CN106946713A - A kind of preparation method of memantine - Google Patents
A kind of preparation method of memantine Download PDFInfo
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- CN106946713A CN106946713A CN201710145610.4A CN201710145610A CN106946713A CN 106946713 A CN106946713 A CN 106946713A CN 201710145610 A CN201710145610 A CN 201710145610A CN 106946713 A CN106946713 A CN 106946713A
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- memantine
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- 229960004640 memantine Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 title abstract 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 23
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000007787 solid Substances 0.000 claims abstract description 16
- CWNOIUTVJRWADX-UHFFFAOYSA-N 1,3-dimethyladamantane Chemical compound C1C(C2)CC3CC1(C)CC2(C)C3 CWNOIUTVJRWADX-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 7
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 claims description 31
- 238000003756 stirring Methods 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229910001868 water Inorganic materials 0.000 claims description 14
- 235000019441 ethanol Nutrition 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 229960000967 memantine hydrochloride Drugs 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- WVIRSYCDAYUOMJ-UHFFFAOYSA-N n-(3,5-dimethyl-1-adamantyl)acetamide Chemical class C1C(C2)CC3(C)CC2(C)CC1(NC(=O)C)C3 WVIRSYCDAYUOMJ-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 238000005352 clarification Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- SMPAPEKFGLKOIC-UHFFFAOYSA-N oxolane;hydrochloride Chemical compound Cl.C1CCOC1 SMPAPEKFGLKOIC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 230000007062 hydrolysis Effects 0.000 abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000284 extract Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- RTPQXHZLCUUIJP-UHFFFAOYSA-N 1,2-dimethyladamantane Chemical compound C1C(C2)CC3CC1C(C)C2(C)C3 RTPQXHZLCUUIJP-UHFFFAOYSA-N 0.000 abstract description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 abstract 2
- 238000001953 recrystallisation Methods 0.000 abstract 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000004202 carbamide Substances 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000031709 bromination Effects 0.000 description 4
- 238000005893 bromination reaction Methods 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- NBRKLOOSMBRFMH-UHFFFAOYSA-N tert-butyl chloride Chemical compound CC(C)(C)Cl NBRKLOOSMBRFMH-UHFFFAOYSA-N 0.000 description 2
- FUZZFPVZJGQAKD-UHFFFAOYSA-N 1,3-dimethyl-5-nitroadamantane Chemical class C1C(C2)CC3(C)CC1(C)CC2([N+]([O-])=O)C3 FUZZFPVZJGQAKD-UHFFFAOYSA-N 0.000 description 1
- YKXYFUCKWRACDY-UHFFFAOYSA-N 1-amino-2-(2-hydroxyethoxy)ethanol Chemical compound NC(O)COCCO YKXYFUCKWRACDY-UHFFFAOYSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000151 anti-reflux effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000001964 calcium overload Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfuric acid amide group Chemical group S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation method of memantine, under 1,3 dimethyladamantane and acetonitrile, concentrated sulfuric acid system, directly reaction generates the dimethyladamantane of 1 acetamido of crude product 3,5；The dimethyladamantane of 1 acetamido of gained crude product 3,5, which need not be purified, is directly used in next step hydrolysis.Solvent is done using ethylene glycol, hydrolyzed under basic conditions obtains crude product Memantine, crude product Memantine is extracted with varsols such as normal heptanes, directly toward the organic solution of addition concentrated hydrochloric acid or hydrochloric acid in extract, crude product memantine solid is obtained, fine work memantine then is made using alcohol ethyl acetate system recrystallization.The present invention can provide a kind of easy to operate, technique simplification, high income, production cost is low, be easy to industrialized production memantine preparation method.
Description
Technical field
The present invention relates to pharmaceutical chemistry, more particularly to a kind of preparation method of memantine.
Background technology
Memantine, the chemical entitled ring of 3.5- dimethyl three [3.3.1.13.7] decyl- 1- amine hydrochlorates, are a kind of voltage
Noncompetitive M- methyl-ASPARTIC ACID of dependence, moderate affinity, receptor antagonist can prevent intracellular Ca2+
Overload, and suppress the exitotoxicity of excitatory amino acid, it is dull-witted to Vascular dementia, alzheimer dementia and AIDS type
There is good curative effect, developed by German Merz companies, nineteen eighty-two, clinic was mainly used in treating Parkinson first in Germany's listing
Disease, U.S. FDA is used as unique treatment severe Alzheimer's disease medicine in October, 2003 approval.
