CN103483205B - Preparation method of high-purity memantine hydrochloride - Google Patents
Preparation method of high-purity memantine hydrochloride Download PDFInfo
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- CN103483205B CN103483205B CN201310475642.2A CN201310475642A CN103483205B CN 103483205 B CN103483205 B CN 103483205B CN 201310475642 A CN201310475642 A CN 201310475642A CN 103483205 B CN103483205 B CN 103483205B
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Abstract
The invention discloses a preparation method of high-purity memantine hydrochloride, which comprises the following steps: by using 1-hydroxy-3,5-dimethyltricyclo[3,3,1,13,7]decane as an initial raw material, ammonifying, hydrolyzing and salifying to crystallize to obtain the high-purity memantine hydrochloride, wherein a sulfuric acid solution is dropwisely added into an acetic acid solution containing 1-hydroxy-3,5-dimethyltricyclo[3,3,1,13,7]decane to obtain an intermediate A 1-dichloroacetamido-3,5-dimethyltricyclo[3,3,1,13,7]decane, thereby realizing the ammonification; the intermediate A is hydrolyzed under the actions of an inorganic strong alkali and a hydrous monobasic alcohol to obtain a memantine alkali; the memantine alkali and hydrochloric acid are salified and crystallized to obtain the memantine hydrochloride. The purity of the memantine hydrochloride is greater than 99.9%; and the method has the advantages of simple technique, low reaction temperature, high safety, high yield and low cost, and is more suitable for industrial production.
Description
One, technical field
The present invention relates to a kind of preparation method of known drug, specifically a kind of preparation method of high-purity memantine hydrochloride, belongs to medical art.
Two, background technology
Memantine (memantine hydrocloride, formula (I)), chemistry 3,5-dimethyl three ring [3,3,1,1 by name
3,7] decane-1-amine hydrochlorate; it is the curing senile dementia medicine developed by German Merz company; it is the noncompetitive antagonist that N-methyl-D-aspartate acceptor has medium avidity; mainly act on the glutamine system in brain, the toxic action of excessive excitatory amino acid can be exempted from by neuroprotective cell.Memantine is not only effective to slight Alzheimer's disease (AD); and significantly can improve the clinical symptom of severe AD; significantly curative effect can be increased when share with acetylcholinesterase depressant; a neuroprotective class medicine with the treatment dementia (especially AD) of market outlook, 2003 by FDA approval be used for the treatment of in, severe AD disease.
Prior art prepares memantine, and what mainly adopt is first synthesize the intermediate with following formula V or formula (VI) feature, and intermediate obtains memantine through hydrolysis (formula V) or hydrogenation (formula (VI)), salify.
The building-up reactions of formula (1) compound and the reaction preparing memantine thereof have following feature:
Act on and obtained formula V with 1-halo-3,5-dimethyladamantane (formula (VII)) and specific acylating reagent (acetonitrile/sulfuric acid, ethanamide, methane amide, urea), formula V hydrolysis, salify obtain memantine (formula (I)).
Common with 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane in described formula V compound, this compound synthesis technology is simple, and concrete preparation method has detailed report in US3391142, CN1488622, CN1488622.And 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane amide structure is stablized, hydrolysis is difficult, long-time high temperature (being greater than 150 DEG C) hydrolysis in the high-boiling point alcohol of highly basic (sodium hydroxide) (glycol ether, glycerol, ethylene glycol etc.) solution.CZ282398B6 discloses by 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane in low-boiling point alcohol (methyl alcohol, ethanol, the Virahol) solution of highly basic (potassium hydroxide), 110 ~ 140 DEG C of confined reactions illustration of 10 ~ 30 hours.
CN1400205 is by bromo-for 1-3,5-dimethyladamantane and urea react 48 hours at about 200 DEG C, N-3 in obtained described formula V compound, 5-dimethyladamantane-1-base urea, then in strong basicity (sodium hydroxide) ethylene glycol solution of 150 ~ 160 DEG C, alcoholysis obtains memantine.
