CN103833555B - A kind of preparation method of memantine - Google Patents
A kind of preparation method of memantine Download PDFInfo
- Publication number
- CN103833555B CN103833555B CN201210482891.XA CN201210482891A CN103833555B CN 103833555 B CN103833555 B CN 103833555B CN 201210482891 A CN201210482891 A CN 201210482891A CN 103833555 B CN103833555 B CN 103833555B
- Authority
- CN
- China
- Prior art keywords
- memantine
- formic acid
- compound
- preparation
- carbamate
- 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.)
- Active
Links
- 229960004640 memantine Drugs 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 title claims abstract description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 70
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 38
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 34
- 235000019253 formic acid Nutrition 0.000 claims abstract description 34
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 15
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- 239000011260 aqueous acid Substances 0.000 claims description 3
- YSNBVWSMODUIRB-UHFFFAOYSA-N 5-bromo-1,2-dimethyladamantane Chemical compound BrC12CC3(C(C(CC(C1)C3)C2)C)C YSNBVWSMODUIRB-UHFFFAOYSA-N 0.000 claims description 2
- 235000021050 feed intake Nutrition 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 26
- 230000004044 response Effects 0.000 abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 5
- 231100000614 poison Toxicity 0.000 abstract description 4
- 230000007096 poisonous effect Effects 0.000 abstract description 4
- 239000000383 hazardous chemical Substances 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- SODQFLRLAOALCF-UHFFFAOYSA-N 1lambda3-bromacyclohexa-1,3,5-triene Chemical compound Br1=CC=CC=C1 SODQFLRLAOALCF-UHFFFAOYSA-N 0.000 abstract 1
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 30
- 238000000034 method Methods 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
- 239000004202 carbamide Substances 0.000 description 10
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229960000967 memantine hydrochloride Drugs 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 150000003673 urethanes Chemical class 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- -1 1-acetyl-amino-3,5-dimethyladamantane Chemical compound 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 0 COC(OC*)=N Chemical compound COC(OC*)=N 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 241000408187 Theagenes Species 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminum chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HSFVBORYBGMNBE-UHFFFAOYSA-N methyl carbamate;urea Chemical compound NC(N)=O.COC(N)=O HSFVBORYBGMNBE-UHFFFAOYSA-N 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- WTHDKMILWLGDKL-UHFFFAOYSA-N urea;hydrate Chemical compound O.NC(N)=O WTHDKMILWLGDKL-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the preparation method of a kind of memantine, it is characterised in that include step: A. with formic acid as solvent, at 50 DEG C to 150 DEG C, carbamate and compound II react 0.25 hour 4 hours, obtain mixture a；B. mixture a is boiled off formic acid, adds hydrochloric acid, hydrolyze 0.5 10 hours at 40 DEG C to 110 DEG C, crystallize of lowering the temperature in the temperature environment of 5 DEG C 30 DEG C, filters and i.e. obtains memantine；Wherein, carbamate is
Description
Technical field
The present invention relates to the preparation method of a kind of memantine, belong to pharmaceutical formulating art.
Background technology
3,5-dimethyl-1-adamantanamine hydrochlorides (memantine Memantine hydrochloride), No. CAS
For 41100-52-1, have a structure that
The form 3 of its unhindered amina, 5-dimethyl-1-amantadine, No. CAS is 19982-08-2, has a structure that
Memantine (Memantine hydrochloride) is a kind of noncompetitive NMDA (N-methyl D-Radix Asparagi
Propylhomoserin) receptor antagonist.This medicine is first medicine in terms for the treatment of AD and vascular dementia with significant curative effect, is also only
The most individual nmda antagonist being developed for Alzheimer.
There is the multiple method preparing memantine at present:
Ritter method；
US3391142 discloses synthetic hydrochloric acid memantine and intermediate 1-acetyl-amino-3,5-dimethyladamantane thereof
Ritter method, toxic solvent acetonitrile and a large amount of (35 moles) corrosivity of having used a large amount of (17 moles) in this technique are strong
Acid----concentrated sulphuric acid, and the extremely difficult hydrolysis of intermediate acetyl compounds, deprotection uses high boiling solvent, brings again solvent
The problem of residual, the preparation process condition of these harshnesses is all difficult to overcome in the industrialization of technique, and brings a large amount of
Environmental contaminants.