Current memantine is substantially with 1,3- dimethyladamantanes as initiation material, is closed by following several method
Into：
Bromination-acetonitrile route：Bromination obtains bromo- 3, the 5- dimethyladamantanes of 1-；Second is carried out in the presence of acetonitrile and the concentrated sulfuric acid
Amide groups, obtains 1- acetamido -3,5- dimethyladamantanes；It is hydrolyzed with NaOH and diethylene glycol (DEG), obtains U.S. dollar
Firm amine；Memantine hydrochloride is made into salt with hydrogen chloride in diethyl ether solution or other organic solvents again.In this route, bromination is anti-
Reflux state should be in, the volatilization of bromine vapor is easily caused, the bromine vapor evaporated not only has larger corrosiveness to equipment,
Also pollute the environment simultaneously；And brominated product is unstable, it is unfavorable for storage；Bromide is also easily hydrolyzed into corresponding alcohol simultaneously,
And bring new impurity into the final product, this is very unfavorable for pharmaceutical synthesis；To be used when being hydrolyzed into amino
Diethylene glycol (DEG), its toxicity is larger and price is somewhat expensive.
Bromination-urea route：First bromo- 3, the 5- dimethyladamantanes of 1- are obtained through bromine bromination；
Then with urea reaction, N-3,5- dimethyladamantane -1- base urea are obtained；It is acidified again with sodium hydroxide hydrolysis, HCl
Obtain memantine hydrochloride.This method advantage is to avoid having used diethylene glycol (DEG), relatively environment-friendly；And raw material urea is cheap.
But it is due to that urea steric hindrance is larger, causes the reaction time longer (typically reacting more than 40 hours at 200 degrees celsius)
, and reaction yield is relatively low.The bromination stage is also gone through simultaneously, and pollution and corrosion harmfulness still exist.
Chlorination route：Tertiary butyl chloride and 1,3- dimethyladamantane with the catalytic action of aluminum trichloride (anhydrous), chlorination
Reaction obtains chloro- 3, the 5- dimethyladamantanes of 1-；It is reacted with acetamide, 1- acetamido -3,5- dimethyl Buddha's warrior attendants are obtained
Alkane；Again memantine hydrochloride is obtained through sodium hydroxide hydrolysis, HCl acidifyings.Elimination reaction easily occurs in itself for tertiary butyl chloride, typically
All it is now to do existing use, operation inconvenience；Need not stop to add aluminum trichloride (anhydrous), and intermediate 1- chloro- 3,5- in chlorination process
The activity of dimethyladamantane is not high, and reaction conversion is difficult, and whole reaction is harsher to temperature requirement.And alchlor is brought
The three wastes it is relatively more, environmental protection pressure is big.
Nitrify route：Under HP (NHPI) catalysis, 1,3- dimethyladamantane is through dense nitre
Acid nitrification obtains 1- nitro -3,5- dimethyladamantanes；Again through Pd/C catalytic hydrogen reductions（Or other catalytic hydrogen reduction sides
Method）Obtain Memantine hydrochloride；Finally memantine hydrochloride is obtained with HCl into salt.Compared to three methods above, although avoid
Using bromine or alchlor, but nitrification can produce a large amount of acid waste waters, it is difficult to handle.During catalytic hydrogen reduction it is dangerous compared with
Greatly, higher is required to equipment and operation, and needs the reduction (24~72 hours) of long period.
Direct acetyl amination route：In the presence of the tert-butyl alcohol, acetonitrile, the concentrated sulfuric acid, 1,3- dimethyladamantane directly reacts
Generate 1- acetamido -3,5- dimethyladamantanes；Again Memantine is obtained through hydrolysis；Then in isopropanol/hydrochloric acid solution into
Memantine is made in salt.Although this route has also used sulfuric acid, compare with nitrification, pollution is much smaller.Synthesis step is few,
Meet atom economy, and do not use bromine, safety and environmental protection is advantageously implemented large-scale production, this technical side proposed
Case is that Optimal improvements have been carried out on this route, shortens technological process so that operation is simpler, while yield is improved,
Reduce cost.
The content of the invention
The invention aims to overcome the deficiencies in the prior art and provide a kind of easy to operate, technique simplification, high income,
Production cost is low, be easy to industrialized production memantine preparation method.
To reach above-mentioned purpose, present invention employs following technical scheme.