WO2010/083996A1 and US5061703 is by bromo-for 1-3,5-dimethyladamantane is 120 DEG C of reactions for a long time in formamide soln, N-3 in obtained described formula V compound, 5-dimethyladamantane-1-methane amide, then in 37% hydrochloric acid, back hydrolysis obtains memantine.
CN101412678 is with 1,3-dimethyladamantane for raw material, and 3,5-dimethyl nitro diamantane in nitrated obtained described formula V compound, then obtain memantine through Pd/C catalytic hydrogenation, yield 78.1%.
To sum up, intermediate (formula V) hydrolysis of synthesizing memantine in prior art all needs high temperature to react for a long time, and equipment requirements is high, and energy consumption is large, and cost is high.Method described in CN101412678, reacts for a long time though avoid high temperature, reduces energy consumption, there is nitration reaction poor selectivity, and many nitros impurity is more, and purify difficult, yield is low, is not suitable for industrial production.
Three, summary of the invention
The present invention aims to provide a kind of preparation method of high-purity memantine hydrochloride, technical problem to be solved be to provide a kind of easy and simple to handle, security good, yield is high, cost is low, product is pure, be more suitable for the synthesis technique of the memantine of suitability for industrialized production.
The preparation method of high-purity memantine hydrochloride of the present invention is with 1-hydroxyl-3,5-dimethyl three ring [3,3,1,1
3,7] decane is starting raw material, through ammonification, hydrolysis, one-tenth salt-pepper noise, obtains high-purity memantine hydrochloride:
Described ammonification is by 1-hydroxyl-3,5-dimethyl three ring [3,3,1,1
3,7] decane (formula II) and two chloromethyl cyanides are dissolved in Glacial acetic acid, then drip the sulphuric acid soln of mass concentration 70-98%, wherein H
2sO
4with 1-hydroxyl-3,5-dimethyl three ring [3,3,1,1
3,7] mol ratio of decane is 2-5:1, stirring reaction 2-4 hour at 40-70 DEG C, pours in frozen water by reaction solution after reaction terminates, stirring and crystallizing, filters and drying obtains intermediate A-1-dichloroacetyl amido-3,5-dimethyl three ring [3,3,1,1
3,7] decane (formula III);
1-hydroxyl-3,5-dimethyl three ring [3,3,1,1 in ammonifying process
3,7] mass ratio of decane and two chloromethyl cyanides is 1:0.8-1; 1-hydroxyl-3,5-dimethyl three ring [3,3,1,1
3,7] mass ratio of decane and Glacial acetic acid is 1:1.8-5.
Drying described in ammonifying process is that drying under reduced pressure is no less than 8 hours at 30-70 DEG C.
Described hydrolysis adds in inorganic alkali solution by described intermediate A, in 50-90 DEG C of stirring reaction 4-6 hour, reaction terminates rear filtration, filtrate concentration and recovery organic solvent, then water-insoluble organic solvents extraction is added, merge organic phase, add siccative (anhydrous sodium sulphate or anhydrous magnesium sulfate) dry after filter and concentrate and obtain intermediate B-memantine alkali (formula IV), be red oil; Described inorganic alkali solution is the mixing solutions that inorganic strong alkali, water and monohydroxy-alcohol are formed; Described water-insoluble organic solvents is selected from one or more in toluene, ethyl acetate, methylene dichloride, normal hexane, methyl tertiary butyl ether, isopropyl ether;
Described in hydrolytic process, mineral alkali is selected from KOH or NaOH, further preferred NaOH.
In inorganic alkali solution described in hydrolytic process, the volume ratio of water and monohydroxy-alcohol is 1:3-5; Described monohydroxy-alcohol is one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol.
The mol ratio of intermediate A described in hydrolytic process and described mineral alkali is 1:6-9; The ratio of the cumulative volume of the quality of intermediate A described in hydrolytic process and water and monohydroxy-alcohol is 1g:5-15mL.
Described one-tenth salt-pepper noise described intermediate B is added in ethanol to dissolve, drip the hydrochloric acid soln salify of mass concentration 36-38%, wherein the mol ratio of HCl and intermediate B is 1-1.1:1, filter in backward filtrate and add precipitation agent, in-5 ~ 10 DEG C of stirring and crystallizing, filtering and namely obtain target product-memantine (formula I) after drying, is white crystal.
