A kind of preparation method of famotidine

Abstract

The invention discloses a preparation method of famotidine and relates to the technical field of drug preparation. The present invention adopts famotidine crude product as raw material, and carries out three recrystallizations in stages, and selects recrystallization liquid A including 10-15% N,N-dimethylformamide, 5-12% dimethyl sulfoxide, 1-3% succinic acid, and the balance being purified water, and recrystallization liquid B including 20-25% linolenic acid, 8-15% N,N-dimethylformamide, 2-5% citric acid, 0.5-1% di-tert-butyl dicarbonate, and the balance being purified water, and recrystallization liquid C including 15-30% methanol, 5-10% p-ethylpropiophenone, 1-5% paraformaldehyde, and the balance being purified water, and the final famotidine finished product has high purity, high yield, and N-nitrosodimethylamine content of 0, is suitable for large-scale production, and has high economic value.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and in particular to a method for preparing famotidine. Background Art

[0002] Famotidine, chemical name: 3-[[2-[(diaminomethylene)-4-thiazolyl]methyl]thio]-N-sulfamoylpropionamidine, is a third-generation guanidinothiazole H2 receptor blocker. It boasts robust efficacy, few adverse reactions, and high affinity for H2 receptors. Its mechanism of action is similar to that of cimetidine. Famotidine effectively inhibits basal gastric acid secretion, nocturnal gastric acid secretion, and food-induced gastric acid secretion. It also inhibits gastric acid secretion induced by histamine and pentagastrin. Its H2 receptor inhibitory effect is 20 times stronger than that of cimetidine. Famotidine also inhibits pepsin secretion and is clinically used for gastric and duodenal ulcers, stress ulcers, acute gastric mucosal bleeding, gastrinoma, and reflux esophagitis. Compared with the proton pump inhibitor omeprazole, famotidine has a relatively low price, stable efficacy and a larger patient base. It is expected that the sales volume of famotidine in my country's market will further increase in the future.

[0003] N-nitrosodimethylamine (NDMA), also known as N-nitrosodimethylamine, is highly carcinogenic, teratogenic, and mutagenic. According to the World Health Organization (WHO) list of carcinogens, NDMA is a Class 2A carcinogen. Famotidine's chemical structure contains genotoxic and carcinogenic warning groups that produce NDMA. Therefore, it is necessary to optimize the synthesis process of famotidine and develop a preparation method to control the NDMA content in famotidine. Summary of the Invention

[0004] In view of the above-mentioned defects of the prior art, the present invention proposes a method for preparing famotidine to solve the problems raised by the above-mentioned background technology.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] A preparation method of famotidine comprises the following steps:

[0007] (1) First recrystallization: dissolving crude famotidine in recrystallization solution A, adding ethanol solution in stages, filtering and soaking to obtain wet product I; the recrystallization solution A comprises, by mass percentage, 10-15% N,N-dimethylformamide, 5-12% dimethyl sulfoxide, 1-3% succinic acid, and the balance is purified water;

[0008] (2) Second recrystallization: wet product I is dissolved in recrystallization solution B, ethanol solution is added in stages, and the product II is obtained after filtration and soaking; the composition of the recrystallization solution B is calculated by weight percentage, including 20-25% linolenic acid, 8-15% N,N-dimethylformamide, 2-5% citric acid, 0.5-1% di-tert-butyl dicarbonate, and the balance is purified water;

[0009] (3) The third recrystallization: dissolving the wet product II in the recrystallization solution C, filtering, soaking and drying to obtain the famotidine finished product; the recrystallization solution C comprises, by mass percentage, 15-30% methanol, 5-10% p-ethylpropiophenone, 1-5% paraformaldehyde, and the balance is purified water.

[0010] Preferably, the crude famotidine is famotidine produced by conventional existing technology, that is, 2-(4-(chloromethyl)thiazol-2-yl)guanidine hydrochloride is prepared by cyclization reaction of guanylthiourea and 1,3-dichloroacetone, which is then reacted with thiourea to prepare (S)-((2-guanidine-4-thiazolyl)methyl)isothiourea dihydrochloride, and finally reacted with N-sulfamido-3-chloropropionamidine hydrochloride to produce famotidine.

[0011] Preferably, the specific preparation method of the first recrystallization in step (1) is as follows: adding recrystallization liquid A to a reactor, then adding famotidine crude product, stirring until completely dissolved, to obtain a mixed solution I; slowly adding 1 / 2 of a 30% ethanol solution by volume while stirring at a temperature of 18 to 23° C. until the solution becomes turbid, and then stirring for 20 to 35 minutes and continuing to add the remaining 1 / 2 of a 30% ethanol solution by volume; finally stirring for 10 to 15 hours and then filtering to obtain a filter cake; soaking the filter cake in purified water for 10 to 20 minutes, and then soaking the filtered filter cake in anhydrous ethanol for 10 to 20 minutes, and then filtering to obtain a wet product I.

