A method for purifying famotidine to obtain a b crystal form

Abstract

The application discloses a method for preparing a B crystal form of famotidine with high purity. The method comprises the following steps: adding famotidine crude product into a mixed solvent of methanol and ethylene glycol monomethyl ether; heating to 30-45 DEG C; adding acid; adding activated carbon; filtering to obtain a filtrate; adding alkali to the filtrate under the condition of 10-30 DEG C to adjust pH to 8.5-9.5; stirring and cooling to-5-20 DEG C to crystallize; and post-treating. The method has the advantages that the prepared famotidine of the B crystal form has good purity, the HPLC purity can be higher than 99.9%, the product has good color and high whiteness, some known impurities are completely removed, and the rest of single impurities are all lower than 0.05%.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for purifying high-purity famotidine, and the famotidine obtained by this method is in crystal form B. Background Technology

[0002] Famotidine (3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]-N-aminosulfonylpropanediamine)

[0003] Structural formula:

[0004]

[0005] Famotidine is a histamine H2 receptor antagonist that can inhibit gastric acid secretion and pepsin. It is suitable for gastric and duodenal ulcers, reflux esophagitis, upper gastrointestinal bleeding, Zollinger-Ellison syndrome, etc.

[0006] Famotidine is considered one of the most effective and highly selective H2-receptor antagonists and is one of the best-selling drugs. Currently, famotidine is available in tablet, capsule, and injectable forms in China. However, significant side effects have been observed during clinical use. Research has found that these side effects are closely related to impurities in the drug, especially in intravenous formulations. To reduce the impurity content in injectable formulations and improve the safety and efficacy of injectable famotidine, it is essential to strictly control the impurity content in the raw materials to ensure medication safety.

[0007] Famotidine has two known crystalline forms, A and B. Crystalline form A has a higher melting point than crystalline form B. Oral formulations of crystalline form B have better bioavailability than crystalline form A. Due to several differences between the two crystalline forms, from a pharmaceutical technology perspective, it is best to use the pure crystalline form. Furthermore, current research and applications both domestically and internationally primarily utilize crystalline form B.

[0008] The synthetic route for famotidine is as follows:

[0009]

[0010] The EP and USP lists famotidine as containing specific impurities listed in the quality standards. These impurities are identified as ten: A, B, C, D, E, F, G, H, I, and J. Their structures and names are as follows:

[0011] Impurity A: 3-[[2-(diaminomethyleneamino)thiazo-4-yl]methylthio]propanediol

[0012]

[0013] Impurity B: 3,5-bis[2-[[2-[(diaminomethylene)amino]thiazolyl-4-yl]methylthio]ethyl]-4H-1,2,4,6-thiatriazine 1,1-dioxide

[0014]

[0015] Impurity C: 3-[[2-(diaminomethyleneamino)thiazolyl-4-yl]methylthio]-N-sulfonamidopropionamide

[0016]

[0017] Impurity D: 3-[[2-(diaminomethyleneamino)thiazolyl-4-yl]methylthio]propionamide

[0018]

[0019] Impurity E: 2,2′-[4,4′-dithiodiylbis(methylene)bis(thiazole-4,2-diyl)]biguanide

[0020]

[0021] Impurity F: 3-[[2-(diaminomethyleneamino)thiazolyl-4-yl]methylthio]propionic acid

[0022]

[0023] Impurity G: N-cyano-3-[[2-(diaminomethyleneamino)thiazo-4-yl]methylthio]propanediidine

[0024]

[0025] Impurity H: [2-(diaminomethyleneamino)thiazolyl-4-yl]carbamoylaminothiocarbamate methyl ester

[0026]

[0027] Impurity I: 3-((2-(diaminomethyleneamino)thiazolyl-4-yl)methyl)sulfoxide)-N-aminosulfonylpropane

[0028]

[0029] Impurity J: Methyl 3-((2-(diaminomethyleneamino)thiazo-4-yl)methylthio)propionate

[0030]

[0031] There are various existing purification methods for famotidine, but they all have various drawbacks. To obtain high-purity famotidine, multiple purification processes are required, the process is cumbersome, and if the temperature is too high during the purification process, the product will degrade, resulting in low yield, high cost, and a heavy burden of recovery. Summary of the Invention

[0032] To solve the above-mentioned technical problems, the present invention provides a method for purifying crude famotidine to obtain high-purity famotidine at a temperature not exceeding 45°C. This method is simple and easy to implement, and is more suitable for large-scale industrial production. The method of the present invention can purify high-purity famotidine B crystal form with a high yield.