Described in salify crystallisation process, precipitation agent is selected from one or more in toluene, ethyl acetate, methylene dichloride, normal hexane, methyl tertiary butyl ether, isopropyl ether.
Drying described in salify crystallisation process is that drying under reduced pressure is no less than 8 hours at 30-70 DEG C.
The synthetic route of memantine of the present invention is as follows,
The present invention adopts impurity counter point to detect obtained memantine, known impurities A(formula XI), impurity B (formula II), impurity C(formula VIII), impurity D(formula IX), impurity E (formula X) and impurity F (formula III) all do not detect, purity is greater than 99.9%(GC method), the results are shown in Table 1, color atlas is shown in Fig. 1.Analytical procedure is as follows:
Sample preparation: precision takes memantine trial-product 1.0g and puts in separating funnel, adds the 5M sodium hydroxide solution of 30ml and the normal hexane of 40ml; Jolting 10min, stratification, gets upper strata normal hexane layer anhydrous sodium sulfate drying, filters, to obtain final product;
Detector: fid detector;
Chromatographic column: HP-5 capillary column (50m × 0.32mm × 0.52 μm);
Column temperature: initial temperature 50 DEG C, maintains 0min, is warming up to 145 DEG C, then is warming up to 250 DEG C with 10 DEG C/min with 5 DEG C/min, maintains 20min;
Injector temperature: 250 DEG C;
Detector temperature: 300 DEG C;
Carrier gas: nitrogen;
Flow velocity: 4.0ml/min;
Sampling volume: 1 μ l.
The related substance detected result of memantine prepared by table 1 the present invention
| Title | Relative retention time | Content |
| Impurity A | 0.77 | Do not detect |
| Memantine | 1.0 | 100% |
| Impurity B | 1.04 | Do not detect |
| Impurity C | 1.08 | Do not detect |
| Impurity D | 1.20 | Do not detect |
| Impurity E | 1.46 | Do not detect |
| Impurity F | 1.0 | Do not detect |
| Other maximum lists are mixed | / | Do not detect |
| Total assorted | / | 0 |
The vapor-phase chromatography that adopts memantine that the present invention obtains detects residual solvent levels (ethanol or Virahol, acetic acid, ethyl acetate all do not detect), and result solvent residual amount all meets existing States Pharmacopoeia specifications.
Compared with prior art, the invention has the beneficial effects as follows: 1-dichloroacetyl amido-3,5-dimethyl three ring [3,3,1,1
3,7] decane (formula III) synthesis with 1-hydroxyl-3,5-dimethyl three ring [3,3,1,1
3,7] decane (formula II) is raw material, reaction nonirritant gas produces, and temperature of reaction is low, safety and environmental protection; 1-dichloroacetyl amido-3,5-dimethyl three ring [3,3,1,1
3,7] decane (formula III) hydrolysis reaction is with conventional monohydroxy-alcohol for solvent, carry out within normal pressure 90 DEG C, equipment requirements is low, and the reaction times is short, and production energy consumption significantly reduces; Avoid High Temperature High Pressure by product and destroy impurity and generate, improve yield, product purity is greater than 99.9%(GC method).
Four. accompanying drawing explanation
Fig. 1 is memantine impurity location GC color atlas (in figure, data are retention time) prepared by the present invention.
Fig. 2 is that memantine related substance prepared by the present invention detects GC color atlas (in figure, data are retention time, and analytical results is in table 1).
Five. embodiment
Below technical scheme of the present invention is described, so that those skilled in the art understand.
Embodiment 1:
1, aminating reaction: 1-dichloroacetyl amido-3,5-dimethyl three ring [3,3,1,1
3,7] synthesis of decane (formula III)
By 1-hydroxyl-3,5-dimethyl three ring [3,3,1,1
3,7] decane 10g(55.5mmol), Glacial acetic acid 18mL, two chloromethyl cyanide 6.1g(55.5mmol) join in 100mL there-necked flask, drip the sulphuric acid soln 18mL of mass concentration 98%, control temperature is at 50-60 DEG C, 2 hours are reacted in 55-60 DEG C of insulated and stirred after dripping off, after reaction terminates, reaction solution is slowly poured in 200ml frozen water, stirring and crystallizing, suction filtration, dry 8 hours of 50 DEG C of decompressions (0.085MPa), obtain intermediate A-1-dichloroacetyl amido-3,5-dimethyl three ring [3,3,1,1
3,7] decane 15.9g, yield 98.8%.
