CN116947644B - A kind of preparation method of memantine hydrochloride - Google Patents
A kind of preparation method of memantine hydrochloride Download PDFInfo
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- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 229960000967 memantine hydrochloride Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title abstract description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 26
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims abstract description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000706 filtrate Substances 0.000 claims abstract description 21
- RTPQXHZLCUUIJP-UHFFFAOYSA-N 1,2-dimethyladamantane Chemical class C1C(C2)CC3CC1C(C)C2(C)C3 RTPQXHZLCUUIJP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910001923 silver oxide Inorganic materials 0.000 claims abstract description 12
- 229910021529 ammonia Inorganic materials 0.000 claims abstract 3
- 239000012065 filter cake Substances 0.000 claims description 8
- QUCXLVDIVQWYJR-UHFFFAOYSA-N 1-bromo-3,5-dimethyladamantane Chemical compound C1C(C2)CC3(C)CC1(C)CC2(Br)C3 QUCXLVDIVQWYJR-UHFFFAOYSA-N 0.000 claims description 6
- PXDRFQZLDWZHPX-UHFFFAOYSA-N 1-chloro-3,5-dimethyladamantane Chemical group C1C(C2)CC3(C)CC1(C)CC2(Cl)C3 PXDRFQZLDWZHPX-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 abstract description 13
- 230000008569 process Effects 0.000 abstract description 11
- 239000003054 catalyst Substances 0.000 abstract description 9
- 239000002253 acid Substances 0.000 abstract description 6
- 239000011230 binding agent Substances 0.000 abstract description 6
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical class C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- 238000012216 screening Methods 0.000 description 7
- 230000008901 benefit Effects 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000002341 toxic gas 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
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/48—Silver or gold
- B01J23/50—Silver
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明属于有机合成技术领域，具体涉及一种盐酸美金刚的制备方法。本发明以卤代二甲基金刚烷为起始原料，以无水N,N‑二甲基甲酰胺为反应溶剂，加入活性催化剂氧化银和缚酸剂三乙胺，于0.5MPa、80～85℃通入氨气反应5～6h，抽滤后滤液再与浓盐酸反应得盐酸美金刚。本发明的盐酸美金刚的制备方法所用溶剂无水N,N‑二甲基甲酰胺无毒，反应在活性催化剂存在下，在一定压力下直接通氨气，碳卤键直接形成碳氮键得到金刚胺化合物，使得制备盐酸美金刚的工艺大大简化，工艺路线较短并易操作，生产成本低，收率和纯度高，适合大规模工业化生产。The invention belongs to the technical field of organic synthesis, and is particularly related to a method for preparing memantine hydrochloride. The present invention uses halogenated dimethyladamantane as a starting material, anhydrous N, N-dimethylformamide as a reaction solvent, adds an active catalyst silver oxide and an acid binding agent triethylamine, passes ammonia at 0.5MPa and 80-85°C for reaction for 5-6h, and after suction filtration, the filtrate is reacted with concentrated hydrochloric acid to obtain memantine hydrochloride. The solvent anhydrous N, N-dimethylformamide used in the preparation method of memantine hydrochloride of the present invention is non-toxic, and the reaction is directly passed through ammonia under a certain pressure in the presence of an active catalyst, and a carbon-halogen bond directly forms a carbon-nitrogen bond to obtain adamantine compounds, so that the process for preparing memantine hydrochloride is greatly simplified, the process route is short and easy to operate, the production cost is low, the yield and purity are high, and it is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of memantine hydrochloride.
Background
Memantine hydrochloride (MEMANTINE HYDROCHLORIDE), also known as 1-amino-3, 5-dimethyladamantane hydrochloride, memantine hydrochloride, is a low-to-medium affinity, voltage-dependent and non-competitive NMDA receptor antagonist developed by Merz, germany, which can prevent apoptosis and improve memory, and is a new generation of drugs for improving cognitive functions. Thus, memantine hydrochloride has great potential for economic and social benefits.
