Preparation method of famotidine

Abstract

The invention discloses a preparation method of famotidine, and relates to the technical field of medicine preparation. According to the method, a famotidine crude product is adopted as a raw material, recrystallization is performed for three times in stages, a recrystallization A solution comprising 10-15% of N, N-dimethylformamide, 5-12% of dimethyl sulfoxide, 1-3% of succinic acid and the balance of purified water and a recrystallization B solution comprising 20-25% of linolenic acid, 8-15% of N, N-dimethylformamide, 2-5% of citric acid, 0.5-1% of di-tert-butyl dicarbonate and the balance of purified water are selected, and the famotidine crude product is obtained through crystallization. Comprising a recrystallization solution C containing 15-30% of methanol, 5-10% of p-ethyl propiophenone, 1-5% of paraformaldehyde and the balance of purified water, the finally obtained famotidine finished product is high in purity and high in yield, the content of N-nitrosodimethylamine is 0, and the famotidine finished product is suitable for large-scale production and has very high economic value.

Description

Technical Field

[0001] The 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 guanidinylthiazole H2 receptor blocker with definite efficacy, few adverse reactions, and high affinity for H2 receptors. Its mechanism of action is similar to that of cimetidine. Famotidine can effectively inhibit the secretion of basal gastric acid, nocturnal gastric acid and gastric acid caused by food stimulation, and can also inhibit the secretion of gastric acid caused by stimulation such as histamine and pentagastrin. Its strength in inhibiting H2 receptors is 20 times stronger than that of cimetidine. In addition, famotidine can also inhibit the secretion of pepsin. It 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 group. 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, has strong carcinogenic, teratogenic and mutagenic toxicity. According to the list of carcinogens published by the World Health Organization (WHO), NDMA belongs to Class 2A carcinogens. Famotidine has genotoxic and carcinogenic warning groups in its chemical structure that produce NDMA, so 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 provides 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 method for preparing famotidine comprises the following steps:

[0007] (1) First recrystallization: dissolving the crude famotidine in a recrystallization solution A, adding ethanol solution in stages, filtering and soaking to obtain a 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 remainder is purified water;

[0008] (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;

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

[0010] Preferably, the crude famotidine is famotidine produced by conventional 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: adding the recrystallization liquid A to a reactor, then adding the 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, stirring for 20 to 35 minutes and then continuing to add the remaining 1 / 2 of the 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 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: add the recrystallization liquid B to the reactor, then add the wet product I, stir until it is completely dissolved, and obtain a mixed solution II; slowly add 1 / 2 of the 30% ethanol solution by volume while stirring at a temperature of 18 to 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 15 to 30 minutes; finally, stir for 8 to 12 hours and then filter to obtain a filter cake; soak the filter cake in purified water for 10 to 20 minutes, and then soak the filtered filter cake in anhydrous ethanol for 8 to 10 minutes, and then filter 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: add the recrystallization liquid C into the reaction kettle, start heating to 60-65°C, then add the wet product II, stir and dissolve quickly at a temperature of 60-75°C, cool to 5-15°C, stir for 50-60 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10-20 minutes and then filter, and dry the obtained filter cake to obtain the famotidine finished product.

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

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

[0021] Preferably, the filter cake drying method is to first dry the filter cake obtained after methanol immersion and filtration at 24-26°C for 100-150 minutes, then heat it to 45°C and dry it in 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 adopts famotidine crude product as raw material, and performs recrystallization three times in stages, each recrystallization can further remove impurities, and through multiple operations, it is helpful to reduce crystal agglomeration and impurity wrapping phenomenon, thereby significantly improving product purity and meeting high-standard quality requirements. The famotidine finished product prepared by the present invention has high purity, high yield, and N-nitrosodimethylamine content of 0, thereby ensuring clinical drug safety, while the reaction raw materials are cheap and easy to obtain, the operation process is simple, suitable for large-scale industrial production, and has high economic value. DETAILED DESCRIPTION

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

[0025] Example 1

[0026] A method for preparing famotidine comprises the following steps:

[0027] (1) First recrystallization: Add the recrystallization liquid A to a reaction kettle, then add the crude famotidine, and stir until it is 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, and then soak the filtered filter cake in anhydrous ethanol for 10 minutes, and then filter to obtain a wet product I;