2, hydrolysis reaction: the synthesis of memantine alkali (formula IV)
To in 250mL single port bottle, add ethanol 80mL, water 20mL and sodium hydroxide 17.6g(0.44mol), stirring and dissolving, drop into intermediate A 15.9g(55.5mmol), 80 DEG C of back flow reaction 4 hours, filter, boil off ethanol, residue adds toluene (20ml × 2) extraction, merges organic phase, anhydrous magnesium sulfate drying is added in organic phase, filter, filtrate concentrates, and obtains intermediate B-memantine alkali 9.1g, for red oil, yield 93.1%.
3, salt-pepper noise is become: the synthesis of memantine (formula I)
Intermediate B 9.1g is dissolved in 30mL Virahol, drip the hydrochloric acid soln 4.2mL of mass concentration 37%, filter, filtrate adds ethyl acetate 100mL, 0-5 DEG C of stirring and crystallizing 8 hours, suction filtration, filter cake ethyl acetate is washed, dry 8 hours of 50 DEG C of decompressions (0.085MPa), obtain target product 9.2g, for white solid, yield 84.0%, purity 99.93%(GC method).Three step total recoverys 77.3%.
Embodiment 2:
1, aminating reaction: 1-dichloroacetyl amido-3,5-dimethyl three ring [3,3,1,1
3,7] synthesis of decane (formula III)
By 1-hydroxyl-3,5-dimethyl three ring [3,3,1,1
3,7] decane 10g(55.5mmol), Glacial acetic acid 30mL, two chloromethyl cyanide 7.6g(69.1mmol) join in 100mL there-necked flask, drip the sulphuric acid soln 18mL of mass concentration 98%, control temperature is at 50-60 DEG C, 3 hours are reacted in 55-60 DEG C of insulated and stirred after dripping off, after reaction terminates, reaction solution is slowly poured in 300ml frozen water, stirring and crystallizing, suction filtration, dry 8 hours of 50 DEG C of decompressions (0.085MPa), obtain intermediate A-1-dichloroacetyl amido-3,5-dimethyl three ring [3,3,1,1
3,7] decane 15.8g, yield 98.1%.
2, hydrolysis reaction: the synthesis of memantine alkali (formula IV)
To in 250mL single port bottle, add ethanol 80mL, water 20mL and sodium hydroxide 15g(0.38mol), stirring and dissolving, drop into intermediate A 15.8g(54.4mmol), 80 DEG C of back flow reaction 4 hours, filter, boil off ethanol, residue adds toluene (20ml × 2) extraction, merges organic phase, anhydrous magnesium sulfate drying is added in organic phase, filter, filtrate concentrates, and obtains intermediate B-memantine alkali 9.4g, for red oil, yield 96.3%.
3, salt-pepper noise is become: the synthesis of memantine (formula I)
Intermediate B 9.4g is dissolved in 30mL Virahol, drip the hydrochloric acid soln 4.5mL of mass concentration 37%, filter, filtrate adds ethyl acetate 100mL, 0-5 DEG C of stirring and crystallizing 8 hours, suction filtration, filter cake ethyl acetate is washed, dry 8 hours of 60 DEG C of decompressions (0.085MPa), obtain target product 9.1g, for white solid, yield 80.4%, purity 99.90%(GC method).Three step total recoverys 76.0%.