A kind of preparation method of memantine, comprises the following steps：
Step one：1,3- dimethyladamantanes and sulfuric acid are mixed, obtains being layered colourless liquid, is cooled to less than 30 degrees Celsius；
Stirring is lower to be added dropwise acetonitrile, and acutely, it is 60-65 degrees Celsius or by 1,3- dimethyladamantanes control inside reactor temperature for heat release
With acetonitrile mixing, less than 30 degrees Celsius are cooled to, stirring is lower to be added dropwise sulfuric acid, and acutely, it is 60- to control inside reactor temperature for heat release
65 degrees Celsius；After completion of dropping, control temperature continues to react to 1,3- dimethyladamantanes at 50-70 degrees Celsius to disappear, then
Room temperature is cooled to, reaction solution pours into stirring in frozen water and is quenched, extracted three times with organic solvent, merges organic phase, through drying, concentration
After obtain white solid powder shape 1- acetamido -3,5- dimethyladamantanes, be directly used in next step reaction；
Step 2：1- acetamidos -3, the 5- dimethyladamantane and ethylene glycol that are obtained in the step one are mixed, added successively
Enter water and NaOH or potassium hydroxide solid；Stirring, is warming up to 140-160 degrees Celsius, reaction to 1- acetamidos -3,5- bis-
Methyl adamantane disappears.Room temperature is cooled to, reaction solution is poured into frozen water, is extracted three times with organic solvent, merged organic phase, be used in combination
Washing is twice and dry；Organic phase activated carbon decolorizing, obtains Memantine hydrochloride, and organic solvent is directly used in next step reaction；
Step 3：Hydrochloric acid is slowly dropped to the organic solvent extraction liquid that the step 2 is obtained while stirring, a large amount of whites are produced
Solid；After completion of dropping, less than 10 degrees Celsius are cooled to frozen water, continues to stir 30 minutes；Filtering, filter is washed with ethyl acetate
Cake, is dried to obtain white solid, i.e. crude product memantine；By crude product alcohol in 20-25 degrees Celsius of dissolved clarification, plus 100g activated carbons
And stir 25-30 minutes；Refilter, ethyl acetate is added toward filtrate, be cooled to 0-5 degrees Celsius, then by stirring, suction filtration, Gu
Body is rinsed and crystallized with cold ethyl acetate and alcohol, vacuum dried, obtains final memantine.
The raw material that the synthesis of 1- acetamidos -3,5- dimethyladamantane is used is 1,3- dimethyladamantanes, acetonitrile and sulphur
Acid, not using other raw materials or solvent.
The raw material that the synthesis of Memantine is used is intermediate 1- acetamido -3, the 5- dimethyl obtained in the step one
Adamantane, and ethylene glycol and alkaline earth hydroxide.
Hydrochloric acid in the step 3 it is also possible to use ethereal HCI or hydrochloric acid tetrahydrofuran is substituted.
Organic solvent used in being extracted in the step 3 is normal heptane, the alkane derivative such as petroleum ether.
The alcohol that memantine in the step 3 is used when crystallizing is methanol or ethanol or propyl alcohol or isopropanol.
Due to the utilization of above-mentioned technical proposal, technical scheme is in 1,3- dimethyladamantanes and acetonitrile, dense sulphur
Under acid system, directly reaction generates crude product 1- acetamido -3,5- dimethyladamantanes；Gained crude product need not be purified, also not
Need concentration to remove solvent, be directly used in next step hydrolysis;Solvent is done using ethylene glycol, hydrolyzed under basic conditions is obtained slightly
Product Memantine, crude product Memantine is extracted with varsols such as normal heptanes, directly having toward addition concentrated hydrochloric acid in extract or hydrochloric acid
Machine solution, the intermediate for obtaining obtaining in Memantine HCl, solid, multiple steps of the technical program can be applied directly to
The reaction of next step, not only with the Advantageous Effects that step is short, technique is simple and easy to operate, also with high income, into
Originally Advantageous Effects that are low, being easy to industrialized production.
Embodiment
With reference to reaction scheme and specific embodiment, the present invention is described in further detail.