[0028] The components of the recrystallization liquid A are calculated by mass percentage, including 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 to the recrystallization A solution is 1 g:3 mL; the mass volume ratio of the crude famotidine to the ethanol solution is 1 g:10 mL;

[0030] (2) Second recrystallization: Add the recrystallization liquid B to the reaction kettle, then add the wet product I, stir until completely dissolved, and 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 components of the recrystallization liquid B are calculated by mass percentage, including 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) The third recrystallization: Add the recrystallization liquid C into the reaction kettle, start heating to 60°C, then add the wet product II, stir and dissolve quickly at 60°C, cool to 5°C, stir for 50 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10 minutes and then filter, and dry the obtained filter cake to obtain the famotidine finished product;

[0035] The components of the recrystallization liquid C are calculated by mass percentage, including 15% methanol, 5% p-ethylpropiophenone, 1% paraformaldehyde, and the balance is purified water;

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

[0037] The filter cake drying method comprises the following steps: firstly drying the obtained filter cake at 24° C. by forced air drying for 100 minutes, and then heating the filter cake to 45° C. by hot air circulation drying for 200 minutes.

[0038] Example 2

[0039] A method for preparing famotidine comprises the following steps:

[0040] (1) First recrystallization: Add the recrystallization liquid A to a reaction kettle, then add the crude famotidine, and stir until it is completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% by volume ethanol solution 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% by volume ethanol solution 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, and then soak the filtered filter cake in anhydrous ethanol for 20 minutes, and then filter to obtain a wet product I;

[0041] The components of the recrystallization liquid A are calculated by mass percentage, including 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 liquid B to the reaction kettle, then add the wet product I, stir until completely dissolved, and obtain a mixed solution II; slowly add 1 / 2 of the 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 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 components of the recrystallization liquid B are calculated by mass percentage, including 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 liquid B is 1g:4mL;

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

[0048] (3) The third recrystallization: Add the recrystallization liquid C into the reaction kettle, start heating to 65°C, then add the wet product II, stir and dissolve quickly at 75°C, cool to 15°C, stir for 60 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 20 minutes and then filter, and dry the obtained filter cake to obtain the famotidine finished product;

[0049] The components of the recrystallization liquid C are calculated by mass percentage, including 30% methanol, 10% p-ethylpropiophenone, 5% paraformaldehyde, and the balance is purified water;

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

[0051] The filter cake drying method comprises the following steps: firstly drying the filter cake obtained after immersion and filtration 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 method for preparing famotidine comprises the following steps:

[0054] (1) First recrystallization: Add the recrystallization liquid A to a reaction kettle, then add the crude famotidine, and stir until it is completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% by volume ethanol solution 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% by volume ethanol solution 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, and then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and then filter to obtain a wet product I;

[0055] The components of the recrystallization liquid A are calculated by mass percentage, including 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 liquid B to the reaction kettle, then add the wet product I, stir until completely dissolved, and 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, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0059] The components of the recrystallization liquid B are calculated by mass percentage, including 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 1 g:8 mL;

[0062] (3) The third recrystallization: Add the recrystallization liquid C into the reaction kettle, start heating to 62° C., then add the wet product II, stir and dissolve quickly at 70° C., cool to 10° C., stir for 55 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10 to 20 minutes, then filter, and dry the obtained filter cake to obtain the famotidine finished product;

[0063] The components of the recrystallization liquid C are calculated by mass percentage, including 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance is purified water;

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

[0065] The filter cake drying method comprises the following steps: firstly drying the filter cake obtained after immersion and filtration at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and performing hot air circulation drying for 220 minutes.

[0066] Comparative Example 1

[0067] The difference between this comparative example and Example 3 is that the recrystallization liquid A does not contain methyl sulfoxide and succinic acid, and the other components and steps remain unchanged.

