New preparation method for bisoprolol fumarate

A technology of bisoprolol fumarate and sulfonic acid, which is applied in the preparation of carboxylate salts, organic compounds, aminohydroxyl compounds, etc. It can solve the problems of unavoidable intermolecular reactions, inability to recrystallize and purify, and many impurities. Problems, achieve high product purity, good purification and separation effect, and reduce impurities

Inactive Publication Date: 2014-03-26
SICHUAN UNIV
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  • Abstract
  • Description
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Problems solved by technology

[0007] The disadvantages of this process are: the intermediate needs repeated extraction, washing and high vacuum distillation operations; the intermediate is n

Method used

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  • New preparation method for bisoprolol fumarate
  • New preparation method for bisoprolol fumarate
  • New preparation method for bisoprolol fumarate

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Experimental program
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Embodiment 1

[0026] The synthesis of the middle 3 of embodiment 1

[0027]

[0028] the intermediate 1 (20g, 63.9mmol) was dissolved in 200ml of anhydrous N,N dimethylformamide, under the protection of argon, slowly added sodium hydride (1.7g, 70.3mmol), the intermediate 2 (14.8g, 70.3mmol), after addition, react at 25°C for 4h until complete reaction.

[0029] Post-processing: Evaporate N,N dimethylformamide to dryness under reduced pressure, add water / isopropyl ether for extraction, and wash the organic layer with 20% sodium hydroxide solution. The organic layer was dried and spin-dried to obtain 15.9 g of white semi-solid (intermediate 3 ), with a yield of 71%.

Embodiment 2

[0030] The synthesis of the middle 3 of embodiment 2

[0031] the intermediate 1 (20g, 63.9mmol) was dissolved in 200ml N,N dimethylformamide, under the protection of argon, slowly added sodium hydroxide (2.8g, 70.3mmol), the intermediate 2 (14.8g, 70.3mmol), after adding, react at 60°C for 4h until complete reaction.

[0032] Post-processing: Evaporate N,N dimethylformamide to dryness under reduced pressure, add water / isopropyl ether for extraction, and wash the organic layer with 20% sodium hydroxide solution. The organic layer was dried and spin-dried to obtain 13.1 g of white semi-solid (intermediate 3 ), with a yield of 58%.

Embodiment 3

[0033] The synthesis of the middle 3 of embodiment 3

[0034]

[0035] the intermediate 1 (20g, 63.9mmol) was dissolved in 200ml of anhydrous N,N dimethylformamide, under the protection of argon, slowly added potassium tert-butoxide (7.8g, 70.3mmol), the intermediate 2 (14.8g, 70.3mmol), after adding, react at 25°C for 5h until complete reaction.

[0036] Post-processing: Evaporate N,N dimethylformamide to dryness under reduced pressure, add water / isopropyl ether for extraction, and wash the organic layer with 20% sodium hydroxide solution. The organic layer was dried and spin-dried to obtain 13.8 g of white semi-solid (intermediate 3 ), with a yield of 61%.

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Abstract

The invention relates to a new preparation method for bisoprolol fumarate. The technical scheme adopted is that under the catalytic action of alkali, an intermediate 1 (toluene-4-mahogany acid3-isopropyl-2-oxo-oxazolidine-5-methyl acetate) and an intermediate 2 {4-(2-Isopropoxyethoxymethyl)-phenol} are heated and reacts in a solvent to obtain an intermediate 3 {5-[4-(2-Isopropoxyethoxymethyl)-phenoxyl]-3-isopropyl oxazolidine-2-ketone}; the intermediate 3 is subjected to hydrolysis and salification to obtain the bisoprolol fumarate. The method has the advantages that high vacuum distillation operation is avoided, the generated impurity during reaction is reduced, and the product is easy to purify.

Description

technical field [0001] The invention designs a new industrializable synthesis process for preparing high-purity bisoprolol fumarate. Background technique [0002] The chemical name of Bisoprolol Fumarate is 1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3-[(1- Methylethyl)amino]-2-propionic acid fumarate, the English name is 1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-(isopropylamino)propan-2-ol fumarate, its The structural formula is shown below. [0003] Bisoprolol fumarate is a highly selective β1-receptor blocker for the heart, which is clinically used to treat hypertension, angina pectoris and arrhythmia. The drug was researched and developed by E.Merk Company in Germany in 1978, and its synthesis process patents are mainly (BE859425; US4258062). Subsequently, the Japanese Academy of Medicine carried out research on improving the yield and reducing by-products in the one-step etherification reaction. [0004] At present, domestic and foreign patents introduce the s...

Claims

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Application Information

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IPC IPC(8): C07C217/34C07C213/08C07C213/02C07C57/15C07C51/41
Inventor 吴勇管玫刘剑功海俐何毅李晓岑
Owner SICHUAN UNIV
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