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Synthesis of 1-(2-dimethylaminoethyl)-5-mercaptotetrazole

A technology of dimethylaminoethyl and mercaptotetrazole, which is applied in the field of medicine, can solve problems such as non-compliance with environmental protection situation, unfavorable industrial transformation, and large safety hazards, and achieve high industrial application value, increased yield, and improved safety. Effect

Active Publication Date: 2021-07-06
SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The process requires three-step reactions to obtain the target product, and the yield is only 48.0%. Both the raw material carbon disulfide and the carbon oxysulfide gas produced in the process have a relatively large odor that does not meet the current environmental protection situation, and sodium azide It is a highly toxic drug, which poses a great safety hazard when used, and is not conducive to industrial transformation

Method used

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  • Synthesis of 1-(2-dimethylaminoethyl)-5-mercaptotetrazole
  • Synthesis of 1-(2-dimethylaminoethyl)-5-mercaptotetrazole
  • Synthesis of 1-(2-dimethylaminoethyl)-5-mercaptotetrazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] (1) In a 500ml three-necked flask, dissolve 40g of N,N-dimethylethylenediamine and 2g of triethylamine in 250ml of dichloromethane and stir well, then add 62g of thiophosgene dropwise at a controlled temperature of 18-20°C for 2 hours. After the addition was completed, the temperature was raised to reflux after 0.5h of heat preservation to continue the reaction for 3h, and the dichloromethane was spin-dried to obtain 63.3g of isothiocyanate;

[0051] (2) In a 500ml three-neck flask, dissolve 52.3g of azidotrimethylsilane in 300ml of acetonitrile and stir evenly, and add the isothiocyanate obtained in step (1) dropwise at a controlled temperature of 38-40°C for 1 hour. After the completion of the insulation reaction for 2h. Cool down to 20°C and add 30wt.% concentrated hydrochloric acid dropwise to adjust the acid to pH=2.5. After filtering, rinse the filter cake three times with 120ml ethanol to obtain 1-(2-dimethylaminoethyl)-5-mercaptotetrazolium hydrochloride Salt 9...

Embodiment 2

[0057] (1) In a 500ml three-necked flask, dissolve 40g of N,N-dimethylethylenediamine and 2g of DMAP in 250ml of dichloromethane and stir well, add 64.5g of thiophosgene dropwise at a temperature of 20-22°C, dropwise for 2.5h Finished; warming up to reflux after 0.6h of heat preservation to continue reaction for 4h, spin-dried dichloromethane to obtain 66.7g of isothiocyanate;

[0058] (2) In a 500ml three-necked flask, dissolve 54.2g of azidotrimethylsilane in 300ml of acetonitrile and stir evenly, and add the isothiocyanate obtained in step (1) dropwise at a controlled temperature of 35-40°C for 1.2 hours. After the addition was completed, the reaction was incubated for 2.5 hours. Cool down to 21°C and add 30wt.% concentrated hydrochloric acid dropwise to adjust the acidity to pH=2.3. After filtering, rinse the filter cake three times with 150ml methanol to obtain 1-(2-dimethylaminoethyl)-5-mercaptotetrazolium hydrochloric acid Salt 91.8g;

[0059] (3) Add 1-(2-dimethylami...

Embodiment 3

[0061] (1) In a 500ml three-necked flask, dissolve 40g of N,N-dimethylethylenediamine and 2g of pyridine in 250ml of dichloromethane and stir well, then add 63.3g of thiophosgene dropwise at a controlled temperature of 20-22°C for 2.5 hours After the addition was completed, the temperature was raised to reflux to continue the reaction for 4 hours after being kept warm for 1 hour, and the dichloromethane was spin-dried to obtain 63.7 g of isothiocyanate;

[0062] (2) In a 500ml three-necked flask, dissolve 53.7g of azidotrimethylsilane in 300ml of acetonitrile and stir evenly, and add the isothiocyanate obtained in step (1) dropwise at a controlled temperature of 40-42°C for 1.5 hours. After the addition was completed, the reaction was incubated for 3 hours. Cool down to 22°C and add 30wt.% concentrated hydrochloric acid dropwise to adjust the acidity to pH=2.3. After filtering, rinse the filter cake three times with 150ml isopropanol to obtain 1-(2-dimethylaminoethyl)-5-mercap...

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Abstract

The invention belongs to the technical field of medicine, and in particular relates to a synthesis method of 1-(2-dimethylaminoethyl)-5-mercaptotetrazole. N,N‑Dimethylethylenediamine reacts with thiophosgene to give isothiocyanate, and reacts isothiocyanate with azidotrimethylsilane to give 1‑(2‑dimethylaminoethyl)‑ 5‑mercaptotetrazolium hydrochloride, 1‑(2‑dimethylaminoethyl)‑5‑mercaptotetrazolium hydrochloride is dissolved in water, decolorized and crystallized to obtain 1‑(2‑dimethylaminoethyl )‑5‑mercaptotetrazole. The present invention uses N,N-dimethylethylenediamine and thiophosgene to synthesize isothiocyanate in one step, which simplifies the synthesis process and greatly improves the yield; the cyclization process uses non-toxic azidotrimethylsilane It replaces the highly toxic sodium azide, improves the safety of the process, and is more suitable for industrial scale-up.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a synthesis method of 1-(2-dimethylaminoethyl)-5-mercaptotetrazole. Background technique [0002] 1-(2-Dimethylaminoethyl)-5-mercaptotetrazole is an important pharmaceutical intermediate, mainly used in the synthesis of the antibiotic cefotiam. Cefotiam hydrochloride is a second-generation semi-synthetic cephalosporin developed by Takeda Corporation of Japan and first listed in Japan in 1981; Haemobacterium, Escherichia coli, Klebsiella, Proteus mirabilis, etc. have better effects, and also have antibacterial effects on Enterobacter, Citrobacter, indole-positive Proteus, etc.; used to treat infections caused by sensitive bacteria, Such as pneumonia, bronchitis, biliary tract infection, peritonitis, urinary tract infection, infection and sepsis caused by surgery and trauma. [0003] At present, there are few reports on the synthesis methods of 1-(2-dimethylaminoethy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D257/04
CPCC07D257/04
Inventor 赵奇侯乐伟赵文勇蔡会敏张蕾李佳
Owner SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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