Furosemide preparation method

Abstract

The invention belongs to the field of pharmaceutical chemicals and particularly relates to a furosemide preparation method. A chemical formula of furosemide is shown as a formula (1) in the specification. The preparation method includes: heating a tetrahydrofuran compound shown as a formula (2) and a 2-aminobenzoic acid compound shown as a formula (3) and / or salts of 2-aminobenzoic acid compound in a reaction solvent, wherein the temperature is controlled to be 80-150 DEG C, and in the formula (2), X refers to halogen, lower alkyl sulfonyloxy, arylsulfonyloxy or araklyl sulfonyloxy; performing nucleophilic reaction under the action of an acid-binding agent and / or catalyst until the reaction of the formula (3) is finished completely, wherein the reaction time is 5-36h; separating and purifying reaction liquid to obtain the furosemide shown as the formula (1). By the furosemide preparation method, high-purity high-yield furosemide preparation can be realized through simple steps without any complex purification steps, the yield is up to 97.0%, and the purity is up to 99.8%. Therefore, the furosemide preparation method has remarkable economic benefits and is pretty advantageous.

Description

technical field

[0001] The invention belongs to the field of medicine and chemical industry, in particular to a preparation method of furosemide. Background technique

[0002] Furosemide is a diuretic drug used in the treatment of congestive heart failure and edema with the molecular formula C 12 h 11 ClN 2 o 5 S, whose structure is as follows:

[0003]

[0004] The existing furosemide synthesis routes mainly include: Chinese Journal of Pharmaceutical Industry 1973; 1:25 reported that 2,4-dichlorobenzoic acid was used as the starting material after chlorosulfonation, ammoniation and condensation with furfurylamine to prepare the formula (1) Furosemide shown. In order to convert more 2,4-dichloro-5-sulfamoylbenzoic acid in this route, the feeding molar ratio of furfuryl amine has been improved to 5.5: 1. Although a large excess of furfuryl amine can be used mechanically after distillation, it needs Use a decompression vacuum system and consume a lot of heat energy; t...

Examples

Embodiment 1

[0036] In the reaction flask, add DMF1000ml, 2-amino-4-chloro-5-sulfamoylbenzoic acid (250.7 grams, 1.0mol), 2-chloromethylfuran (186.4 grams, 1.6mol), potassium bromide (9.5 grams , 0.08mol), heated and stirred at 120 degrees Celsius for 24 hours, after cooling, add 5000ml of water, adjust pH=5 with hydrochloric acid, drop to room temperature, precipitate crystals, filter with suction, rinse the filter cake with ethyl acetate, and dry to obtain 2 -[(2-furylmethyl)amino]-5-(sulfamoyl)-4-chlorobenzoic acid 320.8 g, yield 97.0%, purity 99.8%.

[0037] The purity of furosemide was determined by high performance liquid chromatography (HPLC) under the following conditions:

[0038] Column: Megres TM C18 (Hanbang Technology)

[0039] Eluent: water / tetrahydrofuran / glacial acetic acid=70 / 30 / 1

[0040] Flow rate: 1.0mL / min

[0041] Detection wavelength: 272nmUV

Embodiment 2

[0043] In the reaction flask, add ethylene glycol 1200ml, 2-amino-4-chloro-5-sulfamoylbenzoic acid (250.7 grams, 1.0mol), 2-chloromethylfuran (139.9 grams, 1.2mol), copper iodide (31.7 grams, 0.1mol), 160 degrees centigrade heating and stirring reaction 24 hours, after cooling, add water 5000ml, adjust pH=5 with hydrochloric acid, drop to room temperature, precipitate crystal, suction filter, filter cake rinses with ethyl acetate, bakes 269.2 g of 2-[(2-furylmethyl)amino]-5-(sulfamoyl)-4-chlorobenzoic acid was obtained by drying, with a yield of 81.4% and a purity of 99.6%.

[0044] The purity of furosemide was determined by high performance liquid chromatography (HPLC) under the following conditions:

[0045] Column: Megres TM C18 (Hanbang Technology)

[0046] Eluent: water / tetrahydrofuran / glacial acetic acid=70 / 30 / 1

[0047] Flow rate: 1.0mL / min

[0048] Detection wavelength: 272nmUV

Embodiment 3

[0050]In the reaction flask, add DMF1000ml, 2-amino-4-chloro-5-sulfamoylbenzoic acid (250.7 grams, 1.0mol), 2-chloromethylfuran (256.3 grams, 2.2mol), sodium bromide (14.4 grams , 0.14mol), 100 degrees Celsius heating and stirring reaction for 24 hours, after cooling, add 5000ml of water, adjust pH=5 with hydrochloric acid, drop to room temperature, precipitate crystals, filter with suction, filter cake rinse with ethyl acetate, dry to obtain 2 -[(2-furylmethyl)amino]-5-(sulfamoyl)-4-chlorobenzoic acid 298.7 g, yield 90.3%, purity 99.8%.

