CN103553932A - Method suitable for industrially preparing memanitine hydrochloride - Google Patents
Method suitable for industrially preparing memanitine hydrochloride Download PDFInfo
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- CN103553932A CN103553932A CN201310556110.1A CN201310556110A CN103553932A CN 103553932 A CN103553932 A CN 103553932A CN 201310556110 A CN201310556110 A CN 201310556110A CN 103553932 A CN103553932 A CN 103553932A
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Abstract
The invention discloses a method for preparing memanitine hydrochloride. The method comprises the steps of carrying out ritter reaction on 1-bromo-3,5-dimethyladamantane and acetonitrile under the action of concentrated sulfuric acid to synthesize 1-actamido-3,5-dimethyladmantane, hydrolyzing the 1-actamido-3,5-dimethyladmantane under the alkaline condition to obtain 1-amino-3,5-dimethyladmantane, acidifying 1-amino-3,5-dimethyladmantane with hydrochloric acid to obtain crude memantine, and recrystallizing the crude product to obtain a fine product. According to the method, temperature is controlled in the first-step acetyl-amination process when the system color changes, thus being capable of effectively preventing heat release due to fierce reaction, reducing the danger and being beneficial to industrialization; ethyl acetate or dichloromethane is selected for extraction solution, thus being capable of avoiding the use of high-toxicity benezene or chloroform; the mixed solution of ethanol or isopropanol andethyl acetate is selected for recrystallization, thus being capable of avoiding the use of high-toxicity chloroform.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to treat a kind of preparation method of alzheimer's disease medicine memantine.
Background technology
Nineteen eighty-two, memantine also completed the clinical study of three phases in the Germany listing ， U.S. and other various countries of European Union by Merz company first with trade(brand)name Akatinol, was about to listing.Memantine is during first is used for the treatment of-nmda receptor antagonist of severe Alzheimer's disease (being called for short AD), can suppress excessive release that main excitatory neuron transmits mediator L-glutamic acid, alleviate because L-glutamic acid excessively discharges, the neuronal cell of calcium ion due to is too much poisoning, damage and dead, thereby improve symptom and the function problem of dementia patients, have and being subject to property is good, the feature of drug safety simultaneously.Therefore, this medical instrument has wide economic and social profit.
The synthetic method of memantine salt is more, specific as follows:
Method one: acetonitrile method.The patents such as US3391142A are bromo-3 with 1-, and 5-dimethyladamantane is raw material, first by Ritter, react synthetic 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane, then under alkaline condition, hydrolysis obtains MEM, finally with hcl acidifying salify, obtains memantine.
Method two: Wyler's process.Patent US4122193 ﹑ CN1400205A and CN1544415 are with 1-bromo-3,5-dimethyladamantane is raw material, urea is as the synthetic 1-acetylaminohydroxyphenylarsonic acid 3 that obtains of amidation reagent, 5-dimethyladamantane, then hydrolysis obtains 1-amino-3,5-dimethyladamantane, finally obtains memantine with hcl acidifying salify.
Method three: schematized version.US Patent No. 5599998 is with 1-bromo-3,5-dimethyladamantane is raw material, under ultrasound condition, react with lithium methide and obtain 1-lithium-3,5-dimethyladamantane, 1-lithium-3,5-dimethyladamantane reacts with ammonium chloride and obtains 1-amino-3,5-dimethyladamantane, last acidifying salify obtains memantine.
Method four: chloro method.Patent US5061703 ﹑ CN1193981C and CN1488622A for raw material, obtain 1-by tertiary butyl chloride chlorination chloro-3 with 1,3-dimethyladamantane, and 5-dimethyladamantane is obtaining memantine through Anization ﹑ hydrolysis and salify.
Method five: methane amide method.Patent WO2009115334A2 has proposed with 1,3-dimethyladamantane, for raw material, by amidated, to obtain 1-formamido group-3,5-dimethyladamantane, then obtain memantine through acidifying salify.
