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A kind of preparation method of 3-[(2-guanidino-4-thiazole) methylthio] propanimidic acid methyl ester

A technology of methyl alanimidate and methylsulfanyl, which is applied in the field of intermediate preparation of famotidine, can solve the problem of industrial production of methyl alanimidate, low production cost, decreased quality of life of patients, and Compliance and other issues, to achieve the effect of reducing reaction time, simple and easy preparation, and easy industrial production

Active Publication Date: 2019-02-05
ZHEJIANG WILD WIND PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, with the development of our society, environmental changes, changes in population structure and people's lifestyles, the incidence of peptic ulcer mainly caused by smoking, drinking, emotional stress, drug stimulation, etc. is gradually increasing, becoming a common and frequently-occurring disease. Bring great pain to the patient, leading to a decline in the quality of life of the patient
Due to the following problems in traditional peptic ulcer drugs: one is the effect; the other is the patient's compliance; the third is the economic problem
[0006] In the prior art, there is still no 3-[(2-guanidino-4-thiazole) methylthio] propanimidic acid methyl ester which is easy to industrialized production and has a low production cost method

Method used

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  • A kind of preparation method of 3-[(2-guanidino-4-thiazole) methylthio] propanimidic acid methyl ester
  • A kind of preparation method of 3-[(2-guanidino-4-thiazole) methylthio] propanimidic acid methyl ester
  • A kind of preparation method of 3-[(2-guanidino-4-thiazole) methylthio] propanimidic acid methyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 1) Add 600L of methanolic hydrogen chloride solution (the mass percentage of hydrogen chloride in the methanolic hydrogen chloride solution is 25%) to the reaction kettle. After the feeding is completed, start stirring, control the temperature of the reaction kettle at -3~-1°C, and then add 300kg of the starting material 2- (4-((2-cyanoethylmercapto) methyl) thiazol-2-yl) guanidine (formula I), the addition is completed and the temperature is controlled at -3~-1°C and the stirring reaction is carried out for 4 hours. Introduce hydrogen chloride gas, the ventilation time is about 9 hours, the ventilation is completed, and the reaction is incubated and stirred for 2 hours to obtain the reaction solution containing the compound of the formula II structure;

[0030]

[0031] 2) Add 6000L of drinking water and 800kg of sodium carbonate into the neutralization kettle, stir to dissolve, then control the temperature at -3~-1°C, and slowly add the reaction solution containing ...

Embodiment 2

[0035] 1) Add 500L of methanolic hydrogen chloride solution (the mass percentage of hydrogen chloride in the methanolic hydrogen chloride solution is 20%) to the reaction kettle, after the feeding is completed, start stirring, control the temperature of the reaction kettle at -5~-3°C, and then add 300kg of the starting material 2- (4-((2-cyanoethylmercapto) methyl) thiazol-2-yl) guanidine (formula I), the addition is completed and the temperature is controlled at -5~-3°C and the reaction is stirred for 3 hours. Introduce hydrogen chloride gas, the ventilation time is about 8 hours, the ventilation is finished, and the reaction is incubated and stirred for 1.5 hours to obtain the reaction solution containing the compound of formula II;

[0036]

[0037]2) Add 5000L of drinking water and 800kg of sodium carbonate into the neutralization tank, stir to dissolve, then control the temperature at -5~-3°C, and slowly add the reaction solution containing the compound of formula II pr...

Embodiment 3

[0041] 1) Add 700L of hydrogen chloride methanol solution (the mass percentage of hydrogen chloride in the hydrogen chloride methanol solution is 30%) to the reaction kettle, after the feeding is completed, start stirring, control the temperature of the reaction kettle at -1~0°C, and then add 300kg of the starting material 2-( 4-((2-cyanoethylmercapto)methyl)thiazol-2-yl)guanidine (formula I), after feeding, control the temperature -1~0°C and stir for 5 hours. Into hydrogen chloride gas, the ventilation time is about 10 hours, the ventilation is finished, and the insulated and stirred reaction is carried out for 3 hours to obtain the reaction solution containing the compound of formula II structure;

[0042]

[0043] 2) Add 7000L of drinking water and 800kg of sodium carbonate to the neutralization tank, stir to dissolve, then control the temperature at -1 to 0°C, slowly add the reaction solution containing the compound of formula II prepared in step 1) into the neutralizati...

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Abstract

The invention provides a method for preparing methyl 3-[(2-guandine-4-thiazole)methylthio]propionimidate, comprising the following steps: 1) subjecting 2-(4-(4((2-cyanoethylthio)methyl)thiazole-2-yl)guanidine of formula I structure to reaction with methanol and hydrogen chloride to obtain a compound for formula II structure; 2) subjecting the compound of formula II structure to reaction with sodium carbonate solution to obtain the methyl 3-[(2-guanidine-4-thiazole)methylthio]propionimidate. The method for preparing methyl 3-[(2-guanidine-4-thiazole)methylthio]propionimidate is simple and feasible, results in little impurity, is good in controllability and easy to industrially produce on large scale and has a promising application prospect .

Description

technical field [0001] The invention relates to the field of intermediate preparation of famotidine, in particular to a preparation method of 3-[(2-guanidino-4-thiazole)methylthio]propionimidate methyl ester. Background technique [0002] 3-[(2-guanidino-4-thiazole)methylthio]propionimidate methyl ester (referred to as iminomethyl ether), iminomethyl ether is an intermediate for the manufacture of famotidine, famotidine It is a H2 receptor antagonist and a new type of drug that inhibits gastric acid secretion. In the acidic environment of the tubules of the gastric parietal cells, it is converted into an active sulfinic acid amine derivative, which is linked to H + , K + - on the sulfhydryl group of adenosine triphosphamide (ATP) enzyme (H + , K + -ATPase catalyzes the last step in the process of gastric acid secretion), so inactivation of H + , K + -ATPase, inhibits both centrally and peripherally regulated gastric acid secretion. Famotidine has obvious inhibitory ef...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/48
CPCC07D277/48
Inventor 周卫国张拥军吴永志单挺挺田华东孔荣芳王琰琰
Owner ZHEJIANG WILD WIND PHARMA