[0012] Preferably, the material-liquid ratio during the purified water soaking and the anhydrous ethanol soaking is 1 g:2 mL.

[0013] Preferably, the mass volume ratio of crude famotidine to recrystallization solution A is 1 g: (3-5) mL.

[0014] Preferably, the mass volume ratio of the crude famotidine to the ethanol solution is 1 g: (10-15) mL.

[0015] Preferably, the specific preparation method of the second recrystallization in step (2) is: adding the recrystallization liquid B to the reactor, then adding the wet product I, stirring until completely dissolved, to obtain a mixed solution II; slowly adding 1 / 2 of a 30% volume fraction of ethanol solution while stirring at a temperature of 18 to 23°C until the solution becomes turbid, and then stirring for 15 to 30 minutes and continuing to add the remaining 1 / 2 of a 30% volume fraction of ethanol solution; finally stirring for 8 to 12 hours and then filtering to obtain a filter cake; soaking the filter cake in purified water for 10 to 20 minutes, and then soaking the filtered filter cake in anhydrous ethanol for 8 to 10 minutes, and filtering to obtain a wet product II.

[0016] Preferably, the mass volume ratio of wet product I to recrystallization solution B is 1 g: (2-4) mL.

[0017] Preferably, the mass volume ratio of the wet product I to the ethanol solution is 1 g: (7-10) mL.

[0018] Preferably, the specific preparation method of the third recrystallization in step (3) is as follows: adding the recrystallization liquid C to a reactor, starting to heat it to 60-65° C., then adding the wet product II, stirring and dissolving it quickly at a temperature of 60-75° C., cooling it to 5-15° C., stirring it for 50-60 minutes, and then filtering it to obtain a filter cake; soaking the filter cake in 75% methanol by volume for 10-20 minutes, and then filtering it with suction, and drying the obtained filter cake to obtain the famotidine finished product.

[0019] Preferably, the mass volume ratio of wet product II to recrystallization solution C is 1 g: (12-15) mL.

[0020] Preferably, the material-liquid ratio during methanol soaking is 1g:2mL

[0021] Preferably, the filter cake drying method is to soak the filter cake in methanol and filter it, first drying it at 24-26°C with air blower for 100-150 minutes, then heating it to 45°C and drying it with hot air circulation for 200-250 minutes.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The present invention uses crude famotidine as a raw material and performs three recrystallizations in stages. Each recrystallization can further remove impurities. The multiple operations help reduce crystal agglomeration and impurity encapsulation, thereby significantly improving product purity and meeting high quality requirements. The famotidine finished product prepared by the present invention has high purity, high yield, and zero N-nitrosodimethylamine content, thereby ensuring clinical drug safety. The reaction raw materials are cheap and readily available, the operation process is simple, and the famotidine finished product is suitable for large-scale industrial production, thereby having high economic value. DETAILED DESCRIPTION

[0024] The technical solution of the present invention will be further described in detail below in conjunction with specific implementation methods.

[0025] Example 1

[0026] A preparation method of famotidine comprises the following steps:

[0027] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% ethanol solution by volume at a temperature of 18°C ​​while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 20 minutes; finally, stir for 10 hours and filter to obtain a filter cake; soak the filter cake in purified water for 10 minutes, then soak the filtered filter cake in anhydrous ethanol for 10 minutes, and filter to obtain a wet product I;

[0028] The recrystallization solution A comprises, by weight percentage, 10% N,N-dimethylformamide, 5% dimethyl sulfoxide, 1% succinic acid, and the balance is purified water;

[0029] The mass volume ratio of the crude famotidine product to the recrystallization solution A is 1 g:3 mL; the mass volume ratio of the crude famotidine product to the ethanol solution is 1 g:10 mL;

[0030] (2) Second recrystallization: Add the recrystallized solution B to the reactor, then add the wet product I, and stir until completely dissolved to obtain a mixed solution II; slowly add 1 / 2 of the 30% ethanol solution by volume at a temperature of 18°C ​​while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 15 minutes; finally, stir for 8 hours and filter to obtain a filter cake; soak the filter cake in purified water for 10 minutes, and then soak the filtered filter cake in anhydrous ethanol for 8 minutes, and then filter to obtain a wet product II;

[0031] The recrystallization solution B comprises, by mass percentage, 20% linolenic acid, 8% N,N-dimethylformamide, 2% citric acid, 0.5% di-tert-butyl dicarbonate, and the balance is purified water;

[0032] The mass volume ratio of the wet product I to the recrystallization solution B is 1g:2mL;

[0033] The mass volume ratio of the wet product I to the ethanol solution is 1 g:7 mL;

[0034] (3) Third recrystallization: Add the recrystallized liquid C to the reactor and heat it to 60°C. Then add the wet product II. After stirring and dissolving quickly at 60°C, cool it to 5°C, stir it for 50 minutes, and filter it to obtain a filter cake. Soak the filter cake in 75% by volume methanol for 10 minutes and filter it. The filter cake is dried to obtain the finished famotidine.