Method six: nitrofication process.Patent CN101412678A has reported with 1,3-dimethyladamantane as raw material, by digestion reaction, obtains 1-nitro-3, and 5-dimethyladamantane, through H
2reduction obtains MEM, and last acidifying salify obtains memantine.
Method seven: direct ammoniation process.Patent CN1556094A has proposed with 1,3-dimethyladamantane is raw material, and in bromine effect, next step completes Xiu Dai ﹑ Ritter reaction, without the direct Chun Xie of separation of intermediates ﹑ hydrolysis, obtains 1-amino-3,5-dimethyladamantane, last acidifying salify obtains memantine.
In aforesaid method, method two is with urea as amidation reagent, and temperature of reaction is higher, and reaction conditions is very harsh.Method three grignard reactions need anhydrous and oxygen-free condition, and need ultrasonic device, and operation is harsh, to operator, require higher.First method four need to carry out chloro with aluminum chloride and tertiary butyl chloride under anhydrous condition, needs constantly to add aluminum chloride in chlorination process, troublesome poeration, and the activity of chloro thing is not high, and reaction conversion ratio is low.Method five produces a large amount of nitrogen peroxide steams in reaction process, and need to be with a large amount of alkali neutralizations during aftertreatment.Method six need to be used hydrogen and Pd/C catalyzer, reacts more dangerous.The utilization ratio of method seven raw materials is not high, should " one kettle way " polystep reaction be carried out in same container, and side reaction is more, wayward.US Patent No. 3391142A discloses the method for acetonitrile method synthetic hydrochloric acid memantine, with 1-bromo-3,5-dimethyladamantane is starting raw material, take acetonitrile as ammonification reagent, obtain 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane, then under alkaline condition, hydrolysis obtains 1-amino-3,5-dimethyladamantane, last hydrochloric acid salify obtains memantine.Chinese patent CN01127788.2 improves extraction solvent and recrystallization solvent, extraction solvent replaces benzene with chloroform, recrystallization process replaces volatile inflammable ethanol/ether mixed solvent with chloroform, meanwhile, when alcoholysis, with cheap polyvalent alcohol, replaces expensive glycol ether.Chinese patent CN201110375931.6 stirs difficulty for the sticky thick ﹑ of the first step acetyl amination reaction and improves, and in reaction system, adds a certain amount of organic acid, thereby is beneficial to stirring.We find by experiment, improved acetonitrile method still has some problems urgently to be resolved hurrily: the first step is carried out kharophen can very exothermic while being reacted to a certain degree, when especially experiment is amplified, react wayward, more dangerous, such as 1-bromo-3,100 grams of 5-dimethyladamantane input amounts, in reaction process, temperature can acutely rise to 160 ℃, and material can spray; Hydrolysis reaction aftertreatment use extraction solvent adopt the larger chloroform of toxicity, large to human injury; What during memantine recrystallization, use is also the chloroform that toxicity is larger.These problems can affect suitability for industrialized production, therefore, to the method, carry out reasonably improving particularly necessary.
Summary of the invention
The present invention seeks to solve the weak point of aforesaid method, a kind of optimization synthetic method of memantine is provided, this synthetic method can effectively solve very exothermic in amidate action process and bring dangerous problem, and provides a kind of to environment and little extraction solvent and the recrystallization solvent of harm.
For achieving the above object, the technical solution used in the present invention is: a kind of method of preparing memantine, comprises the following steps:
The first step: 1-is bromo-3, and 5-diformazan fund firm alkane ﹑ acetonitrile and acetic acid mix and is placed in reaction flask, drip the vitriol oil under ice bath, in controlling, temperature, lower than 20 ℃, after dropwising, removes ice bath,, there is colour-change in stirring at room, adds ice bath in system, continue reaction 12h, pour in frozen water, stir and separate out white solid, suction filtration, wash filter cake with water, the dry 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane of obtaining.
