CN103524353A - Preparation method for high-purity memantine hydrochloride - Google Patents
Preparation method for high-purity memantine hydrochloride Download PDFInfo
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Abstract
A disclosed preparation method for high-purity memantine hydrochloride comprises: taking 1-hydroxy-3, 5-dimethyltricyclo[3, 3, 1, 13, 7]decane as a raw material, performing ammonification, hydrolysis, salt forming and crystallization to obtain high-purity memantine hydrochloride. The ammonification process means that a sulfuric acid solution is dropwise added into an acetic acid solution containing 1-hydroxy-3, 5-dimethyltricyclo[3, 3, 1, 13, 7]decane and trichloroacetonitrile for preparation of an intermediate A 1-trichloroacetamido-3, 5-dimethyltricyclo[3, 3, 1, 13, 7]decane. The intermediate A is subjected to hydrolysis under the effect of an inorganic strong base and a water-containing monohydric alcohol for obtaining of a memantine base; and the memantine base is treated with hydrochloric acid for salt formig and crystallization and further for obtaining of memantine hydrochloride. Memantine hydrochloride prepared by employing the preparation method has a purity of more than 99.9%; and the preparation method has the advantages of simple technology, low reaction temperature, good security, high yield and low cost, and is more applicable to industrialized 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 hydrochloric acid memantine, belongs to medical technical field.
Two, background technology
Memantine (memantine hydrocloride, formula (I)), chemistry 3,5-dimethyl, three rings [3,3,1,1 by name
3,7] decane-1-amine hydrochlorate; it is the curing senile dementia medicine by the exploitation of German Merz company; it is the noncompetitive antagonist that N-methyl-D-aspartate acceptor has medium avidity; the glutamine system of Main Function in brain, can neuroprotective cell exempts from the toxic action of excessive excitatory amino acid.Memantine is not only effective to slight Alzheimer's disease (AD); and can significantly improve the clinical symptom of severe AD; when share with acetylcholinesterase depressant, can significantly increase curative effect; a neuroprotective class medicine with the treatment dementia (especially AD) of market outlook, within 2003, being used for the treatment of by FDA approval, severe AD disease.
Prior art is prepared memantine, and what mainly adopt is first to synthesize the intermediate with following formula V or formula (VI) feature, and intermediate makes memantine through hydrolysis (formula V) or hydrogenation (formula (VI)), salify.
The building-up reactions route of memantine (formula (1)) is as follows:
With 1-halo-3,5-dimethyladamantane (formula (VII)) makes formula V with specific acylating reagent (acetonitrile/sulfuric acid, ethanamide, methane amide, urea) effect, and formula V hydrolysis, salify make memantine (formula (I)).
In described formula V compound, with 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane is comparatively common, and 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 stable, and hydrolysis is difficult, long-time high temperature (being greater than 150 ℃) hydrolysis in high-boiling point alcohol (glycol ether, glycerol, the ethylene glycol etc.) solution of highly basic (sodium hydroxide).CZ282398B6 is open by 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyl Buddha's warrior attendant in low-boiling point alcohol (methyl alcohol, ethanol, the Virahol) solution of highly basic (potassium hydroxide), the 110-140 ℃ of illustration of confined reaction 10-30 hour.
CN1400205 is by 1-bromo-3,5-dimethyladamantane reacts 48 hours at approximately 200 ℃ with urea, make the N-3 in described formula V compound, 5-dimethyladamantane-1-base urea, then in strong basicity (sodium hydroxide) ethylene glycol solution of 150-160 ℃, alcoholysis obtains memantine.
WO2010/083996A1 and US5061703 are by 1-bromo-3,5-dimethyladamantane is 120 ℃ of long-time reactions in formamide soln, make the N-3 in described formula V compound, 5-dimethyladamantane-1-methane amide, then in 37% hydrochloric acid, back hydrolysis obtains memantine.
CN101412678 for raw material, makes in described formula V compound 3 through nitrated with 1,3-dimethyladamantane, and 5-dimethyl nitro diamantane, then makes memantine through Pd/C catalytic hydrogenation, yield 78.1%.
