CN1125033C - Synthesis of memantine hydrochloride - Google Patents
Synthesis of memantine hydrochloride Download PDFInfo
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- CN1125033C CN1125033C CN 01127788 CN01127788A CN1125033C CN 1125033 C CN1125033 C CN 1125033C CN 01127788 CN01127788 CN 01127788 CN 01127788 A CN01127788 A CN 01127788A CN 1125033 C CN1125033 C CN 1125033C
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- memantine hydrochloride
- dimethyladamantane
- ether
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Abstract
The present invention belongs to a synthesis method of memantine hydrochloride as medicine for treating cretinism, which comprises the following steps: the acetamination reaction of 1-bromine-3, 5-dimethyl adamantane, acetonitrile and sulfuric acid is carried out; after a product is collected in water, an alcoholysis reaction is carried out under the actions of sodium hydroxide and polyalcohol having no ether linkage; memantine is obtained by the extraction of chloroform; after the acidifying process of hydrochloric acid and the re-crystallization of the chloroform, the memantine hydrochloride is obtained. The synthesis method of memantine hydrochloride simplifies operation and avoids the use of benzene having great harm on human bodies and environment, and compared with the prior art, the synthesis method of memantine hydrochloride has the advantages of simple operation, high safety, good product quality, capability of recovering and reusing solvent, low cost, etc.
Description
The present invention relates to the synthetic method of a kind of dementia curative, N-methyl-D-aspartate (NMDA) receptor antagonist memantine hydrochloride.
Memantine hydrochloride is a kind of good dementia curative of German Merz company development, in Germany's listing, has also finished III phase clinical study in the U.S. and other various countries of European Union, is about to listing.Its chemistry is by name: 1-amino-3,5-dimethyladamantane hydrochloride, this medicine is a nmda receptor antagonist noncompetitive, medium tenacity quick voltage gate, can stop the overload of intracellular Ca2+ and the exitotoxicity of inhibition excitatory amino acid, it all has good curative effect to Vascular dementia and dementia of the Alzheimer type clinical research confirmation, this is at present other kinds in the not available advantage of dementia curative of grinding, thereby the economic and social benefit of this medicine has a high potential.
About synthesizing of memantine hydrochloride, U.S. Pat 3391142 discloses its synthetic method, system is with 1, the 3-dimethyladamantane is through bromination, obtain 1-bromo-3, the 5-dimethyladamantane, under acetonitrile and vitriolic effect, carry out kharophenization again, through benzene extraction, drying, the concentrated 1-acetylaminohydroxyphenylarsonic acid 3 that obtains, carry out alcoholysis with sodium hydroxide and glycol ether behind the 5-dimethyladamantane, benzene extraction concentrates and obtains the Memantine hydrochloride crude product, again through hcl acidifying, ethanol/ether recrystallization purifying and obtain memantine hydrochloride.
The aftertreatment in kharophenization in the aforesaid method and two steps of alcoholysis has all been adopted environment and human body has been endangered bigger benzene as extraction solvent; Adopted the comparatively expensive glycol ether of price as proton donor in the alcoholysis process; Recrystallization process has adopted ethanol/ether mixed solvent, because very low, the high volatility of ether boiling point, steam are difficult to condensation, in ethanol process with ether adding place reflux state, cause ether to volatilize in a large number, loss greatly also very easily causes the combustion explosion accident, thereby above-mentioned literature method haves much room for improvement.
The objective of the invention is to adopt on the basis of the synthetic route identical with aforesaid method, provide a kind of to the littler working method of environment and human body harm and extraction solvent, more cheap alcoholysis proton donor and safer, be easier to operation, the better recrystallization solvent of quality product.
The synthetic method of memantine hydrochloride provided by the invention adopts 1-bromo-3, the 5-dimethyladamantane makes through kharophenization, alcoholysis and hcl acidifying, 1-bromo-3, the 5-dimethyladamantane is after carrying out the kharophen reaction under acetonitrile and the vitriolic effect, reaction solution is poured in the ice and is stirred, precipitation, filtration, washing, obtain 1-acetylaminohydroxyphenylarsonic acid 3, the 5-dimethyladamantane, with sodium hydroxide and not the polyvalent alcohol of ether-containing key carry out alcoholysis, chloroform extraction concentrates and to obtain Memantine hydrochloride, again through hcl acidifying, chloroform recrystallization purifying and obtain memantine hydrochloride.
Wherein the polyvalent alcohol of ether-containing key can not comprise the not pure and mild alicyclic ring alcohol of polyhydric aliphatic of ether-containing key, as ethylene glycol, propylene glycol, glycerol, tetramethylolmethane, phloroglucite, inositol etc., especially can be not divalent alcohol containing ether linkage, particularly ethylene glycol.