Common synthesis methods of memantine hydrochloride mainly comprise a urea method (CN 1594277A), an acetonitrile method (CN 102432473A), a carboxamide method (Huber F A,Gallo G,Faveri C D.Process for the manufacture of memantine and inrermediate product：WO,2009115334A2[P].2009-09-24.)、 nitrification method (Huang Bin, ao Guizhen, in the process of the synthesis of memantine hydrochloride, the improvement of [ J ]. Chinese pharmaceutical industry, 2009,18 (22): 17-18 ]), and the like, but the reaction difficulty of the urea method 1-bromo-3, 5-dimethyl adamantane and urea is higher, the reaction yield is lower than 70%, the industrial production cost is higher, concentrated sulfuric acid and organic acid are used for reaction in the acetonitrile method, the reaction is severe, the toxicity is high, the yield is not high, a large amount of reddish brown toxic gas NO 2 is generated in the reaction process of the carboxamide method, the post treatment is complex, the hydrogenation is catalyzed by Pd/C in the nitrification process, the higher danger exists, and the time is longer, and the cost is high. The existing synthesis methods have the problems of high production cost, large harm to human bodies, low yield and the like at different degrees.
Disclosure of Invention
Aiming at the problems, the invention provides the preparation method of the memantine hydrochloride, which has the advantages of raw materials of commercial general chemicals, high yield, low synthesis cost, application of active catalyst catalysis, short reaction route and time and small harm to human bodies.
The technical scheme of the invention is as follows:
The preparation method of memantine hydrochloride comprises the following specific steps:
(1) Dissolving halogenated dimethyl adamantane in anhydrous N, N-dimethylformamide, adding silver oxide and triethylamine, heating, introducing ammonia gas for ammoniation, cooling to room temperature after the reaction is finished, and suction filtering to obtain filtrate;
(2) And cooling the filtrate to room temperature, adding concentrated hydrochloric acid, stirring at room temperature, filtering, and drying the filter cake to obtain memantine hydrochloride.
The reaction equation is shown in formula I:
preferably, in the step (1), the temperature is 80-85 ℃ and the pressure is 0.5MPa when ammonia gas is introduced.
Preferably, in the step (1), the reaction time is 5 to 6 hours.
Preferably, in the step (1), the mass ratio of the halogenated dimethyl adamantane to the anhydrous N, N-dimethylformamide=1:4.5-5.5.
Preferably, in the step (1), the molar ratio of the halogenated dimethyl adamantane to the triethylamine=1:1.0-1.1.
Preferably, in the step (1), the mass ratio of the halogenated dimethyl adamantane to the silver oxide is 1:0.01-0.05.
Preferably, in step (1), the halogenated dimethyladamantane is 1-chloro-3, 5-dimethyladamantane or 1-bromo-3, 5-dimethyladamantane.
Preferably, in the step (2), the mass ratio of the halogenated dimethyl adamantane to the concentrated hydrochloric acid=1:5-6, and the concentration of the concentrated hydrochloric acid is 35% -38%.
Preferably, in the step (2), the stirring time is 1h.
The beneficial effects of the invention are as follows:
(1) The invention provides a new method for preparing memantine hydrochloride, which avoids using reagents such as acetonitrile, diethyl ether and the like which have great harm to the environment and human bodies in a synthetic route, and the solvent used in the method is basically nontoxic, the raw materials are common, the toxicity is low, the price is low, and the production cost is low;
(2) The method has the advantages of short synthetic route, simple and easy operation by using the active catalyst, no need of purification, reduced operation steps, high product stability, no high pollution gas and byproducts in the production process, relative safety and environmental protection, and suitability for large-scale industrial production;
(3) The method has the advantages that the purity and the yield of the product are improved through the reaction temperature and the pressure and the used reagent when ammonia gas is introduced through a sieving gate, the reaction temperature is higher than 85 ℃, byproducts are increased, the reaction time is lower than 80 ℃, impurities are easy to generate when the pressure is higher than 0.5MPa, the reaction is slow or the reaction is not performed when the pressure is lower than 0.5MPa, and the yield and the purity of the final product are lower than those of the reagents used in the method. The total yield of the final product prepared by the method can reach more than 80 percent, and the purity can reach more than 98 percent.
Detailed Description
The present invention is further described in detail below with reference to examples, wherein the concentration of concentrated hydrochloric acid used in the examples is 36%, and the details are not described in detail below.
