to another reaction bottle, heat to 20-35°C, stir to dissolve. Control the temperature at 20-35°C, drop the prepared metoprolol acetone solution into the succinic acid solution, and control the dropping time to 2-5 hours. After the dropwise addition is completed, control the temperature at 20-35°C, and keep warm for crystallization for 0.5-1.5 hours. After the crystallization is completed, filter and dry to obtain metoprolol succinate with a yield of 97.8% and a purity of 99.65%.

[0051] Example 6: Preparation of Metoprolol Succinate (II)

[0052] Add 26.7g methanol and 26.7g metoprolol to the reaction bottle, stir to dissolve, and set aside. Add 23.6g methanol and 5.9g succinic acid to another reaction bottle, heat to 25-35°C, stir to dissolve. Control the temperature at 25-35°C, drop the prepared metoprolol methanol solution into the succinic acid solution, and control the dropping time to 2-5 hours. After the dropwise addition is completed, control the temperature at 25-35°C, and keep warm for crystallization for 1.5-2.5 hours. After the crystallization is completed, filter and dry to obtain metoprolol succinate with a yield of 95.4% and a purity of 99.75%.

[0053] Example 7: Preparation of Metoprolol Succinate (II)

[0054] Add 53.4g of anhydrous ethanol and 26.7g of metoprolol to a reaction bottle, stir to dissolve, and set aside. Add 23.6g of anhydrous ethanol and 5.9g of succinic acid to another reaction bottle, heat to 25-35°C, stir to dissolve, control the temperature at 25-35°C, drop the prepared metoprolol anhydrous ethanol solution into the succinic acid solution, control the dropping time for 2-5 hours, finish the dropping, control the temperature at 25-35°C, keep warm for crystallization for 1.5-2.5 hours, finish the crystallization, filter, dry, and obtain metoprolol succinate with a yield of 95.3% and a purity of 99.80%.

[0055] Example 8: Preparation of Metoprolol Succinate (II)

[0056] Add 53.4g acetone and 26.7g metoprolol to the reaction bottle, stir to dissolve, and set aside. Add 23.6g acetone and 5.9g succinic acid to another reaction bottle, heat to 35-45°C, stir to dissolve. Control the temperature at 35-45°C, drop the prepared metoprolol acetone solution into the succinic acid solution, and control the dropping time to 2-5 hours. After the dropwise addition is completed, cool down, control the temperature at 25-35°C, and keep warm for crystallization for 1.5-2.5 hours. After the crystallization is completed, filter and dry to obtain metoprolol succinate with a yield of 96.4% and a purity of 99.80%.

[0057] Example 9: Preparation of Metoprolol Succinate (II)

[0058] Add 53.4g of 95% ethanol solution and 26.7g of metoprolol to a reaction bottle, stir to dissolve, and set aside. Add 26.7g of 95% ethanol solution and 7.1g of succinic acid to another reaction bottle, stir to dissolve, control the temperature at 20-30°C, slowly drop the prepared metoprolol 95% ethanol solution into the succinic acid solution, control the dropping time for 2-5 hours, and after the dropping is completed, keep the temperature at 20-30°C for crystallization for 1.5-2.5 hours, and after the crystallization is completed, filter and dry to obtain metoprolol succinate with a yield of 93.7% and a purity of 99.75%.

[0059] Example 10: Preparation of Metoprolol Succinate (II)

[0060] Add 62.4g of anhydrous ethanol and 26.7g of metoprolol to a reaction bottle, stir to dissolve, and set aside. Add 26.7g of anhydrous ethanol and 7.1g of succinic acid to another reaction bottle, stir to dissolve. Control the temperature at 30-40°C, slowly drop the prepared metoprolol anhydrous ethanol solution into the succinic acid solution, control the dropping time for 2-5 hours, and when the dropping is finished, control the temperature at 30-40°C, and keep warm for crystallization for 2-3 hours. After the crystallization is finished, filter and dry to obtain metoprolol succinate with a yield of 95.6% and a purity of 99.70%.

[0061] Example 11: Preparation of Metoprolol Succinate (II)

[0062] Add 62.4g methanol and 26.7g metoprolol to a reaction bottle, stir to dissolve, and set aside. Add 23.6g methanol to another reaction bottle, add 5.9g succinic acid, stir to dissolve. Control the temperature at 20-30°C, drop the prepared metoprolol methanol solution into the succinic acid solution, and after the addition is completed, control the temperature at 20-30°C, and keep warm for crystallization for 2-3 hours. After the crystallization is completed, filter and dry to obtain metoprolol succinate with a yield of 93.8% and a purity of 99.85%.

[0063] Example 12: Preparation of Metoprolol Succinate (II)

[0064] Add 26.7g of 95% ethanol and 26.7g of metoprolol to a reaction bottle, stir to dissolve, and set aside. Add 13.4g of 95% ethanol and 5.9g of succinic acid to another reaction bottle, heat to 35-45°C, stir to dissolve. Control the temperature at 35-45°C, dropwise add the prepared metoprolol 95% ethanol solution to the succinic acid solution, and after the addition is completed, control the temperature at 20-30°C, and keep warm for crystallization for 2-3 hours. After the crystallization is completed, filter and dry to obtain metoprolol succinate with a yield of 95.8% and a purity of 99.70%.

