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Preparation method of acotiamide intermediate

A technology of acotiamide and intermediates, applied in directions such as organic chemistry, can solve problems such as inability to realize industrialized production, unfavorable large-scale production, expensive trifluoromethanesulfonate, etc., and achieve high implementation value and social, economic and environmental protection benefits, The effect of less waste, easy separation and reuse

Active Publication Date: 2016-03-30
山东金城昆仑药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The hydroxyl protecting group used in this process route is conducive to reducing by-products and improving the quality of intermediates, but the protective agent 2-tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTF) used is more expensive, which is not conducive to industrialized production
[0024] In addition, Tianjin University's master's thesis discussed the above-mentioned "process route 1" and "process route 2", and made improvements on the basis of "process route 1", but the change did not affect "process route 1". Great improvement has been produced, and industrialized production cannot be realized

Method used

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  • Preparation method of acotiamide intermediate
  • Preparation method of acotiamide intermediate
  • Preparation method of acotiamide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Preparation of Compound III: Add 2.12g (0.01mol) of II into the reaction flask, then add 1.66g (0.014mol) of thionyl chloride and 10.6ml of toluene, heat the system to reflux, keep the reaction for 1.5h, after the reaction is completed Concentrate under reduced pressure to obtain compound III;

[0055] Preparation of compound IV: Dissolve compound III (theoretical content of 0.01mol) obtained by concentration in tetrahydrofuran, and then add it dropwise to a reaction flask containing 0.84g (0.011mol) of thiourea in 16.0ml of tetrahydrofuran solution. , the temperature of the system was raised to reflux, and after the reaction was completed, the system was concentrated to obtain compound IV;

[0056] Preparation of Compound I: Dissolve Compound IV (theoretical content of 0.01mol) obtained by concentration in 25ml of methanol, then add ethyl bromopyruvate 2.05 (0.0105mol) and potassium carbonate 1.45g (0.0105), heat to reflux, keep Reflux reaction for 2.5±0.5h, evaporate...

Embodiment 2

[0059]Preparation of Compound III: Add 2.12g (0.01mol) of II into the reaction flask, then add 1.90g (0.016mol) of thionyl chloride and 11.6ml of toluene, heat the system to 80±5°C, react for 1.5h, and react Concentrate under reduced pressure after completion to obtain compound III;

[0060] Preparation of Compound IV: Dissolve Compound III (theoretical content of 0.01 mol) obtained by concentration in tetrahydrofuran, and then add it dropwise to a reaction flask containing 0.76 g (0.010 mol) of thiourea in 15.0 ml of tetrahydrofuran solution, and the addition is complete Afterwards, the temperature of the system was raised to reflux, TLC showed that the reaction was completed in 2 hours, and the system was concentrated to obtain compound IV;

[0061] Preparation of compound I: Dissolve compound IV (theoretical content of 0.01mol) obtained by concentration in 30ml of absolute ethanol, then add ethyl bromopyruvate 2.24 (0.0115mol) and potassium carbonate 1.59g (0.0115), and hea...

Embodiment 3

[0064] "One-pot method" to prepare compound Ⅰ: add 2.12g (0.01mol) of Ⅱ into the reaction flask, then add 1.78g (0.015mol) of thionyl chloride and 10.6ml of toluene, heat the system to 80±5℃, and keep it warm React for 1.5h, after the reaction is completed, concentrate under reduced pressure to obtain compound III; dissolve the concentrated compound III in tetrahydrofuran, and then add it dropwise to a reaction flask containing 0.80 g (0.0105 mol) of thiourea in 16.0 ml of tetrahydrofuran solution, drop After the addition, the system was heated to reflux. After the reaction was completed, the system was concentrated to obtain compound IV; the concentrated compound IV was dissolved in 25ml of absolute ethanol, and then ethyl bromopyruvate 2.15 (0.011mol) and carbonic acid were added Potassium 1.52g (0.011mol), heat to reflux, keep reflux for 1h, distill anhydrous alcohol under reduced pressure, add water to stir, filter, wash with water to obtain the crude product; disperse the ...

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Abstract

The invention belongs to the field of medicines, and concretely relates to a preparation method of an acotiamide intermediate. The method comprises the following steps: preparing acyl chloride from 2,4,5-trimethoxybenzoic acid, condensing acyl chloride and thiourea, and carrying out ring closure on the obtained material and haloalkyl pyruvate to prepare the acotiamide intermediate compound I. The structural formula of the acotiamide intermediate is shown in the description. A simple and easily available initial raw material is used in the invention, so the production cost is reduced. The method has the advantages of advanced process route, mild reaction conditions, high reaction yield, few three wastes, no expensive or toxic reagents, easy separation and reuse of a reaction solvent, indiscriminate application of the reaction solvent after distillation, easy industrial production, large enforcement values, and large social, economic and environmentally-friendly benefits.

Description

Technical field [0001] The invention belongs to the field of medicine, and specifically relates to a preparation method of acotiamide intermediate. Background technique [0002] Acotiamide hydrochloride is the world's first approved treatment for functional dyspepsia. [0003] At present, the patents related to the synthesis of acotiamide hydrochloride mainly include CN96194002.6, CN98806579.7, CN201010571046.0, CN201210145398.9, CN201410024859.6, CN201310713514.7 and WO2012077673. [0004] The specific analysis is as follows: [0005] Synthetic route 1 (reference patent: WO9636619, CN96194002.6; application date, May 16, 1996) [0006] [0007] This process route is a patented compound route. The process is relatively stable and the main raw materials are easily available. However, this route uses the dichlorine solvent chloroform (residue limit 60ppm) and HCl gas, which requires high equipment and is not conducive to industrial production. . [0008] 2) Synthetic ro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 赵承彪孙滨马庆双王晓光
Owner 山东金城昆仑药业有限公司
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