A process for the preparation of methoclopramide monohydrochloride monohydrate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of methoxychlorpromazine monohydrochloride monohydrate. The method comprises the following steps: step 1, methoxychlorpromazine base is dissolved in a polar solvent, and hydrochloric acid is added to obtain a mixed solution; step 2, a poor solvent of methoxychlorpromazine monohydrochloride monohydrate is added to the mixed solution, crystallization is carried out, and separation is performed, and methoxychlorpromazine monohydrochloride monohydrate is obtained; the poor solvent is selected from one or a mixture of two or more of isopropyl alcohol, n-butyl alcohol, acetone, butanone, ethyl acetate, butyl acetate, dichloromethane, trichloromethane, toluene, methyl tert-butyl ether, isopropyl ether and diethyl ether. The method has the advantages of simple process, good repeatability, easy operation, high yield, product purity of more than 99.8%, complete compliance with the requirements of European Pharmacopoeia 9.0 and US Pharmacopoeia USP43, and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of methixene hydrochloride monohydrate. BACKGROUND

[0002] Methixene hydrochloride is a dopamine 2 (D2) receptor antagonist, and also has a 5-hydroxytryptamine 4 (5-HT4) receptor agonizing effect, and has a slight inhibiting effect on 5-HT3 receptors. The product can act on dopamine receptors in the medullary emetic chemoreceptor zone (CTZ) to increase the threshold of the CTZ, and has a strong central antiemetic effect. The inhibiting effect on other parts of the central nervous system is slight, and the product has a weak tranquilizing effect and rarely causes a hypnotic effect. The effect on the gastrointestinal tract is mainly in the upper digestive tract, and the product promotes the movement of the stomach and the upper intestinal segment; increases the tension of the resting state gastrointestinal tract sphincter, increases the tension and contraction amplitude of the lower esophageal sphincter, and increases the lower esophageal pressure. The product blocks gastric-oesophageal reflux, strengthens the gastric and esophageal peristalsis, and enhances the ability to clear the esophageal contents, promotes the emptying of the stomach, promotes the relaxation of the pylorus, the duodenum and the upper jejunum, and forms the functional coordination between the stomach and the upper jejunum. These effects can enhance the antiemetic effect of the product. The product is used for the treatment of vomiting caused by chemotherapy, radiotherapy, surgery, craniocerebral injury, sequelae of brain trauma, sea and air operations, and drugs; is used for the symptomatic treatment of nausea and vomiting symptoms caused by various diseases such as acute gastroenteritis, biliary pancreatitis and uremia; is used before diagnostic duodenal intubation to help smooth intubation; and is used in gastrointestinal barium X-ray examination to reduce the nausea and vomiting reaction and promote the passage of barium. Therefore, the product is widely used in clinical practice, and has a good market prospect.

[0003] The product was first put on the market abroad (in 1979) as an injection, and the original research factory is BAXTER, with a specification of 5mg / ml (2ml, 10ml, 30ml). In 1980, ANIPHARMS put tablets on the market in the United States, with a specification of 5mg and 10mg. In 1999, Crinos put a nasal spray on the market in Italy, with a specification of 10mg and 20mg / spray (2ml, 4ml). Methixene hydrochloride injection and oral preparations have been on the market for many years, and the antiemetic effect has been affirmed by many clinical trials. In China, there are many imitation products of the product on the market, but there is no enterprise producing methixene hydrochloride raw material in China, and the raw materials of 5 registered records are methixene base. The raw materials used in the methixene tablet and injection in the reference preparation catalogue published by the state are methixene hydrochloride monohydrate, and therefore the methixene hydrochloride monohydrate salt forming process can effectively solve the availability problem of raw materials encountered in the consistency evaluation work of enterprises developing the product.

[0004] Currently, there are very few processes for methoclopramide base salt formation reported. The process introduced in French Patent 1453845 requires adding hydrochloric acid / isopropyl alcohol solution dropwise under heating to near boiling point in isopropyl alcohol, which can lead to the formation of 2-chloropropane, a genotoxic impurity, and 2-chloropropane can also undergo nucleophilic substitution reaction with the amino group in aniline to obtain an impurity, which is not conducive to drug safety. And the product obtained by multiple experiments is anhydrous.