To sum up, in prior art, the hydrolysis of the intermediate (formula V) of synthetic memantine 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, though avoided high temperature to react for a long time, has reduced energy consumption, has nitration reaction poor selectivity, and many nitros impurity is more, purifies difficult, and 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 hydrochloric acid memantine, 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 hydrochloric acid memantine of the present invention is with 1-hydroxyl-3,5-dimethyl three rings [3,3,1,1
3,7] decane is starting raw material, through ammonification, hydrolysis, salify crystallization, obtains high-purity hydrochloric acid memantine:
Described ammonification is by 1-hydroxyl-3,5-dimethyl three rings [3,3,1,1
3,7] decane (formula II) and Trichloroacetonitrile be dissolved in Glacial acetic acid (acetic acid), then drips the sulphuric acid soln of mass concentration 70%-98%, wherein H
2sO
4with 1-hydroxyl-3,5-dimethyl three rings [3,3,1,1
3,7] mol ratio of decane is 2-5:1, stirring reaction 2-4 hour at 40-70 ℃, pours reaction solution in frozen water into after reaction finishes, and stirring and crystallizing is filtered and is dried and obtains intermediate A-1-tribromo-acetyl amido-3, and 5-dimethyl three encircles [3,3,1,1
3,7] decane (formula III);
1-hydroxyl-3 in ammonifying process, 5-dimethyl three rings [3,3,1,1
3,7] mass ratio of decane and Trichloroacetonitrile is 1:0.8-1; 1-hydroxyl-3,5-dimethyl three rings [3,3,1,1
3,7] mass ratio of decane and Glacial acetic acid is 1:1.8-5.
Dry described in ammonifying process is that drying under reduced pressure is no less than 8 hours at 30-70 ℃.
Described hydrolysis is that described intermediate A is added in inorganic alkali solution, in 50-90 ℃ of stirring reaction 4-6 hour, reaction finishes rear filtration, filtrate concentration and recovery organic solvent, then add water-insoluble organic solvents extraction, merge organic phase, filter and concentrate after adding siccative (anhydrous sodium sulphate or anhydrous magnesium sulfate) dry and obtain intermediate B-memantine alkali (formula IV); Described inorganic alkali solution is the mixing solutions that inorganic strong alkali, water and monohydroxy-alcohol form; 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;
Mineral alkali described in hydrolytic process is selected from KOH or NaOH, further preferred NaOH.
Described in hydrolytic process, in inorganic alkali solution, 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 quality of intermediate A described in hydrolytic process is 1g:5-15mL with the ratio of the cumulative volume of water and monohydroxy-alcohol.
Described salify crystallization is that described intermediate B is added in ethanol and dissolved, 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 ℃ of stirring and crystallizing, after filtering and being dried, obtaining target product-memantine (formula I), 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.
Dry described in salify crystallisation process is that drying under reduced pressure is no less than 8 hours at 30-70 ℃.
The concrete synthetic route of memantine of the present invention is as follows:
The present invention adopts impurity counter point to detect the memantine making, 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, and obtains;
Detector: fid detector;
Chromatographic column: HP-5 capillary column (50m * 0.32mm * 0.52 μ m);
Column temperature: 50 ℃ of initial temperature, maintain 0min, with 5 ℃/min, be warming up to 145 ℃, then be warming up to 250 ℃ with 10 ℃/min, maintain 20min;
Injector temperature: 220 ℃;
Detector temperature: 300 ℃;
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 | 99.963% |
| Impurity B | 1.02 | Do not detect |
| Impurity C | 1.07 | Do not detect |
| Impurity D | 1.15 | Do not detect |
| Impurity E | 1.35 | Do not detect |
| Impurity F | 1.75 | Do not detect |
| Other are maximum single assorted | 1.64 | 0.037% |
| Total assorted | / | 0.037% |
The memantine that the present invention makes adopts vapor-phase chromatography to detect residual solvent levels (ethanol or Virahol, acetic acid, ethyl acetate all do not detect), and result solvent residual amount all meets existing pharmacopeia regulation.