The first step：" amidatioon "
Table 1：Test material table
| Molecular weight | Inventory | Mol ratio | Purity | |
| 1,3- dimethyladamantanes | 164 | 40g | 1 | |
| Acetonitrile | 41 | 95g | 9 | |
| Sulfuric acid | 98 | 235 ml | 18 |
Test procedure：
1）40 g 1,3- dimethyladamantanes and 235ml sulfuric acid mixing, obtain be layered colourless liquid, frozen water be cooled to 30 degree with
Under；
2）Stirring is lower to be added dropwise 95g acetonitriles, and acutely, control system internal temperature is up to no more than 75 degree for heat release；
3）After completion of dropping, control temperature reacts 18h in 50-70 degree, is cooled to room temperature.Pour into 350ml frozen water, stir；
4）Extracted with dichloromethane（100mlX3）, merge organic phase, after drying, concentration, obtain white solid powder 46-48
Gram.
Result of the test：
Batch number：It see the table below (Z1-Y00160722, Z1-Y00160725, Z1-Y00160812)
Product appearance：White powder
Structural identification：Nuclear-magnetism
Testing result：Unanimously
Table 2：First Z1-Y00160722
Table 3：Second batch Z1-Y00160725
Table 4：3rd crowd of Z1-Y00160812
Second step " hydrolysis " and the 3rd step " into salt "：
Table 5：Test material table
| Molecular weight | Inventory | Mol ratio | Lot number | |
| 1- acetamido -3,5- dimethyladamantanes | 221 | 15g | ||
| NaOH | 40 | 15g | ||
| Ethylene glycol | 150ml | |||
| Water | 15ml | |||
| Hydrochloric acid | 7g |
Test procedure 1：
1）In round-bottomed flask, 1- acetamidos -3,5- dimethyladamantane and ethylene glycol are mixed, sequentially add 15ml water and
15g sodium hydrate solids；
2）Stirring, insulation is reacted 12-18 hours in 140-160 degree.1- acetamides are advanced to gas chromatography detection reaction
The reaction of base -3,5- dimethyladamantane is finished；
3）Cooling, is poured into 150ml frozen water, and 100mlX3 is extracted with normal heptane, is merged, washes, is dried；
4）Use activated carbon decolorizing（1g is added to above-mentioned 300ml extracts）, liquid be directly used in next step reaction.
Test procedure 2：
1）7 grams of concentrated hydrochloric acids are slowly dropped to above-mentioned extract under stirring, there are a large amount of white solids to produce, after completion of dropping, are used
Frozen water is cooled to less than 10 degree, continues to stir 30 minutes；
2）Filtering, filter cake is washed with ethyl acetate；
3）40 degree of vacuum drying；
4）Obtain about 9-11g white solids.
Result of the test：
Batch number：It see the table below (Y00160822, Y00160824, Y00160908)
Product appearance：White solid
Structural identification：Nuclear-magnetism, gas chromatography
Testing result：Unanimously
Abnormal conditions explanation：Nothing
Table 6：First Y00160822
Table 7：Second batch Y00160824
Table 8：3rd crowd of Y00160908
By result crude product memantine alcohol in 20-25 degrees Celsius of dissolved clarification, plus 100g activated carbons and stir 25-30 minutes；Again
Filtering, adds ethyl acetate toward filtrate, is cooled to 0-5 degrees Celsius, then by stirring, suction filtration, solid with cold ethyl acetate with
Alcohol is rinsed and crystallized, vacuum dried, obtains final memantine.
It the above is only the concrete application example of the present invention, protection scope of the present invention be not limited in any way.It is all to use
Technical scheme formed by equivalents or equivalence replacement, all falls within rights protection scope of the present invention.
