CN101307051B - Process for synthesizing and detecting scopolamine derivates - Google Patents
Process for synthesizing and detecting scopolamine derivates Download PDFInfo
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- CN101307051B CN101307051B CN2008100238809A CN200810023880A CN101307051B CN 101307051 B CN101307051 B CN 101307051B CN 2008100238809 A CN2008100238809 A CN 2008100238809A CN 200810023880 A CN200810023880 A CN 200810023880A CN 101307051 B CN101307051 B CN 101307051B
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Abstract
The invention provides a synthesis method for scopolamine derivatives. The synthesis method comprises the following steps that: under the existence of carbonate, bicarbonate or other alkaline matter, quaternization reaction is carried out to scopolamine and halogenated hydrocarbon or halogen olefin; dehydration treatment is carried out to reactants and solvent before the reaction; when the reaction begins, the alkaline matter which is two times the molar weight of the scopolamine is added; when the reaction is carried out for four hours, the alkaline matter is filtered out, and filtrate continues to react; the solvent is selected from any one or mixture of ethanol, methanol and acetonitrile.
Description
Technical field
The invention provides the synthetic method of Scopolamine and derivative.Belong to medical preparing technical field.
Background technology
Scopolamine, chemical name 6 β, 7 beta epoxides-1 α H, 5 α H-tropane-3 α-alcohol (-) tropates are anticholinergic drug, with the M-cholinocepter higher avidity are arranged.Clinical route of administration has transdermal, nasal cavity, oral, but because of the M-cholinocepter extensively is distributed in maincenter and periphery, Scopolamine has higher lipotropy, so no matter by which kind of route of administration, Scopolamine all easily passes through hemato encephalic barrier, cental system is produced stronger effect, and poisonous side effect of medicine is big, consumption is wayward, and safety in utilization is low.In recent years, people attempt Scopolamine is carried out structural modification to obtain the compound that result of treatment is good, toxic side effect is little always.Wherein hydrogen bromine Scopolamine, Scopolamine Butylbromide, cimetropium bromide are that this type of modifies more successful example.When routine is carried out structural modification to Scopolamine, need Scopolamine and halocarbon are reacted, but halocarbon is understood the generation hydrogen halide that self reacts earlier, hydrogen halide and Scopolamine salify hinder reaction forward and carry out, and make product be difficult for separating out, and long reaction time.The reaction times that for example obtains Scopolamine Butylbromide reaches 120 hours, even cimetropium bromide, its reaction also needs more than 27 hours.And along with the prolongation in reaction times, by product increases, and is difficult to separating by-products during reaction end.Many employing nonaqueous titrationss that error is big, accuracy is little when detecting the finished product content, even adopt the higher high performance liquid chromatography of accuracy to detect, moving phase also need add the expensive ion pair reagent of prices such as sodium heptanesulfonate, perfluorooctane sulfonate or sodium hexanesulfonate, and such compound through structural modification does not have charateristic avsorption band at ultraviolet region, thereby the detection wavelength that adopts is not more than 210nm, but at this wavelength place end absorption is arranged, influence result's accuracy.
Summary of the invention
In order to overcome the deficiencies in the prior art, one of purpose of the present invention is to provide the synthetic method of Scopolamine derivative.
Add alkaline matter in the reaction system with Scopolamine and halocarbon, hydrogen halide and this alkalescence goods and materials generation acid-base reaction that side reaction produces takes place in halocarbon self, generates the inorganic salt that are insoluble to organic solvent, separates out from solution, reaction forward is carried out, and the shortening of reaction times first mate degree.According to test-results: this quaterisation can be finished in 10 hours.
Need strict control anhydrous state in entire reaction course.Because under the situation that has water to exist, alkaline matter can be partially soluble in the water, in the back flow reaction process, make the Scopolamine ester linkage breaking, generate tropic acid and scopine earlier, because of ternary oxygen ring instability in the scopine structure, isomery turns to scopoline (Scopoline) then.
When reaction proceeds to four hours, the inorganic salt of filtering alkaline matter and generation.The derivative amount of the Scopolamine that generate this moment is less still can not be separated out from solvent, can sneak into the alkaline matter of separating out and the inorganic salt of generation when further reacting again, influences output and purity.
The purpose that the invention provides a kind of method of synthetic Scopolamine derivative is achieved through the following technical solutions:
(I) is as follows for the structural formula of Scopolamine derivative:
Wherein R is alkane or alkene, and X is a halogen.