Compared with prior art, the invention has the beneficial effects as follows: 1-tribromo-acetyl amido-3,5-dimethyl three rings [3,3,1,1
3,7] decane (formula III) is synthetic with 1-hydroxyl-3,5-dimethyl three rings [3,3,1,1
3,7] decane (formula II) is raw material, reaction nonirritant γ-ray emission, temperature of reaction is low, safety and environmental protection; 1-tribromo-acetyl amido-3,5-dimethyl three rings [3,3,1,1
3,7] decane (formula III) hydrolysis reaction take and commonly use monohydroxy-alcohol as solvent, 90 ℃ of normal pressures, with interior, carries out, equipment requirements is low, and the reaction times is short, and production energy consumption significantly reduces; Avoided High Temperature High Pressure by product and destroyed impurity generating, improved 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).
Fig. 2 is that memantine related substance detects GC color atlas (in figure, data are retention time, and analytical results is in Table 1).
Five, embodiment
Embodiment 1:
1, aminating reaction: 1-tribromo-acetyl amido-3,5-dimethyl three rings [3,3,1,1
3,7] decane (formula III) synthetic
By 1-hydroxyl-3,5-dimethyl three rings [3,3,1,1
3,7] decane 10g(55.5mmol), Glacial acetic acid 18mL, Trichloroacetonitrile 8g(55.4mmol) join in 100mL there-necked flask, drip the sulphuric acid soln 18mL of mass concentration 98%, control temperature at 50-60 ℃, after dripping off, in 55-60 ℃ of insulated and stirred, react 2 hours, after reaction finishes, reaction solution is slowly poured in 200ml frozen water into stirring and crystallizing, suction filtration, dry 8 hours of 50 ℃ of decompressions (0.085MPa), obtain intermediate A-1-tribromo-acetyl amido-3,5-dimethyl three rings [3,3,1,1
3,7] decane 17.8g, yield 98.8%.
2, hydrolysis reaction: memantine alkali (formula IV) synthetic
In 250mL single port bottle, add ethanol 80mL, water 20mL and sodium hydroxide 17.6g(0.44mol), stirring and dissolving, drop into intermediate A 17.7g(54.5mmol), 80 ℃ of back flow reaction 4 hours, filter, boil off ethanol, residue adds toluene (20ml * 2) extraction, merges organic phase, in organic phase, add anhydrous magnesium sulfate drying, filter, filtrate is concentrated, obtains intermediate B-memantine alkali 9.2g, for red oil, yield 94.1%.
3, salify crystallization: memantine (formula I) synthetic
Intermediate B 9.2g is dissolved in 30mL Virahol, drip the hydrochloric acid soln 4.2mL of mass concentration 37%, filter, filtrate adds ethyl acetate 100mL, 0-5 ℃ of stirring and crystallizing 8 hours, suction filtration, filter cake washs by ethyl acetate, dry 8 hours of 50 ℃ of decompressions (0.085MPa), obtain target product 9.1g, for white solid, yield 82.2%, purity 99.96%(GC method).Three step total recoverys 76.4%.
Embodiment 2:
1, aminating reaction: 1-tribromo-acetyl amido-3,5-dimethyl three rings [3,3,1,1
3,7] decane (formula III) synthetic
By 1-hydroxyl-3,5-dimethyl three rings [3,3,1,1
3,7] decane 10g(55.5mmol), Glacial acetic acid 30mL, Trichloroacetonitrile 10g(69.3mmol) join in 100mL there-necked flask, drip the sulphuric acid soln 18mL of mass concentration 98%, control temperature at 50-60 ℃, after dripping off, in 55-60 ℃ of insulated and stirred, react 3 hours, after reaction finishes, reaction solution is slowly poured in 300ml frozen water into stirring and crystallizing, suction filtration, dry 8 hours of 50 ℃ of decompressions (0.09MPa), obtain intermediate A-1-tribromo-acetyl amido-3,5-dimethyl three rings [3,3,1,1
3,7] decane 17.9g, yield 99.4%.
2, hydrolysis reaction: memantine alkali (formula IV) synthetic
In 250mL single port bottle, add Virahol 80mL, water 20mL and sodium hydroxide 15g(0.38mol), stirring and dissolving, drop into intermediate A 17.9g(55.1mmol), 80 ℃ of back flow reaction 4 hours, filter, boil off Virahol, residue adds ethyl acetate (20ml * 2) extraction, merges organic phase, in organic phase, add anhydrous magnesium sulfate drying, filter, filtrate is concentrated, obtains intermediate B-memantine alkali 9.5g, for red oil, yield 96.1%.