Second step: by 1-acetylaminohydroxyphenylarsonic acid 3, the firm alkane ﹑ of 5-diformazan fund second two alcohol ﹑ water and sodium hydroxide are placed in reaction flask, be heated to 150-160 ℃, reaction 12h, is chilled to room temperature, with twice of solvent extraction, merge organic phase, organic phase saturated common salt water washing, concentrated, obtain MEM.
The 3rd step: MEM and ethyl acetate are placed in to reaction flask, drip concentrated hydrochloric acid under ice bath, reaction 1h, filters, and obtains memantine crude product.The mixing solutions recrystallization of polar solvent and ester for memantine crude product, obtains fine work.
In technique scheme, 1-acetylaminohydroxyphenylarsonic acid 3, the mol ratio of 5-dimethyladamantane and sodium hydroxide is 1:1 ~ 10, the volume ratio of water and ethylene glycol is 1:5 ~ 15.
In technique scheme, extraction solvent is selected from a kind of in ethyl acetate and methylene dichloride.
In technique scheme, polar solvent is selected from a kind of in Shui ﹑ Jia Chun ﹑ Yi Chun ﹑ Virahol and propyl carbinol; Ester is selected from a kind of in Yi Suan Yi Zhi ﹑ butylacetate and phenylacetate; The volume ratio of ester and polar solvent is 1:5 ~ 15.
In preferred technical scheme, 1-acetylaminohydroxyphenylarsonic acid 3, the mol ratio of 5-dimethyladamantane and sodium hydroxide is 1:5.5, the volume ratio of water and ethylene glycol is 1:10.
In preferred technical scheme, polar solvent is selected from ethanol or Virahol; Ester is selected from ethyl acetate; The volume ratio of ethyl acetate and ethanol or Virahol is 1:10.
Reaction process can be expressed as:
The present invention is with respect to the advantage of additive method:
(1) temperature control when system color changes in the first step kharophen process, can effectively prevent from reacting very exothermic, reduces danger, is conducive to industrialization.
(2) extraction solution is selected ethyl acetate or methylene dichloride, can avoid using benzene or the chloroform that toxicity is large.
(3) recrystallization is selected the mixing solutions of ethanol or Virahol and ethyl acetate, can avoid equally the chloroform that uses toxicity large, and yield is high.
Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and only limit to following examples.Do not departing under the above-mentioned technology prerequisite of the present invention, the corresponding replacement of making according to ordinary skill knowledge and customary means or the modification of change, include within the scope of the invention.
Embodiment mono-:
(1) 1-acetylaminohydroxyphenylarsonic acid 3, the preparation of 5-dimethyladamantane
By 1-bromo-3, (100g, 0.41mol) ﹑ acetonitrile (300ml) and acetic acid (100ml) mixing are placed in reaction flask to 5-dimethyladamantane, drip the vitriol oil under ice bath, in controlling, temperature is lower than 20 ℃, after dropwising, remove ice bath, stirring at room, in system, there is colour-change, from colourless become light yellow, the light yellow scarlet that becomes, interior temperature is between 35 ℃ and 50 ℃, add ice bath, continue reaction 12h, pour in frozen water, stir and separate out white solid, suction filtration, wash filter cake with water, dry 88 grams of 1-acetylaminohydroxyphenylarsonic acids 3, the 5-dimethyladamantane of obtaining.
(2) preparation of MEM
By 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane (88g, 0.397mol) ﹑ ethylene glycol (700ml) ﹑ water (70ml) and sodium hydroxide (88g, 2.20mol) be placed in reaction flask, be heated to 150-160 ℃, reaction 12h, be chilled to room temperature, with dichloromethane extraction (150ml * 2), merge organic phase, saturated aqueous common salt for organic phase (150ml) washing, anhydrous sodium sulfate drying, concentrated, obtain 69.5 grams of MEMs.
