Method for preparing high-purity torasemide and crystal form I thereof

A technology for crystallization of torasemide, which is applied in the field of preparation of high-purity torasemide and its crystal form I, can solve the problems of low product purity and high toxicity, and achieve strong controllability, simple operation, Ease of industrial production

Active Publication Date: 2012-10-03
连云港杰瑞药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The object of the present invention is to provide a kind of preparation method of high-purity torasemide, can overcome the shortcoming that the torasemide preparation method in the prior art adopts isopropyl isocyanate or solvent pyridine toxicity is bigger, and product purity is not high , using 1,1'-carb...

Method used

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  • Method for preparing high-purity torasemide and crystal form I thereof
  • Method for preparing high-purity torasemide and crystal form I thereof
  • Method for preparing high-purity torasemide and crystal form I thereof

Examples

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Effect test

Embodiment 1

[0038] Example 1 Preparation of crude 3-sulfamoyl-4-(3-methylphenyl)aminopyridine (4, MPSA)

[0039] Add 75 g of 4-chloro-3-pyridinesulfonamide (2), 60 ml of m-methylaniline (3), and 400 ml of isopropanol into the reaction flask, and stir at room temperature until the reaction is complete. Evaporate isopropanol under reduced pressure, add sodium hydroxide solution, stir to dissolve, wash twice with dichloromethane 75ml×2, adjust the water phase to PH=5-8 with concentrated hydrochloric acid at room temperature, stir and filter to obtain MPSA (4) crude product 95g, yield 92.5%.

Embodiment 2

[0040] Example 2 Purification of 3-sulfamoyl-4-(3-methylphenyl)aminopyridine (4, MPSA)

[0041] Add 95 g of MPSA (4) crude product, 700 ml of ethyl acetate, and 2 g of activated carbon to the reaction bottle, heat and reflux for 20 minutes, filter, cool and crystallize the filtrate, filter, and dry the filter cake to obtain 75 g of MPSA refined product, with a yield of 76.5%. Purity (HPLC)>99%.

Embodiment 3

[0042] Example 3 Preparation of Torsemide (5)

[0043] Add MPSA (4) refined product (70g, 0.27mol), CDI (43g, 0.27mol) and 700ml of dichloromethane to the reaction bottle, stir the reaction at 10-40°C, TLC detects that the reaction is complete, add isopropylamine (23ml, 0.27 mol), maintain the temperature and stir the reaction, and TLC detects that the reaction is complete.

[0044]Wash the reaction solution with water, concentrate the organic phase to dryness, add 450ml of 1mol / L sodium hydroxide solution, stir for 30 minutes, filter, add 400ml of ethanol to the filtrate, adjust the pH to 5-6 with acetic acid, stir and crystallize at 0-20°C, and rotate at 120°C ~240 rev / min, filter, and dry the filter cake under reduced pressure at 75-85℃ and vacuum degree of 400~760mmHg to obtain white crystalline particles, 82g, yield: 87.2%, average particle size 100~300μm, HPLC purity: 99.8%.

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Abstract

The invention discloses a method for preparing high-purity torasemide and a crystal form I thereof. The method comprises the following steps of: reacting 4-chloro-3-pyridine sulfonamide and m-toluidine serving as raw materials to obtain 3-sulfamoyl-4-(3-methyl phenyl) aminopyridine, refining, and reacting with 1,1'-carbonyldimidazole and isopropamide, directly introducing isopropyl carbamyl, thus obtaining the high-purity torasemide, wherein the purity (high performance liquid chromatography (HPLC)) of the torasemide is more than 99.5 percent. The prepared torasemide has proper granularity, seed crystal is not required for crystal transformation, the torasemide can be directly transformed into the variant crystal form I, and a chemically pure torasemide variant I is obtained. The preparation method is strong in process controllability, easy and convenient to operate and high in reproducibility, and facilitates industrialized production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a preparation method of torasemide, in particular to a preparation method of high-purity torasemide and its crystal form I. Background technique [0002] Torsemide (1) trade name: DEMADEX, chemical name: N-[[(1-methylethyl)amino]carbonyl]-4-[(3-methylphenyl)amino]-3- Pyridinesulfonamide, molecular formula: C 16 h 20 N 4 o 3 S, molecular weight: 348.43, structural formula: [0003] [0004] Torsemide is a new generation of high-efficiency loop diuretics. It was first launched in Belgium in 1993, and was subsequently approved for marketing in Italy, the United States, the United Kingdom and other countries, and entered my country in December 2003. Torsemide is a sulfonylurea pyridine diuretic that exerts diuretic effect by inhibiting the reabsorption of chloride and sodium in the ascending limb of the loop of Henle. Clinically, it is mainly used to treat diseases such as c...

Claims

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Application Information

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IPC IPC(8): C07D213/74
Inventor 张兰平温树启尹璐季锡平吴书勇王寅
Owner 连云港杰瑞药业有限公司
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