Method for preparing nafamostat hydrochloride and nafamostat mesylate

A technology of nafamostat mesylate and nafamostat, which is applied in the field of drug synthesis, can solve the problems of increased production cost and low yield of nafamostat sulfonate, and achieve high cost and good solid state , The effect of reducing the use of production equipment

Inactive Publication Date: 2013-04-03
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the yield of nafamostat hydrochloride as an intermediate is relatively low, it will inevitably l

Method used

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  • Method for preparing nafamostat hydrochloride and nafamostat mesylate
  • Method for preparing nafamostat hydrochloride and nafamostat mesylate
  • Method for preparing nafamostat hydrochloride and nafamostat mesylate

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Embodiment 1

[0031] The preparation of embodiment 1 nafamostat hydrochloride

[0032] 60 ml of pyridine was added to the reaction flask, and 6-amidino-2-naphthol methanesulfonate (28.23 g, 0.10 mol) was added under stirring. The temperature was lowered to 0-5°C in an ice-water bath, and p-guanidinobenzoyl chloride hydrochloride (28.09 g, 0.12 mol) was added in three batches. After feeding the materials, continue to keep the reaction at 0-5°C for 3h. After the reaction was completed, the temperature was naturally raised to room temperature, and the reaction was stirred for 10 h. After filtering, the filter cake was washed twice with 20ml of pyridine, and sucked dry. 29.65 g (HPLC: 93.5%) of a yellow solid was obtained. Melting point: Decompose at about 274°C. Yield: 70.90%.

Embodiment 2

[0033] The preparation of embodiment 2 nafamostat hydrochloride

[0034] 60 ml of pyridine was added to the reaction flask, and 6-amidino-2-naphthol methanesulfonate (28.23 g, 0.10 mol) was added under stirring. The temperature was lowered to 0-5°C in an ice-water bath, and p-guanidinobenzoyl chloride hydrochloride (45 g, 0.18 mol) was added in three batches. After feeding the materials, continue to keep the reaction at 0-5°C for 2h. After the reaction was completed, the temperature was raised to 40° C., and the reaction was stirred for 8 hours. After filtering, the filter cake was washed twice with 20ml of pyridine, and sucked dry. 30.53 g (HPLC: 94.2%) of a yellow solid was obtained. Melting point: Decompose at about 274°C. Yield: 73.0%.

Embodiment 3

[0035] The preparation of embodiment 3 nafamostat hydrochloride

[0036] 60 ml of N,N-diisopropylethylenediamine was added to the reaction flask, and 6-amidino-2-naphthol methanesulfonate (29.12 g, 0.103 mol) was added under stirring. The temperature was lowered in an ice-water bath to -10-5°C, and p-guanidinobenzoyl chloride hydrochloride (72.43 g, 0.31 mol) was added in four batches. After the feed is finished, continue to react at -10~5°C for 5h. After the reaction was completed, the temperature was naturally raised to room temperature, and the reaction was stirred for 10 h. After filtering, the filter cake was washed twice with 20 ml of N,N-diisopropylethylenediamine and sucked dry. A yellow solid was obtained, about 30.78 g (HPLC: 91.8%). Melting point: Decompose at about 274°C. Yield: 71.00%.

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Abstract

The invention relates to a method for preparing nafamostat hydrochloride and nafamostat mesylate. The method comprises the following steps of: reacting n-guanidine benzoyl chloride hydrochloride with a methanesulfonic acid 6-guanyl-2-isonaphthol compound under an action of an alkali organic solvent to prepare nafamostat hydrochloride, wherein the alkali organic solvent does not comprise dicyclohexyl carbodiimide; and reacting the nafamostat hydrochloride and the methanesulfonic acid under a mixed liquid of the water and the organic solvent to prepare the nafamostat mesylate. The preparation method is simple in process, high in yield, low in content of impurities and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of nafamostat hydrochloride and nafamostat mesylate. Background technique [0002] Pancreatitis, especially acute pancreatitis with high morbidity and high mortality, brings serious harm to people's quality of life and life and property. There is an urgent need for effective new drugs for the treatment of pancreatitis to relieve the pain of patients; the drug for the treatment of pancreatitis Research and development also once became the focus of common attention of the scientific and industrial circles. Protease inhibitors are clinically used to treat acute pancreatitis and improve acute pancreatitis, acute exacerbation of chronic pancreatitis, acute pancreatitis after surgery, acute pancreatitis after pancreatography, and traumatic pancreatitis. Therefore, protease inhibitors are widely used clinically. [0003] Nafamostat mesylate belongs to the...

Claims

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Application Information

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IPC IPC(8): C07C279/18C07C277/08C07C309/04C07C303/32
Inventor 魏伟业储刚霍立茹刘彩连黄海燕钟雪斌李玮
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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