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Novel preparation method of alverine citrate

A technology of alverine citrate and ethylamine hydrochloride, which is applied in the field of preparation of alverine citrate, can solve the problems of inconvenient use and storage, difficult to realize, long steps, etc., and achieves reduction of risks and simplification of processes Mild effect of process, reaction conditions

Active Publication Date: 2014-01-15
河北凯盛医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method has long steps, and it is necessary to prepare ethylamphetamine first, and then diphenylpropylethylamine; in addition, it is necessary to use a more dangerous ethylamine solution, which has a low boiling point and a bp of 16.6°C, so it is safe to use and store. Convenient; at the same time, high vacuum distillation operation is required, which is difficult to realize in industry

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0013] Embodiment 1: the preparation of alverine citrate

[0014] The first step: the preparation of diphenylpropylethylamine

[0015] Add 20 g (0.10 mol) of 3-phenylbromopropane, 4.1 g (0.05 mol) of ethylamine hydrochloride, 0.2 g of tetrabutylammonium bromide and 50 ml of sodium hydroxide solution (35%-40%) into a 250 ml flask. Stir and heat up to 85-90°C, keep warm for reaction, and track with TLC (ethyl acetate / petroleum ether=2:1). After the reaction, the aqueous layer was extracted three times with ethyl acetate, and the organic layers were combined. Add anhydrous sodium sulfate to dry. After filtration, the filtrate was concentrated under reduced pressure to obtain 13.5 g of brown-yellow liquid. Yield: 96%.

[0016] The second step: the preparation of alverine citrate

[0017] Dissolve 13.5 g of the above liquid in 100 ml of absolute ethanol, stir to dissolve, then add 9.2 g (0.048 mol) of citric acid into a solution of 100 ml of absolute ethanol, stir at room temp...

Embodiment 2

[0018] Embodiment 2: the preparation of alverine citrate

[0019] The first step: the preparation of diphenylpropylethylamine

[0020] Add 15.5g (0.10mol) of 3-phenylchloropropane, 4.1g (0.05mol) of ethylamine hydrochloride, 0.2g of tetrabutylammonium bromide and 50ml of sodium hydroxide solution (35%-40%) into a 250ml flask. Stir and heat up to 85-90°C, keep the reaction warm, and follow up with TLC. After the reaction, the aqueous layer was extracted three times with ethyl acetate, and the organic layers were combined. Add anhydrous sodium sulfate to dry. After filtration, the filtrate was concentrated under reduced pressure to obtain 12.4 g of brown-yellow liquid. Yield: 88%.

[0021] The second step: the preparation of alverine citrate

[0022] Dissolve 12.4 g of the above liquid in 90 ml of absolute ethanol, stir to dissolve, then add 8.5 g (0.044 mol) of citric acid into a solution of 90 ml of absolute ethanol, stir at room temperature to precipitate a solid. Filte...

Embodiment 3

[0023] Embodiment 3: the preparation of alverine citrate

[0024] The first step: the preparation of diphenylpropylethylamine

[0025] Add 20 g (0.10 mol) of 3-phenylbromopropane, 4.1 g (0.05 mol) of ethylamine hydrochloride and 50 ml of sodium hydroxide solution (35%-40%) into a 250 ml flask. Stir and heat up to 85-90°C, keep the reaction warm, and follow up with TLC. After the reaction, the aqueous layer was extracted three times with ethyl acetate, and the organic layers were combined. Add anhydrous sodium sulfate to dry. After filtration, the filtrate was concentrated under reduced pressure to obtain 10.8 g of brown-yellow liquid. Yield: 76%.

[0026] The second step: the preparation of alverine citrate

[0027] Dissolve 10.8 g of the above liquid in 80 ml of absolute ethanol, stir to dissolve, then add 7.4 g (0.039 mol) of citric acid into a solution of 80 ml of absolute ethanol, stir at room temperature to precipitate a solid. Filter, wash and dry. Recrystallized ...

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Abstract

The invention discloses a novel preparation method of alverine citrate, which comprises the following steps: reacting 3-phenylhalopropane and ethylamine hydrochloride used as initial raw materials in an alkaline system to generate diphenylpropyl ethylamine, and refining under the interaction between the organic layer and the citric acid to obtain the alverine citrate. The process route has the characteristics of accessible raw materials, fewer reaction steps, mild conditions, high yield and the like and is simple to operate, and thus, is an environment-friendly synthesis route which can easily implement industrialization.

Description

technical field [0001] The invention relates to a preparation method of alverine citrate, which belongs to the field of drug synthesis. Alverine citrate is a commonly used antispasmodic drug in clinical practice. technical background [0002] Alverine citrate (Alverine, molecular formula: C 20 h 27 N·C 6 h 8 o 7 , Molecular weight: 473.6), is a synthetic papaverine derivative, listed in Western countries in 1996, it directly acts on smooth muscle, and can selectively act on the smooth muscle of the gastrointestinal tract, uterus and genitourinary organs, and has antispasmodic effect , the structural formula is as follows: [0003] [0004] The reported synthesis process uses benzyl chloride as the raw material to obtain the product through four steps of Grignard reaction, halogenation, amination and salt formation. [0005] Mao Xiantong et al. reported that for the pollution problem in the above-mentioned process route, the technical route was changed, and the Grig...

Claims

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Application Information

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IPC IPC(8): C07C211/27C07C209/68
Inventor 赵凯侯建平赵亚峰苑洪忠赵孝先简勇学
Owner 河北凯盛医药科技有限公司
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