CN103508898B - A kind of preparation method of new alverine citrate - Google Patents
A kind of preparation method of new alverine citrate Download PDFInfo
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- CN103508898B CN103508898B CN201210233874.2A CN201210233874A CN103508898B CN 103508898 B CN103508898 B CN 103508898B CN 201210233874 A CN201210233874 A CN 201210233874A CN 103508898 B CN103508898 B CN 103508898B
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Abstract
The invention discloses a kind of preparation method of new alverine citrate, with 3-phenyl halogenopropane and ethylamine hydrochloride for starting raw material, in alkaline system, reaction generates diphenylpropyl ethamine, organic layer and Citric Acid effect, obtains alverine citrate through refining.This operational path has raw material and is easy to get, and reactions steps is few, mild condition, simple to operate, yield high, is an environmental friendliness and easy industrialized synthetic route.
Description
Technical field
The present invention relates to a kind of preparation method of alverine citrate, belong to pharmaceutical synthesis field.Alverine citrate is the spasmolytic commonly used clinically.
Technical background
Alverine citrate (Alverine, molecular formula: C
20h
27nC
6h
8o
7, molecular weight: 473.6) is the Papaverine derivative of synthetic, within 1996, in western countries' listing, it directly acts on unstriated muscle, optionally acts on the unstriated muscle of gi tract, uterus and Genito-urinary organ, have spasmolysis, structural formula is as follows:
The synthesis technique reported is that raw material obtains product through Grignard reaction, halogenation, amination and salify four step with benzyl chloride.
Mao Xiantong etc. report the pollution problem for existing in above-mentioned operational path, change technological line, get rid of the Grignard reaction making catalyzer with aluminum chloride, the new technology route that to change into methyl phenyl ketone and ethylamine hydrochloride be raw material, alverine citrate (Mao Xiantong etc., the study on the synthesis of spasmolytic alverine citrate intermediate is obtained through Mannich reaction, huang-Minlon reaction and Citric Acid salify three-step reaction.Hubei Chemical, 2000,4:23-24).This operational path method used is classical reaction, but reaction conditions is difficult to reach and larger to the harm of environment when scale operation, reaction needed as reducing carbonyl in huang-Minlon reaction is carried out under the condition of high temperature, and hydrazine reagent used has certain harm and toxicity to environment and people.
Chinese patent CN101838205A discloses the preparation method of a new alverine citrate.The method take phenylpropyl alcohol as starting raw material, phenylpropyl alcohol is obtained 3-phenyl-bromide propane through bromo-reaction, obtained N-ethylamphetamine is reacted again with ethylamine solution, N-ethylamphetamine more in the basic conditions with 3-phenyl bromopropane reaction, and obtain diphenylpropyl ethamine through molecular distillation, and last and Citric Acid effect obtains final product--alverine citrate.The method step is long, needs first to prepare N-ethylamphetamine, then prepares diphenylpropyl ethamine; Need the ethylamine solution using larger danger in addition, this solution boiling point is low, and bp is 16.6 DEG C, uses and stores equal inconvenience; Also will carry out molecular distillation operation, industrial being also difficult to realizes simultaneously.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of new alverine citrate.
In order to overcome patent CN101838205A Problems existing, find through experimental study: with 3-phenyl halogenopropane and ethylamine hydrochloride for starting raw material, in alkaline system, carry out " one pot reaction " generate diphenylpropyl ethamine, organic layer after simple process directly and Citric Acid effect obtain alverine citrate.Instant invention overcomes the deficiency that patent CN101838205A substep prepares diphenylpropyl ethamine, a step has obtained this intermediate; Avoid the molecular distillation operation in former patent simultaneously, simplify technological process; In addition, the ethylamine solution that the present invention uses ethylamine hydrochloride to replace in former patent, reduces the danger in operating process.Therefore compare with conventional art, reaction conditions of the present invention is gentle, and simple to operate, safety, yield is high.
Realize object of the present invention by the following technical solutions: with 3-phenyl-chloride propane (3-phenyl halogenopropane) cheap and easy to get for starting raw material, 3-phenyl halogenopropane and ethylamine hydrochloride are carried out " one pot reaction " in alkaline system and generates diphenylpropyl ethamine, organic layer after simple process without molecular distillation directly and Citric Acid effect obtain alverine citrate, its chemical reaction process is as follows:
Compared with prior art, reaction conditions of the present invention is gentle, and operating process is easy, safety, is the operational path of a both economical practicality
Embodiment
Contribute to understanding the present invention by following example, but content of the present invention is not limited to example.