The synthetic method of Scopolamine derivative as previously mentioned, it is characterized in that under the alkaline matter existence condition, Scopolamine and halocarbon reflux in solvent quaterisation take place, before the reaction Scopolamine, halocarbon and solvent are done no water treatment, amount by 2 times of mole Scopolamines during the reaction beginning drops into alkaline matter, with the alkaline matter filtering in the reaction system, filtrate is proceeded reaction when carrying out 4 hours in reaction, and described solvent is selected from the mixture of ethanol, methyl alcohol and acetonitrile any or they.
The synthetic method of aforementioned as previously mentioned Scopolamine derivative is characterized in that described halocarbon is alkyl halide hydrocarbon or halogen alkene.
The synthetic method of aforementioned as previously mentioned Scopolamine derivative, described alkaline matter are carbonate or supercarbonate.
The invention has the beneficial effects as follows: the invention provides a kind of synthetic method of Scopolamine derivative, shorten the reaction times,, can cut down the consumption of energy by first mate's degree, thereby reduce cost from the industrialized production angle.
The cimetropium bromide that Fig. 1: embodiment 4 obtains separates the situation high-efficient liquid phase chromatogram with Scopolamine to wait;
The cimetropium bromide that Fig. 2: embodiment 5 obtains and Scopolamine etc. separate the situation high-efficient liquid phase chromatogram.
Specific embodiment
Below in conjunction with accompanying drawing, describe the specific embodiment of the present invention in detail:
Embodiment 1: cimetropium bromide synthetic
Add 33.9g Scopolamine, 20.2g brooethyl cyclopropane in the exsiccant reaction flask, 21.2g yellow soda ash and 340ml acetonitrile under agitation condition, refluxed 4 hours, and with filter paper elimination yellow soda ash, filtrate was continued stirring and refluxing 6 hours.Put coldly, separate out crystal, filter, use the acetonitrile recrystallization.Get cimetropium bromide crystal 3 6.8g, productive rate 83.9%.
Embodiment 2: cimetropium bromide synthetic
Add 33.9g Scopolamine, 20.2g brooethyl cyclopropane, 27.6g salt of wormwood and 340ml acetonitrile in the exsiccant reaction flask, refluxed 4 hours under agitation condition, with filter paper elimination salt of wormwood, filtrate was continued stirring and refluxing 6 hours.Put coldly, separate out crystal, filter, use the acetonitrile recrystallization.Get cimetropium bromide crystal 3 5.4g, productive rate 80.7%.
Synthesizing of embodiment 3 Scopolamine Butylbromides
Add 8.6g Scopolamine, the positive n-butyl bromide of 3.6ml, 4.2g sodium bicarbonate and 86ml acetonitrile in the exsiccant reaction flask, under agitation condition, refluxed 4 hours, with filter paper elimination yellow soda ash, filtrate was continued stirring and refluxing 6 hours.Put coldly, separate out crystal, filter, use the acetonitrile recrystallization.Get Scopolamine Butylbromide crystal 8.5g, productive rate 77.3%.
Embodiment 4: the detection of cimetropium bromide
Instrument:
The SHIMADZULC-20AT high performance liquid chromatograph, SPD-20A UV-detector, HT-230A column oven.
Chromatographic condition:
Chromatographic column: C
18Post (0.46 * 25cm, 5 μ m); Moving phase: methyl alcohol-0.01mol/L ammonium formiate (is 4.0 with the formic acid adjust pH) (45: 55, v/v) column temperature: 30 ℃; Flow velocity: 1.Oml/min; Detect wavelength: 215nm.
Measuring method: area normalization method
The configuration of location solution 1: it is an amount of that precision takes by weighing bromine, with moving phase dissolving and be diluted to the solution that concentration is 0.1mg/ml.
The configuration of location solution 2: it is an amount of that precision takes by weighing scopolamine hydrobromide, with moving phase dissolving and be diluted to the solution that concentration is 0.1mg/ml.
The configuration of sample solution: it is an amount of that precision takes by weighing Scopolamine derivative-cimetropium bromide, and dissolving and be diluted to concentration with moving phase is 0.5mg/ml.
The mensuration of sample: respectively get location solution 1, location solution 2, sample solution 20 μ m inject high performance liquid chromatograph, measure, both, the record color atlas has been seen Fig. 1,1# correspondence scopolamine hydrobromide wherein, 2# bromine, 3# cimetropium bromide.