Methanamide, acetamide method；
US5061703, WO2006122238 etc., disclose with Methanamide, acetamide hydrochloric acid, sulphuric acid, formic acid or its
With 3 under the conditions of his acid medium, the method for 5-dimethyladamantane halides reaction, due to the hydroxyl being difficult to avoid that in course of reaction
The generation of base compound, and, due to the more difficult removing of hydroxylate, the difficulty of product purification when the most also increasing post processing.
Urea method；
US4122193 discloses by tube sealing, by 3, the halides of 5-dimethyladamantane, at high temperature under high pressure, with urea
The technique that aminating reaction occurs:
EP1674446 discloses the improvement of urea method, with formic acid as solvent, synthesizes memantine by ammonification；Owing to urea is having
Dissolubility poor in machine solvent and relatively small nucleophilicity so that the temperature of this reaction is higher, and the response time is longer, receive
Rate is low, thus inevitably causes the increase of cost in industrialization.
4, additive method；
US5599998 reports lithiumation ammoniation process, need to use lithium metal, and strong oxidizing property, unstable poisonous examination
Agent chloramines, WO2010007351 discloses Gabriel method, and reaction does not has advantage, deprotection difficulty, and post processing is difficult,
CN101768085 etc. disclose nitrification method of reducing, and nitration reaction condition is harsh, and the response time is long.CN102050744 is open
Agene-aluminum chloride method, needs to use the agene that severe toxicity is explosive, is all to select, it is difficult to industrialized side
Method.
Summary of the invention
It is an object of the invention to provide the preparation method of a kind of memantine.Reaction condition of the present invention is simple, it is not necessary to
Using poisonous and harmful and hazardous materials, reaction temperature is low, and the response time is short, and during post processing, the difficulty of product purification is little, finally produces
Thing collection rate is high, and cost is relatively low.
For solving above-mentioned technical problem, the technical scheme that the present invention provides is as follows: the preparation method of a kind of memantine,
It is characterized in that: include step,
A., with formic acid as solvent, at 50 DEG C to 150 DEG C, compound I and compound II reacts 0.25 hour-4 hours,
Mixture a；Wherein, the molar ratio of compound I and compound II is 1.0-5.0:1, formic acid and the body that feeds intake of compound II
Long-pending mass ratio (ml/g) is 1.0-10.0:1；
B., mixture a boiling off formic acid, adds hydrochloric acid, volume mass ratio (ml/g) of hydrochloric acid and compound II is
1.0-5.0:1, hydrolyzes 0.5-10 hour at 40 DEG C to 110 DEG C, crystallize of lowering the temperature in the temperature environment of-5 DEG C-30 DEG C, filters
Obtain memantine；
Wherein, compound I isCompound II isR is methyl or ethyl.
The preparation method of aforesaid memantine, in described step A, compound I and compound II feeds intake mole
Than being that the volume mass ratio that feeds intake of 1.0-2.0:1, formic acid and compound II is for 1.0-5.0:1；Reaction temperature be 80 DEG C to 150
℃。
The preparation method of aforesaid memantine, in described step A, formic acid is the water of anhydrous formic acid or formic acid
Solution.
In the preparation method of aforesaid memantine, the formic acid concn of described first aqueous acid is more than 80%.
The preparation method of aforesaid memantine, in described step B, hydrolysis time is 2.0-5.0 hour；Hydrolysis temperature
Degree is 90 DEG C-110 DEG C.
The preparation method of aforesaid memantine, in described step B, the temperature of crystallize is 5 DEG C-25 DEG C.
In the preparation method of aforesaid memantine, the mass concentration of described hydrochloric acid is 5%-37%.
In the preparation method of aforesaid memantine, the mass concentration of described hydrochloric acid is preferably 20%-37%.
Compared with prior art, present invention employs carbamate and 1-bromo-3,4-dimethyladamantane as raw material,
Without using poisonous and harmful and hazardous materials,；And present invention employs carbamate as the source of amino in reaction, make
Must react can quickly, homogeneously, smoothly carry out；Reaction condition the most of the present invention is simple, and reaction temperature is low, and the response time is short,
After hydrolysis is acidified into salt, memantine can become to salt out, and end product collection rate is high, and cost is relatively low.