3, salify crystallization: memantine (formula I) synthetic
Intermediate B 9.5g is dissolved in 30mL ethanol, drip the hydrochloric acid soln 4.5mL of mass concentration 37%, filter, filtrate adds ethyl acetate 100mL, 0-5 ℃ of stirring and crystallizing 9 hours, suction filtration, filter cake washs by ethyl acetate, dry 8 hours of 60 ℃ of decompressions (0.085MPa), obtain target product 9.3g, for white solid, yield 81.3%, purity 99.93%(GC method).Three step total recoverys 77.7%.
Claims (9)
1. a preparation method for high-purity hydrochloric acid memantine, comprises ammonification, hydrolysis and each unit process of salify crystallization, it is characterized in that:
Described ammonification is by 1-hydroxyl-3,5-dimethyl three rings [3,3,1,1
3,7] decane and Trichloroacetonitrile be dissolved in Glacial acetic acid, then drips the sulphuric acid soln of mass concentration 70%-98%, wherein H
2sO
4with 1-hydroxyl-3,5-dimethyl three rings [3,3,1,1
3,7] mol ratio of decane is 2-5:1, stirring reaction 2-4 hour at 40-70 ℃, pours reaction solution in frozen water into after reaction finishes, and stirring and crystallizing is filtered and is dried and obtains intermediate A;
Described hydrolysis is that described intermediate A is added in inorganic alkali solution, in 50-90 ℃ of stirring reaction 4-6 hour, reaction finishes rear filtration, filtrate concentration and recovery organic solvent, then add water-insoluble organic solvents extraction, merge organic phase, add to filter and concentrate after desiccant dryness to obtain intermediate B; Described inorganic alkali solution is the mixing solutions that inorganic strong alkali, water and monohydroxy-alcohol form; 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 salify crystallization is that described intermediate B is added in ethanol and dissolved, and drips hydrochloric acid soln salify, filters in backward filtrate and adds precipitation agent, in-5～10 ℃ of stirring and crystallizing, after filtering and being dried, obtains target product.
2. preparation method according to claim 1, is characterized in that:
1-hydroxyl-3 in ammonifying process, 5-dimethyl three rings [3,3,1,1
3,7] mass ratio of decane and Trichloroacetonitrile is 1:0.8-1; 1-hydroxyl-3,5-dimethyl three rings [3,3,1,1
3,7] mass ratio of decane and Glacial acetic acid is 1:1.8-5.
3. preparation method according to claim 1, is characterized in that:
Dry described in ammonifying process is that drying under reduced pressure is no less than 8 hours at 30-70 ℃.
4. preparation method according to claim 1, is characterized in that:
Mineral alkali described in hydrolytic process is selected from KOH or NaOH.
5. according to the preparation method described in claim 1 or 4, it is characterized in that:
Mineral alkali described in hydrolytic process is NaOH.
6. preparation method according to claim 1, is characterized in that:
Described in hydrolytic process, in inorganic alkali solution, 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.
7. preparation method according to claim 1, is characterized in that:
The mol ratio of intermediate A described in hydrolytic process and described mineral alkali is 1:6-9; The quality of intermediate A described in hydrolytic process is 1g:5-15mL with the ratio of the cumulative volume of water and monohydroxy-alcohol.
8. preparation method according to claim 1, is characterized in that:
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.
9. preparation method according to claim 1, is characterized in that:
Dry described in salify crystallisation process is that drying under reduced pressure is no less than 8 hours at 30-70 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN109824534A (en) * | 2019-03-27 | 2019-05-31 | 浙江华海药业股份有限公司 | A kind of synthetic method of N- alkanoyl Memantine |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN109824534A (en) * | 2019-03-27 | 2019-05-31 | 浙江华海药业股份有限公司 | A kind of synthetic method of N- alkanoyl Memantine |
| CN109824534B (en) * | 2019-03-27 | 2024-05-07 | 浙江华海药业股份有限公司 | Synthesis method of N-alkanoyl memantine |
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