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The synthetic method of buflomedil hydrochloride intermediate 1,3,5-trimethoxybenzene

A technology of buflomedil hydrochloride and trimethoxybenzene, which is applied in the field of synthesis of buflomedil hydrochloride intermediate 1,3,5-trimethoxybenzene, can solve the problem of low yield, unfavorable safe operation, unfavorable safety Use and other problems to achieve the effect of high reaction yield, simple post-treatment operation, and less side reactions

Active Publication Date: 2021-10-19
THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In route A, metal sodium needs to be reacted with methanol to form sodium methoxide, and then replaced to obtain 1,3,5-trimethoxybenzene; metal sodium is too active, which is not conducive to safe operation, and the yield of this route is low
[0011] In route B, dimethyl sulfate is a highly toxic substance, which is not conducive to safe use; after replacing it with dimethyl carbonate, although the toxicity is reduced, the yield is still low

Method used

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  • The synthetic method of buflomedil hydrochloride intermediate 1,3,5-trimethoxybenzene
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  • The synthetic method of buflomedil hydrochloride intermediate 1,3,5-trimethoxybenzene

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Embodiment 1

[0034] The synthetic method of 1,3,5-trimethoxybenzene comprises the following steps:

[0035] 1) Mix methanol and catalyst evenly, pass in argon, control the pressure to 7 atmospheres, control the temperature to 135°C, keep it for 30 minutes, add dropwise a solution composed of 1,3,5-tribromobenzene and toluene, and control the The dripping time of the solution is 45 minutes. After the solution is added, triethylamine is started to be added dropwise. The dripping time of triethylamine is controlled to be 10 minutes. , and then continue to react for 11h and the reaction ends.

[0036] The preparation method of the catalyst is as follows: mix and grind sodium oxide and barium oxide, pass through a 700-mesh sieve, take the under-sieve to activate at 800°C, mix and grind the obtained mixture with dextran gel, and pass through a 500-mesh sieve to obtain; The weight ratio of sodium to barium oxide is 1:0.32; the weight ratio of the activated mixture to Sephadex is 1:55; the Sephad...

Embodiment 2

[0040] The synthetic method of 1,3,5-trimethoxybenzene comprises the following steps:

[0041] 1) Mix methanol and catalyst evenly, feed nitrogen, control the pressure to 5 atmospheres, control the temperature to 120°C, keep it for 20 minutes, add dropwise a solution composed of 1,3,5-trichlorobenzene and benzene, and control the solution dropwise Adding time is 35 minutes. After adding the solution, start to add pyridine dropwise. Control the dropping time of pyridine to be 5 minutes. After adding pyridine, raise the temperature to 155° C., raise the pressure to 9 atmospheres, and then continue the reaction for 7 hours to complete the reaction.

[0042] The preparation method of the catalyst is: mix and grind sodium oxide and barium oxide, pass through a 500 mesh, take the under-sieve and activate at 700°C, then mix and grind the activated mixture with dextran gel, pass through a 400 mesh sieve to obtain The weight ratio of sodium oxide to barium oxide is 1:0.25; the weight r...

Embodiment 3

[0046] The synthetic method of 1,3,5-trimethoxybenzene comprises the following steps:

[0047] 1) Mix methanol and catalyst evenly, pass in argon, control the pressure to 8 atmospheres, control the temperature to 145°C, keep it for 35min, add dropwise a solution composed of 1,3,5-triiodobenzene and xylene, and control The solution dripping time is 50min. After the solution is added, N,N-diisopropylethylamine is added dropwise, and the dripping time of N,N-diisopropylethylamine is controlled to be 12min. After the addition of ethylethylamine, the temperature was raised to 170°C, the pressure was raised to 12 atmospheres, and the reaction was continued for 13 hours to complete the reaction.

[0048] The preparation method of the catalyst is as follows: mix sodium oxide and barium oxide, grind them, pass through 800 meshes, take the undersieve and activate them at 850°C, then mix and grind the activated mixture with dextran gel, pass through a 600 meshes sieve to obtain The weig...

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Abstract

According to the synthesis method of buflomedil hydrochloride intermediate 1,3,5-trimethoxybenzene of the present invention, trihalogenated benzene and methanol are reacted under the action of a catalyst to obtain 1,3,5-trimethoxybenzene. The reaction process is as follows: 1) Mix methanol and catalyst evenly, pass in protective gas, control the pressure to 5-8 atmospheres, control the temperature to 120-145° C., keep it for 20-35 minutes, add dropwise the trihalogenated benzene and For solution B composed of solvent A, the time for adding solution B is controlled to be 35-50 minutes. After the addition of solution B, the acid-binding agent is added dropwise. The time for adding the acid-binding agent is controlled to be 5-12 minutes. Increase the temperature to 155-170°C, raise the pressure to 9-12 atmospheres, and then continue the reaction for 7-13 hours to complete the reaction; 2) After cooling the system, filter to remove the solids, add the filtrate to 3-6 times the volume of water, and then Extract with solvent C, dry the extract with a desiccant, concentrate and distill off the solvent to obtain the product. The synthetic method of the invention avoids the use of highly toxic and harmful substances, and simultaneously has a higher yield.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a method for synthesizing buflomedil hydrochloride intermediate 1,3,5-trimethoxybenzene. Background technique [0002] Buflomedil hydrochloride, the chemical name is 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl) butanone hydrochloride, the chemical structure is shown below. [0003] [0004] It is a vasodilator drug for the treatment of brain and peripheral vascular disorders developed by Lafon Company in France. The trade name is Fonzylane, Huoxingling, etc. Buflomedil hydrochloride is a vasoactive compound with multiple pharmacological effects: blocking α-adrenergic receptors, relaxing vascular smooth muscle, inhibiting platelet aggregation, improving microcirculation, increasing and improving red blood cell deformability and filterability, Reduce blood viscosity, weak calcium antagonism and increase oxygen partial pressure, etc. At present, it is widely used clinically...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C41/16C07C43/205
CPCC07C41/16C07C43/2055
Inventor 谭回李维平黄国栋黄贤键唐爱发刘文兰
Owner THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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