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Furosemide preparation method

A technology of furosemide and tetrahydrofuran, which is applied in the preparation field of furosemide, can solve problems such as unfavorable industrialized production, complicated operation and the like, and achieve the effect of remarkable economic benefit and simple steps

Active Publication Date: 2016-05-11
CHANGZHOU YABANG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route uses sodium borohydride to reduce the imine, and the post-treatment often needs to be quenched at low temperature, and more inorganic salts are produced at the same time, which requires more purification of furosemide in order to remove the inorganic salts. The operation is cumbersome and is not conducive to industrial production.

Method used

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Experimental program
Comparison scheme
Effect test

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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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...

Claims

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Application Information

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IPC IPC(8): C07D307/52
CPCC07D307/52
Inventor 陶锋徐树行夏正君王剑张志敏王德祥张楠
Owner CHANGZHOU YABANG PHARMA
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