[0065] Comparative Example 1: Preparation of Metoprolol Succinate (II) by Dropwise Addition of Salts

[0066] Add 23.6g acetone and 5.9g succinic acid to a reaction bottle, stir to dissolve, and set aside. Add 26.7g acetone and 26.7g metoprolol to another reaction bottle, stir to dissolve, control the temperature at 25-35°C, dropwise add the prepared succinic acid acetone solution to the metoprolol acetone solution, control the dropping time for 2-5 hours, finish the dropping, control the temperature at 25-35°C, keep warm for crystallization for 0.5-1.5 hours, finish the crystallization, filter, dry, and obtain metoprolol succinate with a yield of 83.5% and a purity of 99.50%.

[0067] Comparative Example 2: Preparation of Metoprolol Succinate (II) Using Mixed Solvents

[0068] Add 38.1g acetone and 26.7g metoprolol to a reaction flask, stir and dissolve, and standby. Add 108.8g acetone, 7.5g water, and 9.44g succinic acid to another reaction flask, stir and heat and reflux until the succinic acid dissolves. Under reflux conditions, the prepared metoprolol acetone solution is added dropwise to the succinic acid solution, and the dropping time is controlled for 2 to 5 hours, and the dropping is completed. The temperature is controlled at 50 to 65°C, and the temperature is kept warm for 0.5 hours, cooled to 0 to 5°C, stirred and crystallized for 2 hours, and the crystallization is completed, filtered, and dried to obtain metoprolol succinate, with a yield of 85.1% and a purity of 99.75%. The yield is low. When analyzing the crystallization mother liquor, it is found that the crystallization mother liquor contains 4.5g of metoprolol succinate. Since metoprolol succinate is highly soluble in water, the presence of water in the mixed solvent greatly enhances the solubility of metoprolol succinate in the mixed solvent of acetone and water, greatly reduces the crystallization efficiency, and thus leads to a low yield.

Claims

1. A method for preparing metoprolol succinate (II), characterized in that: The following steps are involved: (1) adding metoprolol (I) into an organic solvent and stirring to obtain a metoprolol clear solution; (2) adding succinic acid to an organic solvent, heating and stirring to dissolve, controlling the temperature at 20 to 45° C., to obtain a succinic acid solution; (3) slowly adding the metoprolol solution obtained in step (1) to the succinic acid solution in step (2), and after the addition is completed, the solution is kept at 20 to 45° C. for crystallization, filtered, and dried to obtain metoprolol succinate (II); Wherein, the organic solvent in step (1) and step (2) is the same solvent, selected from methanol, ethanol, and acetone; The mass ratio of the amount of metoprolol (I) used in step (1) to the total amount of the organic solvent used in step (1) and step (2) is 1:1.5-4; The dropping time in step (3) is 2 to 5 hours.

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

1.

4. The preparation method according to claim 3, characterized in that: The mass ratio of the amount of the organic solvent used in the step (1) to the metoprolol (I) in the step (1) is 1 to 2:

1.

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

6. The preparation method according to claim 1, characterized in that: The ethanol is anhydrous ethanol.

7. The preparation method according to claim 1, characterized in that: The crystallization time in step (3) is 0.5 to 3 hours.

8. The preparation method according to any one of claims 1 to 7, characterized in that: In the step (1), metoprolol (I) is prepared by the following method: (a) adding 4-(2-p-methoxyethyl)phenol (III) and epichlorohydrin to a strong alkaline aqueous solution, heating to 30-70°C, stirring for 2-10 hours, and after the reaction is completed, collecting the organic phase by stratification, washing the organic phase with water twice, controlling the temperature at 60-100°C, and distilling under reduced pressure to dryness to obtain a phenol ether mixture (IV); (b) isopropylamine is added to drinking water, the temperature is controlled at 0-40°C, the phenol ether mixture (IV) obtained in step (a) is added to the isopropylamine aqueous solution, and the reaction is carried out for 2-8 hours. After the reaction is completed, the isopropylamine is removed by distillation under reduced pressure at 20-40°C, and then an organic solvent is added to the residue and stirred to dissolve. The organic phase is washed with water twice, the organic phase is collected, and metoprolol (I) is obtained after evaporation. The synthesis route is as follows: Wherein, the molar ratio of 4-(2-p-methoxyethyl)phenol (III) in step (a) to epichlorohydrin in step (a) and isopropylamine in step (b) is 1:1.2-3.0:1.5-3.5; Wherein, the strong base in step (a) is selected from: sodium hydroxide or potassium hydroxide, and the molar ratio of the strong base to 4-(2-p-methoxyethyl)phenol (III) is 1 to 3:1; Wherein, the mass ratio of the amount of 4-(2-p-methoxyethyl)phenol (III) used in step (a), the amount of drinking water used in step (b), and the amount of organic solvent used in step (b) is 1:2-10:2-12.

9. The preparation method according to claim 8, characterized in that: The mass percentage of the strong alkali aqueous solution in step (a) is 2% to 12%.

10. The preparation method according to claim 8, characterized in that: The molar ratio of the strong base to 4-(2-p-methoxyethyl)phenol (III) in the step (a) is 2:

1.

11. The preparation method according to claim 8, characterized in that: The organic solvent in step (b) is selected from: ethyl acetate, methyl tert-butyl ether, and toluene.

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