[0068] A method for preparing famotidine comprises the following steps:

[0069] (1) First recrystallization: Add the recrystallization liquid A to a reaction kettle, then add the crude famotidine, and stir until it is completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% by volume ethanol solution 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% by volume ethanol solution 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, and then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and then filter to obtain a wet product I;

[0070] The components of the recrystallization liquid A include 12% N,N-dimethylformamide and the balance is purified water by mass percentage;

[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 liquid B to the reaction kettle, then add the wet product I, stir until completely dissolved, and 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, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0074] The components of the recrystallization liquid B are calculated by mass percentage, including 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 1 g:8 mL;

[0077] (3) The third recrystallization: Add the recrystallization liquid C into the reaction kettle, start heating to 62° C., then add the wet product II, stir and dissolve quickly at 70° C., cool to 10° C., stir for 55 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10 to 20 minutes, then filter, and dry the obtained filter cake to obtain the famotidine finished product;

[0078] The components of the recrystallization liquid C are calculated by mass percentage, including 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance is purified water;

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

[0080] The filter cake drying method comprises the following steps: firstly drying the filter cake obtained after immersion and filtration at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and performing hot air circulation drying for 220 minutes.

[0081] Comparative Example 2

[0082] The difference between this comparative example and Example 3 is 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 method for preparing famotidine comprises the following steps:

[0084] (1) First recrystallization: Add the recrystallization liquid A to a reaction kettle, then add the crude famotidine, and stir until it is completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% by volume ethanol solution 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% by volume ethanol solution 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, and then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and then filter to obtain a wet product I;

[0085] The components of the recrystallization liquid A are calculated by mass percentage, including 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 liquid B to the reaction kettle, then add the wet product I, stir until completely dissolved, and 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, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0089] The components of the recrystallization liquid B include 10% N,N-dimethylformamide and the balance is purified water by mass percentage;

[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 1 g:8 mL;

[0092] (3) The third recrystallization: Add the recrystallization liquid C into the reaction kettle, start heating to 62° C., then add the wet product II, stir and dissolve quickly at 70° C., cool to 10° C., stir for 55 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10 to 20 minutes, then filter, and dry the obtained filter cake to obtain the famotidine finished product;

[0093] The components of the recrystallization liquid C are calculated by mass percentage, including 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance is purified water;

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

[0095] The filter cake drying method comprises the following steps: firstly drying the filter cake obtained after immersion and filtration at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and performing hot air circulation drying for 220 minutes.

[0096] Comparative Example 3

[0097] The difference between this comparative example and Example 3 is that the recrystallization liquid C does not contain p-ethylpropiophenone and paraformaldehyde, and the other ingredients and steps remain unchanged.

[0098] A method for preparing famotidine comprises the following steps:

[0099] (1) First recrystallization: Add the recrystallization liquid A to a reaction kettle, then add the crude famotidine, and stir until it is completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% by volume ethanol solution 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% by volume ethanol solution 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, and then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and then filter to obtain a wet product I;

[0100] The components of the recrystallization liquid A are calculated by mass percentage, including 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 liquid B to the reaction kettle, then add the wet product I, stir until completely dissolved, and 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, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0104] The components of the recrystallization liquid B are calculated by mass percentage, including 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 1 g:8 mL;

[0107] (3) The third recrystallization: Add the recrystallization liquid C into the reaction kettle, start heating to 62° C., then add the wet product II, stir and dissolve quickly at 70° C., cool to 10° C., stir for 55 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10 to 20 minutes, then filter, and dry the obtained filter cake to obtain the famotidine finished product;

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

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

[0110] The filter cake drying method comprises the following steps: firstly drying the filter cake obtained after immersion and filtration at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and performing hot air circulation drying for 220 minutes.

[0111] Comparative Example 4

[0112] The difference between this comparative example and Example 3 is 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 method for preparing famotidine comprises the following steps:

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

[0115] The components of the recrystallization liquid A are calculated by mass percentage, including 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 liquid B to the reaction kettle, then add the wet product I, stir until completely dissolved, and 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, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter to obtain a wet product II;

[0119] The components of the recrystallization liquid B are calculated by mass percentage, including 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 1 g:8 mL;

[0122] (3) The third recrystallization: Add the recrystallization liquid C into the reaction kettle, start heating to 62° C., then add the wet product II, stir and dissolve quickly at 70° C., cool to 10° C., stir for 55 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10 to 20 minutes, then filter, and dry the obtained filter cake to obtain the famotidine finished product;

[0123] The components of the recrystallization liquid C are calculated by mass percentage, including 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance is purified water;

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

[0125] The filter cake drying method comprises the following steps: firstly drying the filter cake obtained after immersion and filtration at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and performing hot air circulation drying for 220 minutes.