[0035] The recrystallization liquid C comprises, by weight percentage, 15% methanol, 5% p-ethylpropiophenone, 1% paraformaldehyde, and the balance purified water;

[0036] The mass volume ratio of the wet product II to the recrystallization solution C is 1 g:12 mL;

[0037] The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake, drying the filter cake at 24° C. for 100 minutes, and then heating the filter cake to 45° C. and drying the filter cake in hot air circulation for 200 minutes.

[0038] Example 2

[0039] A preparation method of famotidine comprises the following steps:

[0040] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% ethanol solution by volume at a temperature of 23°C while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 35 minutes; finally, stir for 15 hours and filter to obtain a filter cake; soak the filter cake in purified water for 20 minutes, then soak the filtered filter cake in anhydrous ethanol for 20 minutes, and filter to obtain a wet product I;

[0041] The recrystallization solution A comprises, by weight percentage, 15% N,N-dimethylformamide, 12% dimethyl sulfoxide, 3% succinic acid, and the balance is purified water;

[0042] The mass volume ratio of the crude famotidine to the recrystallization solution A is 1 g:5 mL;

[0043] The mass volume ratio of the crude famotidine to the ethanol solution is 1 g:15 mL;

[0044] (2) Second recrystallization: Add the recrystallization solution B to the reactor, then add the wet product I, and stir until completely dissolved to obtain a mixed solution II; slowly add 1 / 2 of the 30% ethanol solution by volume while stirring at a temperature of 23°C until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 30 minutes; finally, stir for 12 hours and filter to obtain a filter cake; soak the filter cake in purified water for 20 minutes, and then soak the filtered filter cake in anhydrous ethanol for 10 minutes, and then filter to obtain a wet product II;

[0045] The recrystallization solution B comprises, by weight percentage, 25% linolenic acid, 15% N,N-dimethylformamide, 5% citric acid, 1% di-tert-butyl dicarbonate, and the balance is purified water;

[0046] The mass volume ratio of the wet product I to the recrystallization solution B is 1g:4mL;

[0047] The mass volume ratio of the wet product I to the ethanol solution is 1g:10mL;

[0048] (3) Third recrystallization: Add the recrystallized liquid C to the reactor and heat it to 65°C. Then add the wet product II. Stir and dissolve it quickly at 75°C. Then cool it to 15°C, stir it for 60 minutes, and filter it to obtain a filter cake. Soak the filter cake in 75% by volume methanol for 20 minutes and filter it. Dry the filter cake to obtain the finished famotidine.

[0049] The recrystallization liquid C comprises, by weight percentage, 30% methanol, 10% p-ethylpropiophenone, 5% paraformaldehyde, and the balance purified water;

[0050] The mass volume ratio of the wet product II to the recrystallization solution C is 1g:15mL;

[0051] The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake; drying the filter cake at 26° C. with forced air for 150 minutes; and then heating the filter cake to 45° C. and drying the filter cake with hot air circulation for 250 minutes.

[0052] Example 3

[0053] A preparation method of famotidine comprises the following steps:

[0054] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% ethanol solution by volume at a temperature of 20°C while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 30 minutes; finally, stir for 12 hours and filter to obtain a filter cake; soak the filter cake in purified water for 15 minutes, then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and filter to obtain a wet product I;

[0055] The recrystallization solution A comprises, by weight percentage, 12% N,N-dimethylformamide, 10% dimethyl sulfoxide, 2% succinic acid, and the balance is purified water;

[0056] The mass volume ratio of the crude famotidine to the recrystallization solution A is 1 g:4 mL;

[0057] The mass volume ratio of the crude famotidine to the ethanol solution is 1 g:14 mL;

[0058] (2) Second recrystallization: Add the recrystallization solution B to the reactor, then add the wet product I, and stir until completely dissolved to obtain a mixed solution II; slowly add 1 / 2 of the 30% ethanol solution by volume while stirring at a temperature of 22°C until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 18 minutes; finally, stir for 11 hours and filter to obtain a filter cake; soak the filter cake in purified water for 18 minutes, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0059] The recrystallization solution B comprises, by mass percentage, 22% linolenic acid, 10% N,N-dimethylformamide, 3% citric acid, 0.8% di-tert-butyl dicarbonate, and the balance is purified water;

[0060] The mass volume ratio of the wet product I to the recrystallization solution B is 1g:3mL;

[0061] The mass volume ratio of the wet product I to the ethanol solution is 1g:8mL;

[0062] (3) Third recrystallization: Add the recrystallized liquid C to the reactor and heat it to 62°C. Then add the wet product II. Stir and dissolve it quickly at 70°C. Then cool it to 10°C and stir for 55 minutes. Then filter it to obtain a filter cake. Soak the filter cake in 75% by volume methanol for 10 to 20 minutes and filter it. The filter cake is dried to obtain the finished famotidine.

