Synthesizing method of 2-pyridine methyl sulfide and synthesizing process of related drugs

A technology of picolyl sulfide and synthesis method, which is applied in the direction of organic chemistry, can solve problems such as environmental pollution of halogenated substances, and achieve the effects of good applicability, high yield, and easy operation

Active Publication Date: 2019-01-04
TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this synthetic method is severely limited due to the use of highly functionalized halides as starting materials
In addition, the halides generated in the reaction have environmental pollution problems

Method used

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  • Synthesizing method of 2-pyridine methyl sulfide and synthesizing process of related drugs
  • Synthesizing method of 2-pyridine methyl sulfide and synthesizing process of related drugs
  • Synthesizing method of 2-pyridine methyl sulfide and synthesizing process of related drugs

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Experimental program
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Effect test

Embodiment 1

[0037]

[0038] 2-Methylpyridine nitroxide (507mg, 4.65mmol) was dissolved in ethyl acetate (12ml) at room temperature, then trifluoroacetic anhydride (2.44g, 11.6mmol) was added. The reaction was refluxed for two hours. The completion of the reaction was monitored by TLC, and the reaction solution was concentrated to obtain the trifluoroacetate intermediate, which was directly used for the next step. The reaction intermediate was dissolved in toluene (6ml), then 4-methylthiophenol (577mg, 4.65mmol), tetrabutylammonium bromide (300mg, 0.93mmol) were added, and the reaction was heated under reflux for five hours, and the reaction was monitored by TLC At the end, add saturated sodium carbonate aqueous solution to the reaction solution to adjust the pH to 7-8, then separate the liquids, extract the aqueous phase with ethyl acetate three times, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and use PE-PE / EA (50:1~1:3) was used as ...

Embodiment 2

[0040]

[0041] The synthetic method of embodiment 2 is the same as above-mentioned synthetic general method.

[0042] Reaction yield: 71%; Structural parameters: 1 H NMR (400MHz, CDCl 3 )δ8.54(d, J=4.4Hz, 1H), 7.62-7.58(m, 1H), 7.32(d, J=7.6Hz, 1H), 7.16-7.7.13(m, 4H), 6.98(t , J=4.0 Hz, 1H), 4.26(s, 2H), 2.28(s, 3H). 13 C NMR (100MHz, CDCl 3 )δ157.4,148.9, 138.2,136.3,135.3,129.8,128.4,126.9,126.1,122.7,121.7,40.1,21.0.HRMS (+ESI-TOF)m / z:[M+H] + Calcd for C 13 h 14 NS 216.0841; Found 216.0840.

Embodiment 3

[0044]

[0045] The synthetic method of embodiment 3 is the same as above-mentioned synthetic general method.

[0046] Reaction yield: 70%; Structural parameters: 1 H NMR (400MHz, CDCl 3 )δ8.51(d, J=4.8Hz, 1H), 7.59-7.55(m, 1H), 7.26(d, J=8.8Hz, 2H), 7.18(d, J=8.0Hz, 1H), 7.13( dd,J=5.2,6.8Hz,1H),6.77(d,J=8.8Hz,2H),4.13(s,2H),3.75(s,3H). 13 C NMR (100 MHz, CDCl 3)δ159.3, 158.1, 149.3, 136.6, 134.0, 125.6, 123.3, 122.0, 114.6, 55.3, 42.7.HRMS(+ESI-TOF)m / z:[M+H] + Calcd for C 13 h 14 NOS 232.0791; Found 232.0777.

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Abstract

The invention relates to a simple synthesizing method of 2-pyridine methyl sulfide and related drugs. The method is characterized in that 2-methyl pyridine n-oxide is used as the raw material and pyridine n-oxide or dichloromethane is used as the solvent to have reaction with trifluoroacetic anhydride to obtain a trifluoroacetate intermediate, purification is not needed, the trifluoroacetate intermediate is allowed to have reaction with thiophenol under the catalysis of lithium bromide or tetrabutyl ammonium bromide and by using toluene or ethyl acetate as the solvent to generate the 2-pyridine methyl sulfide. The method is simple to operate, cheap in reagents, easy in reagent obtaining, mild in reaction conditions, wide in substrate applicability, good in position selectivity, high in yield and the like. In addition, the method is successfully applied to the synthesizing of omeprazole sulfide and rabeprazole sulfide, and the synthesizing method does not need catalysts.

Description

technical field [0001] The invention belongs to the field of new compound synthesis and drug application, and relates to a synthesis method of 2-pyridylmethyl sulfide and a new synthesis process of related drugs. technical background [0002] Thioethers are ubiquitous in nature and are important synthetic precursors for many drugs or functional materials. 2-Pyridylmethylsulfide is a very important class of thioethers because it is the precursor of many biologically active compounds. In addition, it is also an important intermediate of several marketed drugs, including omeprazole, pantoprazole, lansoprazole, rabeprazole. [0003] The traditional synthesis method of thioethers uses organic halides and mercaptans as reaction raw materials, and prepares them under the action of a base, which is similar to the Williamson ether synthesis reaction. However, this synthetic method is severely limited due to the use of highly functionalized halides as starting materials. In additio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/32C07D213/70C07D405/12C07D413/12C07D213/61C07D213/80C07D213/803C07D401/12
CPCC07D213/32C07D213/61C07D213/70C07D213/80C07D213/803C07D401/12C07D405/12C07D413/12
Inventor 王栋郁彭刘振林王振涛
Owner TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY
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