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(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 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

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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/, 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 , 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 / 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 , 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, , 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 car- [0006] The method of US patent 4122193 uses 1- bro- bonate, potassium hydrogen carbonate or their mixture.

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[0015] The organic solvent used for extraction may be with water. Concentrating under reduced pressure to one selected from , 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, , hexane, 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 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. This invention makes some improvement based ing to 120°C and holding for 2 hours. Cooling to the room on the literature’s method, such as adding formic ac- temperature and adding 385ml of 10% hydrochloric acid id to the mixture of 1-bromo-3,5-dimethyl adaman- 25 to hydrolyze at 100°C for about 1 hour. Adjusting with tane and urea so that the reaction can be completed 30% sodium hydroxide solution to a pH of 12, extracting at a lower temperature and there is no need of tube with butyl acetate twice, combining the organic layers sealing. The product is homogenous without ag- and washing with water. Concentrating under reduced glomerations and easy for post treatment. It has pressure to yield a limpid yellow solution as crude 1- ami- overcome the difficulty for industrialization and cre- 30 no-3,5-dimethyl adamantane. To the crude, adding ated an advantage for mass production. 150ml of ethanol and concentrated hydrochloric acid, 2. Due to the presence of formic acid in the aminating heating to dissolve and crystallizing to yield white solid. reaction, the product of 3,5- dimethyl adamantane is Drying the solid and re-crystallizing with water to yield protected in the form of methanamide to avoid oxi- 60.4g of pure Memantine Hydrochloride. The yield is dation, and the reaction solution maintains light35 68.1% (GC 99.1%). color. After the hydrolysis and salification, the purity of the yielded Memantine Hydrochloride crude can Example 3 reach 99.0% and that of the re-crystallized product can reach 99.98% (see Fig.1). The yield is 69.5% [0028] To 100g of 1- bromo-3, 5-dimethyl adamantane and the is 332°C (DSC), which is re- 40 and 110g of urea, adding 60ml of anhydrous formic acid, ported by 290-295°C in the literature. heating to 150°C and hold for 1 hour. Cooling to the room temperature and adding 95ml of concentrated hydrochlo- Description of the drawing ric acid to hydrolyze at 100°C for 1 hour. Adjusting with 30% sodium hydroxide solution until the solution be- [0022] Fig.1 is the GC spectrum of purified Memantine 45 comes basic. Extracting with twice, combining Hydrochloride. the organic layers and washing with water. Concentrating under reduced pressure to yield a limpid yellow solution Embodiments as crude 1-amino-3,5-dimethyl adamantane. To the crude, adding 150ml of ethanol and concentrated hydro- Example 1 50 chloric acid, heating to dissolve and crystallizing to yield white solid. Drying the solid and re-crystallizing with ac- [0023] To 100g of 1-bromo-3,5-dimethyl adamantane etone to yield 61.7g of pure Memantine Hydrochloride. and 86g of urea, adding 80ml of 80wt% formic acid, heat- The yield is 69.5% (GC 99.9%). ing to 80°C and holding for 3 hours. Cooling to the room temperature and adding 95ml of concentrated hydrochlo- 55 Example 4 ric acid to hydrolyze at 80°C for about 1 hour. Adjusting with 30% sodium hydroxide to a pH of 12, extracting with [0029] To 100g of 1- bromo-3, 5-dimethyl adamantane toluene twice, combining the organic layers and washing and 86g of urea, adding 80ml of 80wt% formic acid, heat-

3 5 EP 1 674 446 B1 6 ing to 80°C and holding for 3 hours. Cooling to the room 6. The method according to claim 1, characterized in temperature and adding 75ml of 85% phosphoric acid to that the said inorganic acid is one selected from hy- hydrolyze at 80°C for 1 hour. Adjusting with 10% potas- drochloric acid, hydrobromic acid, sulphuric acid, sium hydroxide aqueous solution to a pH of 12. Extracting phosphoric acid or their mixture. with toluene twice, combining the organic layers and5 washing with water. Concentrating under reduced pres- 7. The method according to claim 1, characterized in sure to yield a limpid yellow solution as crude 1-amino- that the said reaction solution has a pH of 10 to 14 3,5-dimethyl adamantane. To the crude, adding 150ml adjusted by inorganic base and its aqueous solution. of ethanol and concentrated hydrochloric acid, heating to dissolve and crystallizing to yield a white solid. Drying 10 8. The method according to claim 1, characterized in the solid and re-crystallizing with ethanol to yield 61.0g that the said inorganic base is one selected from of pure Memantine Hydrochloride. The yield is 68.8% sodium hydroxide, potassium hydroxide, sodium (GC 99.5%). carbonate, potassium carbonate, sodium hydrogen 1 [0030] HNMR (CDCl3, 400MHZ): δ0.833 (6H, sin- carbonate, potassium hydrogen carbonate or their glet), 1.156 (2H, quartet), 1.328 (4H, quartet), 1.683 (4H, 15 mixture. quartet), 1.869 (2H, broad signal), 2.179 (1H, broad sig- nal), 8.28 (3H, broad signal). 9. The method according to claim 1, characterized in [0031] MS (Q-Tof micro, ESI+): 179(M+), 164, 122, that the organic solvent used for extraction is one 108, 93 and 55. selected form hydrocarbon, ester, ether or their mix- 20 [0032] Element Analysis (C 12H21N.HCl): actual results ture. (calculated value%): C 66.77 (66.80), H 10.40 (10.28), N 6.48(6.49) and Cl 16.39(16.43) 10. The method according to any one from claim 1 to 9, characterized in that Memantine Hydrochloride is obtained by recrystallizing the said salt with recrys- Claims 25 tallizing solvent, the said recrystallizing solvent is one selected from alcohol, ketone, water or their mix- 1. A method of preparing Memantine Hydrochloride ture. characterized by the following processing steps:

maintaining 1-bromo-3,5-dimethyl adamantane 30 Patentansprüche and urea/formic acid at 50-180°C for 0.25-5h; after the completion of reaction, adding inorgan- 1. Verfahren zur Herstellung von Memantinhydrochlo- ic acid aqueous solution and performing hydro- rid, gekennzeichnet durch die Verfahrensschritte: lyzation at a pH of 1-3; adjusting with inorganic base aqueous solution until the reaction solution 35 Halten von1- Brom-3,5-dimethyladamantanund becomes basic; after the extraction with organic Harnstoff / Ameisensäure bei 50 - 180 °C für , salifying the extract with hydrochloric 0,25 - 5 h; nach Beendigung der Umsetzung, acid to yield the target product Memantine Hy- Zugeben einer wässrigen Lösung einer anorga- drochloride. nischenSäure und Durchführen einer Hydrolyse 40 bei einem pH von 1 - 3; Einstellen mit einer wäss- 2. The method according to claim 1, characterized in rigen Lösung einer anorganischen Base bis die that said urea- formic acid serves as reaction solvent Reaktionslösung basisch wird; nach der Extrak- for ammonization and the said formic acid is anhy- tion mit organischen Lösungsmitteln, den Ex- drous formic acid or formic acid aqueous solution. trakt mit Salzsäure in das Salz überführen, um 45 das Zielprodukt Memantinhydrochlorid zu erhal- 3. The method according to claim 1, characterized in ten. that the molar ratio of 1-bromo-3,5-dimethyl ada- mantane, urea and formic acid is 1:0.5∼10:1∼15. 2. Das Verfahren nach Anspruch 1, dadurch gekenn- zeichnet, dass Harnstoff - Ameisensäure als Lö- 4. The method according to claim 3, characterized in 50 sungsmittel für die Ammonisierungsreaktion dient that the molar ratio of 1-bromo-3,5-dimethyl ada- und die Ameisensäure wasserfreie Ameisensäure mantane and urea and formic acid is 1:2 ∼5:5∼10 and oder eine wässrige Lösung von Ameisensäure ist. the reaction temperature is from 60°C to 150°C. 3. Das Verfahren nach Anspruch 1, dadurch gekenn- 5. The method according to claim 1, characterized in 55 zeichnet, dass das molare Verhältnis von 1-Brom- that the hydrolysis temperature is from 50°C to 3,5-dimethyladamantan, Harnstoff und Ameisen- 100°C and the duration is from 0.5h to 5h. säure 1 : 0,5 ∼ 10 : 1 ∼ 15 ist.