Example 1
Anhydrous N, N-dimethylformamide (995.5 g) and 1-chloro-3, 5-dimethyl adamantane (199 g) are added into an autoclave, silver oxide (2.13 g) and triethylamine (101.8 g) are added in a dark place, then the temperature is raised to 80 ℃, the pressure is controlled to be 0.5MPa, ammonia gas is introduced for 5.5 hours, after the reaction is finished, the ammonia gas is stopped, the temperature is reduced, the suction filtration is carried out to obtain filtrate, concentrated hydrochloric acid (1000 g) is added after the filtrate is cooled, the suction filtration is carried out after the filtrate is stirred at room temperature for 1 hour, 178g of memantine hydrochloride is obtained after the filter cake is dried, the yield is 82.4%, and the purity is 98.2%. The obtained product has a color state of white powder, and a melting point ：292℃.1H-NMR(CDC13)：0.85(s,6H),1.15(m,2H),1.26(q,J＝12.5Hz,4H),1.65(d,J＝11.5Hz,4H),1.85(s,2H),8.27(s,3H).
Example 2
Anhydrous N, N-dimethylformamide (899.6 g) and 1-chloro-3, 5-dimethyl adamantane (199 g) are added into an autoclave, silver oxide (5.97 g) and triethylamine (110.9 g) are added in a dark place, then the temperature is raised to 85 ℃, the pressure is controlled to be 0.5MPa, ammonia gas is introduced for reaction for 5 hours, after the reaction is finished, the ammonia gas is stopped, the temperature is reduced, suction filtration is carried out to obtain filtrate, concentrated hydrochloric acid (1095 g) is added after the filtrate is cooled, suction filtration is carried out after stirring at room temperature for 1 hour, and a filter cake is dried to obtain 181g of memantine hydrochloride, the yield is 83.9%, and the purity is 98.4%.
Example 3
Anhydrous N, N-dimethylformamide (1091.2 g) and 1-chloro-3, 5-dimethyl adamantane (199 g) are added into an autoclave, silver oxide (9.91 g) and triethylamine (105.6 g) are added in a dark place, then the temperature is raised to 83 ℃, the pressure is controlled to be 0.5MPa, ammonia gas is introduced for reaction for 6 hours, after the reaction is finished, the ammonia gas is stopped, the temperature is reduced, suction filtration is carried out to obtain filtrate, concentrated hydrochloric acid (1191 g) is added after the filtrate is cooled, suction filtration is carried out after stirring at room temperature for 1h, and 183g of memantine hydrochloride is obtained after the filter cake is dried, the yield is 84.8%, and the purity is 98.5%.
Example 4
Anhydrous N, N-dimethylformamide (1095.4 g) and 1-bromo-3, 5-dimethyl adamantane (243 g) are added into an autoclave, silver oxide (3.25 g) and triethylamine (102.102 g) are added in a dark place, then the temperature is raised to 80 ℃, the pressure is controlled to be 0.5MPa, ammonia gas is introduced for 5 hours, after the reaction is finished, the ammonia gas is stopped, the temperature is reduced, the suction filtration is carried out to obtain filtrate, concentrated hydrochloric acid (1220 g) is added after the filtrate is cooled, the suction filtration is carried out after the filtrate is stirred at room temperature for 1 hour, 180g of memantine hydrochloride is obtained after the filter cake is dried, the yield is 83.4%, and the purity is 98.4%.
Example 5
Anhydrous N, N-dimethylformamide (1331.2 g) and 1-bromo-3, 5-dimethyl adamantane (243 g) are added into an autoclave, silver oxide (11.92 g) and triethylamine (110.5 g) are added in a dark place, then the temperature is raised to 85 ℃, the pressure is controlled to be 0.5MPa, ammonia gas is introduced for 6 hours, after the reaction is finished, the ammonia gas is stopped, the temperature is reduced, the suction filtration is carried out to obtain filtrate, concentrated hydrochloric acid (1450 g) is added after the filtrate is cooled, the suction filtration is carried out after the filtrate is stirred at room temperature for 1 hour, 177g of memantine hydrochloride is obtained after the filter cake is dried, the yield is 82.1%, and the purity is 98.3%.
Example 6
Anhydrous N, N-dimethylformamide (1215.5 g) and 1-bromo-3, 5-dimethyl adamantane (243 g) are added into an autoclave, silver oxide (8.55 g) and triethylamine (105.9 g) are added in a dark place, then the temperature is raised to 82 ℃, the pressure is controlled to be 0.5MPa, ammonia gas is introduced for 5.5 hours, after the reaction is finished, the ammonia gas is stopped, the temperature is reduced, the filtrate is obtained by suction filtration, concentrated hydrochloric acid (1337 g) is added after the filtrate is cooled, the filtrate is stirred for 1 hour at room temperature, the suction filtration is carried out, the filter cake is dried, and 175g of memantine hydrochloride is obtained, the yield is 81.1%, and the purity is 98.1%.