The inventors discovered that, urea-formic acid method can overcome intermediate to be not easy the problem of hydrolysis well, but, due to urea
Water solublity preferably (the most fat-soluble less), thus the dissolubility that urea is in formic acid is less, due to formic acid solvation with
And the polarizability that urea itself is less, cause the nucleophilicity of amino on urea more weak, in order to make reaction complete, formic acid be solvent also
Under catalysis, urea needs higher temperature, and longer response time with the reaction of compound II.In order to overcome this defect, I
Attempt by having the most fat-soluble, be the most conveniently easy to get, low-cost industrialization product----carbamate
As the source of amino, so that reaction is faster, homogeneously, smoothly carry out, the reaction intermediate of gained again can be in acid simultaneously
Hydrolyzing rapidly under the conditions of property or alkalescence, its product purity is higher, after hydrochloric acid is acidified into salt, can lower the temperature easily
Separate out, thus efficiently, high yield, high-purity ground obtain memantine.
By calculating and actual measurement, as shown in table 1, it has been found that carbamate is at formic acid or formic acid and organic solvent
In mixture, dissolubility is fabulous such that it is able to realize homogeneous reaction well, improves response speed, it is achieved we improve reaction
Efficiency, the intention of reduction cost.
Table 1 methyl carbamate and the ClogP of urea and the dissolubility (25 DEG C) in 98% formic acid compare
| Methyl carbamate | Urea | |
| ClogP (lipid) | -0.704* | -1.66* |
| Dissolubility in 98% formic acid | 2.248 grams per milliliters (25 DEG C) * * | 0.996 grams per milliliter (25 DEG C) * * |
* represent and obtained by Chemoffice computed in software
* represents measured value
Surprisingly, it was found that due to dissolubility good in formic acid nucleophilicity more preferable with relative urea, amino
The response speed of formic acid esters and compound II quickly, can be reacted complete for 0.25 hour, and the response time is greatly shortened, product
In follow-up hydrolysis, after having preferable hydrolysing activity, and hydrolysis, purity is the highest, can pass through hydrochloric acid easily
Acidifying, one-tenth salts out, and without extracting with organic solvent such that it is able to obtain Memantine hydrochloride with the high yield of 87% easily
Just, and product purity is high, and GC purity is more than 99.0%, after filtration drying, i.e. can reach USP crude drug relevant criterion.
Below in conjunction with embodiment, the present invention is further illustrated, but is not intended as the foundation limiting the present invention.
Detailed description of the invention
Embodiment 1
By bromo-for 1-3,5-dimethyladamantane 24 grams and methyl carbamate 8 grams are placed in reaction bulb, add 50 milliliters
The formic acid of 98%, is stirred at room temperature dissolving, argon shield, is heated to 90 DEG C and reacts 0.5 hour.Being cooled to room temperature, decompression boils off first
Acid, is subsequently adding concentrated hydrochloric acid 24 milliliters, stirring, is heated to 90 DEG C, reacts 3 hours.Being cooled to 25 DEG C, crystal slowly separates out, and treats
Crystallize is complete, filters and i.e. obtains memantine.
GC purity: 99.5%, yield: 76%；
GC condition: instrument Agilent 6960；Chromatographic column: Agilent HP-5；Int:340℃；Det:340℃flow:
3.0 ml/min；GC purity: 99.8%；
MS (ESI): m/z=180.2 [M+H+]；
1HNMR(400MHz,CDCl3):δ0.793(s,6H),1.161-1.064(dd,2H),1.283-1.279(dd,
4H),1.455-1.372(dd,4H),1.621-1.615(d,2H),2.148-2.132(t,1H)；
13C NMR(400MHz,CDCl3): δ 21.32 (CH3), 27.30 (CH2), 32.51 (CH2), 45.49 (CH2),
53.53(CH),121.26,122.62,123.09,124.88,125.03,125.33(CF3),126.13,126.27,
127.35,128.04,128.85,129.51,129.56,130.19,130.69,131.55,132.10,133.87,140.78。
Embodiment 2
By bromo-for 1-3,5-dimethyladamantane 24 grams and urethanes 36 grams are placed in reaction bulb, add 240 milliliters
The formic acid of 98%, is stirred at room temperature dissolving, argon shield, is heated to 90 DEG C and reacts 1 hour.Being cooled to room temperature, decompression boils off formic acid,
Being subsequently adding mass concentration is 10% hydrochloric acid 60 milliliters, stirring, is heated to 110 DEG C, reacts 4 hours.Being cooled to 0 DEG C, crystal is analysed
Go out, treat that crystallize is complete, filter and i.e. obtain memantine.