Wherein after the kharophenization, the precipitation temperature that reaction solution is poured in the water is good with 0-5 ℃, and the time was advisable with 10-14 hour.
The present invention is at 1-bromo-3, after 5-dimethyladamantane and acetonitrile and strong sulfuric acid response finish, with this reaction solution pour into stir in the ice after, through precipitation, filter, washing, can obtain 1-acetylaminohydroxyphenylarsonic acid 3, the 5-dimethyladamantane need not to adopt benzene extraction, drying, spissated step, for accelerating 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane separating out in water adopts low-temperature sludge preferable, can guarantee higher yield in 10-14 hour.
At 1-acetylaminohydroxyphenylarsonic acid 3, in the alcoholysis step of 5-dimethyladamantane, adopt the polyvalent alcohol of ether-containing key not to replace glycol ether to carry out alcoholysis, obtain good result, then price is more cheap to adopt ethylene glycol.The aftertreatment in this step adopts chloroform to replace benzene as extraction solvent.
In the recrystallization purifying of memantine hydrochloride, adopt chloroform to replace ethanol/ether as solvent, make operation safer, easier, can stably obtain monocrystalline, product purity and crystal formation are better, and used chloroform of recrystallization and last step extract used chloroform recovery set usefulness mutually, greatly reduce cost.
The synthetic method of memantine hydrochloride provided by the invention is on the basis of adopting synthetic route same as the prior art, simplified operation, avoided use to human body and the great benzene of environmental hazard, employed solvent of recrystallization process and method compare to prior art have simple to operate, security good, good product quality, recyclablely apply mechanically, advantage such as cost is low, the polyvalent alcohol of the not ether-containing key of alcoholysis process, especially ethylene glycol replace glycol ether also to greatly reduce cost.Improvements over the prior art of the present invention are for favourable condition has been created in the synthetic technology application in practice of memantine hydrochloride.
Embodiment 1
1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane synthetic:
With 1-bromo-3,5-dimethyladamantane (20.0g), acetonitrile (58g) adds in the reaction flask, load onto reflux condensate device, slowly drip the vitriol oil (150ml) under the stirring at room, rate of addition is 1 droplet/second, system has heat-flash to emit gradually, when splashing into the about 65ml vitriol oil, reaction system refluxes voluntarily and becomes redness, has heat-flash and reddish-brown smog to emit, can suspend dropping this moment, after easing up, question response continue to drip again, the system viscous fluid that becomes colorless subsequently, and have foam to occur, keep 1 droplet/second the speed of dripping, stirring at room more than 12 hours again after dripping off, light yellow viscous fluid, be poured in the 500 gram trash ices, stir, left standstill about 5 ℃ 12 hours, suction filtration gets white solid, wash with water 2-3 time, drain 1-acetylaminohydroxyphenylarsonic acid 3, the 5-dimethyladamantane weighs about 28 grams (thick wet product), can be directly used in next step reaction, its purifying can be used the ethanol-water mixed solvent recrystallization.Fusing point 97-98 ℃.
1-amino-3,5-dimethyladamantane hydrochloride synthetic:
With above-mentioned 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane crude product drops in the reaction flask, adds ethylene glycol (330ml); water (15ml) and sodium hydroxide (20g); under nitrogen protection, stirring and refluxing 12 hours, oil bath temperature is controlled at 150-160 ℃; cooling; add 130ml water, with chloroform (analytical pure) extraction 3-4 time, combined chloroform layer; use anhydrous magnesium sulfate drying; suction filtration, rotary evaporation concentrates, and gets yellow oil; be 1-amino-3; 5-dimethyladamantane crude product to the hydrochloric acid soln that wherein adds 21ml 14%, gets white solid; drain; chloroform (analytical pure) recrystallization 2-3 time used in a small amount of washing, gets 1-amino-3; 5-dimethyladamantane hydrochloride (being memantine hydrochloride) elaboration; weigh 14 grams, fusing point 290-295 ℃ (distillation), total recovery 79%.
Embodiment 2
Change the ethylene glycol among the embodiment 1 into glycerol, charging capacity and operating method are constant, get memantine hydrochloride, weigh 13.8 grams, fusing point 290-295 ℃ (distillation), total recovery 77.8%.
Embodiment 3
Change the ethylene glycol among the embodiment 1 into tetramethylolmethane, charging capacity and operating method are constant, get memantine hydrochloride, weigh 13.8 grams, fusing point 290-295 ℃ (distillation), total recovery 77.8%.