[0063] The recrystallization liquid C comprises, by mass percentage, 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance purified water;

[0064] The mass volume ratio of the wet product II to the recrystallization solution C is 1 g:13 mL;

[0065] The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake, drying the filter cake at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and drying the filter cake with hot air circulation for 220 minutes.

[0066] Comparative Example 1

[0067] This comparative example differs from Example 3 in that the recrystallization solution A does not contain methyl sulfoxide and succinic acid, and the other components and steps remain unchanged.

[0068] A preparation method of famotidine comprises the following steps:

[0069] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% ethanol solution by volume at a temperature of 20°C while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 30 minutes; finally, stir for 12 hours and filter to obtain a filter cake; soak the filter cake in purified water for 15 minutes, then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and filter to obtain a wet product I;

[0070] The recrystallization liquid A comprises, by weight percentage, 12% N,N-dimethylformamide and the balance purified water;

[0071] The mass volume ratio of the crude famotidine to the recrystallization solution A is 1 g:4 mL;

[0072] The mass volume ratio of the crude famotidine to the ethanol solution is 1 g:14 mL;

[0073] (2) Second recrystallization: Add the recrystallization solution B to the reactor, then add the wet product I, and stir until completely dissolved to obtain a mixed solution II; slowly add 1 / 2 of the 30% ethanol solution by volume while stirring at a temperature of 22°C until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 18 minutes; finally, stir for 11 hours and filter to obtain a filter cake; soak the filter cake in purified water for 18 minutes, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0074] The recrystallization solution B comprises, by mass percentage, 22% linolenic acid, 10% N,N-dimethylformamide, 3% citric acid, 0.8% di-tert-butyl dicarbonate, and the balance is purified water;

[0075] The mass volume ratio of the wet product I to the recrystallization solution B is 1g:3mL;

[0076] The mass volume ratio of the wet product I to the ethanol solution is 1g:8mL;

[0077] (3) Third recrystallization: Add the recrystallized liquid C to the reactor and heat it to 62°C. Then add the wet product II. Stir and dissolve it quickly at 70°C. Then cool it to 10°C and stir for 55 minutes. Then filter it to obtain a filter cake. Soak the filter cake in 75% by volume methanol for 10 to 20 minutes and filter it. The filter cake is dried to obtain the finished famotidine.

[0078] The recrystallization liquid C comprises, by mass percentage, 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance purified water;

[0079] The mass volume ratio of the wet product II to the recrystallization solution C is 1 g:13 mL;

[0080] The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake, drying the filter cake at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and drying the filter cake with hot air circulation for 220 minutes.

[0081] Comparative Example 2

[0082] This comparative example differs from Example 3 in that the recrystallization solution B does not contain linolenic acid, citric acid and di-tert-butyl dicarbonate, and the other ingredients and steps remain unchanged.

[0083] A preparation method of famotidine comprises the following steps:

[0084] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% ethanol solution by volume at a temperature of 20°C while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 30 minutes; finally, stir for 12 hours and filter to obtain a filter cake; soak the filter cake in purified water for 15 minutes, then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and filter to obtain a wet product I;

[0085] The recrystallization solution A comprises, by weight percentage, 12% N,N-dimethylformamide, 10% dimethyl sulfoxide, 2% succinic acid, and the balance is purified water;

[0086] The mass volume ratio of the crude famotidine to the recrystallization solution A is 1 g:4 mL;

[0087] The mass volume ratio of the crude famotidine to the ethanol solution is 1 g:14 mL;

[0088] (2) Second recrystallization: Add the recrystallization solution B to the reactor, then add the wet product I, and stir until completely dissolved to obtain a mixed solution II; slowly add 1 / 2 of the 30% ethanol solution by volume while stirring at a temperature of 22°C until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 18 minutes; finally, stir for 11 hours and filter to obtain a filter cake; soak the filter cake in purified water for 18 minutes, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0089] The recrystallization solution B comprises, by weight percentage, 10% N,N-dimethylformamide and the remainder purified water;

[0090] The mass volume ratio of the wet product I to the recrystallization solution B is 1g:3mL;

[0091] The mass volume ratio of the wet product I to the ethanol solution is 1g:8mL;

[0092] (3) Third recrystallization: Add the recrystallized liquid C to the reactor and heat it to 62°C. Then add the wet product II. Stir and dissolve it quickly at 70°C. Then cool it to 10°C and stir for 55 minutes. Then filter it to obtain a filter cake. Soak the filter cake in 75% by volume methanol for 10 to 20 minutes and filter it. The filter cake is dried to obtain the finished famotidine.

[0093] The recrystallization liquid C comprises, by mass percentage, 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance purified water;

[0094] The mass volume ratio of the wet product II to the recrystallization solution C is 1 g:13 mL;

[0095] The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake, drying the filter cake at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and drying the filter cake with hot air circulation for 220 minutes.

[0096] Comparative Example 3

[0097] This comparative example differs from Example 3 in that the recrystallization liquid C does not contain p-ethylpropiophenone and paraformaldehyde, and the other ingredients and steps remain unchanged.