(3) preparation of memantine
By 1-amino-3,5-diformazan fund (69g, 0.385mol) ﹑ ethyl acetate (150ml) is placed in reaction flask, drips concentrated hydrochloric acid (43g) under ice bath, and reaction 1h, filters, and is dried and obtains 75 grams of memantine crude products.Mixing solutions recrystallization by memantine Virahol (460ml) and ethyl acetate (46ml) for crude product, is cooled to room temperature, then is placed in refrigerator 2h, suction filtration, the dry 57 grams of fine work, three step total recoverys 64% of obtaining.
Embodiment bis-:
(1) 1-acetylaminohydroxyphenylarsonic acid 3, the preparation of 5-dimethyladamantane
By 1-bromo-3, (100g, 0.41mol) ﹑ acetonitrile (300ml) and acetic acid (100ml) mixing are placed in reaction flask to 5-dimethyladamantane, drip the vitriol oil under ice bath, in controlling, temperature is lower than 20 ℃, after dropwising, remove ice bath, stirring at room, in system, there is colour-change, from colourless become light yellow, the light yellow scarlet that becomes, interior temperature is between 35 ℃ and 50 ℃, add ice bath, continue reaction 12h, pour in frozen water, stir and separate out white solid, suction filtration, wash filter cake with water, dry 88 grams of 1-acetylaminohydroxyphenylarsonic acids 3, the 5-dimethyladamantane of obtaining.
(2) preparation of MEM
By 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane (87g, 0.39mol) ﹑ ethylene glycol (700ml) ﹑ water (70ml) and sodium hydroxide (87g, 2.15mol) be placed in reaction flask, be heated to 150-160 ℃, reaction 12h, be chilled to room temperature, be extracted with ethyl acetate (150ml * 2), merge organic phase, saturated aqueous common salt for organic phase (150ml) washing, anhydrous sodium sulfate drying, concentrated, obtain 69 grams of MEMs.
(3) preparation of memantine
By MEM, (69g, 0.385mol) ﹑ ethyl acetate (150ml) is placed in reaction flask, drips concentrated hydrochloric acid (43g) under ice bath, and reaction 1h, filters, and is dried and obtains 74.5 grams of memantine crude products.Mixing solutions recrystallization by memantine Virahol (454ml) and ethyl acetate (45ml) for crude product, is cooled to room temperature, then is placed in refrigerator 2h, suction filtration, the dry 56 grams of fine work, three step total recoverys 63% of obtaining.
Embodiment tri-:
(1) 1-acetylaminohydroxyphenylarsonic acid 3, the preparation of 5-dimethyladamantane
By 1-bromo-3, (100g, 0.41mol) ﹑ acetonitrile (300ml) and acetic acid (100ml) mixing are placed in reaction flask to 5-dimethyladamantane, drip the vitriol oil under ice bath, in controlling, temperature is lower than 20 ℃, after dropwising, remove ice bath, stirring at room, in system, there is colour-change, from colourless become light yellow, the light yellow scarlet that becomes, interior temperature is between 35 ℃ and 50 ℃, add ice bath, continue reaction 12h, pour in frozen water, stir and separate out white solid, suction filtration, wash filter cake with water, dry 88 grams of 1-acetylaminohydroxyphenylarsonic acids 3, the 5-dimethyladamantane of obtaining.
(2) preparation of MEM
By 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane (88g, 0.397mol) ﹑ ethylene glycol (700ml) ﹑ water (70ml) and sodium hydroxide (88g, 2.20mol) be placed in reaction flask, be heated to 150-160 ℃, reaction 12h, be chilled to room temperature, with dichloromethane extraction (150ml * 2), merge organic phase, saturated aqueous common salt for organic phase (150ml) washing, anhydrous sodium sulfate drying, concentrated, obtain 69.5 grams of MEMs.
(3) preparation of memantine
By 1-amino-3,5-diformazan fund (69g, 0.385mol) ﹑ ethyl acetate (150ml) is placed in reaction flask, drips concentrated hydrochloric acid (43g) under ice bath, and reaction 1h, filters, and is dried and obtains 75 grams of memantine crude products.Mixing solutions recrystallization by memantine ethanol (250ml) and ethyl acetate (25ml) for crude product, is cooled to room temperature, then is placed in refrigerator 2h, suction filtration, the dry 50 grams of fine work, three step total recoverys 56% of obtaining.
