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A kind of preparation method of pinaverium bromide intermediate 2-bromo-4,5-dimethoxybenzyl bromide

A technology of dimethoxybenzyl bromide and pinaverium bromide, which is applied in the field of preparation of 2-bromo-4,5-dimethoxybenzyl bromide, can solve the problems of high production cost, large amount required, and large environmental pollution, etc. problems, to avoid the formation of multi-substituted products, promote free radical substitution reactions, and avoid by-products

Active Publication Date: 2020-11-13
ZHEJIANG NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The prior art uses 3,4-dimethoxybenzyl alcohol or 3,4-dimethoxybenzaldehyde as the basic raw material, which is expensive and has high production costs, and uses toxic liquid bromine or phosphorus tribromide as the bromination reagent , dangerous operation, and great environmental pollution; although 3,4-dimethoxytoluene is used as the basic raw material, the raw material is cheap and easy to obtain, but NBS is used as the brominating agent, the price of NBS is expensive, the effective bromine content is low, and the required amount Large, and the product yield is only 38.6%, so the production cost of this technology is higher, not suitable for industrialization

Method used

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  • A kind of preparation method of pinaverium bromide intermediate 2-bromo-4,5-dimethoxybenzyl bromide
  • A kind of preparation method of pinaverium bromide intermediate 2-bromo-4,5-dimethoxybenzyl bromide
  • A kind of preparation method of pinaverium bromide intermediate 2-bromo-4,5-dimethoxybenzyl bromide

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Experimental program
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Effect test

Embodiment 1

[0053] 3,4-Dimethoxytoluene (7.6g, 50mmol), sodium bromate (6.0g, 40mmol), sodium bromide (8.2g, 80mmol) and carbon tetrachloride (18mL) were added to a stirring, In the reaction flask of the reflux condenser, thermometer and tail gas absorption device, heat to reflux, slowly add 1 / 2 volume of sulfuric acid (diluted 60mmol concentrated sulfuric acid with 4mL water, add it within about 1.5h), track with gas chromatography, After the substrate fully participates in the reaction, quickly add 1 / 3 volume of the initiator solution (0.25g ABVN is dissolved in 7mL carbon tetrachloride to obtain), after the system appears violent reflux, continue to slowly add the remaining sulfuric acid and the initiator solution (about Add within 4.5h), continue to react until the product no longer forms or when by-products increase significantly (about 1.5h), cool down to room temperature, filter, and the filtrate is washed with 10ml sodium bicarbonate solution (5%), let stand to separate the liquid,...

Embodiment 2

[0055] 3,4-Dimethoxytoluene (7.6g, 50mmol), sodium bromate (6.0g, 40mmol), sodium bromide (8.2g, 80mmol) and carbon tetrachloride (18mL) were added to a stirring, In the reaction flask of the reflux condenser, thermometer and tail gas absorption device, heat to reflux, slowly add 1 / 2 volume of sulfuric acid (diluted 60mmol concentrated sulfuric acid with 4mL water, add it within about 1.5h), track with gas chromatography, After the substrate fully participates in the reaction, quickly add 1 / 3 volume of the initiator solution (0.16g AIBN is dissolved in 7mL carbon tetrachloride to obtain), after the system appears violent reflux, continue to slowly add the remaining sulfuric acid and the initiator solution (about Add within 4.5h), continue to react until the product no longer forms or when the by-products increase significantly (about 1.5h), cool down to room temperature, filter, and the filtrate is washed with 10ml sodium bicarbonate solution (5%), separated, and the organic ph...

Embodiment 3

[0057] 3,4-Dimethoxytoluene (7.6g, 50mmol), sodium bromate (6.0g, 40mmol), sodium bromide (8.2g, 80mmol) and carbon tetrachloride (38mL), were added to a stirring, Into the reaction flask of the reflux condenser, thermometer and tail gas absorption device, heat to reflux, slowly add 1 / 2 volume of sulfuric acid (diluted with 60mmol of concentrated sulfuric acid with 4mL of water, add it within about 1h), track with gas chromatography, the bottom After the substance completely participates in the reaction, quickly add 1 / 3 volume of initiator solution (0.25g of azobisisoheptanonitrile dissolved in 7mL of carbon tetrachloride to obtain), after the system appears violent reflux, continue to slowly add the remaining sulfuric acid and trigger (about 4.5h added), continue to react until the product is no longer formed or by-products increase significantly (about 1.5h), down to room temperature, filtered, the filtrate was washed with 10ml sodium bicarbonate solution (5%), separated liq...

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Abstract

The invention provides a preparation method for a pinaverium bromide intermediate 2-bromo-4,5-dimethoxybenzyl bromide. The method comprises the following steps: in a nonpolar solvent, bromine released by a redox reaction of a bromate and a bromide under a sulfuric acid effect is used as a bromine source, the bromine and 3,4-dimethoxymethylbenzene represented by a formula (1) are subjected to an aromatic ring C-H bond electrophilic bromination reaction, after the reaction is fully completed, an initiator and sulfuric acid are added, a benzylic methyl C-H bond free radical bromination reaction is performed, and therefore the 2-bromo-4,5-dimethoxybenzyl bromide represented by a formula (8) is obtained, wherein the reaction equation is shown in the description. According to the invention, a one-pot method is adopted, the raw materials are cheap and easy to obtain, operation is simple, convenient and safe, production costs are reduced, the yield of the 2-bromo-4,5-dimethoxybenzyl bromide represented by the formula (8) is remarkably improved, wherein the yield is up to 85%, and the preparation method is very suitable for industrialized production.

Description

Technical field: [0001] The invention relates to the field of organic chemistry, and relates to a preparation method of 2-bromo-4,5-dimethoxybenzyl bromide. Background technique: [0002] Pinaverium Bromide, also known as Deshute, is called pinaverium bromide in English. It is a calcium antagonist drug with a highly selective antispasmodic effect on the gastrointestinal tract. It was launched in 1975 and has been sold in more than 50 countries. The market prospect Extremely vast. 2-Bromo-4,5-dimethoxybenzyl bromide is a key intermediate in the synthesis of pinaverium bromide. The prior art generally adopts the reaction of 3,4-dimethoxybenzyl alcohol and liquid bromine to obtain 2-bromo-4,5-dimethoxybenzyl bromide [J.Org.Chem., 1987, 52,704-706; J.Org.Chem.,2000,65,6398-6411; CN102060807]; or obtain 2-bromo-4,5-dimethoxy by reacting 3,4-dimethoxybenzyl alcohol with liquid bromine Base benzyl alcohol, and then react 2-bromo-4,5-dimethoxybenzyl alcohol with phosphorus tribro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C41/22C07C43/225
CPCC07C41/22C07C43/225
Inventor 肖孝辉陈煜峰
Owner ZHEJIANG NORMAL UNIVERSITY
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