[0098] A preparation method of famotidine comprises the following steps:

[0099] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% ethanol solution by volume at a temperature of 20°C while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 30 minutes; finally, stir for 12 hours and filter to obtain a filter cake; soak the filter cake in purified water for 15 minutes, then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and filter to obtain a wet product I;

[0100] The recrystallization solution A comprises, by weight percentage, 12% N,N-dimethylformamide, 10% dimethyl sulfoxide, 2% succinic acid, and the balance is purified water;

[0101] The mass volume ratio of the crude famotidine to the recrystallization solution A is 1 g:4 mL;

[0102] The mass volume ratio of the crude famotidine to the ethanol solution is 1 g:14 mL;

[0103] (2) Second recrystallization: Add the recrystallization solution B to the reactor, then add the wet product I, and stir until completely dissolved to obtain a mixed solution II; slowly add 1 / 2 of the 30% ethanol solution by volume while stirring at a temperature of 22°C until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 18 minutes; finally, stir for 11 hours and filter to obtain a filter cake; soak the filter cake in purified water for 18 minutes, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0104] The recrystallization solution B comprises, by mass percentage, 22% linolenic acid, 10% N,N-dimethylformamide, 3% citric acid, 0.8% di-tert-butyl dicarbonate, and the balance is purified water;

[0105] The mass volume ratio of the wet product I to the recrystallization solution B is 1g:3mL;

[0106] The mass volume ratio of the wet product I to the ethanol solution is 1g:8mL;

[0107] (3) Third recrystallization: Add the recrystallized liquid C to the reactor and heat it to 62°C. Then add the wet product II. Stir and dissolve it quickly at 70°C. Then cool it to 10°C and stir for 55 minutes. Then filter it to obtain a filter cake. Soak the filter cake in 75% by volume methanol for 10 to 20 minutes and filter it. The filter cake is dried to obtain the finished famotidine.

[0108] The recrystallization liquid C comprises, by weight percentage, 25% methanol and the remainder purified water;

[0109] The mass volume ratio of the wet product II to the recrystallization solution C is 1 g:13 mL;

[0110] The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake, drying the filter cake at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and drying the filter cake with hot air circulation for 220 minutes.

[0111] Comparative Example 4

[0112] This comparative example differs from Example 3 in that the ethanol solution is not added in batches during the first recrystallization (the ethanol solution is added all at once), and the other components and steps remain unchanged.

[0113] A preparation method of famotidine comprises the following steps:

[0114] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add a 30% by volume ethanol solution at a temperature of 20°C while stirring until the solution becomes turbid; stir for another 12 hours and filter to obtain a filter cake; soak the filter cake in purified water for 15 minutes, then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and filter to obtain a wet product I;

[0115] The recrystallization solution A comprises, by weight percentage, 12% N,N-dimethylformamide, 10% dimethyl sulfoxide, 2% succinic acid, and the balance is purified water;

[0116] The mass volume ratio of the crude famotidine to the recrystallization solution A is 1 g:4 mL;

[0117] The mass volume ratio of the crude famotidine to the ethanol solution is 1 g:14 mL;

[0118] (2) Second recrystallization: Add the recrystallization solution B to the reactor, then add the wet product I, and stir until completely dissolved to obtain a mixed solution II; slowly add 1 / 2 of the 30% ethanol solution by volume while stirring at a temperature of 22°C until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 18 minutes; finally, stir for 11 hours and filter to obtain a filter cake; soak the filter cake in purified water for 18 minutes, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0119] The recrystallization solution B comprises, by mass percentage, 22% linolenic acid, 10% N,N-dimethylformamide, 3% citric acid, 0.8% di-tert-butyl dicarbonate, and the balance is purified water;

[0120] The mass volume ratio of the wet product I to the recrystallization solution B is 1g:3mL;

[0121] The mass volume ratio of the wet product I to the ethanol solution is 1g:8mL;

[0122] (3) Third recrystallization: Add the recrystallized liquid C to the reactor and heat it to 62°C. Then add the wet product II. Stir and dissolve it quickly at 70°C. Then cool it to 10°C and stir for 55 minutes. Then filter it to obtain a filter cake. Soak the filter cake in 75% by volume methanol for 10 to 20 minutes and filter it. The filter cake is dried to obtain the finished famotidine.

[0123] The recrystallization liquid C comprises, by mass percentage, 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance purified water;

[0124] The mass volume ratio of the wet product II to the recrystallization solution C is 1 g:13 mL;

[0125] The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake, drying the filter cake at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and drying the filter cake with hot air circulation for 220 minutes.

[0126] Comparative Example 5

[0127] This comparative example differs from Example 3 in that the ethanol solution is not added in batches during the first and second recrystallizations (the ethanol solution is added all at once), and the other components and steps remain unchanged.