[0126] Comparative Example 5

[0127] The difference between this comparative example and Example 3 is that the ethanol solution is not added in batches during the first recrystallization and the second recrystallization (the ethanol solution is added all at once), and the other components and steps remain unchanged.

[0128] A method for preparing famotidine comprises the following steps:

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

[0130] The components of the recrystallization liquid A are calculated by mass percentage, including 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 liquid B to the reaction kettle, then add the wet product I, and stir until it is 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 then filter to obtain a wet product II;

[0134] The components of the recrystallization liquid B are calculated by mass percentage, including 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 1 g:8 mL;

[0137] (3) The third recrystallization: Add the recrystallization liquid C into the reaction kettle, start heating to 62° C., then add the wet product II, stir and dissolve quickly at 70° C., cool to 10° C., stir for 55 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10 to 20 minutes, then filter, and dry the obtained filter cake to obtain the famotidine finished product;

[0138] The components of the recrystallization liquid C are calculated by mass percentage, including 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance is purified water;

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

[0140] The filter cake drying method comprises the following steps: firstly drying the filter cake obtained after immersion and filtration at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and performing hot air circulation drying for 220 minutes.

[0141] Comparative Example 6

[0142] The difference between this comparative example and Example 3 is that the recrystallization liquid A and the recrystallization liquid B are replaced with hydrochloric acid ethanol solution, and the other components and steps remain unchanged.

[0143] A method for preparing famotidine comprises the following steps:

[0144] (1) First recrystallization: Add the recrystallization liquid A to a reaction kettle, then add the crude famotidine, and stir until it is completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% by volume ethanol solution 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% by volume ethanol solution 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, and then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and then filter to obtain a wet product I;

[0145] The recrystallization liquid A is a 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 liquid B to the reaction kettle, then add the wet product I, stir until completely dissolved, and 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, 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 1 g:8 mL;

[0152] (3) The third recrystallization: Add the recrystallization liquid C into the reaction kettle, start heating to 62° C., then add the wet product II, stir and dissolve quickly at 70° C., cool to 10° C., stir for 55 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10 to 20 minutes, then filter, and dry the obtained filter cake to obtain the famotidine finished product;

[0153] The components of the recrystallization liquid C are calculated by mass percentage, including 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance is purified water;

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

[0155] The filter cake drying method comprises the following steps: firstly drying the filter cake obtained after immersion and filtration at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and performing hot air circulation drying 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 method for preparing famotidine comprises the following steps:

[0159] (1) First recrystallization: Add the recrystallization liquid A to a reaction kettle, then add the crude famotidine, and stir until it is completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% by volume ethanol solution 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% by volume ethanol solution 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, and then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and then filter to obtain a wet product I;

[0160] The components of the recrystallization liquid A are calculated by mass percentage, including 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 liquid B to the reaction kettle, then add the wet product I, and stir until it is 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, and then soak the filtered filter cake in anhydrous ethanol for 9 minutes, and then filter and dry to obtain the famotidine product;

[0164] The components of the recrystallization liquid B are calculated by mass percentage, including 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 1 g:8 mL;

[0167] The drying method is that the filter cake obtained after filtration is first dried at 25° C. by forced air drying for 120 minutes, and then heated to 45° C. by hot air circulation drying 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 method for preparing famotidine comprises the following steps:

[0171] (1) First recrystallization: Add the recrystallization liquid A to a reaction kettle, then add the crude famotidine, and stir until it is completely dissolved to obtain a mixed solution I; slowly add 1 / 2 of a 30% by volume ethanol solution 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% by volume ethanol solution 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, and then soak the filtered filter cake in anhydrous ethanol for 15 minutes, and then filter to obtain a wet product I;

[0172] The components of the recrystallization liquid A are calculated by mass percentage, including 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) The third recrystallization: Add the recrystallization liquid C into the reaction kettle, start heating to 62° C., then add the wet product I, stir and dissolve quickly at 70° C., cool to 10° C., stir for 55 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10 to 20 minutes, then filter, and dry the obtained filter cake to obtain the famotidine finished product;

[0176] The components of the recrystallization liquid C are calculated by mass percentage, including 25% methanol, 8% p-ethylpropiophenone, 2% paraformaldehyde, and the balance is purified water;

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

[0178] The filter cake drying method comprises the following steps: firstly drying the filter cake obtained after immersion and filtration at 25° C. with forced air for 120 minutes, and then heating the filter cake to 45° C. and performing hot air circulation drying for 220 minutes.

