CN103508898A - Novel preparation method of alverine citrate - Google Patents
Novel preparation method of alverine citrate Download PDFInfo
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- CN103508898A CN103508898A CN201210233874.2A CN201210233874A CN103508898A CN 103508898 A CN103508898 A CN 103508898A CN 201210233874 A CN201210233874 A CN 201210233874A CN 103508898 A CN103508898 A CN 103508898A
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- phenyl
- alverine citrate
- propane
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- alverine
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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
The present invention relates to a kind of preparation method of alverine citrate, belong to the synthetic field of medicine.Alverine citrate is conventional clinically spasmolytic.
Technical background
Alverine citrate (Alverine, molecular formula: C
20h
27nC
6h
8o
7, molecular weight: 473.6), be the Papaverine derivative of synthetic, the listing of 1996 Nian western countries, it directly acts on unstriated muscle, optionally acts on the unstriated muscle of gi tract, uterus and Genito-urinary organ, has spasmolysis, and structural formula is as follows:
The synthesis technique of having reported is to take benzyl chloride through Grignard reaction, halogenation, amination and salify four steps, to make product as raw material.
Mao Xiantong etc. have reported the pollution problem existing in above-mentioned operational path, change technological line, got rid of the Grignard reaction of making catalyzer with aluminum chloride, change into and take the new technology route that methyl phenyl ketone and ethylamine hydrochloride be raw material, through Mannich reaction, huang-Minlon reaction and Citric Acid salify three-step reaction, make alverine citrate (Mao Xiantong etc., the study on the synthesis of spasmolytic alverine citrate intermediate.Hubei chemical industry, 2000,4:23-24).This operational path method used is classical reaction, but reaction conditions is difficult to reach and is larger to the harm of environment when scale operation, as the reaction needed of reducing carbonyl in huang-Minlon reaction is carried out under the condition of high temperature, hydrazine reagent used has certain harm and toxicity to environment and people.
Chinese patent CN101838205A has announced the preparation method of a new alverine citrate.The method be take phenylpropyl alcohol as starting raw material, phenylpropyl alcohol is made to 3-phenyl-bromide propane through bromo-reaction, react and make N-ethylamphetamine with ethylamine solution again, N-ethylamphetamine again under alkaline condition with 3-phenyl bromopropane reaction, and make two hydrocinnamyl ethamine through molecular distillation, and last and Citric Acid effect makes final product--alverine citrate.The method step is long, need to first prepare N-ethylamphetamine, then prepares two hydrocinnamyl ethamine; Need in addition to use the ethylamine solution that has larger danger, this solution boiling point is low, and bp is 16.6 ℃, uses and store 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.
The problem existing in order to overcome patent CN101838205A, through experimental study, find: take 3-phenyl halogenopropane and ethylamine hydrochloride as starting raw material, in alkaline system, carry out " one pot reaction " and generate two hydrocinnamyl ethamine, organic layer after simple process directly and Citric Acid effect make alverine citrate.The present invention has overcome the deficiency that patent CN101838205A prepares two hydrocinnamyl ethamine step by step, and a step made this intermediate; Avoid the molecular distillation operation in former patent simultaneously, simplified technological process; In addition, the present invention uses ethylamine hydrochloride to replace the ethylamine solution in former patent, has reduced the danger in operating process.Therefore with conventional art, compare, reaction conditions of the present invention is gentle, simple to operate, safety, and yield is high.
Realize by the following technical solutions object of the present invention: the 3-phenyl-chloride propane cheap and easy to get (3-phenyl halogenopropane) of take is starting raw material, 3-phenyl halogenopropane and ethylamine hydrochloride are carried out to " one pot reaction " in alkaline system and generate two hydrocinnamyl ethamine, organic layer after simple process without molecular distillation directly and Citric Acid effect make 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, and safety is the operational path of a both economical practicality
Embodiment
By following example, contribute to understand the present invention, but content of the present invention is not limited to example.