Claims (4)
1. a preparation method for high-purity memantine hydrochloride, comprises ammonification, hydrolysis and becomes each unit process of salt-pepper noise, it is characterized in that:
Described ammonification is by 1-hydroxyl-3,5-dimethyl three ring [3,3,1,1
3,7] decane and two chloromethyl cyanides are dissolved in Glacial acetic acid, then drip the sulphuric acid soln of mass concentration 70-98%, wherein H
2sO
4with 1-hydroxyl-3,5-dimethyl three ring [3,3,1,1
3,7] mol ratio of decane is 2-5:1, stirring reaction 2-4 hour at 40-70 DEG C, pours in frozen water by reaction solution after reaction terminates, stirring and crystallizing, filters and drying obtains intermediate A;
Described hydrolysis adds in inorganic alkali solution by described intermediate A, in 50-90 DEG C of stirring reaction 4-6 hour, reaction terminates rear filtration, filtrate concentration and recovery organic solvent, then water-insoluble organic solvents extraction is added, merge organic phase, filter and concentrate after adding desiccant dryness and obtain intermediate B; Described inorganic alkali solution is the mixing solutions that inorganic strong alkali, water and monohydroxy-alcohol are formed; Described water-insoluble organic solvents is selected from one or more in toluene, ethyl acetate, methylene dichloride, normal hexane, methyl tertiary butyl ether, isopropyl ether;
Described one-tenth salt-pepper noise described intermediate B is added in ethanol to dissolve, and drips hydrochloric acid soln salify, filter in backward filtrate and add precipitation agent, in-5 ~ 10 DEG C of stirring and crystallizing, filters and namely obtain target product after drying;
1-hydroxyl-3,5-dimethyl three ring [3,3,1,1 in ammonifying process
3,7] mass ratio of decane and two chloromethyl cyanides is 1:0.8-1; 1-hydroxyl-3,5-dimethyl three ring [3,3,1,1
3,7] mass ratio of decane and Glacial acetic acid is 1:1.8-5;
Described in hydrolytic process, mineral alkali is selected from KOH or NaOH; In inorganic alkali solution described in hydrolytic process, the volume ratio of water and monohydroxy-alcohol is 1:3-5; Described monohydroxy-alcohol is one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol; The mol ratio of intermediate A described in hydrolytic process and described mineral alkali is 1:6-9; The ratio of the cumulative volume of the quality of intermediate A described in hydrolytic process and water and monohydroxy-alcohol is 1g:5-15mL;
Described in salify crystallisation process, precipitation agent is selected from one or more in toluene, ethyl acetate, methylene dichloride, normal hexane, methyl tertiary butyl ether, isopropyl ether.
2. preparation method according to claim 1, is characterized in that:
Drying described in ammonifying process is that drying under reduced pressure is no less than 8 hours at 30-70 DEG C.
3. preparation method according to claim 1, is characterized in that:
Mineral alkali described in hydrolytic process is NaOH.
4. preparation method according to claim 1, is characterized in that:
Drying described in salify crystallisation process is that drying under reduced pressure is no less than 8 hours at 30-70 DEG C.
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| JP2016169166A (en) * | 2015-03-11 | 2016-09-23 | 株式会社トクヤマ | Production method of 1-amino-3,5-dimethyladamantane hydrochloride |
| CN105372343A (en) * | 2015-10-09 | 2016-03-02 | 北京万全德众医药生物技术有限公司 | Method for separating and measuring substances related to memantine hydrochloride intermediate through gas chromatography |
| CN111233670A (en) * | 2020-03-09 | 2020-06-05 | 四川尚锐生物医药有限公司 | Memantine hydrochloride impurity compound and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1908748A1 (en) * | 2006-10-05 | 2008-04-09 | Krka | Process for the preparation of memantine and its hydrochloric acid salt form |
| CN101389594A (en) * | 2006-02-21 | 2009-03-18 | 赫克萨尔股份公司 | Process for the preparation of adamantanamines |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389594A (en) * | 2006-02-21 | 2009-03-18 | 赫克萨尔股份公司 | Process for the preparation of adamantanamines |
| EP1908748A1 (en) * | 2006-10-05 | 2008-04-09 | Krka | Process for the preparation of memantine and its hydrochloric acid salt form |
Non-Patent Citations (1)
| Title |
|---|
| 盐酸美金刚的合成;邹永 等;《中国医药工业杂志》;20031231;第34卷(第5期);11，15 * |
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