New 6-amidino-2-naphthol methanesulfonate synthesis method

A technology of naphthol mesylate and synthetic method, which is applied in the field of drug synthesis of organic chemistry, can solve problems affecting product quality and yield, HCl gas waste, air pollution, etc., and achieve consistent product quality, low environmental pollution, The effect of low equipment requirements

Active Publication Date: 2014-07-02
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 and pollutes the atmosphere, and the alcohol needs to be distilled out after the reaction. Long-term heating will cause the decomposition of 6-hydroxy-2-naphthiminomethyl ester hydrochloride, which directly affects the quality of the product. and yield

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0009] Add 350 grams of 6-hydroxy-2-naphthalene carboxaldehyde (2.0mol), 278 grams of hydroxylamine hydrochloride (4.0mol) and 3500 milliliters of dimethyl sulfoxide in a 5000-milliliter there-necked flask, stir and heat to 100° C., heat the reaction for 1 hour, reduce After reaching room temperature, the reaction solution was mixed with a large amount of water, and a solid was precipitated under stirring. After filtration, the filter cake was washed with water to obtain a wet crude product, which was directly recrystallized with ethanol / aqueous 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. with stirring, and add 430 ml of acetyl chloride (5.0 mol) dropwise. After dropping, react for a period of time at 0~5 ℃, put in 85 g (0.5mol) of 6-cyano-2-naphthol, react at 10 ℃ for 10 hours, add isopropyl ether, stir for 1 hour and filter, filter cake with isopropyl ether. After washing with propyl ether, it was directly mixed with ml methanol after drying, heated to 50° C., passed through dry ammonia gas for 3 hours, and evaporated 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. The wet product was suspended in methanol, a certain amount of methanesulfonic acid was added dropwise to dissolve, and isopropyl ether was added to separate out the solid, filtered, washed with isopropyl ether, and recrystallized with ethanol to obtain 70 grams of ye...

Embodiment 3

[0013] Measure 800 ml of absolute ethanol in a three-necked flask, cool to 0-5° C. with stirring, and add 430 ml of acetyl chloride dropwise. After dripping, react for a period of time at 0~5℃, put in 85 g of 6-cyano-2-naphthol, react at 10℃ for 10 hours, add methyl tert-butyl ether, stir for 1 hour and filter, filter cake with methyl Washed with tert-butyl ether, dried in the air and mixed with ethanol directly, heated to 50° C., passed through dry ammonia gas for 3 hours, evaporated 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. The wet product was suspended in methanol, a certain amount of methanesulfonic acid was added dropwise to dissolve, and methyl tert-butyl ether was added to precipitate a solid, which was filtered, washed with methyl tert-butyl ether, and recrystallized from ethanol to obtain 75 g of a yellow solid with ...

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Abstract

The present invention relates to a new synthesis method for a nafamostat mesylate intermediate 6-amidino-2-naphthol methanesulfonate. According to the new method, 6-hydroxy-2-naphthaldehyde is adopted as a raw material, dimethyl sulfoxide is adopted as a reaction solvent, the dimethyl sulfoxide and hydroxylamine hydrochloride are subjected to an addition elimination reaction to obtain 6-cyano-2-naphthol, the 6-cyano-2-naphthol is subjected to a pinner reaction in a HCl/methanol solution to obtain 6-hydroxy-2-naphthalene imino methyl ester hydrochloride, ammonia gas is introduced to carry out an aminolysis reaction to obtain 6-amidino-2-naphthol, and the 6-amidino-2-naphthol sequentially reacts with sodium bicarbonate and methanesulfonic acid to convert into the 6-amidino-2-naphthol methanesulfonate. According to the present invention, in the new synthesis method, the 6-cyano-2-naphthol preparation in the first step adopts the completely-new method, the use of the highly toxic copper cyanide in the traditional method is avoided, the operations are simple, and the conditions are mild; and the second step adopts the improved pinner method, wherein the reaction of acetyl chloride and methanol is adopted to produce HCl to replace direct introduction of HCl gas into the reaction system, such that the improved method has strong operability and industrialization is easily achieved.

Description

Technical field: [0001] The invention belongs to the field of drug synthesis in organic chemistry, and relates to a new method for synthesizing nafamostat mesylate, an intermediate of a drug for treating acute pancreatitis, 6-amidino-2-naphthol mesylate. Background technique: [0002] Nafamostat mesylate was first developed by Torii Pharmaceutical Co., Ltd. of Japan. 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 dimethanesulfonate. The earliest synthesis of nafamostat mesilate was 6-bromo-2-naphthol as raw material, and 6-cyano-2-naphthol was obtained by cyanation reaction with copper cyanide, and then in anhydrous methanol or anhydrous ethanol. Introduce HCl gas to saturation, add 6-cyano-2-naphthol to generate pinner reaction to obtain 6-hydroxy-2-naphthylimid...

Claims

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Application Information

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Patent Type & Authority Applications(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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