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【结 构 式】 
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【药物名称】Rivastigmine tartrate, ENA-713, SDZ-212-713, SDZ-ENA-713, Exelon MR, Exelon TDS, Prometax, Exelon 【化学名称】(S)-N-Ethyl-N-methylcarbamic acid 3-[1-(dimethylamino)ethyl]phenyl ester hydrogen(R,R)-tartrate 【CA登记号】129101-54-8, 123441-03-2 (free base) 【 分 子 式 】C18H28N2O8 【 分 子 量 】400.43246 |
【开发单位】Novartis (Originator), Esteve (Licensee) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Acetylcholinesterase Inhibitors, Butyrylcholinesterase Inhibitors |
合成路线1
| 【1】 Jaweed M, Siddiqui M, Upadhye BK, et al. 2007. Process for preparing enantiomerically pure rivastigmine. W0 2007026373 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 25331 | 3-hydroxyacetophenone; 1-(3-hydroxyphenyl)-1-ethanone | 121-71-1 | C8H8O2 | 详情 | 详情 |
| (II) | 12964 | 3-[1-(Dimethylamino)ethyl]phenol | C10H15NO | 详情 | 详情 | |
| (III) | 12966 | 3-[1-(dimethylamino)ethyl]phenyl ethyl(methyl)carbamate | C14H22N2O2 | 详情 | 详情 | |
| (IV) | 66627 | 2,3-bis((4-methylbenzoyl)oxy)succinic acid mixtures | C20H18O8 | 详情 | 详情 |
合成路线2
| 【1】 Murillo Gamdo JV, Armengol Montserrat M, Juarez J. 2007. Method of obtaining phenyl carbamates. WO 2007014973（本专利属于Ragactives，S L，Spain; Interquim，S. A.) |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11041 | 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone | 100-06-1 | C9H10O2 | 详情 | 详情 |
| (II) | 66628 | 1-(3-methoxyphenyl)-N-methylethanamine | C10H15NO | 详情 | 详情 | |
| (III) | 66629 | 3-(1-(methylamino)ethyl)phenol | C9H13NO | 详情 | 详情 | |
| (IV) | 66630 | C10H15BrO4S.C9H13NO | 详情 | 详情 | ||
| (V) | 66631 | (S)-3-(1-(methylamino)ethyl)phenol | C9H13NO | 详情 | 详情 | |
| (VI) | 66632 | (S)-3-(1-(methylamino)ethyl)phenyl ethyl(methyl)carbamate | C13H20N2O2 | 详情 | 详情 |
合成路线3
| 【1】 Cha KH, Lim DS. Lee HW, et aL. 2006. N-methylation and carbamoylation method for the preparation of rivastigmine and its salts. W0 2006068386(本专利属于Dong Kook Pharm. Co, Ltd,S Korea) |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 66633 | (S)-3-(1-(methylamino)ethyl)phenol | C9H13NO | 详情 | 详情 | |
| (II) | 66634 | (S)-3-(1-(dimethylamino)ethyl)phenol hydrochloride | C10H15NO.HCl | 详情 | 详情 | |
| (III) | 66635 | (S)-3-(1-(dimethylamino)ethyl)phenol | 105601-04-5 | C10H15NO | 详情 | 详情 |
| (IV) | 66636 | (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate hydrochloride | C14H22N2O2.HCl | 详情 | 详情 |
合成路线4
| 【1】 Gaitonde A, Mangle M. 2005. Process for the preparation of aminoalkylphenyl carbamates in particular rivastigmine hydragentartrate. GB 2409453(本专利属于Generics UK Limited, UK) |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 25331 | 3-hydroxyacetophenone; 1-(3-hydroxyphenyl)-1-ethanone | 121-71-1 | C8H8O2 | 详情 | 详情 |
| (II) | 66637 | 2-(ethyl(methyl)amino)acetyl chloride | C5H10ClNO | 详情 | 详情 | |
| (III) | 66638 | 3-acetylphenyl ethyl(methyl)carbamate | C12H15NO3 | 详情 | 详情 | |
| (IV) | 66639 | 3-(1-(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate hydrochloride | C14H22N2O2.HCl | 详情 | 详情 |
合成路线5
| 【1】 Fieldhouse R 2005. Stereoselective process for the preparation of tertiary amines attached to a secondary carbon center using a chiral transition metal transfer hydrogenation catalyst. W0 2005058804(本专利属于Avecia Pharmaceuticals Limited, UK) |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 40588 | N-methyl-1-ethanamine; N-ethyl-N-methylamine | 624-78-2 | C3H9N | 详情 | 详情 |
| (II) | 12965 | 1-[(Chlorocarbonyl)(methyl)amino]ethane | 42252-34-6 | C4H8ClNO | 详情 | 详情 |
| (III) | 66638 | 3-acetylphenyl ethyl(methyl)carbamate | C12H15NO3 | 详情 | 详情 | |
| (IV) | 66640 | (R）-3-(amino(hydroxy)methyl)phenyl ethyl(methyl)carbamate | C11H16N2O3 | 详情 | 详情 |
合成路线6
| 【1】 Zhou N. Xu XX. Zhou ZS 2004. Process for prepantion of 3-[(1S)-l-(dimethylamino) ethy]phenyl N-ethyl-N-methylcarbamate and its salts.中国专利申请公开说明书．CN 1486973 (Sanwei Pharmacertical Co, Ltd, Shanghai, Peop Rep China) |
合成路线7
Reaction of 3-[1-(dimethylamino)ethyl]phenol (I) with N-ethyl-N-methylcarbamoyl chloride (II) and sodium hydride in tetrahydrofuran gives racemic N-ethyl-N-methylcarbamic acid 3-[1-(dimethylamino)ethyl]phenyl ester (III), which is resolved by recrystallization with (+)-D-di-O,O'-(p-toluoyl)tartaric acid in methanol followed by treatment with base.
| 【1】 Enz, A. (Novartis Deutschland GmbH); Phenylcarbamate. AU 8812554; BE 1001467; CH 675720; DE 3805744; FR 2611707; GB 2203040; JP 1988238054; JP 1997118617; JP 1997165362 . |
| 【2】 Amstutz, R.; Walkinshaw, M.; Marzi, M.; Enz, A.; Boelsterli, J.; Cyclic phenyl-carbamates of the myotin-type and their action on acetylcholinesterase. Helv Chim Acta 1990, 73, 739-53. |
| 【3】 Rabasseda, X.; Castaner, J.; Prous, J.; SDZ-ENA-713. Drugs Fut 1994, 19, 7, 656. |
Extended Information