Embodiment 1: the preparation of alverine citrate
The first step: the preparation of diphenylpropyl ethamine
3-phenyl-bromide propane 20g (0.10mol) is added, ethylamine hydrochloride 4.1g (0.05mol), Tetrabutyl amonium bromide 0.2g and sodium hydroxide solution (35%-40%) 50ml in 250ml flask.Stirring is warming up to 85-90 DEG C, insulation reaction, and TLC follows the tracks of (ethyl acetate/petroleum ether=2: 1).After reaction terminates, extract water layer three times by ethyl acetate, merge organic layer.Add anhydrous sodium sulfate drying.Filter, filtrate reduced in volume obtains brown color liquid 13.5g.Yield: 96%.
Second step: the preparation of alverine citrate
Be dissolved in by aforesaid liquid 13.5g in 100ml dehydrated alcohol, join 9.2g (0.048mol) Citric Acid and be dissolved in the solution of 100ml dehydrated alcohol after stirring and dissolving, stirring at room temperature separates out solid.Filtration, washing, drying.Alverine citrate 15.2g is obtained with dehydrated alcohol recrystallization.Yield: 66.9%.
1HNMR(DMSO)δ：1.11～1.13(m，3H，-CH
2-
CH 3 )；1.88(s，4H，2-
CH 2 -COOH)；2.51～2.66(m，8H，2-CH
2-
CH 2 -CH
2-，2-Φ-
CH 2 -CH
2)；2.98～3.06(m，6H，2-N-
CH 2 -CH
2-，-N-
CH 2 -CH
3)；7.20～7.30(m，10H，Ph-H)。
13CNMR(DMSO)δ：8.79，24.98，31.99，44.25，46.95，50.79，71.68，126.05，128.26，128.37，140.70，171.63，176.96。
Embodiment 2: the preparation of alverine citrate
The first step: the preparation of diphenylpropyl ethamine
3-phenyl-chloride propane 15.5g (0.10mol) is added, ethylamine hydrochloride 4.1g (0.05mol), Tetrabutyl amonium bromide 0.2g and sodium hydroxide solution (35%-40%) 50ml in 250ml flask.Stirring is warming up to 85-90 DEG C, insulation reaction, and TLC follows the tracks of.After reaction terminates, extract water layer three times by ethyl acetate, merge organic layer.Add anhydrous sodium sulfate drying.Filter, filtrate reduced in volume obtains brown color liquid 12.4g.Yield: 88%.
Second step: the preparation of alverine citrate
Be dissolved in by aforesaid liquid 12.4g in 90ml dehydrated alcohol, join 8.5g (0.044mol) Citric Acid and be dissolved in the solution of 90ml dehydrated alcohol after stirring and dissolving, stirring at room temperature separates out solid.Filtration, washing, drying.Alverine citrate 13.5g is obtained with dehydrated alcohol recrystallization.Yield: 65.9%.
Embodiment 3: the preparation of alverine citrate
The first step: the preparation of diphenylpropyl ethamine
3-phenyl-bromide propane 20g (0.10mol), ethylamine hydrochloride 4.1g (0.05mol) and sodium hydroxide solution (35%-40%) 50ml is added in 250ml flask.Stirring is warming up to 85-90 DEG C, insulation reaction, and TLC follows the tracks of.After reaction terminates, extract water layer three times by ethyl acetate, merge organic layer.Add anhydrous sodium sulfate drying.Filter, filtrate reduced in volume obtains brown color liquid 10.8g.Yield: 76%.
Second step: the preparation of alverine citrate
Be dissolved in by aforesaid liquid 10.8g in 80ml dehydrated alcohol, join 7.4g (0.039mol) Citric Acid and be dissolved in the solution of 80ml dehydrated alcohol after stirring and dissolving, stirring at room temperature separates out solid.Filtration, washing, drying.Alverine citrate 11.2g is obtained with dehydrated alcohol recrystallization.Yield: 63.2%.
