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The synthetic method of nafamostat mesylate intermediate-6-amidino-2-naphthol mesylate

A naphthol, amidine-based technology, applied in the field of organic chemistry drug synthesis, can solve problems such as affecting product quality and yield, HCl gas waste, air pollution, etc., and achieve consistent product quality, low environmental pollution, and low equipment requirements. Effect

Active Publication Date: 2017-12-08
BEIJING LABWORLD BIO MEDICINE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The Pinner reaction is usually carried out under the acidic conditions of HCl / methanol (ethanol). Generally, HCl is passed into the alcohol solution to be saturated. In the laboratory, the amount of HCl can be determined by weighing, but it is not easy in the industrial production process. Control often results in the waste of HCl gas, causing pollution to the atmosphere, and the alcohol needs to be distilled off after the reaction. Long-term heating will cause the decomposition of 6-hydroxy-2-naphthiminomethyl ester hydrochloride, which directly affects the product. quality and yield

Method used

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  • The synthetic method of nafamostat mesylate intermediate-6-amidino-2-naphthol mesylate
  • The synthetic method of nafamostat mesylate intermediate-6-amidino-2-naphthol mesylate

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Experimental program
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Effect test

Embodiment 1

[0009] Add 350 grams of 6-hydroxyl-2-naphthaldehyde (2.0mol), 278 grams of hydroxylamine hydrochloride (4.0mol) and 3500 milliliters of dimethyl sulfoxide in a 5000 milliliter three-necked flask, stir and heat to 100° C., heat preservation reaction for 1 hour, drop After reaching room temperature, the reaction liquid was mixed with a large amount of water, and a solid was precipitated under stirring. After filtering, the filter cake was washed with water to obtain a wet crude product, which was directly recrystallized with ethanol / water solution to obtain 237 g of off-white refined product with a yield of 70%.

Embodiment 2

[0011] Measure 740 ml of anhydrous methanol into a three-necked flask, cool to 0-5° C. under stirring, and add 430 ml of acetyl chloride (5.0 mol) dropwise. After dropping, react for a period of time at 0-5°C, add 85 grams (0.5mol) of 6-cyano-2-naphthol, react at 10°C for 10 hours, add isopropyl ether and stir for 1 hour to filter, and filter cake with isopropyl ether. Wash with propyl ether, dry and mix with methanol directly, heat to 50°C, pass through dry ammonia gas for 3 hours, and evaporate to dryness under reduced pressure to obtain a yellow solid. It was mixed with saturated sodium bicarbonate solution and stirred for a period of time, filtered and washed with water until neutral. Suspend the wet product in methanol, add a certain amount of methanesulfonic acid dropwise to dissolve, add isopropyl ether to precipitate a solid, filter, wash with isopropyl ether, and recrystallize with ethanol to obtain 70 g of a yellow solid with a melting point of 227-229°C and a yield ...

Embodiment 3

[0013] Measure 800 ml of absolute ethanol in a three-necked flask, cool to 0-5°C while stirring, and add 430 ml of acetyl chloride dropwise. After dropping, react at 0-5°C for a period of time, add 85 grams of 6-cyano-2-naphthol, react at 10°C for 10 hours, add methyl tert-butyl ether and stir for 1 hour to filter, filter cake with methyl Wash with tert-butyl ether, dry it, mix it with ethanol directly, heat to 50°C, pass through dry ammonia gas for 3 hours, and evaporate to dryness under reduced pressure to obtain a yellow solid. It was mixed with saturated sodium bicarbonate solution and stirred for a period of time, filtered and washed with water until neutral. Suspend the wet product in methanol, add a certain amount of methanesulfonic acid solution dropwise, add methyl tert-butyl ether to precipitate a solid, filter, wash with methyl tert-butyl ether, and recrystallize with ethanol to obtain 75 grams of a yellow solid with a melting point of 227 ° C ~ 230°C, yield 53%.

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Abstract

The present invention relates to a new synthetic method of nafamostat mesylate intermediate - 6-amidino-2-naphthol mesylate. The new method uses 6-hydroxyl-2-naphthaldehyde as a raw material, and uses dimethyl sulfoxide as a reaction solvent to react with hydroxylamine hydrochloride for addition and elimination to obtain 6-cyano-2-naphthol, 6-cyano-2-naphthol A pinner reaction occurs in HCl / methanol solution to obtain 6-hydroxyl-2-naphthiminomethyl ester hydrochloride, and then feed ammonia to carry out ammonolysis reaction to obtain 6-amidino-2-naphthol, 6-amidino ‑2‑naphthol is successively reacted with sodium bicarbonate and methanesulfonic acid to be converted into 6‑amidino‑2‑naphthol mesylate. In the new synthetic method, the preparation of the first step 6-cyano-2-naphthol adopts a brand-new method, which avoids the use of highly toxic copper cyanide in the traditional method, and is simple to operate and mild in condition; the second step adopts an improved The pinner method uses the reaction of acetyl chloride and methanol to generate HCl instead of directly passing HCl gas into the reaction system. The improved method is more operable and easier to realize industrialization.

Description

technical field [0001] The invention belongs to the field of drug synthesis of organic chemistry, and relates to a new method for synthesizing 6-amidino-2-naphthol mesylate, an intermediate of nafamostat mesylate, a drug for treating acute pancreatitis. Background technique [0002] Nafamostat mesylate was first developed by Torii Pharmaceutical Co., Ltd. of Japan, and the listed manufacturers are Torii Pharmaceutical Co., Ltd. and Wanyou Pharmaceutical Co., Ltd. It was launched in Japan in October 1986 and is mainly used for the treatment of acute pancreatitis. . Its chemical name is 6-amidino-2-naphthyl-4-guanidinobenzoate dimesylate. The earliest synthesis of nafamostat mesylate is to use 6-bromo-2-naphthol as a raw material to obtain 6-cyano-2-naphthol through cyanation reaction with copper cyanide, and then to obtain 6-cyano-2-naphthol in anhydrous methanol or absolute ethanol Into HCl gas to saturation, add 6-cyano-2-naphthol for pinner reaction to obtain 6-hydroxyl-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C257/18C07C309/04C07C303/32
Inventor 宛六一付冀峰李树明
Owner BEIJING LABWORLD BIO MEDICINE TECH
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