The retention time of the characteristic peak of the characteristic peak of cimetropium bromide and the characteristic peak of bromine atoms and scopolamine hydrobromide is respectively 5.154min, 4.071min, 3.333min, and resolution is separated fully greater than 5, three peaks.
Embodiment 5: the detection of cimetropium bromide
Instrument: SHIMADZULC-20AT high performance liquid chromatograph, SPD-20A UV-detector, HT-230A column oven.
Chromatographic condition:
Chromatographic column: C
18Post (0.46 * 25cm, 5 μ m); Moving phase: methyl alcohol-0.01mol/L ammonium acetate (is 4.0 with the Glacial acetic acid adjust pH) (45: 55, v/v) column temperature: 30 ℃; Flow velocity: 1.0ml/min; Detect wavelength: 215nm.
The configuration of location solution 1: it is an amount of that precision takes by weighing bromine, and dissolving and be diluted to concentration with moving phase is 0.1mg/ml.
The configuration of location solution 2: it is an amount of that precision takes by weighing scopolamine hydrobromide, with moving phase dissolving and be diluted to the solution that concentration is 0.1mg/ml.
The configuration of sample solution: it is an amount of that precision takes by weighing cimetropium bromide, with moving phase dissolving and be diluted to the solution that concentration is 0.5mg/ml.
Measure: respectively get location solution 1, location solution 2, sample solution 20 μ m and injects high performance liquid chromatograph, the record color atlas is seen Fig. 2,1# correspondence scopolamine hydrobromide wherein, 2# bromine, 3# cimetropium bromide.
The retention time at the peak of cimetropium bromide peak and bromine and the peak of scopolamine hydrobromide is respectively 5.374min, 4.044min, 3.328min, and resolution is all separated fully greater than 5, three peaks.
Below disclose the present invention with preferred embodiment, so it is not in order to restriction the present invention, and all employings are equal to replaces or technical scheme that the equivalent transformation mode is obtained, all drops within protection scope of the present invention.
Claims (1)
1. general formula is the synthetic method of the Scopolamine derivative of (I),
Wherein:
X is a halogen;
R is independently for being selected from following organic group: alkyl or alkenyl,
It is characterized in that under the alkaline matter existence condition, Scopolamine and halocarbon reflux in solvent quaterisation take place, wherein before the reaction Scopolamine, halocarbon and solvent are done no water treatment, amount by 2 times of mole Scopolamines during the reaction beginning drops into alkaline matter, reaction is carried out 4 hours with the alkaline matter filtering in the reaction system, filtrate is proceeded reaction, and described solvent is selected from the mixture of ethanol, methyl alcohol and acetonitrile any or they, and described halocarbon is alkyl halide hydrocarbon or halogen alkene; Described alkaline matter is carbonate or supercarbonate.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102146079B (en) * | 2011-02-28 | 2013-02-13 | 广州瑞尔医药科技有限公司 | Preparation method of scopolamine butylbromide |
| CN103864777A (en) * | 2014-03-27 | 2014-06-18 | 张家港威胜生物医药有限公司 | Simple synthesis method of scopolamine butylbromide |
| CN108152398A (en) * | 2017-12-14 | 2018-06-12 | 广州白云山汉方现代药业有限公司 | A kind of method using LC-MS detection scopolamine butylbromide synthetic reaction |
| CN109053721B (en) * | 2018-06-27 | 2021-03-23 | 广州白云山汉方现代药业有限公司 | Preparation method of medicinal scopolamine butylbromide |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3853886A (en) * | 1972-04-18 | 1974-12-10 | Angeli Inst Spa | Certain n-substituted scopolammonium compounds |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3853886A (en) * | 1972-04-18 | 1974-12-10 | Angeli Inst Spa | Certain n-substituted scopolammonium compounds |
Non-Patent Citations (4)
| Title |
|---|
| 王普善等.溴化异丙基东莨菪碱的合成.中国医药工业杂志12 4.1981,12(4),1-3. |
| 王普善等.溴化异丙基东莨菪碱的合成.中国医药工业杂志12 4.1981,12(4),1-3. * |
| 邢为凡等.溴丁东莨菪碱的合成.中国医药工业杂志13 3.1982,13(3),6. |
| 邢为凡等.溴丁东莨菪碱的合成.中国医药工业杂志13 3.1982,13(3),6. * |
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