GC purity: 99.0%, yield: 85%.
Embodiment 3
By bromo-for 1-3,5-dimethyladamantane 24 grams and methyl carbamate 15 grams are placed in reaction bulb, add 100 milliliters
The formic acid of 88%, is stirred at room temperature dissolving, argon shield, is heated to 140 DEG C and reacts 1.5 hours.Being cooled to room temperature, decompression boils off first
Acid, is subsequently adding the hydrochloric acid 50 milliliters of 20%, stirring, is heated to 105 DEG C, reacts 3 hours.Being cooled to 5 DEG C, crystal separates out, and treats
Crystallize is complete, filters and i.e. obtains memantine.
GC purity: 99.2%, yield: 79%.
Embodiment 4
By bromo-for 1-3,5-dimethyladamantane 24 grams and urethanes 44.5 grams are placed in reaction bulb, add 200 millis
Rise the formic acid of 98%, dissolving, argon shield are stirred at room temperature, be heated to 50 DEG C and react 4 hours.Being cooled to room temperature, decompression boils off first
Acid, is subsequently adding the hydrochloric acid 120 milliliters that mass concentration is 5%, stirring, is heated to 100 DEG C, reacts 5 hours.It is cooled to 25 DEG C,
Crystal slowly separates out, and treats that crystallize is complete, filters and i.e. obtain memantine.
GC purity: 99.4%, yield: 76%.
Embodiment 5
By bromo-for 1-3,5-dimethyladamantane 24 grams and methyl carbamate 7.5 grams are placed in reaction bulb, add 50 milliliters
The formic acid of 98%, is stirred at room temperature dissolving, argon shield, is heated to 80 DEG C and reacts 2.5 hours.Being cooled to room temperature, decompression boils off first
Acid, is subsequently adding concentrated hydrochloric acid 40 milliliters, stirring, is heated to 95 DEG C, reacts 2 hours.Being cooled to 20 DEG C, crystal slowly separates out, and treats
Crystallize is complete, filters and i.e. obtains memantine.
GC purity: 99.5%, yield: 87%.
Embodiment 6
By bromo-for 1-3,5-dimethyladamantane 24 grams and methyl carbamate 18 grams are placed in reaction bulb, add 50 milliliters
The formic acid of 98%, is stirred at room temperature dissolving, argon shield, is heated to 90 DEG C and reacts 3 hours.Being cooled to room temperature, decompression boils off formic acid,
It is subsequently adding concentrated hydrochloric acid 30 milliliters, stirring, it is heated to 90 DEG C, reacts 3 hours.Being cooled to 25 DEG C, crystal slowly separates out, and treats crystallize
Completely, filter and i.e. obtain memantine.
GC purity: 99.0%, yield: 80%.
Claims (7)
1. the preparation method of a memantine, it is characterised in that: include step,
A., with formic acid as solvent, at 80 DEG C to 150 DEG C, carbamate and compound II react 0.25 hour-4 hours,
Mixture a；Wherein, the molar ratio of carbamate and compound II is 1.0-2.0:1, and formic acid and compound II feed intake
Volume mass ratio is for 1.0-5.0:1 ml/g；
B. mixture a is boiled off formic acid, adds hydrochloric acid, the volume mass of hydrochloric acid and compound II than for 1.0-5.0:1 milliliter/
Gram, hydrolyze 0.5-10 hour at 40 DEG C to 110 DEG C, crystallize of lowering the temperature in the temperature environment of-5 DEG C-30 DEG C, filter and i.e. obtain hydrochloric acid
Memantine；
Wherein, carbamate isCompound II is 1-bromo-3,4-dimethyladamantane, and R is methyl or ethyl.
The preparation method of memantine the most according to claim 1, it is characterised in that: in described step A, formic acid is
Anhydrous formic acid or first aqueous acid.
The preparation method of memantine the most according to claim 2, it is characterised in that: described first aqueous acid
Formic acid concn is more than 80%.
The preparation method of memantine the most according to claim 1, it is characterised in that: in described step B, during hydrolysis
Between be 2.0-5.0 hour；Hydrolysis temperature is 90 DEG C-110 DEG C.
The preparation method of memantine the most according to claim 1, it is characterised in that: in described step B, crystallize
Temperature is 5 DEG C-25 DEG C.
The preparation method of memantine the most according to claim 1, it is characterised in that: the mass concentration of described hydrochloric acid
For 5%-37%.