[0051] The purity of furosemide was determined by high performance liquid chromatography (HPLC) under the following conditions:

[0052] Column: Megres TM C18 (Hanbang Technology)

[0053] Eluent: water / tetrahydrofuran / glacial acetic acid=70 / 30 / 1

[0054] Flow rate: 1.0mL / min

[0055] Detection wavelength: 272nmUV

technical field

[0001] The invention belongs to the field of medicine and chemical industry, in particular to a preparation method of furosemide. Background technique

[0002] Furosemide is a diuretic drug used in the treatment of congestive heart failure and edema with the molecular formula C 12 h 11 ClN 2 o 5 S, whose structure is as follows:

[0003]

[0004] The existing furosemide synthesis routes mainly include: Chinese Journal of Pharmaceutical Industry 1973; 1:25 reported that 2,4-dichlorobenzoic acid was used as the starting material after chlorosulfonation, ammoniation and condensation with furfurylamine to prepare the formula (1) Furosemide shown. In order to convert more 2,4-dichloro-5-sulfamoylbenzoic acid in this route, the feeding molar ratio of furfuryl amine has been improved to 5.5: 1. Although a large excess of furfuryl amine can be used mechanically after distillation, it needs Use a decompression vacuum system and consume a lot of heat energy; t...

Examples

Embodiment 1

[0036] In the reaction flask, add DMF1000ml, 2-amino-4-chloro-5-sulfamoylbenzoic acid (250.7 grams, 1.0mol), 2-chloromethylfuran (186.4 grams, 1.6mol), potassium bromide (9.5 grams , 0.08mol), heated and stirred at 120 degrees Celsius for 24 hours, after cooling, add 5000ml of water, adjust pH=5 with hydrochloric acid, drop to room temperature, precipitate crystals, filter with suction, rinse the filter cake with ethyl acetate, and dry to obtain 2 -[(2-furylmethyl)amino]-5-(sulfamoyl)-4-chlorobenzoic acid 320.8 g, yield 97.0%, purity 99.8%.

[0037] The purity of furosemide was determined by high performance liquid chromatography (HPLC) under the following conditions:

[0038] Column: Megres TM C18 (Hanbang Technology)

[0039] Eluent: water / tetrahydrofuran / glacial acetic acid=70 / 30 / 1

[0040] Flow rate: 1.0mL / min

[0041] Detection wavelength: 272nmUV

Embodiment 2

[0043] In the reaction flask, add ethylene glycol 1200ml, 2-amino-4-chloro-5-sulfamoylbenzoic acid (250.7 grams, 1.0mol), 2-chloromethylfuran (139.9 grams, 1.2mol), copper iodide (31.7 grams, 0.1mol), 160 degrees centigrade heating and stirring reaction 24 hours, after cooling, add water 5000ml, adjust pH=5 with hydrochloric acid, drop to room temperature, precipitate crystal, suction filter, filter cake rinses with ethyl acetate, bakes 269.2 g of 2-[(2-furylmethyl)amino]-5-(sulfamoyl)-4-chlorobenzoic acid was obtained by drying, with a yield of 81.4% and a purity of 99.6%.

[0044] The purity of furosemide was determined by high performance liquid chromatography (HPLC) under the following conditions:

[0045] Column: Megres TM C18 (Hanbang Technology)

[0046] Eluent: water / tetrahydrofuran / glacial acetic acid=70 / 30 / 1

[0047] Flow rate: 1.0mL / min

[0048] Detection wavelength: 272nmUV

Embodiment 3

[0050]In the reaction flask, add DMF1000ml, 2-amino-4-chloro-5-sulfamoylbenzoic acid (250.7 grams, 1.0mol), 2-chloromethylfuran (256.3 grams, 2.2mol), sodium bromide (14.4 grams , 0.14mol), 100 degrees Celsius heating and stirring reaction for 24 hours, after cooling, add 5000ml of water, adjust pH=5 with hydrochloric acid, drop to room temperature, precipitate crystals, filter with suction, filter cake rinse with ethyl acetate, dry to obtain 2 -[(2-furylmethyl)amino]-5-(sulfamoyl)-4-chlorobenzoic acid 298.7 g, yield 90.3%, purity 99.8%.

[0051] The purity of furosemide was determined by high performance liquid chromatography (HPLC) under the following conditions:

[0052] Column: Megres TM C18 (Hanbang Technology)

[0053] Eluent: water / tetrahydrofuran / glacial acetic acid=70 / 30 / 1

[0054] Flow rate: 1.0mL / min

[0055] Detection wavelength: 272nmUV

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