[0005] The salt formation method reported in Chinese Patent CN113354553A uses acetone, isopropyl alcohol, acetonitrile, tetrahydrofuran, etc. as solvents, and adds concentrated hydrochloric acid dropwise at 0-5℃. It is found through experiments that it is difficult to obtain monohydrate by this process, and most of the time, dihydrochloride is obtained, and the product is sticky.

[0006] The method reported in the literature Arch. Pharm, 313, 297-300, 1980 is to use a mixture of acetone and water as solvent, and add concentrated hydrochloric acid dropwise for dissolution, and then add a large amount of acetone for crystallization. In the actual operation process, the amount of acetone and water is very small in the early stage, and it is almost impossible to effectively stir after mixing with the base body, which is not suitable for industrial production, and it is difficult to crystallize after adding a large amount of acetone.

[0007] In summary, there is still a lack of suitable methoclopramide monohydrochloride monohydrate crystallization method in the prior art, and the crystallization process of organic hydrate is very sensitive to crystallization conditions such as solvent, and slight changes will have a significant impact on whether it can be crystallized, the amount of crystallization water, and the purity of the crystallized product. Therefore, how to obtain high-purity methoclopramide monohydrochloride monohydrate is still a problem that needs to be solved in the field. SUMMARY

[0008] In view of the problems in the prior art, the present application provides a preparation method of methoclopramide monohydrochloride monohydrate, aiming to optimize the crystallization conditions and realize the preparation of high-purity methoclopramide monohydrochloride monohydrate.

[0009] A preparation method of methoclopramide monohydrochloride monohydrate, comprising the following steps:

[0010] Step 1, dissolving methoclopramide base in a polar solvent to obtain a mixed solution by adding hydrochloric acid;

[0011] Step 2, adding a poor solvent of methoclopramide monohydrochloride monohydrate to the mixed solution to crystallize and separate, and the product is obtained.

[0012] The poor solvent is selected from one or a mixture of two or more of isopropyl alcohol, n-butanol, acetone, butanone, ethyl acetate, butyl acetate, dichloromethane, trichloromethane, toluene, methyl tert-butyl ether, isopropyl ether, and diethyl ether.

[0013] Preferably, the poor solvent is acetone, ethyl acetate or methyl tert-butyl ether.

[0014] Preferably, the ratio of the methoclopramide base to the polar solvent is 1 g: 2 ml to 10 ml.

[0015] Preferably, in step 1, the pH of the mixed solution is 2.0 to 6.0, preferably 4.0 to 6.0.

[0016] Preferably, in step 1, the temperature for dissolving and adding hydrochloric acid is 25°C to 80°C.

[0017] Preferably, in step 1, the hydrochloric acid is 20% to 38% aqueous HCl solution.

[0018] Preferably, in step 1, the polar solvent is selected from one or more of N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, methanol, ethanol, tetrahydrofuran, acetonitrile and a mixture of two or more thereof.

[0019] Preferably, in step 2, the temperature for crystallization is -5°C to 30°C.

[0020] Preferably, in step 2, the temperature for crystallization is 0°C to 20°C.

[0021] Preferably, the ratio of the polar solvent to the poor solvent is 1:0.5 to 5.0 by volume.

[0022] The present application provides a preparation method of methoclopramide monohydrochloride monohydrate. By optimizing the crystallization conditions, high-purity methoclopramide monohydrochloride monohydrate can be prepared. In addition, the method of the present application also has the advantages of simple operation, high yield and high product stability.

[0023] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and common means in the art, other modifications, replacements or changes can be made without departing from the above basic technical idea of the present application.

[0024] The above content of the present application will be further explained in detail by way of specific embodiments. However, it should not be understood that the scope of the above subject matter of the present application is limited to the following examples. Any technology realized based on the above content of the present application belongs to the scope of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 NMR hydrogen spectrum of methoclopramide monohydrochloride monohydrate prepared in Example 1. DETAILED DESCRIPTION

[0026] The reagents and materials used in the following examples are commercially available unless otherwise specified.