[0033] The technical solution of the present invention is as follows:

[0034] A method for purifying famotidine, comprising the following steps:

[0035] (1) Add crude famotidine to a mixed solvent of methanol and ethylene glycol monomethyl ether;

[0036] (2) Heat to 30-45℃;

[0037] (3) Add acid;

[0038] (4) Add activated carbon;

[0039] (5) Filter to obtain the filtrate;

[0040] (6) Add alkali to the filtrate at a temperature of 10-30℃ to adjust the pH to 8.5-9.5;

[0041] (7) Stir and cool to -5 to 20°C to allow crystallization;

[0042] (8) Post-processing.

[0043] The volume ratio of methanol to ethylene glycol monomethyl ether added in step (1) is 1:3-3:1.

[0044] The mass-volume ratio of crude famotidine (m) to mixed solvent (v) added in step (1) is 1m / 15 to 30v, preferably 1m / 20v.

[0045] According to the present invention, the heating temperature in step (2) is 40-45°C.

[0046] According to the present invention, in step (3), the acid is selected from formic acid, glacial acetic acid, hydrochloric acid, sulfuric acid, and phosphoric acid, preferably glacial acetic acid.

[0047] In step (3), the molar ratio of crude famotidine (mol) to glacial acetic acid (mol) is 1mol / 1 to 4mol, preferably 1mol / 2 to 3mol.

[0048] According to the present invention, after adding activated carbon in step (4), the color is maintained at a constant temperature for 10 to 60 minutes, preferably 30 minutes.

[0049] According to the present invention, the alkali added in step (6) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, ammonia, triethylamine, and diisopropylethylamine, preferably sodium hydroxide and ammonia, and more preferably ammonia.

[0050] In step (6), the ammonia concentration is 25-28% (concentrated ammonia). The temperature at which the ammonia is added is 20-25°C.

[0051] The molar ratio of glacial acetic acid (mol) to ammonia (mol) is 1mol / 1 to 2mol, preferably 1mol / 1.5mol, and the pH is adjusted to 8.5 to 9.5.

[0052] According to the present invention, in step (7), the internal temperature is cooled to 0-15°C, more preferably 5-10°C, under stirring conditions.

[0053] According to the present invention, in step (8), the solid is filtered, washed, and dried. The drying is carried out at 40-45°C with forced air drying for 5-8 hours, followed by reduced pressure drying for 2-4 hours.

[0054] The present invention also provides a method for preparing famotidine B crystal form, the method comprising the steps described above.

[0055] Beneficial effects:

[0056] Existing refining methods only focus on ensuring that the total impurity content and related impurities of the refined B-type product are within the required limits. There has never been a method that can completely remove one or more of the aforementioned specific impurities.

[0057] This invention, through extensive experimentation, has discovered a method for preparing high-purity famotidine (B crystal form) that involves fewer steps, simpler operation, lower raw material consumption, lower purification temperature, higher yield, and is easily scalable for industrial production. The famotidine purified by this method exhibits high purity, with HPLC purity exceeding 99.9%, and the product also demonstrates excellent color and high whiteness. Even more surprisingly, some known impurities are completely removed from the purified product, and all remaining single impurities are below 0.05%. Attached Figure Description

[0058] Figure 1 : Refined quality spectrum of Example 1; negative ESI-MS at m / z: 336.0 [MH] + There is an ion peak at that location.

[0059] The corresponding molecular formula of famotidine is C8H. 15N7O2S3, famotidine has a molecular weight of 337.04;

[0060] Figure 2 HPLC purity test chromatogram of the purified product in Example 1;

[0061] Figure 3 X-ray powder diffraction pattern (B crystal form) of the refined product in Example 1;

[0062] Figure 4 X-ray powder diffraction pattern of the refined product of Comparative Example 1 (Crystal form A). Detailed Implementation

[0063] The following detailed description, in conjunction with specific embodiments, illustrates the aminofullerenes of the present invention, their preparation methods, and applications. It should be understood that the following embodiments are merely illustrative and explanatory of the invention and should not be construed as limiting the scope of protection of the invention. All technologies implemented based on the above description of the present invention are covered within the scope of protection intended by the present invention.

[0064] Unless otherwise stated, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Experimental methods not specified in the examples were performed according to conventional methods and conditions.

[0065] The HPLC detection conditions in this invention are as follows:

[0066] Specific implementation methods:

[0067] Sample purity test conditions

[0068] A Waters Symmetry C18 high-performance liquid chromatograph (250 mm × 4.6 mm, 5 μm) was used. The mobile phase A was a mixture of methanol / acetonitrile / mobile phase (sodium hexanesulfonate 1.9 g / water 1 L, pH = 3.5) = 6 v: 94 v: 900 v, and the mobile phase B was acetonitrile. Gradient elution was performed according to the program in the table below. The detection wavelength was 265 nm.