[0128] A preparation method of famotidine comprises the following steps:

[0129] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add a 30% by volume ethanol solution at a temperature of 20°C while stirring until the solution becomes turbid; stir for another 12 hours and filter to obtain a filter cake; soak the filter cake in purified water for 15 minutes, then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and filter to obtain a wet product I;

[0130] The recrystallization solution A comprises, by weight percentage, 12% N,N-dimethylformamide, 10% dimethyl sulfoxide, 2% succinic acid, and the balance is purified water;

[0131] The mass volume ratio of the crude famotidine to the recrystallization solution A is 1 g:4 mL;

[0132] The mass volume ratio of the crude famotidine to the ethanol solution is 1 g:14 mL;

[0133] (2) Second recrystallization: Add the recrystallization solution B to the reactor, then add the wet product I, and stir until completely dissolved to obtain a mixed solution II; slowly add a 30% ethanol solution by volume while stirring at a temperature of 22°C until the solution becomes turbid, and then stir for 11 hours and filter to obtain a filter cake; soak the filter cake in purified water for 18 minutes, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and filter to obtain a wet product II;

[0134] The recrystallization solution B comprises, by mass percentage, 22% linolenic acid, 10% N,N-dimethylformamide, 3% citric acid, 0.8% di-tert-butyl dicarbonate, and the balance is purified water;

[0135] The mass volume ratio of the wet product I to the recrystallization solution B is 1g:3mL;

[0136] The mass volume ratio of the wet product I to the ethanol solution is 1g:8mL;

[0137] (3) Third recrystallization: Add the recrystallized liquid C to the reactor and heat it to 62°C. Then add the wet product II. Stir and dissolve it quickly at 70°C. Then cool it to 10°C and stir for 55 minutes. Then filter it to obtain a filter cake. Soak the filter cake in 75% by volume methanol for 10 to 20 minutes and filter it. The filter cake is dried to obtain the finished famotidine.

[0138] The recrystallization liquid C comprises, by mass percentage, 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance purified water;

[0139] The mass volume ratio of the wet product II to the recrystallization solution C is 1 g:13 mL;

[0140] The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake, drying the filter cake at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and drying the filter cake with hot air circulation for 220 minutes.

[0141] Comparative Example 6

[0142] This comparative example differs from Example 3 in that the recrystallization solution A and the recrystallization solution B are replaced with hydrochloric acid ethanol solution, and the other components and steps remain unchanged.

[0143] A preparation method of famotidine comprises the following steps:

[0144] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% ethanol solution by volume at a temperature of 20°C while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 30 minutes; finally, stir for 12 hours and filter to obtain a filter cake; soak the filter cake in purified water for 15 minutes, then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and filter to obtain a wet product I;

[0145] The recrystallization solution A is 0.1 mol / L hydrochloric acid ethanol solution;

[0146] The mass volume ratio of the crude famotidine to the recrystallization solution A is 1 g:4 mL;

[0147] The mass volume ratio of the crude famotidine to the ethanol solution is 1 g:14 mL;

[0148] (2) Second recrystallization: Add the recrystallization solution B to the reactor, then add the wet product I, and stir until completely dissolved to obtain a mixed solution II; slowly add 1 / 2 of the 30% ethanol solution by volume while stirring at a temperature of 22°C until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 18 minutes; finally, stir for 11 hours and filter to obtain a filter cake; soak the filter cake in purified water for 18 minutes, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0149] The recrystallization solution B is 0.1 mol / L hydrochloric acid ethanol solution;

[0150] The mass volume ratio of the wet product I to the recrystallization solution B is 1g:3mL;

[0151] The mass volume ratio of the wet product I to the ethanol solution is 1g:8mL;

[0152] (3) Third recrystallization: Add the recrystallized liquid C to the reactor and heat it to 62°C. Then add the wet product II. Stir and dissolve it quickly at 70°C. Then cool it to 10°C and stir for 55 minutes. Then filter it to obtain a filter cake. Soak the filter cake in 75% by volume methanol for 10 to 20 minutes and filter it. The filter cake is dried to obtain the finished famotidine.

[0153] The recrystallization liquid C comprises, by mass percentage, 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance purified water;

[0154] The mass volume ratio of the wet product II to the recrystallization solution C is 1 g:13 mL;

[0155] The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake, drying the filter cake at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and drying the filter cake with hot air circulation for 220 minutes.

[0156] Comparative Example 7

[0157] This comparative example differs from Example 3 in that there is no third recrystallization, and the other components and steps remain unchanged.

