Fudosteine synthesis method

A synthesis method and dropwise addition technology are applied in the preparation of sulfide, organic chemistry and other directions, and can solve the problems of many impurities, high cost and high residue.

Active Publication Date: 2014-09-10
ZHEJIANG GUOBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The problem of this process is that the inorganic salt is not easy to remove, the residue is high (≥0.05%), and bromopropanol is relatively expensive and the cost is high
[0010] Although this method solves the residue problem, the reaction is incomplete and the yield is low (≤80%)
[0011] In Chinese patent ZL200510059733.3, L-cysteine ​​and propylene alcohol are used to prepare fudosteine ​​under thermal triggering. Although this process is relatively simple, there are problems with many impurities and low product purity (≤95%). Low rate (≤85%)
[0012] In the document "Study on the Synthesis of Fudosteine", L-cysteine ​​reacts with allyl alcohol, and potassium persulfate and sodium sulfite are used as a free radical initiation system to prepare fudosteine. There are also high residues (≥0.05%). question

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1 1. Take 30g (0.25mol) of L-cysteine, put it into a 1000ml four-necked flask, add 330g of purified water, mix, stir and dissolve at 25°C, add 21.6g (0.37mol) of propenyl alcohol, and then add After adding 0.03g of elemental iron, slowly add 3g of hydrogen peroxide with a concentration of 1% dropwise at a temperature of 0°C-5°C, dropwise for 5min, after dropping, keep warm for 30min at a temperature of 0°C-5°C, After heat preservation, heat up to 70°C, filter, heat up the filtrate, and recover the solvent under reduced pressure at a vacuum degree above 0.08Mpa. After solids are precipitated, stop the recovery, heat up to complete dissolution, and then slowly add 20 times the weight ratio dropwise while cooling. When cooled to 20°C, stir for 1 hour, shake off the filter, dry the filter cake, add 0.5 times the weight ratio of purified water for recrystallization, heat up to reflux, keep warm for 30min, and then slowly drop while cooling Add 5 times the weight rat...

Embodiment 2

[0022] Example 2 1. Take 30g (0.25mol) of L-cysteine, put it into a 1000ml four-necked flask, add 330g of purified water, mix, stir and dissolve at 25°C, add 15.1g (0.26mol) of allyl alcohol, and then add 6g of elemental aluminum, after adding, slowly add 10gH at a concentration of 1% at a temperature of 10°C-15°C 2 o 2 , add dropwise for 10 minutes, after dropping, keep warm for 30 minutes at a temperature of 10°C-15°C, finish keeping warm, heat up to 70°C, filter, heat up the filtrate, recover the solvent under reduced pressure at a vacuum degree of 0.08Mpa or more, and wait for solids to precipitate out. Stop recovery, heat up to complete dissolution, then slowly add anhydrous ethanol dropwise with a weight ratio of 20 times while cooling, when cooled to 20°C, stir for another hour, shake off the filter, dry the filter cake, and add 0.5 times the weight ratio Recrystallize in purified water, heat up to reflux, keep warm for 30 minutes, then slowly add 5 times the weight ...

Embodiment 3

[0023] Example 3 1. Take 30g (0.25mol) of L-cysteine, put it into a 1000ml four-necked flask, add 330g of purified water, mix, stir and dissolve at 25°C, add 43.14g (0.74mol) of propenyl alcohol, and then add 0.6g of elemental zinc, after adding, slowly add 10g of tert-butyl hydroperoxide with a concentration of 5% dropwise at a temperature of 10°C-15°C, dropwise for 10min, after dropping, at a temperature of 10°C-15°C Insulate for 1 hour, heat up to 70°C, filter, heat up the filtrate, recover the solvent under reduced pressure at a vacuum of 0.08Mpa, stop the recovery after solids are precipitated, heat up to complete dissolution, then slowly add dropwise while cooling Anhydrous ethanol with a weight ratio of 30 times is cooled to 30°C, then stirred for 1 hour, filtered, and the filter cake is dried, then recrystallized with purified water with a weight ratio of 3 times, heated to reflux, kept for 30 minutes, and then cooled , while slowly adding 15 times the weight ratio o...

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PUM

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Abstract

The present invention mainly discloses a synthetic method of fudosteine, which adopts redox system to catalyze free radical reaction, uses L-cysteine ​​as starting material, mixes it with appropriate amount of purified water, and mixes it with appropriate amount of purified water at a certain temperature Stir to dissolve at low temperature, add allyl alcohol, then add transition metal or its salts, gradually add water-soluble peroxide dropwise at a temperature of 0°C-50°C, keep warm for a period of time, filter to remove insoluble matter, and recover unreacted filtrate under reduced pressure Complete solvent and appropriate amount of water. After recovery, ethanol was added for crystallization. The obtained solid is re-crystallized with purified water and dried to obtain the finished product fudosteine ​​(I). The synthesis method of the present invention has mild conditions, high product yield (≥90%), high content (≥99%), and low inorganic salt residue (≤0.01%), which is a very competitive synthetic route.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to a method for synthesizing fudosteine, which belongs to the technical field of drug synthesis. Background technique [0002] Fudosteine ​​is an expectorant with a new mechanism of action. It was approved in Japan in October 2001 to be produced and marketed by Mitsubishi Pharmaceutical Co., Ltd. and SSP Pharmaceutical Co., Ltd. Fudosteine ​​has the advantages of strong efficacy, few side effects, wide indications, and great market potential. [0003] There are two main methods for synthesizing fudosteine, one is the reaction of L-cysteine ​​with halogenated propanol, and the other is the reaction of L-cysteine ​​with allyl alcohol. [0004] In U.S. Patent No. 5,047,428, L-cysteine ​​and bromopropanol are used to react in ethanol aqueous solution of sodium hydroxide to obtain fudosteine, which is then acidified with hydrochloric acid to remove inorganic salts, and then washed with ammonia ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C323/58C07C319/18
Inventor 蒋狄锋刘聪陆乐姚礼高侯仲轲邱家军
Owner ZHEJIANG GUOBANG PHARMA
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