CN1400205A - Preparation method of memantine hydrochloride - Google Patents
Preparation method of memantine hydrochloride Download PDFInfo
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- CN1400205A CN1400205A CN 02134628 CN02134628A CN1400205A CN 1400205 A CN1400205 A CN 1400205A CN 02134628 CN02134628 CN 02134628 CN 02134628 A CN02134628 A CN 02134628A CN 1400205 A CN1400205 A CN 1400205A
- Authority
- CN
- China
- Prior art keywords
- bromo
- dimethyladamantane
- method described
- sodium hydroxide
- memantine hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 229960000967 memantine hydrochloride Drugs 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006136 alcoholysis reaction Methods 0.000 claims abstract description 10
- 239000004202 carbamide Substances 0.000 claims abstract description 10
- 238000000605 extraction Methods 0.000 claims abstract description 10
- QUCXLVDIVQWYJR-UHFFFAOYSA-N 1-bromo-3,5-dimethyladamantane Chemical compound C1C(C2)CC3(C)CC1(C)CC2(Br)C3 QUCXLVDIVQWYJR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- 239000012141 concentrate Substances 0.000 claims description 6
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002723 alicyclic group Chemical group 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 229920005862 polyol Polymers 0.000 claims 2
- 150000003077 polyols Chemical class 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 9
- 206010012289 Dementia Diseases 0.000 abstract description 5
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229940044551 receptor antagonist Drugs 0.000 abstract description 2
- 239000002464 receptor antagonist Substances 0.000 abstract description 2
- 230000020477 pH reduction Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 4
- -1 phloroglucite Chemical compound 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 229940059574 pentaerithrityl Drugs 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The preparation method of medicine for curing dementia, N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine hydrochloride includes the following steps: using polybasic alcohol as solvent; making 1-bromo-3,5-dimethyl adamantane and urea according to the mole ratio of 1:0.25-10 react for 0.5-48 hr. at 20-200 deg.C; after the reaction is completed, adding sodium hydroxide into the reaction solution according to that the mole ratio of 1-bromo-3,5-dimethyl adamantane and sodium hydroxide is 1:0.1-10, making alcoholysis at 50-200 deg.C, chloroform extraction, concentration, acidification with hydrochloric acid and salt-forming so as to obtain the invented menantine hydrochloride. It features safe and simple operation and low cost, etc.
Description
Technical field
The present invention relates to the preparation method of dementia curative, N-methyl-D-aspartate (NMDA) receptor antagonist memantine hydrochloride.
Technical background
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, is with 1; the 3-dimethyladamantane obtains 1-bromo-3 through bromination, the 5-dimethyladamantane; under acetonitrile and vitriolic effect, carry out kharophenization again; obtain 1-ethanoyl-3, the 5-dimethyladamantane, this compound carries out alcoholysis with sodium hydroxide and glycol ether; benzene extraction; concentrate and to obtain 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 there is weak point in above-mentioned literature method.
Summary of the invention
The objective of the invention is to adopt a new synthetic route to prepare memantine hydrochloride, its advantage is to adopt more cheap and raw material, more simple processing method environmental protection, need not isolating reaction and obtain product through two step successive, intermediates, simplified reactions steps greatly.
The preparation method of memantine hydrochloride provided by the invention is with 1-bromo-3, and 5-dimethyladamantane and urea reaction are again after the alcoholysis, through extraction, concentrated, hcl acidifying salify.
A kind of comparatively ideal preparation method is to be solvent with the polyvalent alcohol, with 1-bromo-3,5-dimethyladamantane and urea 1: 0.25 in molar ratio～10 reacted 0.5-48 hour down at 25～200 ℃, after reacting completely, press 1-bromo-3, the mol ratio of 5-dimethyladamantane and sodium hydroxide is 1: 0.1～10, adds sodium hydroxide in reaction solution, under 50～200 ℃, carry out alcoholysis, through chloroform extraction, concentrate, promptly get memantine hydrochloride through the hcl acidifying salify again.
Use therein solvent polyvalent alcohol comprises the pure and mild alicyclic ring alcohol of polyhydric aliphatic, as ethylene glycol, propylene glycol, glycerol, tetramethylolmethane, phloroglucite, inositol etc., especially can be dibasic alcohol, particularly ethylene glycol, glycol ether.
1-bromo-3,5-dimethyladamantane and urea preferred in molar ratio 1: 2～5, preferred 100～180 ℃ of temperature of reaction.
1-bromo-3, the mol ratio of 5-dimethyladamantane and sodium hydroxide be preferably 1: 5～and 8.
Preferred 100～170 ℃ of alcoholysis temperature.
The present invention has adopted a new synthetic route, and the acetonitrile of having abandoned in the above-mentioned United States Patent (USP) to be adopted, benzene, vitriol oil etc. have the reagent of bigger harm to environment and human body.In the recrystallization purifying of memantine hydrochloride, adopt chloroform to replace ethanol/ether as solvent, make operation safer, easier, can stably obtain monocrystalline, detect through nucleus magnetic resonance, mass spectrum, infrared spectra and ultimate analysis, product purity and crystalline form are better, and the used chloroform of recrystallization and last step extract used chloroform recovery set usefulness mutually, greatly reduced cost.
Preferred forms
Embodiment 1
With 1-bromo-3,5-dimethyladamantane (20g), urea (30g) adds in the reaction flask, adds 160ml ethylene glycol, oil bath is warming up to 70-80 ℃, reacts 30 hours, is cooled to room temperature, to wherein adding 27g sodium hydroxide, 100ml ethylene glycol, oil bath is warming up to 80 ℃, reacted 20 hours, cooling adds 30ml water, with chloroform extraction 2-3 time, the combined chloroform layer is used anhydrous magnesium sulfate drying, suction filtration, rotary evaporation concentrates, and gets yellow oil, be 1-amino-3,5-dimethyladamantane crude product is 37% hydrochloric acid soln to wherein adding weight concentration, white solid, drain, chloroform recrystallization 2-3 time used in a small amount of washing, gets 1-amino-3,5-dimethyladamantane hydrochloride (being memantine hydrochloride) elaboration, weigh 12.4 grams, fusing point 290-295 ℃ (distillation), total recovery 70%.
Embodiment 2
With 1-bromo-3,5-dimethyladamantane (20g), urea (12.5g) adds in the reaction flask, adds the 160ml glycol ether, oil bath is warming up to 170-180 ℃, reacts 5 hours, is cooled to room temperature, to wherein adding 20g sodium hydroxide, the 100ml glycol ether, oil bath is warming up to 160 ℃, back flow reaction 12 hours, cooling adds 30ml water, with chloroform extraction 2-3 time, the combined chloroform layer is used anhydrous magnesium sulfate drying, suction filtration, rotary evaporation concentrates, and gets yellow oil, be 1-amino-3,5-dimethyladamantane crude product is 14% hydrochloric acid soln to wherein adding weight concentration, white solid, drain, chloroform recrystallization 2-3 time used in a small amount of washing, gets 1-amino-3,5-dimethyladamantane hydrochloride (being memantine hydrochloride) elaboration, weigh 13.8 grams, fusing point 290-295 ℃ (distillation), total recovery 78%.
Embodiment 3
With 1-bromo-3,5-dimethyladamantane (20g), urea (5g) adds in the reaction flask, adds the 160ml glycerol, oil bath is warming up to 120-130 ℃, reacts 10 hours, is cooled to room temperature, to wherein adding 3.5g sodium hydroxide, the 100ml glycerol, oil bath is warming up to 120 ℃, back flow reaction 15 hours, cooling adds 30ml water, with chloroform extraction 2-3 time, the combined chloroform layer is used anhydrous magnesium sulfate drying, suction filtration, rotary evaporation concentrates, and gets yellow oil, be 1-amino-3,5-dimethyladamantane crude product is 5% hydrochloric acid soln to wherein adding weight concentration, white solid, drain, chloroform recrystallization 2-3 time used in a small amount of washing, gets 1-amino-3,5-dimethyladamantane hydrochloride (being memantine hydrochloride) elaboration, weigh 13.3 grams, fusing point 290-295 ℃ (distillation), total recovery 75%.
Claims (8)
1, a kind of preparation method of memantine hydrochloride is with 1-bromo-3, and 5-dimethyladamantane and urea reaction are again after the alcoholysis, through extraction, concentrated, hcl acidifying salify.
2, according to the method described in the claim 1, it is characterized in that with the polyvalent alcohol being solvent, with 1-bromo-3,5-dimethyladamantane and urea 1: 0.25 in molar ratio～10 reacted 0.5-48 hour down at 25～200 ℃, after reacting completely, pressed 1-bromo-3, the mol ratio of 5-dimethyladamantane and sodium hydroxide is 1: 0.1～10, in reaction solution, add sodium hydroxide, under 50～200 ℃, carry out alcoholysis, through chloroform extraction, concentrate, promptly get memantine hydrochloride through the hcl acidifying salify again.
3,, it is characterized in that described polyol solvent is selected from the pure and mild alicyclic ring alcohol of polyhydric aliphatic according to the method described in the claim 2.
4,, it is characterized in that described polyol solvent is selected from dibasic alcohol according to the method described in claim 2 or 3.
5,, it is characterized in that described dibasic alcohol is selected from ethylene glycol, glycol ether according to the method described in the claim 4.
6, according to the method described in claim 2 or 3, it is characterized in that described 1-bromo-3,5-dimethyladamantane and urea are 1: 2～5 in molar ratio, temperature of reaction is 100～180 ℃.
7, according to the method described in claim 2 or 3, it is characterized in that described 1-bromo-3, the mol ratio of 5-dimethyladamantane and sodium hydroxide is 1: 5～8.
8,, it is characterized in that described alcoholysis temperature is 100～170 ℃ according to the method described in claim 2 or 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02134628 CN1400205A (en) | 2002-08-30 | 2002-08-30 | Preparation method of memantine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02134628 CN1400205A (en) | 2002-08-30 | 2002-08-30 | Preparation method of memantine hydrochloride |
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| Publication Number | Publication Date |
|---|---|
| CN1400205A true CN1400205A (en) | 2003-03-05 |
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Family Applications (1)
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| CN 02134628 Pending CN1400205A (en) | 2002-08-30 | 2002-08-30 | Preparation method of memantine hydrochloride |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005023753A1 (en) * | 2003-09-10 | 2005-03-17 | Shanghai Institute Of Pharmaceutical Industry | A method of preparing memantine hydrochloride |
| CN100363329C (en) * | 2004-01-09 | 2008-01-23 | 南京大学 | Method of synthesizing amantadine hydrochloride |
| EP1908748A1 (en) * | 2006-10-05 | 2008-04-09 | Krka | Process for the preparation of memantine and its hydrochloric acid salt form |
| US7462743B2 (en) | 2005-01-11 | 2008-12-09 | Teva Pharmaceutical Fine Chemicals S.R.L. | Polymorphs of memantine hydrochloride |
| WO2010112946A1 (en) | 2009-03-31 | 2010-10-07 | Rudjer Boskovic Institute | Adamantane bisurea derivatives, method of preparation and application in anion sensing |
| CN102070463A (en) * | 2009-06-11 | 2011-05-25 | 辽宁利锋科技开发有限公司 | Medicine memantine with adamantane structure, and derivative and analog thereof, and application to new antineoplastic indication |
| CN101768085B (en) * | 2008-12-31 | 2013-01-23 | 南京理工大学 | Method for synthesizing amantadine |
| CN103288650A (en) * | 2012-02-28 | 2013-09-11 | 广州白云山制药股份有限公司广州白云山制药总厂 | Hydrochloric acid 1-amino-3, 5-dimethyl adamantane preparation method |
| CN103664640A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Preparation method of memantine hydrochloride |
| CN105294450A (en) * | 2014-05-29 | 2016-02-03 | 广州喜鹊医药有限公司 | Amantadine nitrate compound with neuroprotective effect, and preparation therefor and medical application thereof |
| JP2017039656A (en) * | 2015-08-19 | 2017-02-23 | 大日本印刷株式会社 | Method for manufacturing highly-pure memantine hydrochloride |
| CN109206320A (en) * | 2017-06-29 | 2019-01-15 | 江苏英力科技发展有限公司 | A kind of method of continuous production adamantanamine hydrochloride |
| CN111072491A (en) * | 2019-12-14 | 2020-04-28 | 老河口瑞祥化工有限公司 | Preparation method of memantine hydrochloride |
-
2002
- 2002-08-30 CN CN 02134628 patent/CN1400205A/en active Pending
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005023753A1 (en) * | 2003-09-10 | 2005-03-17 | Shanghai Institute Of Pharmaceutical Industry | A method of preparing memantine hydrochloride |
| US7355080B2 (en) | 2003-09-10 | 2008-04-08 | Shanghai Institute Of Pharmaceutical Industry | Method of preparing memantine hydrochloride |
| CN100363329C (en) * | 2004-01-09 | 2008-01-23 | 南京大学 | Method of synthesizing amantadine hydrochloride |
| US7462743B2 (en) | 2005-01-11 | 2008-12-09 | Teva Pharmaceutical Fine Chemicals S.R.L. | Polymorphs of memantine hydrochloride |
| EP1908748A1 (en) * | 2006-10-05 | 2008-04-09 | Krka | Process for the preparation of memantine and its hydrochloric acid salt form |
| WO2008040560A1 (en) * | 2006-10-05 | 2008-04-10 | Krka, D.D., Novo Mesto | Process for the preparation of memantine and its hydrochloric acid salt form |
| EA019303B1 (en) * | 2006-10-05 | 2014-02-28 | Крка, Д.Д. Ново Место | Process for the preparation of memantine and its hydrochloric acid salt form |
| CN101768085B (en) * | 2008-12-31 | 2013-01-23 | 南京理工大学 | Method for synthesizing amantadine |
| WO2010112946A1 (en) | 2009-03-31 | 2010-10-07 | Rudjer Boskovic Institute | Adamantane bisurea derivatives, method of preparation and application in anion sensing |
| CN102070463A (en) * | 2009-06-11 | 2011-05-25 | 辽宁利锋科技开发有限公司 | Medicine memantine with adamantane structure, and derivative and analog thereof, and application to new antineoplastic indication |
| CN103288650A (en) * | 2012-02-28 | 2013-09-11 | 广州白云山制药股份有限公司广州白云山制药总厂 | Hydrochloric acid 1-amino-3, 5-dimethyl adamantane preparation method |
| 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 |
| CN103664640A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Preparation method of memantine hydrochloride |
| CN105294450A (en) * | 2014-05-29 | 2016-02-03 | 广州喜鹊医药有限公司 | Amantadine nitrate compound with neuroprotective effect, and preparation therefor and medical application thereof |
| 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 |
| JP2017039656A (en) * | 2015-08-19 | 2017-02-23 | 大日本印刷株式会社 | Method for manufacturing highly-pure memantine hydrochloride |
| CN109206320A (en) * | 2017-06-29 | 2019-01-15 | 江苏英力科技发展有限公司 | A kind of method of continuous production adamantanamine hydrochloride |
| CN111072491A (en) * | 2019-12-14 | 2020-04-28 | 老河口瑞祥化工有限公司 | Preparation method of memantine hydrochloride |
| CN111072491B (en) * | 2019-12-14 | 2022-11-04 | 老河口瑞祥化工有限公司 | Preparation method of memantine hydrochloride |
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