[0027] Example 1

[0028] The reaction formula of this example is as follows:

[0029]

[0030] The specific operation is as follows: 50.1 g of meclizine base (0.167 mol) is mixed with 250 ml of DMF, heated to 40-45°C, stirred to dissolve, 17 g of concentrated hydrochloric acid (0.168 mol) is added dropwise to adjust pH = 5.0, after dropping, 400 ml of acetone is added to stir and cool, stirred at 20°C for 4 hours, filtered, washed with acetone, and dried at 40°C under reduced pressure for 5 hours to obtain 45.3 g of meclizine monohydrochloride monohydrate, with a yield of 76.57%, HPLC purity of 99.87%, and a melting point of 183.5-184°C. The nuclear magnetic hydrogen spectrum is shown in Figure 1 , solvent DMSO-d6, and the attribution is shown in the following table:

[0031]

[0032]

[0033] The nuclear magnetic hydrogen spectrum shows that the product synthesized in this example is meclizine monohydrochloride monohydrate.

[0034] Example 2

[0035] 50.1 g of meclizine base (0.167 mol) is mixed with 250 ml of DMF, heated to 40-45°C, stirred to dissolve, 17 g of concentrated hydrochloric acid (0.168 mol) is added dropwise to adjust pH = 5.0, after dropping, 400 ml of acetone is added to stir and cool, stirred at 20°C for 4 hours, filtered, washed with acetone, and dried at 40°C under reduced pressure for 5 hours to obtain 45.3 g of meclizine monohydrochloride monohydrate, with a yield of 76.57%, HPLC purity of 99.87%, and a melting point of 183.5-184°C. The nuclear magnetic hydrogen spectrum is shown in

[0036] Example 3

[0037] 50.1 g of meclizine base (0.167 mol) is mixed with 250 ml of DMF, heated to 40-45°C, stirred to dissolve, 17 g of concentrated hydrochloric acid (0.168 mol) is added dropwise to adjust pH = 5.0, after dropping, 400 ml of acetone is added to stir and cool, stirred at 20°C for 4 hours, filtered, washed with acetone, and dried at 40°C under reduced pressure for 5 hours to obtain 45.3 g of meclizine monohydrochloride monohydrate, with a yield of 76.57%, HPLC purity of 99.87%, and a melting point of 183.5-184°C. The nuclear magnetic hydrogen spectrum is shown in

[0038] Example 4

[0039] 50.1 g of meclizine base (0.167 mol) was mixed with 200 ml of methanol, dissolved by stirring while heating to 50-60°C, 17 g of concentrated hydrochloric acid (0.168 mol) was added dropwise to adjust the pH to 5.2, methyl tert-butyl ether 400 ml was added after the dropping was completed, and stirring was performed while cooling to 0-5°C for 4 hours. Filtration, washing with methyl tert-butyl ether, and drying at 40°C under reduced pressure for 5 hours gave 47.0 g of meclizine monohydrochloride monohydrate, with a yield of 79.44%, a melting point of 182.5-183.5°C, and an HPLC purity of 99.72%.

[0040] Example 5

[0041] 50.1 g of meclizine base (0.167 mol) was mixed with 150 ml of dimethyl sulfoxide, dissolved by stirring while heating to 30-40°C, 17 g of concentrated hydrochloric acid (0.168 mol) was added dropwise to adjust the pH to 5.3, methyl tert-butyl ether 500 ml was added after the dropping was completed, and stirring was performed while cooling to 0-5°C for 4 hours. Filtration, washing with methyl tert-butyl ether, and drying at 40°C under reduced pressure for 5 hours gave 47.7 g of meclizine monohydrochloride monohydrate, with a yield of 80.62%, a melting point of 183-184.5°C, and an HPLC purity of 99.75%.