[0158] A preparation method of famotidine comprises the following steps:

[0159] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% ethanol solution by volume at a temperature of 20°C while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 30 minutes; finally, stir for 12 hours and filter to obtain a filter cake; soak the filter cake in purified water for 15 minutes, then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and filter to obtain a wet product I;

[0160] The recrystallization solution A comprises, by weight percentage, 12% N,N-dimethylformamide, 10% dimethyl sulfoxide, 2% succinic acid, and the balance is purified water;

[0161] The mass volume ratio of the crude famotidine to the recrystallization solution A is 1 g:4 mL;

[0162] The mass volume ratio of the crude famotidine to the ethanol solution is 1 g:14 mL;

[0163] (2) Second recrystallization: Add the recrystallized solution B to the reactor, then add the wet product I, and stir until completely dissolved to obtain a mixed solution II; slowly add 1 / 2 of the 30% ethanol solution by volume at a temperature of 22°C while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 18 minutes; finally, stir for 11 hours and filter to obtain a filter cake; soak the filter cake in purified water for 18 minutes, then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and filter and dry to obtain the famotidine product;

[0164] The recrystallization solution B comprises, by mass percentage, 22% linolenic acid, 10% N,N-dimethylformamide, 3% citric acid, 0.8% di-tert-butyl dicarbonate, and the balance is purified water;

[0165] The mass volume ratio of the wet product I to the recrystallization solution B is 1g:3mL;

[0166] The mass volume ratio of the wet product I to the ethanol solution is 1g:8mL;

[0167] The drying method is as follows: the filter cake obtained after filtration is first dried at 25° C. with forced air for 120 minutes, and then heated to 45° C. and dried in hot air circulation for 220 minutes.

[0168] Comparative Example 8

[0169] This comparative example differs from Example 3 in that there is no second recrystallization, and the other components and steps remain unchanged.

[0170] A preparation method of famotidine comprises the following steps:

[0171] (1) First recrystallization: Add the recrystallization solution A to a reactor, then add the crude famotidine, and stir until completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% ethanol solution by volume at a temperature of 20°C while stirring until the solution becomes turbid, and then continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 30 minutes; finally, stir for 12 hours and filter to obtain a filter cake; soak the filter cake in purified water for 15 minutes, then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and filter to obtain a wet product I;

[0172] The recrystallization solution A comprises, by weight percentage, 12% N,N-dimethylformamide, 10% dimethyl sulfoxide, 2% succinic acid, and the balance is purified water;

[0173] The mass volume ratio of the crude famotidine to the recrystallization solution A is 1 g:4 mL;

[0174] The mass volume ratio of the crude famotidine to the ethanol solution is 1 g:14 mL;

[0175] (2) Third recrystallization: Add the recrystallized liquid C to the reactor and heat it to 62°C. Then add the wet product I and stir it at 70°C to dissolve it completely. Then cool it to 10°C and stir it for 55 minutes. Then filter it with suction to obtain a filter cake. Soak the filter cake in 75% by volume methanol for 10 to 20 minutes and filter it with suction. The filter cake is dried to obtain the finished famotidine.

[0176] The recrystallization liquid C comprises, by mass percentage, 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance purified water;

[0177] The mass volume ratio of the wet product I to the recrystallized liquid C is 1 g:13 mL;

[0178] The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake, drying the filter cake at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and drying the filter cake with hot air circulation for 220 minutes.

[0179] Experimental Example 1

[0180] 1.1 The detection method of N-nitrosodimethylamine (NDMA) was based on the method of Ye Qiongxian et al. (Gas chromatography for the detection of N-nitrosodimethylamine in bromfenac sodium, Shanxi Chemical Industry, 2023[4], 29-31). Crude famotidine (purchased from Hunan Dino Pharmaceutical Co., Ltd.) was used as the control group. The yield and purity of famotidine were tested by HPLC area normalization method. For details, refer to Wang Liang (Improvement of the synthetic process of famotidine, Anhui Chemical Industry, 2024[2], 102-107).

[0181] 1.2 The Technical Guidelines for the Study of Nitrosamine Impurities in Chemical Drugs (Trial Implementation) stipulate that the acceptable intake limit of NDMA is 96 ng / d, while the maximum intake of famotidine tablets is 40 mg / d (20 mg tablets twice a day for adults). The ratio of the two is 2.40×10 -6 (i.e. 2.40 ppm) is the permissible limit of NDMA in famotidine tablets.

[0182] 1.3 Test Results

[0183] As shown in Table 1:

[0184] Table 1 Famotidine finished product test

[0185]

[0186] As shown in Table 1, the famotidine product yields of Examples 1-3, Comparative Examples 1-8, and the reference product are similar, but the NDMA content and purity differ. In particular, the NDMA content of Examples 1-3 is 0, demonstrating strong drug safety. Comparison of Example 3 with Comparative Examples 1 to 3 shows that the selected components in recrystallization liquid A, recrystallization liquid B, and recrystallization liquid C have a significant effect on the NDMA content and purity of the famotidine finished product. If a certain component is missing, it will lead to an imbalance in the overall component ratio and incomplete reaction, thereby reducing its purity, the NDMA content is high, and there is a risk of medication; Comparison of Example 3 with Comparative Examples 4 and 5 shows that the addition of ethanol solution in batches is beneficial to increasing the solubility and stability of the famotidine finished product, and can better control the temperature and concentration of the reaction system, avoid local overheating or overconcentration, thereby reducing the occurrence of side reactions, thereby improving the purity and yield of the product; Comparison of Example 3 with Comparative Example 6 shows that, compared with the ethanol solution, the addition of ethanol with hydrochloric acid is likely to reduce the purity of the product, because hydrochloric acid destroys the stability of the famotidine finished product, increases the content of related substances, and reduces the purity. By comparing Example 3 with Comparative Examples 7 and 8, it can be seen that the complete three-time recrystallization can improve the purity of the famotidine finished product. One recrystallization cannot completely remove all impurities. Impurities with similar structures but difficult to separate by other methods can be removed through multiple recrystallizations, and the impurity content can be gradually reduced. The performance of the famotidine finished product is further optimized, and the generation of NDMA is reduced, which has a very good application prospect.