Embodiment 1: the preparation of alverine citrate
The first step: the preparation of two hydrocinnamyl ethamine
In 250ml flask, add 3-phenyl-bromide propane 20g (0.10mol), ethylamine hydrochloride 4.1g (0.05mol), Tetrabutyl amonium bromide 0.2g and sodium hydroxide solution (35%-40%) 50ml.Stirring is warming up to 85-90 ℃, insulation reaction, and TLC follows the tracks of (ethyl acetate/petroleum ether=2: 1).After reaction finishes, by ethyl acetate, extract water layer three times, merge organic layer.Add anhydrous sodium sulfate drying.Filter, filtrate decompression concentrates to obtain brown color liquid 13.5g.Yield: 96%.
Second step: the preparation of alverine citrate
Aforesaid liquid 13.5g is dissolved in 100ml dehydrated alcohol, joins 9.2g (0.048mol) Citric Acid and be dissolved in the solution of 100ml dehydrated alcohol after stirring and dissolving, stirring at room is separated out solid.Filter, wash, be dried.With dehydrated alcohol recrystallization, obtain alverine citrate 15.2g.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 two hydrocinnamyl ethamine
In 250ml flask, add 3-phenyl-chloride propane 15.5g (0.10mol), ethylamine hydrochloride 4.1g (0.05mol), Tetrabutyl amonium bromide 0.2g and sodium hydroxide solution (35%-40%) 50ml.Stirring is warming up to 85-90 ℃, insulation reaction, and TLC follows the tracks of.After reaction finishes, by ethyl acetate, extract water layer three times, merge organic layer.Add anhydrous sodium sulfate drying.Filter, filtrate decompression concentrates to obtain brown color liquid 12.4g.Yield: 88%.
Second step: the preparation of alverine citrate
Aforesaid liquid 12.4g is dissolved in 90ml dehydrated alcohol, joins 8.5g (0.044mol) Citric Acid and be dissolved in the solution of 90ml dehydrated alcohol after stirring and dissolving, stirring at room is separated out solid.Filter, wash, be dried.With dehydrated alcohol recrystallization, obtain alverine citrate 13.5g.Yield: 65.9%.
Embodiment 3: the preparation of alverine citrate
The first step: the preparation of two hydrocinnamyl ethamine
In 250ml flask, add 3-phenyl-bromide propane 20g (0.10mol), ethylamine hydrochloride 4.1g (0.05mol) and sodium hydroxide solution (35%-40%) 50ml.Stirring is warming up to 85-90 ℃, insulation reaction, and TLC follows the tracks of.After reaction finishes, by ethyl acetate, extract water layer three times, merge organic layer.Add anhydrous sodium sulfate drying.Filter, filtrate decompression concentrates to obtain brown color liquid 10.8g.Yield: 76%.
Second step: the preparation of alverine citrate
Aforesaid liquid 10.8g is dissolved in 80ml dehydrated alcohol, joins 7.4g (0.039mol) Citric Acid and be dissolved in the solution of 80ml dehydrated alcohol after stirring and dissolving, stirring at room is separated out solid.Filter, wash, be dried.With dehydrated alcohol recrystallization, obtain alverine citrate 11.2g.Yield: 63.2%.
Embodiment 4: the preparation of alverine citrate
The first step: the preparation of two hydrocinnamyl ethamine
In 100ml flask, add 3-phenyl-chloride propane 15.5g (0.01mol), ethylamine hydrochloride 4.1g (0.05mol) and dehydrated alcohol 60ml, then add Anhydrous potassium carbonate 10.4g (0.075mol), stirs and be warming up to backflow, insulation reaction.TLC follows the tracks of.After reaction finishes, filter, filtrate is not treated is directly used in next step reaction.