Comparative example 1 temperature and pressure screening
1.1 Temperature screening
This comparative example provides a process for the preparation of memantine hydrochloride, which differs from example 1 in that the reaction temperature in example 1 is independently varied, and the other is the same as in example 1, and the product yield and purity are shown in table 1.
TABLE 1 purity of product yield
In the whole experimental process, the reaction time is prolonged when the temperature is lower than 80 ℃, the yield is reduced, byproducts are increased when the temperature is higher than 85 ℃, the purity is influenced, and therefore, the optimal reaction temperature of memantine hydrochloride is 80-85 ℃.
1.2 Pressure screening
This comparative example provides a process for the preparation of memantine hydrochloride, which differs from example 1 in that the reaction pressure in example 1 is independently varied, and the other is the same as in example 1, and the product yield and purity are shown in table 2.
TABLE 2 purity of product yield
In the whole experimental process, the pressure is lower than 0.5MPa, the reaction time can be prolonged even the reaction is not carried out, the temperature is higher than 0.5MPa, byproducts can be increased to influence the purity of the product, and therefore, the reaction pressure of the memantine hydrochloride is controlled to be 0.5MPa. Comparative example 2 screening of catalyst, acid-binding agent, reaction solvent
2.1 Screening of catalysts
This comparative example provides a process for the preparation of memantine hydrochloride, which differs from example 1 in that the type of catalyst used in example 1 is changed separately, and the other is the same as in example 1, and the product yield and purity are shown in table 3.
TABLE 3 purity of product yield
2.2 Screening of acid binding Agents
This comparative example provides a process for the preparation of memantine hydrochloride, which differs from example 1 in that the type of acid binding agent used in example 1 is independently changed, and the other is the same as in example 1, and the yield and purity of the product are shown in Table 4.
TABLE 4 purity of product yield
2.3 Screening of reaction solvents
This comparative example provides a process for the preparation of memantine hydrochloride, which differs from example 1 in that the anhydrous N, N-dimethylformamide as the reaction solvent in example 1 is replaced by dimethyl sulfoxide, and otherwise is identical to example 1, with a final product yield of 76.2% and a purity of 97.3%.
In conclusion, the change of the catalyst, the acid binding agent and the reaction solvent can reduce the yield of the product to a certain extent, generate impurities and influence the purity of the product. Therefore, the invention selects silver oxide as a catalyst, triethylamine as an acid binding agent and anhydrous N, N-dimethylformamide as a reaction solvent to prepare the memantine hydrochloride.
The foregoing are all preferred embodiments of the present invention, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to only the above-described embodiments. Various substitutions and alterations are made according to the ordinary skill and familiar means of the art without departing from the technical spirit of the invention, and all such substitutions and alterations are intended to be included in the scope of the invention.
Claims (9)
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| CN102942490A (en) * | 2012-12-02 | 2013-02-27 | 陕西方舟制药有限公司 | Synthesis of memantine hydrochloride |
| CN106946713A (en) * | 2017-03-13 | 2017-07-14 | 张家港九力新材料科技有限公司 | A kind of preparation method of memantine |
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| GB1274652A (en) * | 1968-08-27 | 1972-05-17 | Lilly Industries Ltd | Adamantanyl-alkylamine derivatives and their preparation |
| JPH11106360A (en) * | 1997-03-11 | 1999-04-20 | Daicel Chem Ind Ltd | Adamantane derivative and its production |
| JP4463622B2 (en) * | 2004-05-20 | 2010-05-19 | 株式会社トクヤマ | Process for producing 1,3-adamantanediols |
| CN109824518A (en) * | 2017-11-23 | 2019-05-31 | 辽宁博美医药科技有限公司 | A kind of preparation method of memantine hydrochloride |
| CN110699700B (en) * | 2019-10-30 | 2020-06-30 | 肯特催化材料股份有限公司 | Preparation method of adamantyl trimethyl ammonium hydroxide |
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| CN102942490A (en) * | 2012-12-02 | 2013-02-27 | 陕西方舟制药有限公司 | Synthesis of memantine hydrochloride |
| CN106946713A (en) * | 2017-03-13 | 2017-07-14 | 张家港九力新材料科技有限公司 | A kind of preparation method of memantine |
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