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Synthesis technology of bisoprolol

A synthesis process, the technology of bisoprolol, is applied in the field of industrialization of high-purity bisoprolol synthesis process, and can solve the problems of high reaction temperature requirements, low yield, low product purity, etc.

Inactive Publication Date: 2010-12-01
张综利
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The shortcoming of this technique is: the reaction temperature requirement is high; The intermediate product needs repeated extraction, washing and underpressure distillation operation under the high vacuum condition; Product purity is low (40%), yield is low (30%), is not suitable for industrial amplification

Method used

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  • Synthesis technology of bisoprolol
  • Synthesis technology of bisoprolol
  • Synthesis technology of bisoprolol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] (1) Alcohol hydroxyl etherification

[0022] Add 6L of isopropoxyethanol into a 10L reaction kettle, lower it to 0°C, add 600g of macroporous strongly acidic styrene-based cation exchange resin D001 type catalyst, add 700g of 4-hydroxybenzyl alcohol in batches, and react at 0°C for 2 hours, Then the temperature was raised to 30°C, and the reaction was continued for 5h. Filtration (recovering the resin), alkalinizing the filtrate with a small amount of potassium carbonate, distilling under reduced pressure (recovering excess 4-hydroxybenzyl alcohol), dissolving the residue in 4L toluene, washing twice with distilled water, and directly using it for the next reaction .

[0023] (2) Etherification of phenolic hydroxyl groups

[0024] Add 220g of sodium hydroxide aqueous solution (that is, the aqueous solution prepared by adding 220g of sodium hydroxide to 1000g of water) to the toluene solution obtained in the previous step reaction, add 2600g of epichlorohydrin, react a...

Embodiment 2

[0030] (1) Alcohol hydroxyl etherification

[0031] Add 8L of isopropoxyethanol into a 10L reaction kettle, lower it to 0°C, add 800g of macroporous strongly acidic styrene-based cation exchange resin D001-CC type catalyst, add 800g of 4-hydroxybenzyl alcohol in batches, and react at 0°C 2h, then the temperature was raised to 30°C, and the reaction was continued for 5h. Filtration (recovering the resin), alkalinizing the filtrate with a small amount of potassium carbonate, distilling under reduced pressure (recovering excess 4-hydroxybenzyl alcohol), dissolving the residue in 4L toluene, washing twice with distilled water, and directly using it for the next reaction .

[0032] (2) Etherification of phenolic hydroxyl groups

[0033] Add 220g of sodium hydroxide aqueous solution (that is, the aqueous solution prepared by adding 220g of sodium hydroxide to 1000g of water) to the toluene solution obtained in the previous step reaction, add 3000g of epichlorohydrin, react at 65°C...

Embodiment 3

[0039] (1) Alcohol hydroxyl etherification

[0040]Add 10L of isopropoxyethanol into a 10L reaction kettle, lower to 0°C, add 750g of macroporous strongly acidic styrene-based cation exchange resin D61 type catalyst, add 750g of 4-hydroxybenzyl alcohol in batches, and react at 0°C for 2 hours, Then the temperature was raised to 30°C, and the reaction was continued for 5h. Filtration (recovering the resin), alkalinizing the filtrate with a small amount of potassium carbonate, distilling under reduced pressure (recovering excess 4-hydroxybenzyl alcohol), dissolving the residue in 4L toluene, washing twice with distilled water, and directly using it for the next reaction .

[0041] (2) Etherification of phenolic hydroxyl groups

[0042] Add 220g of sodium hydroxide aqueous solution (that is, add 220g of sodium hydroxide to 1000g of water to prepare the aqueous solution) to the toluene solution obtained in the previous step reaction, add 2000g of epichlorohydrin, react at 65°C f...

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Abstract

The invention relates to a synthesis technology of bisoprolol. The technical scheme of the technology comprises the following steps: (1) using 4-hydroxybenzyl alcohol and isopropoxyethanol to perform the etherification reaction, using strongly acidic styrene type cation exchange resin as catalyst to ensure the alcoholic hydroxyl group etherification reaction to perform under the conditions of room temperature and no solvent; (2) adding sodium hydroxide and epoxychloropropane in the reaction product in the step (1) to ensure phenolic hydroxyl group to perform the etherification reaction; and (3) adding the reaction product in the step (2) in isopropamide, reacting by using boron hydride as catalyst, and preparing bisoprolol. By using the synthesis technology of the invention, the alcoholic hydroxyl group etherification reaction can be performed under the conditions of room temperature and no solvent, the processes of extraction, washing and reduced pressure distillation are simplified; boron hydride is used as catalyst to ensure the amination reaction to perform under a low temperature; the overall yield is increased to above 50%; and the synthesis technology is suitable for industrial production. The solvent used by the technology of the invention can be recycled through distillation; resinic solid acid catalyst can be recycled; and yield and product purity are high.

Description

technical field [0001] The invention relates to an industrialized synthetic process for high-purity bisoprolol. Background technique [0002] Bisoprolol is a highly selective β1-receptor blocker for the heart, clinically used for the treatment of hypertension, angina pectoris and arrhythmia. Bisoprolol medicine was researched and developed by German E.Merk company in 1978, and the synthetic technique patent of bisoprolol mainly is (BE859425; US4258062). Subsequently, the Japanese Academy of Medical Sciences made progress in improving the yield of etherification products and reducing side reactions during the synthesis of bisoprolol. [0003] At present, the synthesis process of bisoprolol introduced by domestic and foreign patents is basically as follows: 4-hydroxybenzyl alcohol is used as a starting material, and alcohol hydroxyl etherification reaction occurs under the condition of high temperature, organic solvent, protonic acid or Lewis acid as a catalyst ; And epichlo...

Claims

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Application Information

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IPC IPC(8): C07C217/32C07C213/04
CPCY02P20/584
Inventor 张综利
Owner 张综利
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