[0187] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing famotidine, characterized in that, The following steps are involved: (1) First recrystallization: dissolving crude famotidine in recrystallization solution A, adding ethanol solution in stages, filtering and soaking to obtain wet product I; the recrystallization solution A comprises, by mass percentage, 10-15% N,N-dimethylformamide, 5-12% dimethyl sulfoxide, 1-3% succinic acid, and the balance is purified water; (2) Second recrystallization: dissolving wet product I in recrystallization solution B, adding ethanol solution in stages, filtering and soaking to obtain wet product II; the recrystallization solution B comprises, by mass percentage, 20-25% linolenic acid, 8-15% N,N-dimethylformamide, 2-5% citric acid, 0.5-1% di-tert-butyl dicarbonate, and the balance is purified water; (3) The third recrystallization: dissolving the wet product II in the recrystallization solution C, filtering, soaking and drying to obtain the famotidine finished product; the recrystallization solution C comprises, by mass percentage, 15-30% methanol, 5-10% p-ethylpropiophenone, 1-5% paraformaldehyde, and the balance is purified water.

2. The preparation method of famotidine according to claim 1, wherein The specific preparation method of the first recrystallization in step (1) is as follows: adding recrystallization liquid A into a reactor, then adding famotidine crude product, stirring until completely dissolved, to obtain a mixed solution I; slowly adding 1 / 2 of a 30% ethanol solution by volume while stirring at a temperature of 18-23° C. until the solution becomes turbid, and then stirring for 20-35 minutes and continuing to add the remaining 1 / 2 of the 30% ethanol solution by volume; finally stirring for 10-15 hours and then filtering to obtain a filter cake; soaking the filter cake in purified water for 10-20 minutes, and then soaking the filtered filter cake in anhydrous ethanol for 10-20 minutes, and then filtering to obtain a wet product I.

3. The preparation method of famotidine according to claim 2, wherein The mass volume ratio of crude famotidine to recrystallization solution A is 1 g: (3-5) mL.

4. The preparation method of famotidine according to claim 2, wherein The mass volume ratio of crude famotidine to ethanol solution is 1 g: (10-15) mL.

5. The preparation method of famotidine according to claim 1, wherein The specific preparation method of the second recrystallization in step (2) is as follows: adding recrystallization liquid B to a reactor, then adding wet product I, stirring until completely dissolved, to obtain a mixed solution II; slowly adding 1 / 2 of a 30% ethanol solution by volume while stirring at a temperature of 18 to 23° C. until the solution becomes turbid, and then stirring for 15 to 30 minutes and continuing to add the remaining 1 / 2 of the 30% ethanol solution by volume; finally stirring for 8 to 12 hours and then filtering to obtain a filter cake; soaking the filter cake in purified water for 10 to 20 minutes, and then soaking the filtered filter cake in anhydrous ethanol for 8 to 10 minutes, and filtering to obtain a wet product II.

6. The method for preparing famotidine according to claim 5, wherein The mass volume ratio of wet product I to recrystallization solution B is 1g:(2~4)mL.

7. The preparation method of famotidine according to claim 5, characterized in that, The mass volume ratio of wet product I to ethanol solution is 1g:(7-10)mL.

8. The preparation method of famotidine according to claim 1, wherein The specific preparation method of the third recrystallization in step (3) is as follows: adding the recrystallization liquid C into a reactor, starting to heat it to 60-65° C., then adding the wet product II, stirring and quickly dissolving it at a temperature of 60-75° C., cooling it to 5-15° C., stirring it for 50-60 minutes, and then filtering it with suction to obtain a filter cake; soaking the filter cake in 75% by volume methanol for 10-20 minutes, and then filtering it with suction, and drying the obtained filter cake to obtain the famotidine finished product.

9. The method for preparing famotidine according to claim 8, wherein The mass volume ratio of wet product II to recrystallization solution C is 1g:(12~15)mL.

10. The method for preparing famotidine according to claim 8, wherein The filter cake drying method comprises the following steps: soaking the filter cake in methanol and filtering the filter cake, drying the filter cake at 24-26° C. with forced air for 100-150 minutes, and then heating the filter cake to 45° C. and drying the filter cake with hot air circulation for 200-250 minutes.

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