Claims (4)
1. a kind of preparation method of memantine, it is characterised in that comprise the following steps：
Step one：1,3- dimethyladamantanes and sulfuric acid are mixed, obtains being layered colourless liquid, is cooled to less than 30 degrees Celsius；
Stirring is lower to be added dropwise acetonitrile, and acutely, it is 60-65 degrees Celsius or by 1,3- dimethyladamantanes control inside reactor temperature for heat release
With acetonitrile mixing, less than 30 degrees Celsius are cooled to, stirring is lower to be added dropwise sulfuric acid, and acutely, it is 60- to control inside reactor temperature for heat release
65 degrees Celsius；After completion of dropping, control temperature continues to react to 1,3- dimethyladamantanes at 50-70 degrees Celsius to disappear, then
Room temperature is cooled to, reaction solution pours into stirring in frozen water and is quenched, extracted three times with organic solvent, merges organic phase, through drying, concentration
After obtain white solid powder shape 1- acetamido -3,5- dimethyladamantanes, be directly used in next step reaction；
Step 2：1- acetamidos -3, the 5- dimethyladamantane and ethylene glycol that are obtained in the step one are mixed, added successively
Enter water and NaOH or potassium hydroxide solid；Stirring, is warming up to 140-160 degrees Celsius, reaction to 1- acetamidos -3,5- bis-
Methyl adamantane disappears, and is cooled to room temperature, reaction solution is poured into frozen water, is extracted three times with organic solvent, merges organic phase, is used in combination
Washing is twice and dry；Organic phase activated carbon decolorizing, obtains Memantine hydrochloride, and organic solution is directly used in next step reaction；
Step 3：Hydrochloric acid is slowly dropped to the organic solvent extraction liquid that the step 2 is obtained while stirring, a large amount of whites are produced
Solid；After completion of dropping, less than 10 degrees Celsius are cooled to frozen water, continues to stir 30 minutes；Filtering, filter is washed with ethyl acetate
Cake, is dried to obtain white solid, i.e. crude product memantine；By crude product alcohol in 20-25 degrees Celsius of dissolved clarification, plus 100g activated carbons
And stir 25-30 minutes；Refilter, ethyl acetate is added toward filtrate, be cooled to 0-5 degrees Celsius, then by stirring, suction filtration, Gu
Body is rinsed and crystallized with cold ethyl acetate and alcohol, vacuum dried, obtains final memantine.
2. a kind of preparation method of memantine according to claim 1, it is characterised in that：Salt in the step 3
Acid it is also possible to use ethereal HCI or hydrochloric acid tetrahydrofuran is substituted.
3. a kind of preparation method of memantine according to claim 1, it is characterised in that：Extracted in the step 3
Used organic solvent is the alkane derivatives such as normal heptane or petroleum ether.
4. a kind of preparation method of memantine according to claim 1, it is characterised in that：Salt in the step 3
The alcohol used during sour Memantine crystallization is methanol or the mixture of ethanol or propyl alcohol or isopropanol or above-mentioned alcohol.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109251219A (en) * | 2018-12-07 | 2019-01-22 | 无锡福祈制药有限公司 | A new class of Memantine analog and its synthetic method |
| CN111072491A (en) * | 2019-12-14 | 2020-04-28 | 老河口瑞祥化工有限公司 | Preparation method of memantine hydrochloride |
| CN115073304A (en) * | 2022-06-28 | 2022-09-20 | 北京云鹏鹏程医药科技有限公司 | Post-treatment preparation method of memantine hydrochloride |
| CN116947644A (en) * | 2023-07-26 | 2023-10-27 | 山东轩鸿生物医药有限公司 | A kind of preparation method of memantine hydrochloride |
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| WO2009057140A2 (en) * | 2007-10-30 | 2009-05-07 | Msn Laboratories Limited | Improved process for memantine hydrochloride |
| WO2009153806A2 (en) * | 2008-05-09 | 2009-12-23 | Sairam Organics Pvt. Ltd. | Process for preparing memantine hydrochloride substantially free of !mpurities |
| WO2014024202A1 (en) * | 2012-08-07 | 2014-02-13 | Zcl Chemicals Limited | An improved process for the preparation of memantine hydrochloride |
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| WO2009057140A2 (en) * | 2007-10-30 | 2009-05-07 | Msn Laboratories Limited | Improved process for memantine hydrochloride |
| WO2009153806A2 (en) * | 2008-05-09 | 2009-12-23 | Sairam Organics Pvt. Ltd. | Process for preparing memantine hydrochloride substantially free of !mpurities |
| WO2014024202A1 (en) * | 2012-08-07 | 2014-02-13 | Zcl Chemicals Limited | An improved process for the preparation of memantine hydrochloride |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109251219A (en) * | 2018-12-07 | 2019-01-22 | 无锡福祈制药有限公司 | A new class of Memantine analog and its synthetic method |
| 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 |
| CN115073304A (en) * | 2022-06-28 | 2022-09-20 | 北京云鹏鹏程医药科技有限公司 | Post-treatment preparation method of memantine hydrochloride |
| CN116947644A (en) * | 2023-07-26 | 2023-10-27 | 山东轩鸿生物医药有限公司 | A kind of preparation method of memantine hydrochloride |
| CN116947644B (en) * | 2023-07-26 | 2025-01-24 | 山东轩鸿生物医药有限公司 | A kind of preparation method of memantine hydrochloride |
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Application publication date: 20170714 |