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Preparation method of trimebutine

The technology of a compound, phenylbutanol, is applied in the preparation of organic compounds, chemical instruments and methods, and the preparation of aminohydroxyl compounds. It can solve the problems of many impurities, affecting product quality and yield, and not easy to operate. Less pollution, high product yield and purity, and the effect of avoiding ether impurities and double bond olefin impurities

Pending Publication Date: 2022-02-01
浙江东亚药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the water separation process, at high temperature, the intermediate 2-(dimethylamino)-2-phenylbutanol can undergo intermolecular dehydration under the catalysis of p-toluenesulfonic acid to generate ether impurities, and due to the benzyl position Hydrogen is active, and it is also prone to intramolecular dehydration to generate olefin impurities containing double bonds. There are many impurities, which will affect product quality and yield, and the post-treatment is difficult and not easy to operate.

Method used

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  • Preparation method of trimebutine
  • Preparation method of trimebutine
  • Preparation method of trimebutine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of formula Ⅲ compound 2-amino-2-phenylbutanol

[0032]

[0033] Put 134.3g of solvent tetrahydrofuran into a clean four-necked flask, start stirring, and then put in 17.9g (0.1mol) of raw materials 2-amino-2-phenylbutyric acid and 8.3g (0.22mol) of sodium borohydride, and then stir Control the temperature of the system at 10-20°C in the state, and slowly add 12.7g (0.13mol) of sulfuric acid dropwise. After the dropwise addition, keep it warm at room temperature for 12 hours. , the system temperature of the reaction solution was lowered to 10°C, and then 53.7g (0.27mol) of sodium hydroxide aqueous solution with a mass percentage of 20% was added dropwise, and the dropping temperature was controlled at 10-15°C. After the addition was completed, the temperature was raised to reflux for 2h , stop heating and let stand to separate layers, collect the upper organic phase, and concentrate the collected organic phase under reduced pressure to recover tetrahydrofu...

Embodiment 2

[0035] Preparation of formula Ⅳ compound 2-amino-2-phenylbutanol

[0036]

[0037] Get above-mentioned formula III compound 2-amino-2-phenylbutanol 14.5g (0.086mol) that adopts embodiment 1 to obtain, massfraction is that 85% formic acid 11.6g (0.22mol) and massfraction are 37% formaldehyde 20.9g g (0.26mol) is put into a clean four-necked flask in turn, and the temperature is raised to reflux for 6 hours. During the reaction, the central control can be sampled. The pH value of the system is 10-11, and then extracted twice with toluene (20g×2), the toluene layers obtained by the two extractions are combined, and the toluene layer is washed twice with water (15g×2), and the toluene layer obtained is carried out The solvent was distilled off under reduced pressure to obtain 15.8 g of the corresponding intermediate compound of formula IV, 2-amino-2-phenylbutanol, as a brown viscous liquid with a GC content of 95% and a yield of 95%.

Embodiment 3

[0039] The preparation of formula I compound trimebutine

[0040]

[0041] Add water 31.6g, sodium bicarbonate 9.61g (0.12mol), acetone 50g and formula IV compound 2-amino-2-phenylbutanol 15.8g (0.082mol) successively in a clean four-necked reaction flask, and cool down the system After reaching 5°C to 10°C, slowly add dropwise a mixture of 22.62g (0.098mol) of the compound of formula V and 29g of acetone. During the dropwise addition, control the temperature at 5°C to 10°C. Carry out insulation reaction 2h, after reaction finishes, carry out decompression distillation and reclaim acetone, filter, the wet product solid product that obtains is rinsed with water twice (15g * 2), dry, obtain final product trimebutine 29.14g, off-white To light yellow crystalline powder, the HPLC purity is 99.5%, the single impurity is <0.1%, and the yield is 92%.

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Abstract

The invention relates to a preparation method of trimebutine, belonging to the technical field of medicine synthesis. In order to solve the problems of heavy pollution and low yield in the prior art, the invention provides the preparation method of trimebutine. The preparation method comprises the following steps: under the action of a catalyst, carrying out reduction reaction on 2-amino-2-phenylbutyric acid in an organic solvent under the action of hydroboron to obtain an intermediate 2-amino-2-phenylbutanol, wherein the catalyst is selected from a protonic acid or a Lewis acid. The preparation method comprises the following steps: carrying out amine methylation reaction on 2-amino-2-phenyl butanol, formaldehyde and formic acid to obtain 2-(dimethylamino)-2-phenyl-butanol; and in the presence of an acid-binding agent, subjecting raw materials 3,4,5-trimethoxybenzoyl chloride and 2-(dimethylamino)-2-phenylbutanol to an esterification reaction to obtain a final product. According to the invention, a methyl group can be selectively introduced to an amino group, the methyl group cannot be introduced to the alcoholic hydroxyl group, ether and double-bond olefin impurities are effectively avoided, and the effects of high product yield and high product purity are achieved.

Description

technical field [0001] The invention relates to a preparation method of trimebutine, which belongs to the technical field of medicine synthesis. Background technique [0002] Trimebutine Maleate (Trimebutine Maleate) is a gastrointestinal motility drug researched and developed by the French company Jouveinal. It was first launched in France in 1970. In 2000, trimebutine maleate was launched in China. It is mainly suitable for the improvement of symptoms such as loss of appetite, nausea, vomiting, belching, abdominal distension, borborygmi, abdominal pain, diarrhea and constipation caused by gastrointestinal motility disorders and irritable bowel syndrome. Irritable bowel syndrome (Irritable Bowel Syndrome, IBS) is a common functional bowel disease, with abdominal pain or abdominal discomfort as the main symptom, which can be improved after defecation, often accompanied by changes in bowel habits, lack of morphology to explain symptoms and biochemical abnormalities. [000...

Claims

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Application Information

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IPC IPC(8): C07C213/06C07C219/22C07C213/00C07C213/08C07C215/28
CPCC07C213/06C07C213/00C07C213/08C07C215/28C07C219/22
Inventor 陈玲娣张道明刘亚清池骋刚丽霞池正明
Owner 浙江东亚药业股份有限公司
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