[0069]

[0070] Preparation example: Famotidine crude product

[0071] (1) Preparation of 2-diaminomethyleneamino-4-chloromethylthiazole hydrochloride (intermediate-1):

[0072] Add 500 ml of acetone to a 2000 ml three-necked flask, then add amidothiourea (93.1 g, 0.788 mol). While stirring, add a solution of dichloroacetone (100 g, 0.788 mol) / acetone (200 ml). Stir at room temperature for 10 hours, filter, and wash the solid with acetone (100 ml × 2). Add the wet solid to a 2000 ml three-necked flask, then add 700 ml of anhydrous ethanol. Heat under stirring until refluxed and completely dissolved. Cool to 0–5 °C while stirring and continue to maintain the temperature for crystallization for 5 hours. Filter, wash the solid with cold anhydrous ethanol (50 ml × 3), and dry under vacuum at 50 °C for 6 hours to obtain 130.5 g of off-white solid, yield 72.9%.

[0073] (2) Preparation of 2-diaminomethyleneamino-4-amidinylthiomethylthiazolium dihydrochloride (intermediate-2):

[0074] Add 500 ml of anhydrous ethanol, intermediate-1 (125 g, 0.550 mol), and thiourea (41.9 g, 0.550 mol) to a 2000 ml three-necked flask. Heat under reflux with stirring for 5 hours, then cool to 15–20 °C with stirring. Filter and wash the solid with anhydrous ethanol (50 ml × 3). Add the wet solid to the 2000 ml three-necked flask, then add 800 ml of 95% ethanol. Heat under reflux with stirring until completely dissolved. Cool to 5–10 °C with stirring, filter, and wash the solid with cold anhydrous ethanol (100 ml × 2). Dry under vacuum at 50 °C for 6 hours to obtain 142.1 g of off-white solid, yield 85.2%.

[0075] (3) Preparation of crude famotidine:

[0076] To a 2000 ml three-necked flask, add intermediate-2 (135 g, 0.445 mol), 95% ethanol (400 ml), and deionized water (800 ml). Cool to 0–5 °C with stirring, then add N-aminosulfonyl-β-chloropropanedin (118.6 g, 0.534 mol). Maintaining the temperature at 0–5 °C, add 750 ml of 3N sodium hydroxide solution dropwise with stirring. Continue stirring at 10–15 °C for 5 hours. Filter, wash the solid with deionized water (100 ml × 6), and dry under vacuum at 50 °C for 15 hours to obtain 95.3 g of crude product, yield 63.5%.

[0077] The crude famotidine was analyzed by HPLC and the purity was 96.687%. It contained impurities A (0.711%), B (0.229%), C (0.416%), D (0.571%), E (0.366%), F (0.273%), G (0.175%), J (0.134%), and other unknown impurities totaling 0.438%.

[0078] Example 1:

[0079] Weigh 15g of crude famotidine and add it to a 500ml three-necked flask. Then add 75ml of methanol and 225ml of ethylene glycol monomethyl ether. Heat the mixture to 40-45℃ with stirring. Add 6ml of glacial acetic acid and stir until the solid dissolves (use pH paper to test the reaction solution; pH≈5.5). Add 1.5g of activated carbon and stir at 40-45℃ for 30 minutes. Filter the solution and transfer the filtrate to a clean 500ml three-necked flask. Cool the solution to 20-25℃ with stirring in an ice-water bath. Add 12ml of concentrated ammonia solution at once (the internal temperature will rise slightly). Stir for 30 minutes and cool the solution to 5-10℃ (pH ≈ 9.0 using pH paper). Filter the solution and wash the solid with 15ml of purified water five times. Dry the wet solid at 40-45℃ with forced air for 6 hours, and then dry it under reduced pressure at 40-45℃ for 4 hours to obtain 13.8g of dried product, yield 92.0%. Appearance: white solid, HPLC: 99.929%, melting point: 163-164℃ (heating rate 3℃ / min), product is B crystal form.