[0042] Example 6

[0043] 50.1 g of meclizine base (0.167 mol) was mixed with 250 ml of DMF, dissolved by stirring while heating to 40-45°C, 25% dilute hydrochloric acid (0.168 mol) was added dropwise to adjust the pH to 5.1, ethyl acetate 500 ml was added after the dropping was completed, and stirring was performed while cooling to 0-5°C for 4 hours. Filtration, washing with ethyl acetate, and drying at 40°C under reduced pressure for 5 hours gave 48.7 g of meclizine monohydrochloride monohydrate, with a yield of 82.32%, a melting point of 183-185°C, and an HPLC purity of 99.77%.

[0044] Example 7

[0045] 50.1 g of meclizine base (0.167 mol) was mixed with 250 ml of DMF, dissolved by stirring while heating to 40-45°C, 30% dilute hydrochloric acid (0.167 mol) was added dropwise to adjust the pH to 5.8, ethyl acetate 500 ml was added after the dropping was completed, and stirring was performed while cooling to 0-5°C for 4 hours. Filtration, washing with ethyl acetate, and drying at 40°C under reduced pressure for 5 hours gave 49.17 g of meclizine monohydrochloride monohydrate, with a yield of 83.11%, a melting point of 183-185°C, and an HPLC purity of 99.78%.

[0046] Comparative Example 1

[0047] The methoxychlorpromazine free base (50.1 g), isopropyl alcohol (40.0 g), purified water (1.0 g) were added into a 100 ml three-necked flask, and concentrated hydrochloric acid (1.69 g, 1.0 equivalent) was added dropwise at 0-5°C, and the mixture was stirred and crystallized, filtered, washed with a small amount of isopropyl alcohol, and the filter cake was dried at 40°C under vacuum to obtain a solid with a melting point less than 150°C, which was basically considered to be a mixture of dihydrochloride and base.

[0048] Comparative Example 2

[0049] 50.1 g of methoxychlorpromazine base (0.167 mol) was mixed with 250 ml of DMF, heated to 40-45°C and stirred to dissolve, 37% dilute hydrochloric acid (0.190 mol) was added dropwise to adjust pH <2, and then 500 ml of ethyl acetate was added and stirred to cool to 0-5°C, and stirred for 10 hours, filtered, washed with ethyl acetate, and dried at 40°C under reduced pressure for 5 hours to obtain 48 g of white solid, with a yield of 81%, a melting point less than 150°C, and no pure target product methoxychlorpromazine monohydrochloride monohydrate was obtained.

[0050] As can be seen from the above examples, the purity of methoxychlorpromazine monohydrochloride monohydrate prepared by the method of the present application is 99.70%-99.87%, which is very high. In addition, the method of the present application is simple, reproducible, easy to operate, and has high yield, fully meeting the requirements of European Pharmacopoeia 9.0 and United States Pharmacopoeia USP43, and is suitable for industrial production.

Claims

1. A method for preparing metoclopramide monohydrochloride monohydrate, characterized in that, Includes the following steps: Step 1: Dissolve the metoclopramide base in a polar solvent and add hydrochloric acid to obtain a mixed solution. The ratio of the metoclopramide base to the polar solvent is 1 g: 2 ml to 10 ml. The polar solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, or methanol. Step 2: Add a poor solvent for metoclopramide monohydrochloride monohydrate to the mixed solution, crystallize, and separate to obtain the product; The undesirable solvent is ethyl acetate or methyl tert-butyl ether; the amount of polar solvent and undesirable solvent used is in a volume ratio of 1:0.5~5.

0.

2. The preparation method according to claim 1, characterized in that: In step 1, the temperature for dissolving and adding hydrochloric acid is 25℃~80℃.

3. The preparation method according to claim 1, characterized in that: In step 1, the pH of the mixed solution is 2.0 to 6.

0.

4. The preparation method according to claim 1, characterized in that: In step 1, the hydrochloric acid is a 25%~37% aqueous solution of HCl.

5. The preparation method according to claim 1, characterized in that: In step 2, the crystallization temperature is -5℃ to 30℃.

6. The preparation method according to claim 5, characterized in that: In step 2, the crystallization temperature is 0℃~20℃.

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