Industrial production method of midazolam derivative

A midazolam, industrial manufacturing technology, applied in the field of industrial manufacturing of midazolam derivatives, can solve the problems of lengthy synthetic routes, lower production efficiency, higher production costs, etc., to increase operational difficulties, increase costs, reduce The effect of three waste discharge

Inactive Publication Date: 2016-10-19
王志训
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] From the above synthetic route, it can be found that in the existing technology, the synthesis of this compound often has problems such as lengthy synthetic route, complicated steps, complicated by-products, and difficult separation, which in turn reduces production efficiency and increases production cost.

Method used

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  • Industrial production method of midazolam derivative
  • Industrial production method of midazolam derivative
  • Industrial production method of midazolam derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] The reaction equation is as follows:

[0061]

[0062] Put 500ml of toluene, 250g of A, and 130g of B into the reaction kettle respectively, add 10g of titanium tetrachloride and reflux for 4 hours to complete the reaction. The reaction product is filtered, hydrolyzed, extracted with ether, concentrated and recrystallized with ethyl acetate to obtain 260g of pure product.

[0063] In the above reaction, the molar ratio of compound A to compound B can also be 1:1 or 1:1.2 or 1:1.5 or 1:1.8 or 1:2, etc., and the solvent can also be selected from cyclohexane and other boiling point Solvent in the range of 40-100 ° C, try to use a high molar ratio catalyst in this reaction such as A: catalyst = 1:0.01 or 1:0.1 or 1:0.5 or 1:1.2 or 1:2, the yield is improved To an insignificant extent, excess catalyst can be recycled.

Embodiment 2

[0065]The reaction equation is as follows:

[0066]

[0067] Put 500ml of tetrahydrofuran and 90g of B into the reaction kettle, and slowly add C78.5g dropwise while stirring. After no gas is released, react for 0.5 hours, add A280g, add 10g of titanium tetrachloride and reflux for 2 hours to complete the reaction. Filtration, hydrolysis, extraction with ethyl acetate, concentration and recrystallization with ethyl acetate:ethanol=2:1 gave pure product 280g.

[0068] In the above reaction, the one-pot input method was tried to carry out the reaction, and the yield was slightly lower than the result of the step-by-step one-pot method. The molar ratio of compounds A, B and C can also be 1:1:1 or 1:1.2:1 or 1:1.5:1.1 or 1:1.8:1.5 or 1:2:1.6, and the solvent can also be selected For cyclohexane and other solvents with a boiling point in the range of 40-100°C, try to use a high molar ratio catalyst in this reaction such as A:catalyst=1:0.01 or 1:0.1 or 1:0.5 or 1:1.2 or 1: 2. ...

Embodiment 3

[0070] The reaction equation is as follows:

[0071]

[0072] Put 500ml of tetrahydrofuran and 90g of B into the reaction kettle, add C60g dropwise while stirring, reflux for 2 hours, slowly add A245g in batches, add 20g of titanium tetrachloride and reflux for 8 hours to complete the reaction, and the reaction product is filtered, hydrolyzed, diethyl ether Extraction, concentration and recrystallization from ethanol afforded 277 g of pure product.

[0073] In the above reaction, try to adopt the one-pot input method for the reaction or react the raw materials A and B first and then add the raw material C, and the yield is equivalent to the result of the step-by-step one-pot method. The molar ratio of compounds A, B and C can also be 1:1:1 or 1:1.2:1 or 1:1.5:1.1 or 1:1.8:1.5 or 1:2:1.6 etc. Compound C can also be Selected from such as ethyl acetate, phenyl acetate, benzyl acetate, etc., the solvent can also be selected as cyclohexane and other solvents with a boiling poin...

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Abstract

The present invention relates to an industrial production method of a midazolam derivative. The industrial production method is characterized in that a compound A and a compound B are subjected to a ring-forming reaction under the condition of a catalyst. According to the present invention, the production method is simple, and is different from the complex production way and the stringent production conditions in the prior art; the synthesis of the target product can be achieved through the one step; the yield can be increased by at least 50% compared to the multi-step synthesis in the prior art; and the production process and the synthesis route are optimized, such that the advantages of less side reaction, convenient post-treatment and mild production condition during the production process are provided, and the method is suitable for the industrial production mode.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to an industrial manufacturing method of midazolam derivatives. Background technique [0002] Midazolam is an anxiolytic, sedative, hypnotic, muscle relaxant, and anticonvulsant drug. Because of its fast pharmacological action, fast metabolism and short duration, it is widely used in the treatment of various insomnia and sleep rhythm disorders. Injections are also widely used in endoscopy and preoperative administration. Therefore, its prodrugs often receive extensive attention in the pharmaceutical field. [0003] The structural formulas of the most commonly used derivatives are shown below: [0004] [0005] In the traditional preparation method, it is often used to synthesize the intermediate shown in the following structural formula first and then carry out the ring-forming reaction, [0006] [0007] And in the existing preparation method, the synthetic method for abov...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D243/16C07D487/04
Inventor 王志训
Owner 王志训
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