[0080] Example 2:

[0081] Weigh 15g of crude famotidine and add it to a 500ml three-necked flask. Then add 225ml of methanol and 75ml of ethylene glycol monomethyl ether. Heat the mixture to 40-45℃ with stirring. Add 6ml of glacial acetic acid and stir until the solid dissolves (use pH paper to test the reaction solution; pH≈5.5). Add 1.5g of activated carbon and stir at 40-45℃ for 30 minutes. Filter the solution and transfer the filtrate to a clean 500ml three-necked flask. Cool the solution to 20-25℃ with stirring in an ice-water bath. Add 12ml of concentrated ammonia solution at once (the internal temperature will rise slightly). Stir for 30 minutes and cool the solution to 5-10℃ (using pH paper to test the reaction solution, pH≈9.0). Filter the solution and wash the solid with 15ml of purified water five times. Dry the wet solid at 40-45℃ with forced air for 6 hours, and then dry it under reduced pressure at 40-45℃ for 4 hours to obtain 13.6g of dried product, yield 90.6%. Appearance: off-white solid, HPLC: 99.358%, melting point: 163-164℃ (heating rate 3℃ / min), product is B crystal form.

[0082] Comparative Example 1:

[0083] Weigh 15g of crude famotidine and add it to a 500ml three-necked flask. Add 300ml of methanol and heat to reflux (approximately 65℃) with stirring until the solid is completely dissolved. Add 1.5g of activated carbon, reflux and stir for 30 minutes, filter, and transfer the filtrate to a clean 500ml three-necked flask. Cool the flask to 20-25℃ with stirring in an ice-water bath, and further cool to 5-10℃. Filter the flask, wash the solid with 15ml of purified water five times, dry the wet solid at 40-45℃ with forced air for 6 hours, and then dry under reduced pressure at 40-45℃ for 4 hours to obtain 13.4g of dried product, yield 89.3%. Appearance: off-white solid, HPLC: 99.073%, melting point: 169-171℃ (heating rate 3℃ / min), product is crystal form A.

[0084] Comparative Example 2:

[0085] Weigh 15g of crude famotidine and add it to a 500ml three-necked flask. Add 300ml of ethylene glycol monomethyl ether and heat to approximately 75℃ with stirring until the solid is completely dissolved. Add 1.5g of activated carbon and stir at 75℃ for 30 minutes. Filter and transfer the filtrate to a clean 500ml three-necked flask. Cool the flask to 20-25℃ with stirring in an ice-water bath, and further cool to 5-10℃. Filter and wash the solid with 15ml of purified water five times. Dry the wet solid at 40-45℃ with forced air for 6 hours, and then dry under reduced pressure at 40-45℃ for 4 hours to obtain 12.8g of dried product, yield 85.3%. Appearance: white solid; HPLC: 99.271%; melting point: 169-171℃ (heating rate 3℃ / min); product is crystal form A.

[0086] Table 1: Comparison of impurities and purity between the crude product and the refined product of Example 1

[0087]

[0088] Table 2: Quality Standard Requirements for Famotidine

[0089]

[0090]

[0091] Comparing Table 1 and Table 2, the purity and impurity content of the refined products in the examples in Table 1 far exceed the quality standards required by various pharmacopoeias. Such purity of famotidine raw material will further ensure the safety of patients using the medication.

[0092] The specific embodiments of the present invention have been described above by way of example. However, the scope of protection of the present invention is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for purifying famotidine, comprising the following steps: (1) Add crude famotidine to a mixed solvent of methanol and ethylene glycol monomethyl ether; (2) Heat to 30-45℃; (3) Add glacial acetic acid until the solid dissolves; (4) Add activated carbon; (5) Filter to obtain filtrate; (6) Add ammonia solution with a concentration of 25% to 28% to the filtrate at a temperature of 10 to 30°C to adjust the pH to 8.5 to 9.5; (7) Stir and cool to 0-20℃ to allow crystallization; (8) Filtering crystals, washing, and drying; in, In step (1), the volume ratio of methanol to ethylene glycol monomethyl ether is 1:3-3:1, and the mass-volume ratio of crude famotidine (m) to mixed solvent (v) is 1m / 15~30v; In step (3), the molar ratio of crude famotidine (mol) to glacial acetic acid (mol) is 1 mol / 1 to 4 mol; After adding activated carbon in step (4), keep warm and decolorize for 10 to 60 minutes; In step (8), the drying is carried out at 40-45°C with forced air drying for 5-8 hours, followed by reduced pressure drying for 2-4 hours.

2. According to the purification method of claim 1, the heating temperature in step (2) is 40-45℃.

3. According to the purification method of claim 1, the temperature at which ammonia water is added in step (6) is 20-25°C; in, Ammonia dosage: glacial acetic acid (mol) / ammonia (mol) = 1mol / 1~2mol, adjust pH to 8.5~9.

5.

4. In the purification method according to claim 1, in step (7), the internal temperature is cooled to preferably 5-10°C under stirring conditions.

5. A method for preparing famotidine B crystal form, comprising the purification method as described in any one of claims 1-4.

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