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【结 构 式】 
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【药物名称】Phenserine tartrate 【化学名称】(-)-5-O-(N-Phenylcarbamoyl)eseroline L-tartrate 【CA登记号】156910-61-1, 116839-68-0 ((+)-enantiomer), 101246-66-6 (free base), 159652-53-6 (racemate) 【 分 子 式 】C24H29N3O8 【 分 子 量 】487.51403 |
【开发单位】National Institutes of Health (Originator), Axonyx (Licensee) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Acetylcholinesterase Inhibitors, Antiamyloidogenic Agents |
合成路线1
Hydrolysis of physostigmine (I) with either NaOMe in ethanol or NaOBu in refluxing butanol (better yield) gives eseroline (II), which is condensed with phenyl isocyanate (III) by means of NaOMe in benzene, Na in benzene or Na in ether/benzene.
| 【1】 Castañer, J.; Sorbera, L.A.; Phenserine Tartrate. Drugs Fut 2003, 28, 1, 18. |
| 【2】 Polonovski, M.; Study on the alkaloids of the Calabar bean (V). Action of phenyl isocyanate: Phenylic homologs of eserine and genserine. Bull Soc Chim Fr Mem 1916, 19, 46. |
| 【3】 Maggi, A.; Brufani, M.; Lappa, S.; Filocamo, L.; New acetylcholinesterease inhibitors. Drugs Fut 1997, 22, 4, 397. |
| 【4】 Yu, Q.-S.; Schonenberger, B.; Brossi, A.; Reactions of (-)-physostigmine and (-)-N-methylphysostigmine in refluxing butanol and at high temperature: Facile preparation of (-)-eseroline. Heterocycles 1987, 26, Suppl. 3, 1271-5. |
| 【5】 Castellano, C.; Pomponi, M.; Brufani, M.; Pagella, P.G.; Oliverio, A.; Marta, M.; Pavone, F.; New analogs of physostigmine: Alternative drugs for Alzheimer's disease?. Life Sci 1988, 43, 23, 1921. |
| 【6】 Greig, N.H.; et al.; Phenserine and ring C hetero-analogs: Drug candidates for the treatment of Alzheimer's disease. Med Res Rev 1995, 15, 1, 3. |
| 【7】 Brzostowska, M.; et al.; Phenylcarbamates of (-)-eseroline, (-)-N1-noreseroline and (-)-physovenol: Selective inhibitors of acetyl and,or butyrylcholinesterase. Med Chem Res 1992, 2, 4, 238. |
| 【8】 Pomponi, M.; Brufani, M.; Marta, M.; Pavone, F.; Oliverio, A.; Castellano, C. (Consiglio Nazionale delle Ricerche); Physostigmine derivs. with acetylcholinesterase inhibition properties, and the relative production process. EP 0154864; EP 0354594 . |
| 【9】 Brossi, A.; Brzostowska, M.; Rapoport, S.I.; Greig, N.; He, X.-S. (US Department of Health & Human Services); Substd. phenserines as specific inhibitors of acetylcholinesterase. EP 0606366; JP 1995503703; US 5171750; WO 9306105 . |
| 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) | 40606 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methylcarbamate | 57-47-6 | C15H21N3O2 | 详情 | 详情 |
| (II) | 20365 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol | C13H18N2O | 详情 | 详情 | |
| (III) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
合成路线2
Condensation of 5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-one (IV) with 2-chloro-N,N-dimethylethyl-amine (V) by means of NaNH2 in toluene gives 3-[2-(di-methylamino)ethyl]-5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-one (VI), which is reduced with Vitride (sodium bis(2-methoxyethoxy)aluminum dihydride) in toluene to yield the secondary alcohol (VII). Optical resolution of (VII) by means of (+)-2,3-di-O-(p-toluoyl)tartaric acid provides the (2S,3S)-diastereomer (VIII), which by reaction with methyl iodide in ethyl ether affords the ammonium salt (IX). Cyclization of compound (IX) by means of methylamine in acetonitrile provides esermethole (X), the methyl ether of eseroline, which is demethylated by means of BBr3 in dichloromethane to give eseroline (II). Finally, eseroline is condensed with phenyl isocyanate (VIII) by means of Na in ethyl ether.
| 【1】 Castañer, J.; Sorbera, L.A.; Phenserine Tartrate. Drugs Fut 2003, 28, 1, 18. |
| 【2】 Brossi, A.; Bi, S.; Greig, N.H.; Pei, X.-F.; 125. Total synthesis of racemic and optically active compounds related to physostigmine and ring-C heteroanalogues from 3-[2'-(dimethylamino)ethyl]-2,3-dihydro-5-methoxy-1,3-dimethyl-1H-indol-2-ol. Helv Chim Acta 1994, 77, 5, 1412. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 20365 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol | C13H18N2O | 详情 | 详情 | |
| (III) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (IV) | 58084 | 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one | C11H13NO2 | 详情 | 详情 | |
| (V) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
| (VI) | 58085 | 3-[2-(dimethylamino)ethyl]-5-methoxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one | C15H22N2O2 | 详情 | 详情 | |
| (VII) | 58086 | 3-[2-(dimethylamino)ethyl]-5-methoxy-1,3-dimethyl-2-indolinol | C15H24N2O2 | 详情 | 详情 | |
| (VIII) | 58087 | (2S,3S)-3-[2-(dimethylamino)ethyl]-5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-ol | C15H24N2O2 | 详情 | 详情 | |
| (IX) | 36822 | 2-[(2S,3S)-2-hydroxy-5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-3-yl]-N,N,N-trimethyl-1-ethanaminium iodide | C16H27IN2O2 | 详情 | 详情 | |
| (X) | 58088 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aS,8aR)-5-methoxy-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole | C14H20N2O | 详情 | 详情 |
合成路线3
Condensation of 5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-one (IV) with 2-chloroacetonitrile (XI) by means of a chiral phase transfer catalyst gives 2-(5-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-y)-acetonitrile, which is separated into enantiomers by chromatography. Reductocyclization of the (S)-enantiomer (XII) by means of Vitride affords (3aS)-N1-noresermethole (XIII), which is submitted to a reductive methylation to provide esermethole (X). O-demethylation of (X) by means of BBr3 or AlCl3 gives eseroline (II), which is finally condensed with phenyl isocyanate.
| 【1】 Castañer, J.; Sorbera, L.A.; Phenserine Tartrate. Drugs Fut 2003, 28, 1, 18. |
| 【2】 Greig, N.H.; Pei, X.-F.; Brossi, A.; Phenserine, a novel anticholinesterase related to physostigmine: Total synthesis and biological properties. Aust J Chem 1996, 49, 2, 171. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 20365 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol | C13H18N2O | 详情 | 详情 | |
| (III) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (IV) | 58084 | 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one | C11H13NO2 | 详情 | 详情 | |
| (X) | 58088 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aS,8aR)-5-methoxy-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole | C14H20N2O | 详情 | 详情 | |
| (XI) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (XII) | 58089 | 2-[(3S)-5-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]acetonitrile | C13H14N2O2 | 详情 | 详情 | |
| (XIII) | 58090 | (3aS,8aR)-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aS,8aR)-5-methoxy-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole | C13H18N2O | 详情 | 详情 |