(19) & (11) EP 1 674 446 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 211/38 (2006.01) C07C 209/08 (2006.01) 10.08.2011 Bulletin 2011/32 A61P 25/28 (2006.01) (21) Application number: 03785457.7 (86) International application number: PCT/CN2003/001094 (22) Date of filing: 19.12.2003 (87) International publication number: WO 2005/023753 (17.03.2005 Gazette 2005/11) (54) A METHOD OF PREPARING MEMANTINE HYDROCHLORIDE VERFAHREN ZUR HERSTELLUNG VON MEMANTINHYDROCHLORID PROCEDE DE PREPARATION DE CHLORHYDRATE DE MEMANTINE (84) Designated Contracting States: • ZHAO, Lizhi AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Shanghai 200040 (CN) HU IE IT LI LU MC NL PT RO SE SI SK TR • GE, Mengya Dongyang, Zhejiang 322118 (CN) (30) Priority: 10.09.2003 CN 03150892 (74) Representative: Humphreys, Ceris Anne et al (43) Date of publication of application: Abel & Imray 28.06.2006 Bulletin 2006/26 20 Red Lion Street London WC1R 4PQ (GB) (73) Proprietors: • Shanghai Institute of Pharmaceutical Industry (56) References cited: Shanghai 200040 (CN) CN-A- 1 335 299 CN-A- 1 400 205 • Zhejiang Kangyu Pharmaceutical Co., Ltd. CZ-A3- 9 601 813 US-A- 4 122 193 Dongyang, US-A- 5 061 703 Zhejiang 322-118 (CN) • DATABASECA [Online] CHEMICAL ABSTRACTS (72) Inventors: SERVICE, COLUMBUS, OHIO, US; BURKHARD, • ZHANG, Fuli JIRI ET AL: "Aminoadamantanes and their salts" Shanghai 200040 (CN) XP002538199 retrieved from STN Database • HU, Meng accession no. 1973:124152 & CS 146 405 A 15 Shanghai 200040 (CN) December 1972 (1972-12-15) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 674 446 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 674 446 B1 2 Description mo-3,5-dimethyl adamantane as the raw material, which reacts with urea at 220°C in tube sealing to yield agglom- Field of Invention erate product. The product is milled and mixed with water into mash, then acidified to adjust pH between 3 and 5. [0001] This invention relates to a synthesis method of 5 The impurity is removed by ether extraction. The aque- Memantine Hydrochloride, which is a drug for the treat- ous layer is basified to a pH of between 12 and 13. After ment of moderate to severe Alzheimer’s disease (AD). extracted with ether several times, the organic layers is combined, dried, salified by inletting HCl gas to yield Me- Technical Background mantine Hydrochloride. This method adopts tube seal- 10 ing, and the high reaction temperature may cause the [0002] Memantine Hydrochloride of Merz-Germany agglomeration of product. It is, therefore, hard to indus- has come into the market since 1982 and is still used for trialize. treatment of Parkinson’s disease, Neuropathic Myotonia and Dementia Syndrome with a trade name Akatinol in Description of the Invention a few countries such as Germany now. It attracted great 15 attention of clinic and market again when Memantine Hy- [0007] This invention aims to develop a new prepara- drochloride was found to act as NMDA (N-methyl-D-as- tion method of Memantine Hydrochloride to overcome partate) receptor antagonist. Now, Memantine Hydro- the above-mentioned technical limitation and to provide chloride has been approved as an effective drug for the a new process that facilitates the industrialization of this treatment of moderate to severe AD by the European 20 product. Union and it has become the first approved drug for the [0008] The gist of this invention is as follows: treatment of moderate to severe AD. In USA, the phase 1-bromo-3,5-dimethyl adamantane is aminated with III clinical study has been completed and NDA has been urea/formic acid, where formic acid is also used as sol- submitted to FDA. Since there hasn’t been any effective vent, hydrolyzed with inorganic acid aqueous solution, medicine for the treatment of moderate to severe AD, 25 basified, extracted with solvent, and salified with hydro- Memantine Hydrochloride is in the highest flight in the chloric acid. Then the target product Memantine Hydro- field of dementia treatment now. Moreover, it has pro- chloride is collected. found potentialities in acting as a medicine in the field of [0009] The detailed preparation method involves the moderate to severe Vascular Dementia treatment, which following steps: has no effective clinic option; therefore, it is a great val- 30 1-bromo-3,5-dimethyl adamantane, urea and formic acid uable clinical medicine and has a profound market po- are reacted a molar ratio of 1:0.5∼10:1∼15 at 50-180°C tentiality. for 0.25-5h. After the reaction, inorganic acid aqueous [0003] With regard to the synthesis of Memantine Hy- solution is added. Hydrolyzation is performed at a pH drochloride, there are two methods reported in the liter- from 1 to 3 at 50-100°C for 0.5 to 5h. The pH value of ature, one is US patent 3391142 using acetonitrile / sul- 35 the solution is adjusted with inorganic acid aqueous so- furic acid and the other is US patent 4122193 using urea lution to a pH from 10 to 14. After being extracted with in the synthesis. organic solvent, the extract is salified with hydrochloric [0004] In the method of US patent 3391142, 1,3- dime- acid. The target product Memantine Hydrochloride is col- thyl adamantane is bromized to yield 1- bromo-3,5-dime- lected. The yield can exceed 69.5% and the product pu- thyl adamantane, which is then subjected to acetylation 40 rity can exceed 99.0%. and ammonization in the presence of acetonitrile and sul- [0010] Based on this invention, the re-crystallization furic acid, extracted with benzene, dried and concentrat- solvent can be used to re- crystallize the said salt to yield ed to yield 1-acetamino-3,5-dimethyl adamantane. After Memantine Hydrochloride. the alcoholysis with sodium hydroxide anddiethylene gly- [0011] The urea-formic acid acts as the reaction rea- col, extraction in benzene and concentration, crude me- 45 gent of aminstration and the said formic acid is anhydrous mantine was obtained, which was then salified with hy- formic acid or formic acid aqueous solution of various drochloric acid, re- crystallized with ethanol/ ether and pu- concentrations. The formic acid is also used as solvent. rified to yield Memantine Hydrochloride. [0012] The molar ratio between 1-bromo- 3,5-dimethyl [0005] This method uses acetonitrile, benzene and adamantane and urea and formic acid is preferably 1: ether, which are hazardous to environment and human, 50 2∼5:5∼10 and the reaction temperature is preferably in the process of acetylation, ammonization and re- crys- 60-150°C. tallization. Furthermore, this method is difficult to hydro- [0013] The said inorganic acid may be one selected lyze acetyl compound, produces many by-products and from hydrochloric acid, hydrobromic acid, sulfuric acid, darkens the product due to the reaction of long duration. phosphoric acid or their mixture. The product purity is hard to meet the pharmaceutical 55 [0014] The said inorganic base may be one selected use standards Therefore, it is necessary to improve this from sodium hydroxide, potassium hydroxide, sodium method. carbonate, potassium carbonate, sodium hydrogen car- [0006] The method of US patent 4122193 uses 1- bro- bonate, potassium hydrogen carbonate or their mixture. 2 3 EP 1 674 446 B1 4 [0015] The organic solvent used for extraction may be with water. Concentrating under reduced pressure to one selected from hydrocarbon, ester, ether or their mix- yield a limpid yellow solution as the crude 1-amino-3,5- ture. dimethyl adamantane. To the crude, adding 150ml of eth- [0016] The said hydrocarbon includes benzene, tolu- anol and concentrated hydrochloric acid, heating to dis- ene, xylene, cyclohexane, hexane, petroleum ether, etc. 5 solve and crystallizing to yield white solid. Drying the solid [0017] The said ester includes ethyl acetate, butyl ac- and re-crystallizing with ethanol to yield 61.0g of pure etate, etc. Memantine Hydrochloride. The yield of product is 68.8% [0018] The said ether includes sulfuric ether, isopropyl (GC 99.5%). 1 ether, etc. [0024] HNMR (CDCl3, 400MHZ): δ0.833 (6H, sin- [0019] The re-crystallization solvent is preferably alco- 10 glet), 1.156 (2H, quartet), 1.328 (4H, quartet), 1.683 (4H, hol such as methanol, ethanol, propanol, isopropanol, quartet), 1.869 (2H, broad signal), 2.179 (1H, broad sig- butanol and tertiary butanol, ketone such as acetone and nal), 8.28(3H, broad signal). butanone, water and their mixture. [0025] MS (Q-Tof micro, ESI+): 179(M+), 164, 122, [0020] This invention provides a new preparation 108, 93 and 55. 15 method that uses low-cost and facile raw materials, ho- [0026] Element Analysis (C 12H21N.HCl): actual results mogeneous phase and mild reaction conditions and sim- (calculated value%): C 66.77(66.80), H 10.40(10.28), N ple post treatment, obtains high yield and high purity and 6.48(6.49), Cl 16.39(16.43) is easy for mass production. [0021] Using the method of this invention for preparing Example 2 Memantine Hydrochloride brings the following advantag- 20 es: [0027] To 100g of 1- bromo-3, 5-dimethyl adamantane and 86g of urea, adding 72ml of 94wt% formic acid, heat- 1.