A modified method for synthesis of amantadine hydrochloride
Keywords:
amantadine hydrochloride, adamantine, N-(1-adamantyl)acetamide, antiviral, antidyskinetic.Abstract
Introduction: Amantadine hydrochloride (I) was well-known as an antiviral drug used to prevent and treat influenza A infections. Besides, it also was used to relieve the symptoms of Parkinson's disease in the early period. Several methods for the preparation of I have been reported. These procedures started with adamantane (II) in four or three reaction steps to produce amantadine hydrochloride with overall yields ranging from 45% to 58%.Objectives: Improving method for synthesis of amantadine hydrochloride could introduce to industrial scale.
Methods: Step-by-step optimization to reduce the use of reagents, solvents, as well as the conditions of each step were screened to be milder and more environment-friendly.
Results: All factors related to the yield of reaction to synthesize the intermediate and final compounds were screened to give the highest yield of each step. Finally, a two-step procedure for the synthesis of (I) from (II) via N-(1-adamantyl)formamide (III) with improving overall yield of 78% and a purity of 99.2% was established, and the structure of the product was confirmed by 1H-NMR,13C-NMR, IR and MS. The synthesis of N-(1-adamantyl)formamide (VI) from (II) also was successfully accomplished within only one step. This method avoided the use of liquid bromine or fuming sulfuric acid as reactants. The subsequent conversion of (VI) to (I) was carried out under milder reaction conditions without using hazardous solvents.
Conclusions: An improved synthesis for amantadine hydrochloride (I) have been provided. This research can be an industrially convenient production of amantadine hydrochloride. Because the raw materials and reagents used in this research are cheap and available which also were screened to save their use. Moreover, the total preparation time was significantly reduced to save energy as well as labor.
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References
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16. Tsutsui H, Ichikawa T, Narasaka K. Preparation of Primary Amines by the Alkylation of O-Sulfonyloximes of Benzophenone Derivatives with Grignard Reagents. Bull. Chem.Soc. Jpn. 1999[access: 25/05/2016]; 72(8): 1869-78. Available from: https://www.journal.csj.jp/doi/pdf/10.1246/bcsj.72.1869
17. Kitamura M, Chiba S, Narasaka K. Synthesis of primary amines and N-methylamines by the electrophilic amination of grignard reagents with 2-imidazolidinone O-sulfonyloxime. Bull. Chem.Soc. Jpn. 2003[access: 22/12/2015] ; 76(5): 1063-70. Available from : https://www.journal.csj.jp/doi/pdf/10.1246/bcsj.76.1063
18. Kitamura M, Suga T, Chiba S, Narasaka K. Synthesis of Primary Amines by the Electrophilic Amination of Grignard Reagents with 1,3-Dioxolan-2-one O-Sulfonyloxime. Org. Lett. 2004[access: 20/10/2016] ; 6(24): 4619-21. Available from: https://pubs.acs.org/doi/pdf/10.1021/ol0479951
19. Zhang Z, inventor; Synthesis method for Amantadine Hydrochloride. China Patent CN 102050744B. 2011 Nov 30.
20. Stetter H, Mayer J, Schwarz M, Wulff K, Über Verbindungen mit Urotropin-Struktur, XVI. Beiträge zur Chemie der Adamantyl-(1)-Derivate. Eur. J. Inorg. Chem. 1960[access: 10/10/2015]. 93(1):226-30. Available from: https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cber.19600930133
21. Moiseev IK, Doroshenko RI, Ivanova VI. Synthesis of amantadine through medium of nitrate 1-adamantanol. Pharm. Chem. J. 1976[access: 22/08/2015]; 10:450-51. Available from: https://link.springer.com/article/10.1007%2FBF00757832
22. Periandy N, Kilaru S, Thennati R, inventor; Novel process for the preparation of aminoadamantane derivatives. World Intellectual Property Organization Patent WO2005062724 A2. 2005 Jul 14.
23. Wolfgang H, inventor; Studiengesellschaft Kohle mbH, assignee. Process for the production of N-tert-alkyl amides and, if desired, N-tert. alkyl amines. United State patent US 3,152,180. 1964 Oct. 6.
24. Yao F, Xie L, Guo YF, inventor; Synthetic method of adamantanamine hydrochloride. China Patents CN105294445A. 2016 Feb 3.
2. Hubsher G, Haider M, Okun MS. Amantadine: the journey from fighting flu to treating Parkinson disease. Neurology. 2012[access: 02/09/2015]; 78(14):1096-99. Available from: https://n.neurology.org/content/78/14/1096
3. Kojima A, Ito K, Kono N, inventor; Method for production of amines and quaternary ammonium salt with adamantane skeleton. Japan Patent JP 2011-051976A. 2011 Mar 17.
4. He JX, Wang HB, Zhou HY. Synthesis of Amantadine Hydrochloride. Chinese Journal of Pharmaceuticals. 2013[access: 12/12/2015]; 44(1): 1-3. Available from: http://www.cjph.com.cn/EN/volumn/volumn_1150.shtml#
5. Qiu Y, Li L, Wang J, Wu , Lin Z, Chen X, inventor; Adamantanamine hydrochloride preparation method. China Patent CN 102875387A. 2013 Jan 16.