Embodiment 4: the preparation of alverine citrate
The first step: the preparation of diphenylpropyl ethamine
3-phenyl-chloride propane 15.5g (0.01mol) is added in 100ml flask, ethylamine hydrochloride 4.1g (0.05mol) and dehydrated alcohol 60ml, then add Anhydrous potassium carbonate 10.4g (0.075mol), stir and be warming up to backflow, insulation reaction.TLC follows the tracks of.After reaction terminates, filter, filtrate is not treated is directly used in next step reaction.
Second step: the preparation of alverine citrate
Join in 80ml dehydrated alcohol by 9.6g (0.05mol) Citric Acid, stirring and dissolving, then add the first step gained filtrate, stirring at room temperature is reacted, and separates out white solid, filtration, washing, drying.Alverine citrate 10.0g is obtained with dehydrated alcohol recrystallization.Yield: 42%.
Embodiment 5: the preparation of alverine citrate
The first step: the preparation of diphenylpropyl ethamine
3-phenyl-bromide propane 20g (0.10mol) is added, ethylamine hydrochloride 4.1g (0.05mol) and dehydrated alcohol 60ml in 100ml flask.Then add Anhydrous potassium carbonate 10.4g (0.075mol), stir and be warming up to backflow, insulation reaction, TLC follows the tracks of.After reaction terminates, filter, filtrate is not treated is directly used in next step reaction.
Second step: the preparation of alverine citrate
Join in 80ml dehydrated alcohol by 9.6g (0.05mol) Citric Acid, stirring and dissolving, then add the first step gained filtrate, stirring at room temperature is reacted, and separates out white solid, filtration, washing, drying.Alverine citrate 11.6g is obtained with dehydrated alcohol recrystallization.Yield: 48%.
Claims (3)
1. the preparation method of a new alverine citrate, it is characterized in that step (1) with 3-phenyl halogenopropane and ethylamine hydrochloride for starting raw material, in alkaline system, reaction generates diphenylpropyl ethamine, and wherein 3-phenyl halogenopropane is selected from is 3-phenyl-chloride propane, 3-phenyl-bromide propane; Step (2) and Citric Acid react obtained alverine citrate, and wherein in alkaline system, alkali is selected from NaOH or K
2cO
3.
2. the preparation method of alverine citrate according to claim 1, it is characterized in that alkaline system is by alkali and solvent composition, wherein solvent is selected from a kind of or its any two kinds and the above mixture in water, methyl alcohol, ethanol, acetone, THF, acetonitrile, DMF solvent.
3. the preparation method of the alverine citrate according to any one of claim 1-2, is characterized in that optionally using Tetrabutyl amonium bromide as catalyzer in step (1).
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| CN105348110B (en) * | 2015-12-18 | 2018-10-02 | 杨凌科森生物制药有限责任公司 | A kind of alverine citrate crystal-form compound and combinations thereof |
| CN105461569B (en) * | 2015-12-31 | 2017-06-06 | 南京海融医药科技股份有限公司 | A kind of alverine citrate novel crystal forms and preparation method thereof |
| CN108658786B (en) * | 2018-05-28 | 2019-12-03 | 吉林大学 | A kind of remaining method of N- ethyl -3- phenylpropylamine in reduction alverine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85101106A (en) * | 1983-10-22 | 1987-01-17 | 赫彻斯特股份公司 | The preparation method of tertiary amine |
| US20040143009A1 (en) * | 2002-11-05 | 2004-07-22 | L'oreal | Amines, uses thereof |
| CN101838205A (en) * | 2009-03-16 | 2010-09-22 | 重庆北碚现代应用药物研究所 | New method for preparing alverine citrate |
-
2012
- 2012-06-26 CN CN201210233874.2A patent/CN103508898B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85101106A (en) * | 1983-10-22 | 1987-01-17 | 赫彻斯特股份公司 | The preparation method of tertiary amine |
| US20040143009A1 (en) * | 2002-11-05 | 2004-07-22 | L'oreal | Amines, uses thereof |
| CN101838205A (en) * | 2009-03-16 | 2010-09-22 | 重庆北碚现代应用药物研究所 | New method for preparing alverine citrate |
Non-Patent Citations (1)
| Title |
|---|
| 枸椽酸阿尔维林的合成;杨丹等;《中国医药工业杂志》;20120310;第43卷(第3期);第164-166页 * |
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