The preparation method of memantine the most according to claim 6, it is characterised in that: the mass concentration of described hydrochloric acid
For 20%-37%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210482891.XA CN103833555B (en) | 2012-11-23 | 2012-11-23 | A kind of preparation method of memantine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210482891.XA CN103833555B (en) | 2012-11-23 | 2012-11-23 | A kind of preparation method of memantine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103833555A CN103833555A (en) | 2014-06-04 |
| CN103833555B true CN103833555B (en) | 2016-12-21 |
Family
ID=50797496
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210482891.XA Active CN103833555B (en) | 2012-11-23 | 2012-11-23 | A kind of preparation method of memantine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103833555B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6444702B1 (en) * | 2000-02-22 | 2002-09-03 | Neuromolecular, Inc. | Aminoadamantane derivatives as therapeutic agents |
| CN1240668C (en) * | 2003-09-10 | 2006-02-08 | 上海医药工业研究院 | Method for preparing memantine hydrochloride |
| CN102093228B (en) * | 2011-01-18 | 2013-12-11 | 广东工业大学 | Method for synthesizing 1, 3-adamantane diamine |
-
2012
- 2012-11-23 CN CN201210482891.XA patent/CN103833555B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Fluorous-Tagged Carbamates for the Pd-Catalyzed Amination of Aryl Halides;Juan A. Vega等;《J. Org. Chem.》;20071231;第72卷;第8146-8148页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103833555A (en) | 2014-06-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108047077B (en) | Preparation method of oseltamivir chiral impurity | |
| CN104610250A (en) | 1,2,3-thiadiazole-5-formamidine compound containing three N-heterocycles and synthesis | |
| JP6852215B2 (en) | Voglibose Impurity I Hydrochloride Preparation Method | |
| JP5006311B2 (en) | Substituted tetrafluorobenzylaniline compound and method for producing pharmaceutically acceptable salt thereof | |
| US7355080B2 (en) | Method of preparing memantine hydrochloride | |
| CN103073439B (en) | Synthesis method of ambroxol hydrochloride compound | |
| CN101838212B (en) | Method for synthesizing L-carnitine by using (R)-(-)-3-chlorine-1,2-propylene glycol as chiral initiative raw material | |
| CN103833555B (en) | A kind of preparation method of memantine | |
| CN103145636B (en) | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof | |
| CN104557576A (en) | Method for preparing high-purity pregabalin | |
| CN107445867A (en) | A kind of synthetic method of KWD-2183 impurity B | |
| CN104650140B (en) | A kind of preparation method of high-purity good fortune department Fluconazole | |
| CN105801438A (en) | Synthetic method of mirabegron intermediate | |
| CN102557967A (en) | Preparation method of ambroxol hydrochloride | |
| CN109867637A (en) | The preparation method of fumidil amido alcohol | |
| CN103288764B (en) | Quinhydroxy ketone alanine ester hydrochloride and preparation method thereof | |
| CN109867640A (en) | A kind of preparation method of fumidil amido alcohol | |
| CN109867639A (en) | The method for preparing fumidil amido alcohol | |
| EP3126324B1 (en) | A process for preparation of levothyroxine and salts thereof | |
| CN107501128A (en) | A kind of method of gentle carbamide compounds carbonylation arylation reaction | |
| CN111333529A (en) | Preparation method of pregabalin | |
| KR20150041280A (en) | Method for the preparation of Mitiglinide Calcium Dihydrate | |
| CN102827060B (en) | Synthetic method of 5-trifluoromethyl pyrrole-2-formic acid | |
| US8586792B2 (en) | Process for the preparation of 4-iodo-3-nitrobenzamide | |
| CN107383076A (en) | A kind of synthetic method of the chlorophenylboronic acid pinacol ester of 3 amino 4 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: No. 306 Li Bing Road, Zhangjiang, Pudong New Area, Shanghai, October 2012 Patentee after: SHANGHAI JINGXIN BIOLOGICAL MEDICAL Co.,Ltd. Patentee after: Shaoxing Jingxin Pharmaceutical Co.,Ltd. Address before: No. 306 Li Bing Road, Zhangjiang, Pudong New Area, Shanghai, October 2012 Patentee before: SHANGHAI JINGXIN BIOLOGICAL MEDICAL Co.,Ltd. Patentee before: SHANGYU JINGXIN PHARMACEUTICAL Co.,Ltd. |