[0179] Experimental Example 1

[0180] 1.1 The detection method of N-nitrosodimethylamine (NDMA) was based on Ye Qiongxian et al. (Detection of N-nitrosodimethylamine in bromfenac sodium by gas chromatography, Shanxi Chemical Industry, 2023[4], 29-31), with crude famotidine (purchased from Hunan Dino Pharmaceutical Co., Ltd.) as the control group. The yield and purity of famotidine were tested by HPLC area normalization method, with specific reference to Wang Liang (Improvement of the synthesis 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) stipulate that the acceptable intake limit of NDMA is 96 ng / d, while the maximum intake of famotidine tablets is 40 mg / d (twice a day for adults, one tablet at a time, 20 mg per tablet). 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 can be seen from Table 1, the famotidine finished product yields of Examples 1 to 3, Comparative Examples 1 to 8 and the reference product are similar, but the NDMA content and purity are different. In particular, the NDMA content of Examples 1 to 3 is 0, showing strong drug safety. By comparing Example 3 with Comparative Examples 1 to 3, it can be seen that the selected components in recrystallization liquid A, recrystallization liquid B and recrystallization liquid C have a great influence 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, and the NDMA content is high, which poses a risk of medication; By comparing Example 3 with Comparative Examples 4 and 5, it can be seen 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; By comparing Example 3 with Comparative Example 6, it can be seen that compared with ethanol solution, the addition of ethanol with hydrochloric acid is likely to reduce the purity of the product, because hydrochloric acid will destroy the stability of the famotidine finished product, increase the content of related substances, and lead to a decrease in purity. By comparing Example 3 with Comparative Examples 7 and 8, it can be seen that the complete three recrystallizations 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 principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing famotidine, characterized in that: The following steps are involved: (1) First recrystallization: dissolving the crude famotidine in a recrystallization solution A, adding ethanol solution in stages, filtering and soaking to obtain a 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 liquid C, filtering, soaking and drying to obtain the famotidine finished product; the recrystallization liquid C comprises, by mass percentage, 15-30% methanol, 5-10% p-ethylpropiophenone, 1-5% paraformaldehyde, and the remainder is purified water.

2. The method for preparing famotidine according to claim 1, characterized in that: The specific preparation method of the first recrystallization in step (1) is as follows: adding recrystallization liquid A into a reaction kettle, 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, stirring for 20 to 35 minutes, and then continuing to add the remaining 1 / 2 of the 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 filtering to obtain a wet product I.

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

4. The method for preparing famotidine according to claim 2, characterized in that, The mass volume ratio of crude famotidine to ethanol solution is 1 g: (10-15) mL.

5. The method for preparing famotidine according to claim 1, characterized in that, The specific preparation method of the second recrystallization in step (2) is as follows: add the recrystallization liquid B into a reaction kettle, then add the wet product I, stir until it is completely dissolved, and obtain a mixed solution II; slowly add 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 continue to add the remaining 1 / 2 of the 30% ethanol solution by volume after stirring for 15 to 30 minutes; finally, stir for 8 to 12 hours and then filter to obtain a filter cake; soak the filter cake in purified water for 10 to 20 minutes, and then soak the filtered filter cake in anhydrous ethanol for 8 to 10 minutes, and then filter to obtain a wet product II.

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

7. The method for preparing 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 method for preparing famotidine according to claim 1, characterized in that: The specific preparation method of the third recrystallization in step (3) is as follows: add the recrystallization liquid C into a reaction kettle, start heating to 60-65° C., then add the wet product II, stir and dissolve quickly at a temperature of 60-75° C., cool to 5-15° C., stir for 50-60 minutes, and then filter to obtain a filter cake; soak the filter cake in 75% by volume methanol for 10-20 minutes and then filter, and dry the obtained filter cake to obtain the famotidine finished product.

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

10. The method for preparing famotidine according to claim 8, characterized in that: The filter cake drying method comprises the following steps: firstly drying the filter cake obtained after immersion and filtration at 24-26° C. by forced air drying for 100-150 minutes, and then heating the filter cake to 45° C. by hot air circulation drying for 200-250 minutes.

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