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【结 构 式】 
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【药物名称】Ladostigil tartrate, TV-3219(racemic; HCl), TV-3326 【化学名称】N-Ethyl-N-methylcarbamic acid 3(R)-(2-propynylamino)-2,3-dihydro-1H-inden-5-yl ester L-tartrate 【CA登记号】209394-46-7, 209394-27-4 (free base), 209394-47-8 (monoethanesulfonate), 209394-39-8 (monofumarate), 209394-18-3 (monoHCl), 2093 【 分 子 式 】C20H26N2O8 【 分 子 量 】422.43882 |
【开发单位】Hebrew University (Originator), Teva (Licensee) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Butyrylcholinesterase Inhibitors, MAO-A Inhibitors, MAO-B Inhibitors |
合成路线1
Treatment of (R)-1-aminoindan (I) with trifluoroacetic anhydride in toluene affords trifluoroacetyl derivative (II), which is condensed with chloroacetyl chloride (III) by means of AlCl3 in 1,2-dichloroethane to provide compound (IV). Oxidation of chloroacetyl derivative (IV) with 3-chloroperoxybenzoic acid (mCPBA) and TFA in CH2Cl2 allows formation of chloroacetoxy (V), which is converted into the hydroxy form (VI) by heating in hot methanol/H2O in the presence of K2CO3. N-Protection of (VI) is then performed by treatment with di-t-butyl dicarbonate and Et3N in THF to furnish Boc derivative (VII), which is then converted into derivative (IX) by O-acylation with N-Me, N-Et carbamoyl chloride (VIII) by means of NaH in acetonitrile. Removal of the Boc group of (IX) by treatment with HCl (gas) in dioxane gives hydrochloride (X), which is finally N-alkylated with propargyl bromide (XI) by means of K2CO3 in acetonitrile to yield the desired product.
| 【1】 Youdim, M.B.H.; Herzig, Y.; Sterling, J.; Goren, T.; Chorev, M. (Technion - Israel Institute of Technology; Teva Pharmaceutical Industries Ltd.; Yissum Research Development Co.); Aminoindan derivs.. EP 0966435; JP 2001506269; WO 9827055 . |
| 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) | 14863 | (1R)-2,3-Dihydro-1H-inden-1-ylamine; (R)-(-)-1-Aminoindan; (1R)-2,3-Dihydro-1H-inden-1-amine | 10277-74-4 | C9H11N | 详情 | 详情 |
| (II) | 46687 | N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2,2,2-trifluoroacetamide | C11H10F3NO | 详情 | 详情 | |
| (III) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (IV) | 46688 | N-[(1R)-6-(2-chloroacetyl)-2,3-dihydro-1H-inden-1-yl]-2,2,2-trifluoroacetamide | C13H11ClF3NO2 | 详情 | 详情 | |
| (V) | 46689 | (3R)-3-[(2,2,2-trifluoroacetyl)amino]-2,3-dihydro-1H-inden-5-yl 1lambda(3)-dichlorane-1-carboxylate | C12H10Cl2F3NO3 | 详情 | 详情 | |
| (VI) | 46690 | (3R)-3-amino-2,3-dihydro-1H-inden-5-ol | C9H11NO | 详情 | 详情 | |
| (VII) | 46691 | tert-butyl (1R)-6-hydroxy-2,3-dihydro-1H-inden-1-ylcarbamate | C14H19NO3 | 详情 | 详情 | |
| (VIII) | 46692 | 1,2-dimethyl-1-hydrazinecarbonyl chloride | C3H7ClN2O | 详情 | 详情 | |
| (IX) | 46693 | (3R)-3-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl 1,2-dimethyl-1-hydrazinecarboxylate | C17H25N3O4 | 详情 | 详情 | |
| (X) | 46694 | (3R)-3-amino-2,3-dihydro-1H-inden-5-yl 1,2-dimethyl-1-hydrazinecarboxylate | C12H17N3O2 | 详情 | 详情 | |
| (XI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |