CN100345819C - Preparation method for substituted symmetrel compounds or salt thereof - Google Patents
Preparation method for substituted symmetrel compounds or salt thereof Download PDFInfo
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- CN100345819C CN100345819C CNB031483453A CN03148345A CN100345819C CN 100345819 C CN100345819 C CN 100345819C CN B031483453 A CNB031483453 A CN B031483453A CN 03148345 A CN03148345 A CN 03148345A CN 100345819 C CN100345819 C CN 100345819C
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Abstract
The present invention relates to a preparation method for substituted symmetrel compounds shown in the formula (I) or salts thereof, wherein each group is shown in the specification.
Description
Invention field
The present invention relates to a kind of amantadine compounds of replacement or the preparation method of its salt.
Background of invention
The amantadine compounds of multiple replacement all has good pharmaceutical use.
Wherein, amantadine hydrochloride is a kind of anti-virus infection class medicine.It can suppress virion and penetrate host cell, also can suppress virus and duplicate in early days and the shelling of blocking virus and the intrusion of nucleic acid host cell.It can effectively prevent and treat all A type influenza strains clinically, and German water pestivirus, Type B influenza virus, general influenza virus, respiratory syncytial virus and some RNA viruses are also had certain activity.
In addition, memantineHCl is a kind of good dementia curative.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, and this is that other are all kinds of in the not available advantage of dementia curative of grinding at present, thereby the economic and social benefit of this medicine has a high potential.
The preparation method of disclosed this Symmetrel compounds mainly contains two kinds in the document, and it is respectively:
Method one (US3391142):
Utilize Ritter reaction that the bromo diamantane is converted into the acetamido diamantane in this method, its under alkaline condition in glycol ether deacetylate, obtain memantine hydrochloride with the salt acid treatment afterwards.In this synthetic method, vitriol oil consumption is big, complex operation, danger in reaction and the last handling process, and use vitriol oil contaminate environment seriously in a large number.Simultaneously, in the deacetylation reaction, reaction solvent is comparatively expensive, and its temperature of reaction is higher, and the reaction times is longer, generates more by product in the reaction process.Various shortcoming in the above technology all is unfavorable for suitability for industrialized production.
Method two (US5061703):
Utilize 15% aqueous hydrochloric acid to do solvent piptonychia acyl group in this method, reaction yield is lower, is unfavorable for controlling cost in suitability for industrialized production.
Among two kinds of preparation methods that mentioned in the above-mentioned document, because complicated operation, aftertreatment are loaded down with trivial details, perhaps by product reaches factors such as reaction yield is low more and causes that suitability for industrialized production is difficult for realizing, the cost height, therefore is necessary to seek a kind of economy, preparation method efficiently.
Goal of the invention
The purpose of this invention is to provide a kind of economy, prepare the method that replaces amantadine compounds or its salt efficiently.
Summary of the invention
As previously mentioned, prepare in the method that replaces amantadine compounds or its salt, thereby have complicated operation, aftertreatment is loaded down with trivial details, by product is many or the low shortcomings such as suitability for industrialized production difficulty, cost height that cause of reaction yield known.
In view of the good pharmaceutical use that replaces the amantadine compounds, we are devoted to improve its production technique, simplify operation, improve yield, and then reduce the production cost of this compounds.By experiment, we find to utilize the halo adamantane compound of replacement and the Carbox amide of replacement to react, and the benzamide type adamantane compound that preparation replaces removes formyl radical afterwards under acidic conditions, finally obtain target product.Adopt this preparation method can reach its intended purposes: not only greatly to simplify production technique, reduced environmental pollution to greatest extent, and improved yield, reduced production cost, helped industrialized production.
Preparation process of the present invention is as follows:
Stage one:
The halo diamantane that replaces is mixed with the Carbox amide of replacement, and in appropriate solvent or do not adopt other solvents directly to carry out nucleophilic substitution reaction, the temperature of reaction is 70～250 ℃.Reaction back organic solvent extraction product, washing concentrates after the drying treatment, and the crude product that obtains is passed through recrystallization purifying, or the not purified the next step that is directly used in.
Stage two
In the water-soluble or suitable hydrophilic solvent of the purified or not purified product that stage one is obtained, add an amount of mineral acid or organic acid, carry out the reaction of piptonychia acyl group, amantadine compounds or its salt that preparation replaces.
Of the present invention have a following advantage:
1. technology is simple, pollutes for a short time, is easy to realize suitability for industrialized production;
2. yield height, cost is low.
Following embodiment is to describe in detail the present invention, and unrestricted the present invention.
Embodiment
Embodiment 1 preparation 3,5-dimethyl-1-formamido-diamantane
In the 500mL there-necked flask, add 220mL colourless transparent liquid methane amide, add 49.4g colourless transparent liquid 3 again under stirring, 5-dimethyl-1-bromine diamantane is in 140 ℃ of reacting by heating 6h.Add entry after reaction finishes, use chloroform extraction then, merge organic phase, washing, anhydrous magnesium sulfate drying obtains yellow oil 46.3g, the not treated the next step that is directly used in after concentrating.
Embodiment 2 preparation memantineHCls
According to 3 of the method preparation of describing among the embodiment 1,5-dimethyl-1-formamido-diamantane crude product and 300mL ethanol are mixed in the 500mL there-necked flask, stir, and slowly drip 36.5% concentrated hydrochloric acid 33mL with 46.0g, finish reaction behind the reflux 1.5h.Concentrating under reduced pressure obtains the wet product of white solid, recrystallization, and drying obtains white solid 32.3g, yield 74.9%, fusing point: 258 ℃.
Claims (5)
1. the preparation method of a formula (I) compound (Memantine hydrochloride) or its salt may further comprise the steps:
(1), the compound and the methane amide of formula (II) reacted, the compound of preparation formula (III),
X is Cl, B or I in the formula;
(2), the compound with formula (III) removes formyl radical, the compound of preparation formula (I) in the mixed solvent of ethanol and hydrochloric acid.
2. in accordance with the method for claim 1, the temperature of reaction that it is characterized in that step (1) is 70～250 ℃.
3. in accordance with the method for claim 1, the temperature of reaction that it is characterized in that step (1) is 120～180 ℃.
4. in accordance with the method for claim 1, the temperature of reaction that it is characterized in that step (1) is 140 ℃.
5. according to the method for claim 1, it is characterized in that may further comprise the steps:
(1), 3,5 dimethyl-1-bromine diamantane are added in the methane amide react, obtain 3,5-dimethyl-1-formamido-diamantane;
(2), step (1) obtain 3,5-dimethyl-1-formamido-diamantane crude product mixes with ethanol, adds the concentrated hydrochloric acid reaction and obtains memantine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031483453A CN100345819C (en) | 2003-07-01 | 2003-07-01 | Preparation method for substituted symmetrel compounds or salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031483453A CN100345819C (en) | 2003-07-01 | 2003-07-01 | Preparation method for substituted symmetrel compounds or salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1566075A CN1566075A (en) | 2005-01-19 |
| CN100345819C true CN100345819C (en) | 2007-10-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB031483453A Expired - Lifetime CN100345819C (en) | 2003-07-01 | 2003-07-01 | Preparation method for substituted symmetrel compounds or salt thereof |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102006009279A1 (en) * | 2006-03-01 | 2007-09-06 | Justus-Liebig-Universität Giessen | Process for the preparation of 1-formamido-3,5-dimethyladamantane |
| DE102006009278B4 (en) * | 2006-03-01 | 2010-06-02 | Justus-Liebig-Universität Giessen | Process for the direct formamidation or acetamidation of admantane and Admantanderivaten and their use for the production of Aminoadmantanen |
| CN101935286A (en) * | 2009-06-26 | 2011-01-05 | 出光兴产株式会社 | Preparation method of quaternary ammonium salt with adamantyl group |
| CN102531919A (en) * | 2011-11-09 | 2012-07-04 | 广东肇庆星湖生物科技股份有限公司 | Preparation method of memantinehydrochloride |
| CN103387507B (en) * | 2012-05-08 | 2016-05-25 | 上海医药工业研究院 | A kind of preparation method of 1-amide groups adamantane |
| CN104447352B (en) * | 2013-09-20 | 2017-01-25 | 山东方明药业集团股份有限公司 | Memantine hydrochloride preparation method |
| CN104693039B (en) * | 2015-01-06 | 2016-11-16 | 中山大学 | A kind of amantadine derivatives and its preparation method and application |
| CN111909041B (en) * | 2020-08-12 | 2023-06-16 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of medicine for treating neurological diseases |
| CN112341340B (en) * | 2020-09-30 | 2023-02-17 | 山东罗欣药业集团恒欣药业有限公司 | Green and efficient preparation method of medicine for treating Alzheimer's disease |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5061703A (en) * | 1989-04-14 | 1991-10-29 | Merz + Co. Gmbh & Co. | Adamantane derivatives in the prevention and treatment of cerebral ischemia |
-
2003
- 2003-07-01 CN CNB031483453A patent/CN100345819C/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5061703A (en) * | 1989-04-14 | 1991-10-29 | Merz + Co. Gmbh & Co. | Adamantane derivatives in the prevention and treatment of cerebral ischemia |
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| CN1566075A (en) | 2005-01-19 |
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Effective date of registration: 20210113 Address after: 570314 no.279 Nanhai Avenue, Xiuying District, Haikou City, Hainan Province Patentee after: AVENTIS PHARMA (HAINAN) Co.,Ltd. Address before: 100089, Wanquan mansion, three Jin Zhuang, Haidian District, Beijing, Sijiqing Patentee before: BEIJING D-VENTUREPHARM TECHNOLOGY DEVELOPMENT Co.,Ltd. |
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