Claims (5)
1, a kind of synthetic method of memantine hydrochloride, adopt 1-bromo-3, the 5-dimethyladamantane is through kharophenization, alcoholysis and hcl acidifying make, it is characterized in that 1-bromo-3, the 5-dimethyladamantane is after carrying out the kharophen reaction under acetonitrile and the vitriolic effect, reaction solution is poured in the ice and is stirred, precipitation, filter, washing, obtain 1-acetylaminohydroxyphenylarsonic acid 3, the 5-dimethyladamantane, with sodium hydroxide and not the polyvalent alcohol of ether-containing key carry out alcoholysis, chloroform extraction, concentrate and to obtain Memantine hydrochloride, again through hcl acidifying, chloroform recrystallization purifying and obtain memantine hydrochloride.
2, according to the method described in the claim 1, the polyvalent alcohol that it is characterized in that described not ether-containing key is divalent alcohol containing ether linkage not.
3,, it is characterized in that described not divalent alcohol containing ether linkage is an ethylene glycol according to the method described in the claim 2.
4, according to the method described in claim 1 or 2, it is characterized in that wherein kharophen reaction after, the precipitation temperature that reaction solution is poured in the ice after stirring is 0-5 ℃.
5,, it is characterized in that described sedimentation time is 10-14 hour according to the method described in the claim 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01127788 CN1125033C (en) | 2001-08-29 | 2001-08-29 | Synthesis of memantine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01127788 CN1125033C (en) | 2001-08-29 | 2001-08-29 | Synthesis of memantine hydrochloride |
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| CN1335299A CN1335299A (en) | 2002-02-13 |
| CN1125033C true CN1125033C (en) | 2003-10-22 |
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| CN 01127788 Expired - Fee Related CN1125033C (en) | 2001-08-29 | 2001-08-29 | Synthesis of memantine hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005069742A2 (en) * | 2003-12-10 | 2005-08-04 | Sun Pharmaceutical Industries Limited | Crystal form ii of memantine hydrochloride |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1240668C (en) * | 2003-09-10 | 2006-02-08 | 上海医药工业研究院 | Method for preparing memantine hydrochloride |
| CN100363329C (en) * | 2004-01-09 | 2008-01-23 | 南京大学 | Method of synthesizing amantadine hydrochloride |
| ATE444950T1 (en) | 2005-01-11 | 2009-10-15 | Teva Pharm Fine Chemicals Srl | METHOD FOR PRODUCING 1-AMINO-3,5-DIMETHYLADAMANTAN HYDROCHLORIDE |
| ITMI20050833A1 (en) | 2005-05-10 | 2006-11-11 | A M S A S P A Anonima Materie Sintetiche Affini | NEW PROCEDURE FOR THE SYNTHESIS OF AMINOADAMANTANI |
| US20110306796A1 (en) * | 2008-12-12 | 2011-12-15 | Alembic Limited | Process for the preparation of 1-bromo-3,5-dimethyl adamantane |
| JP5129782B2 (en) * | 2009-05-20 | 2013-01-30 | 出光興産株式会社 | Method for producing adamantanols |
| CN101993377A (en) * | 2009-08-07 | 2011-03-30 | 出光兴产株式会社 | Method for producing amine and quaternary ammonium salt having adamantane skeleton |
| CN102432473A (en) * | 2011-11-23 | 2012-05-02 | 广州博济医药生物技术股份有限公司 | Synthetic method of memantine hydrochloride |
| CN103288650B (en) * | 2012-02-28 | 2015-09-30 | 广州白云山制药股份有限公司广州白云山制药总厂 | A kind of preparation method of hydrochloric acid MEM |
| CN102875387A (en) * | 2012-10-23 | 2013-01-16 | 滨州泓瑞医药科技有限公司 | Amantadine hydrochloride preparation method |
| CN105294450B (en) * | 2014-05-29 | 2024-05-17 | 广州喜鹊医药有限公司 | Amantadine nitrate compound with neuroprotection effect, preparation and medical application thereof |
| CN111072491B (en) * | 2019-12-14 | 2022-11-04 | 老河口瑞祥化工有限公司 | Preparation method of memantine hydrochloride |
| CN115073304A (en) * | 2022-06-28 | 2022-09-20 | 北京云鹏鹏程医药科技有限公司 | Post-treatment preparation method of memantine hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005069742A2 (en) * | 2003-12-10 | 2005-08-04 | Sun Pharmaceutical Industries Limited | Crystal form ii of memantine hydrochloride |
| WO2005069742A3 (en) * | 2003-12-10 | 2006-04-20 | Sun Pharmaceutical Ind Ltd | Crystal form ii of memantine hydrochloride |
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| CN1335299A (en) | 2002-02-13 |
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