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4. Das Verfahren nach Anspruch 3, dadurch gekenn- de l’extrait avec de l’acide chlorhydrique, ce qui zeichnet, dass das molare Verhältnis von 1-Brom- donne le produit cible consistant en chlorhydrate 3,5-dimethyladamantan und Harnstoff und Amei- de mémantine. sensäure 1 : 2 ∼5: 5 ∼ 10 ist und die Reaktionstem- peratur von 60 °C bis 150 °C ist. 5 2. Procédé suivant la revendication 1, caractérisé en ce que ledit urée-acide formique sert de solvant 5. Das Verfahren nach Anspruch 1, dadurch gekenn- réactionnel pour l’ammonisation et ledit acide formi- zeichnet, dass die Hydrolysetemperatur 50 °C bis que est l’acide formique anhydre ou une solution 100 °C ist und die Dauer von 0,5 h bis 5 h ist. aqueuse d’acide formique. 10 6. Das Verfahren nach Anspruch 1, dadurch gekenn- 3. Procédé suivant la revendication 1, caractérisé en zeichnet, dass die anorganische Säure eine ist, ce que le rapport molaire du 1-bromo-3,5-diméthy- ausgewählt aus Salzsäure, Bromwasserstoffsäure, ladamantane, de l’urée et de l’acide formique est de Schwefelsäure, Phosphorsäure oder einer Mi- 1:0,5-10:1-15. schung derselben. 15 4. Procédé suivant la revendication 3, caractérisé en 7. Das Verfahren nach Anspruch 1, dadurch gekenn- ce que le rapport molaire du 1-bromo-3,5-diméthy- zeichnet, dass die Reaktionslösung einen pH von ladamantane, de l’urée et de l’acide formique est de 10 bis 14 hat, eingestellt mit anorganischer Base und 1:2∼5:5∼10 et la température réactionnelle va de einer wässrigen Lösung derselben. 20 60°C à 150°C.

8. Das Verfahren nach Anspruch 1, dadurch gekenn- 5. Procédé suivant la revendication 1, caractérisé en zeichnet, dass die anorganische Base eine ist, aus- ce que la température d’hydrolyse va de 50°C à gewählt aus Natriumhydroxid, Kaliumhydroxid, Na- 100°C et la durée va de 0,5 h à 5 h. triumcarbonat, Kaliumcarbonat, Natriumhydrogen- 25 carbonat, Kaliumhydrogencarbonat oder einer Mi- 6. Procédé suivant la revendication 1, caractérisé en schung derselben. ce que ledit acide inorganique est un acide inorga- nique choisi entre l’acide chlorhydrique, l’acide 9. Das Verfahren nach Anspruch 1, dadurch gekenn- bromhydrique, l’acide sulfurique, l’acide phosphori- zeichnet, dass das für die Extraktion verwendete 30 que et leur mélange. organische Lösungsmittel eines ist, ausgewählt aus Kohlenwasserstoff, Ester, Ether oder einer Mi- 7. Procédé suivant la revendication 1, caractérisé en schung derselben. ce que ladite solution réactionnelle a un pH de 10 à 14 ajusté avec une base inorganique et sa solution 10. Das Verfahren nach irgendeinem der Ansprüche 1 35 aqueuse. bis 9, dadurch gekennzeichnet, dass das Meman- tinhydrochlorid durch Umkristallisieren des Salzes 8. Procédé suivant la revendication 1, caractérisé en mit einem Lösungsmittel zur Umkristallisierung er- ce que ladite base inorganique est une base inor- halten wird, wobei das Lösungsmittel zur Umkristal- ganique choisie entre l’hydroxyde de sodium, l’hy- lisierung eines ist, ausgewählt aus Alkohol, Keton, 40 droxyde de potassium, le carbonate de sodium, le Wasser oder einer Mischung derselben. carbonate de potassium, le carbonate acide de so- dium, le carbonate acide de potassium et leur mé- lange. Revendications 45 9. Procédé suivant la revendication 1, caractérisé en 1. Procédé pour préparer du chlorhydrate de méman- ce que le solvant organique utilisé pour l’extraction tine, caractérisé par les étapes de traitement est un solvant organique choisi entre un hydrocar- suivantes : bure, un ester, un éther et leur mélange.

maintien de 1-bromo-3,5-diméthyladamantane 50 10. Procédé suivant l’une quelconque des revendica- et d’urée/ acide formique à 50/180°C pendant tions 1 à 9, caractérisé en ce que le chlorhydrate 0,25-5 h ; une fois la réaction parvenue à son de mémantine est obtenu par recristallisation dudit terme, addition d’une solution aqueuse d’un aci- sel avec un solvant de recristallisation, ledit solvant de inorganique et conduite d’une hydrolyse à un de recristallisation étant un solvant de recristallisa- pH de 1-3 ; ajustement avec la solution aqueuse 55 tion choisi entre un alcool, une cétone, l’eau et leur de base inorganique jusqu’à ce que la solution mélange. réactionnelle devienne basique ; après extrac- tion avec des solvants organiques, salification

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 3391142 A [0003] [0004] • US 4122193 A [0003] [0006]

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