Second step: the preparation of alverine citrate
9.6g (0.05mol) Citric Acid is joined in 80ml dehydrated alcohol, and stirring and dissolving, then adds the first step gained filtrate, and stirring at room reaction, separates out white solid, filters, washs, is dried.With dehydrated alcohol recrystallization, obtain alverine citrate 10.0g.Yield: 42%.
Embodiment 5: the preparation of alverine citrate
The first step: the preparation of two hydrocinnamyl ethamine
In 100ml flask, add 3-phenyl-bromide propane 20g (0.10mol), 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 finishes, filter, filtrate is not treated is directly used in next step reaction.
Second step: the preparation of alverine citrate
9.6g (0.05mol) Citric Acid is joined in 80ml dehydrated alcohol, and stirring and dissolving, then adds the first step gained filtrate, and stirring at room reaction, separates out white solid, filters, washs, is dried.With dehydrated alcohol recrystallization, obtain alverine citrate 11.6g.Yield: 48%.
Claims (9)
1. a preparation method for new alverine citrate, is characterized in that it is starting raw material that step (1) be take 3-phenyl halogenopropane and ethylamine hydrochloride, and in alkaline system, reaction generates two hydrocinnamyl ethamine; Step (2) is reacted and is made alverine citrate with Citric Acid.
2. according to claim 1,3-phenyl halogenopropane can be 3-phenyl-chloride propane, 3-phenyl-bromide propane, 3-phenyl-iodide propane, wherein preferred 3-phenyl-chloride propane or 3-phenyl-bromide propane.
3. according to claim 1, alkali is selected from oxyhydroxide, carbonate and the supercarbonate of alkali metal.
4. according to claim 3, be characterised in that alkali is selected from NaOH, KOH, Na
2cO
3, K
2cO
3, NaHCO
3, KHCO
3.
5. according to claim 1, alkaline system is selected from a kind of or its any two kinds and above mixture and the alkali composition in water, methyl alcohol, ethanol, acetone, THF, acetonitrile, DMF equal solvent.
6. according to claim 1,3-phenyl halogenopropane reacts also and can use phase-transfer catalyst with ethylamine hydrochloride in basic solution, such as polyethylene glycols (as PEG-400, PEG-600 etc.), quaternary ammonium salt (as tetrabutylammonium chloride, Tetrabutyl amonium bromide etc.), crown ether-like (18-hat-6 etc.).
7. according to claim 1, be characterised in that, after ending step (1), organic layer carries out step (2) after treatment.
8. according to claim 1, be characterised in that step (2) finish after through recrystallization, can obtain highly purified alverine citrate.
9. according to Claim 8, the recrystallization solvent of preparation high purity alverine citrate can be a kind of or its any two kinds and the above mixture in methyl alcohol, ethanol, acetonitrile, acetone, ethyl acetate, butanone, tetrahydrofuran (THF), DMF.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348110A (en) * | 2015-12-18 | 2016-02-24 | 杨凌科森生物制药有限责任公司 | Alverine citrate crystal form compound and composition thereof |
| CN105461569A (en) * | 2015-12-31 | 2016-04-06 | 南京海融医药科技有限公司 | Novel citric acid alverine crystal form and preparation method thereof |
| CN108658786A (en) * | 2018-05-28 | 2018-10-16 | 吉林大学 | A kind of remaining method of N- ethyl -3- phenylpropylamines 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 |
|---|
| 杨丹等: "枸椽酸阿尔维林的合成", 《中国医药工业杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348110A (en) * | 2015-12-18 | 2016-02-24 | 杨凌科森生物制药有限责任公司 | Alverine citrate crystal form compound and composition thereof |
| CN105461569A (en) * | 2015-12-31 | 2016-04-06 | 南京海融医药科技有限公司 | Novel citric acid alverine crystal form and preparation method thereof |
| CN108658786A (en) * | 2018-05-28 | 2018-10-16 | 吉林大学 | A kind of remaining method of N- ethyl -3- phenylpropylamines in reduction alverine |
| 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 |
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| CN103508898B (en) | 2016-03-23 |
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