Claims (5)
1. a method for applicable preparation of industrialization memantine, is characterized in that, comprises the following steps:
The first step: 1-is bromo-3, and 5-diformazan fund firm alkane ﹑ acetonitrile and acetic acid mix and is placed in reaction flask, drip the vitriol oil under ice bath, in controlling, temperature, lower than 20 ℃, after dropwising, removes ice bath,, there is colour-change in stirring at room, adds ice bath in system, continue reaction 12h, pour in frozen water, stir and separate out white solid, suction filtration, wash filter cake with water, the dry 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane of obtaining;
Second step: by 1-acetylaminohydroxyphenylarsonic acid 3, the firm alkane ﹑ of 5-diformazan fund second two alcohol ﹑ water and sodium hydroxide are placed in reaction flask, be heated to 150-160 ℃, reaction 12h, is chilled to room temperature, with twice of solvent extraction, merge organic phase, organic phase saturated common salt water washing, concentrated, obtain MEM;
The 3rd step: MEM and ethyl acetate are placed in to reaction flask, drip concentrated hydrochloric acid under ice bath, reaction 1h, filters, and obtains memantine crude product, and the mixing solutions recrystallization of polar solvent and ester for memantine crude product, obtains fine work.
2. preparation method according to claim 1, is characterized in that, 1-acetylaminohydroxyphenylarsonic acid 3, and the mol ratio of 5-dimethyladamantane and sodium hydroxide is 1:1 ~ 10, the volume ratio of water and ethylene glycol is 1:5 ~ 15.
3. preparation method according to claim 1, is characterized in that, extraction solvent is selected from a kind of in ethyl acetate and methylene dichloride.
4. preparation method according to claim 1, is characterized in that, polar solvent is selected from a kind of in Shui ﹑ Jia Chun ﹑ Yi Chun ﹑ Virahol and propyl carbinol; Ester is selected from a kind of in Yi Suan Yi Zhi ﹑ butylacetate and phenylacetate.
5. preparation method according to claim 4, is characterized in that, the volume ratio of ester and polar solvent is 1:5 ~ 15.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018082596A1 (en) * | 2016-11-03 | 2018-05-11 | Sunshine Lake Pharma Co., Ltd. | Solid forms of an adamantyl compound, compositions and uses thereof |
| CN111072491A (en) * | 2019-12-14 | 2020-04-28 | 老河口瑞祥化工有限公司 | Preparation method of memantine hydrochloride |
| US10800734B2 (en) | 2016-05-07 | 2020-10-13 | Sunshine Lake Pharma Co., Ltd. | Memantine compounds and their preparation and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1488622A (en) * | 2003-08-12 | 2004-04-14 | 江苏省原子医学研究所 | Method for preparing memantine hydrochloride |
| 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 |
-
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- 2013-11-12 CN CN201310556110.1A patent/CN103553932B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1488622A (en) * | 2003-08-12 | 2004-04-14 | 江苏省原子医学研究所 | Method for preparing memantine hydrochloride |
| 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 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10800734B2 (en) | 2016-05-07 | 2020-10-13 | Sunshine Lake Pharma Co., Ltd. | Memantine compounds and their preparation and uses thereof |
| WO2018082596A1 (en) * | 2016-11-03 | 2018-05-11 | Sunshine Lake Pharma Co., Ltd. | Solid forms of an adamantyl compound, compositions and uses thereof |
| CN109862887A (en) * | 2016-11-03 | 2019-06-07 | 广东东阳光药业有限公司 | A kind of crystal form of adamantane aminated compounds, composition and application thereof |
| CN109862887B (en) * | 2016-11-03 | 2021-09-10 | 广东东阳光药业有限公司 | Crystal form, composition and application of amantadine compound |
| 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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