6. Vu BD, Nguyen VT, Le TS, Phan DC. An Improved Synthsis of Amantadine Hydrochloride. Org. Process Res. Dev. 2017[access: 28/09/2017]; 21(11):1758-60. Available from: https://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00242
7. Thinh NV, Pham VH, Vu BD, Dang TA, Tran KV, Phan DC. Mirowave Method for Synthesis of Amantadine Hydrochloride. Chang Mai J. Sci. 2018[access: 01/10/2018]; 45(6): 2454-58. Available from: https://epg.science.cmu.ac.th/ejournal/journalDetail.php?journal_id=9530
8.Marvin P, Watts JC, inventor; EI Du Pont Nemours and Co., assignee. Pharmaceutical compositions and methods utilizing 1-aminoadamantane and its derivatives. United State Patent US 3,310,469. 1967 Mar 21.
9. Kraus GA, inventor; Iowa State University Research Foundation (ISURF), assignee. Method for the synthesis of adamantane amines United State Patent US 5,599,998. 1997 Feb 4.
10. Shao G, Yang M, Wu C. Synthesis of amantadine hydrochloride. Chemical Intermediate, 2009[access: 15/10/2017]; 7: 55-56. Available from: https://caod.oriprobe.com/articles/16554366/Synthesis_of_-Amantadine_Hydrochloride.htm
11. Vincent CW, Bruce AR, inventor; Wyeth Holding LLC, assignee. Method of preparing 1-adamantanamine. United State Patent US 3,388,164. 1968 Jun 11.
12. Eriks K, Jack M, inventor; Eli Lilly and Co., assignee. Adamantyl secondary amines. United State Patent US 3,391,142 A. 1968 Jul 2.
13. Butov GM, Pershin VV, Burmistrov VV, inventor; State educational institution of higher professional education Volgograd State Technical University (VolgSTU), assignee. Method of producing hydrochlorides of amine-derivatives of adamantine. Russia patent RU2440971C1. 2012 Jan 27.
14. Jirgensons A, Kauss V, Kalvinsh I, Gold MR. A Practical Synthesis of tert-Alkylamines via the Ritter Reaction with Chloroacetonitrile. Synthesis. 2000[access: 15/01/2016]; 2000(12):1709-12. Available from: https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-2000-8208.pdf
15. Schickaneder CP, inventor; Hexal AG., assignee. Process for the Preparation of Adamantanamines. United State Patent US 20090082596A1. 2009 Mar 26.
16. Tsutsui H, Ichikawa T, Narasaka K. Preparation of Primary Amines by the Alkylation of O-Sulfonyloximes of Benzophenone Derivatives with Grignard Reagents. Bull. Chem.Soc. Jpn. 1999[access: 25/05/2016]; 72(8): 1869-78. Available from: https://www.journal.csj.jp/doi/pdf/10.1246/bcsj.72.1869
17. Kitamura M, Chiba S, Narasaka K. Synthesis of primary amines and N-methylamines by the electrophilic amination of grignard reagents with 2-imidazolidinone O-sulfonyloxime. Bull. Chem.Soc. Jpn. 2003[access: 22/12/2015] ; 76(5): 1063-70. Available from : https://www.journal.csj.jp/doi/pdf/10.1246/bcsj.76.1063
18. Kitamura M, Suga T, Chiba S, Narasaka K. Synthesis of Primary Amines by the Electrophilic Amination of Grignard Reagents with 1,3-Dioxolan-2-one O-Sulfonyloxime. Org. Lett. 2004[access: 20/10/2016] ; 6(24): 4619-21. Available from: https://pubs.acs.org/doi/pdf/10.1021/ol0479951
19. Zhang Z, inventor; Synthesis method for Amantadine Hydrochloride. China Patent CN 102050744B. 2011 Nov 30.
20. Stetter H, Mayer J, Schwarz M, Wulff K, Über Verbindungen mit Urotropin-Struktur, XVI. Beiträge zur Chemie der Adamantyl-(1)-Derivate. Eur. J. Inorg. Chem. 1960[access: 10/10/2015]. 93(1):226-30. Available from: https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cber.19600930133
21. Moiseev IK, Doroshenko RI, Ivanova VI. Synthesis of amantadine through medium of nitrate 1-adamantanol. Pharm. Chem. J. 1976[access: 22/08/2015]; 10:450-51. Available from: https://link.springer.com/article/10.1007%2FBF00757832
22. Periandy N, Kilaru S, Thennati R, inventor; Novel process for the preparation of aminoadamantane derivatives. World Intellectual Property Organization Patent WO2005062724 A2. 2005 Jul 14.
23. Wolfgang H, inventor; Studiengesellschaft Kohle mbH, assignee. Process for the production of N-tert-alkyl amides and, if desired, N-tert. alkyl amines. United State patent US 3,152,180. 1964 Oct. 6.
24. Yao F, Xie L, Guo YF, inventor; Synthetic method of adamantanamine hydrochloride. China Patents CN105294445A. 2016 Feb 3.
Published
2020-08-02
How to Cite
1.
Vu BD, Le BH, Bui TH, Do DA, Phan DC, Do Q. A modified method for synthesis of amantadine hydrochloride. Rev Cubana Med Milit [Internet]. 2020 Aug. 2 [cited 2025 Apr. 4];49(3):e0200713. Available from: https://revmedmilitar.sld.cu/index.php/mil/article/view/713
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