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【结 构 式】 
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【药物名称】Huperizine A, Huperzine A, Hup A, Cerebra 【化学名称】(-)-(5R,9R,11E)-5-Amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methanocycloocteno[b]pyridin-2(1H)-one 【CA登记号】102518-79-6 【 分 子 式 】C15H18N2O 【 分 子 量 】242.32351 |
【开发单位】Hi-Tech Pharmacal (Licensee), Savient Pharmaceuticals (Licensee) 【药理作用】Alzheimer's Dementia, Treatment of , Cerebrovascular Diseases, Treatment of, Cognition Disorders, Treatment of, Immunologic Neuromuscular Disorders, Treatment of, Myasthenia Gravis, Agents for, NEUROLOGIC DRUGS, Stroke, Treatment of, Acetylcholinesterase Inhibitors |
合成路线1
The first total synthesis of hyperzine A as racemic is carried out as follows: The reaction of pyrrolidine (I) with cyclohexane-1,4-dione monoethyleneketal (II) by means of p-toluenesulfonic acid in refluxing benzene gives the enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane affording the bicyclic pyridone (V). The benzylation of (V) with benzyl chloride and KH in THF yields the N-benzyl derivative (VI), which is dehydrogenated by means of phenylselenium chloride in THF, followed by a treatment with NaIO4 in refluxing methanol to give the protected pyridone (VII). The debenzylation of (VII) with Pd(OH)2 in acetic acid yields the free pyridone (VIII), which is aromatized with methyl iodide and silver carbonate to the 2-methoxypyridine (IX). Elimination of the ketal group of (IX) with HCl in refluxing acetone affords the tetrahydroquinolone (X), which is carboxylated by means of dimethyl carbonate and KH to give 2-methoxy-6-oxo-5,6,7,8-tetrahydroquinoline-5-carboxylic acid methyl ester (XI). The cyclization of (XI) with 2-methylacrolein (XII) by means of sodium methoxide in methanol or tetramethylguanidine in dichloromethane yields the tricyclic compound (XIII), which is mesylated with mesyl chloride to the mesylate (XIV). Elimination of the mesyl group of (XIV) with refluxing acetic acid - sodium acetate affords the olefinic compound (XV), which is submitted to a Wittig condensation with ethylidenetriphenylphosphorane in ether giving the diolefinic compound (XVI) as a mixture of the E- and Z-isomers. Selective hydrolysis of (XVI) with NaOH in THF - methanol yields acid (XVII) as the E-isomer, which is treated with SOCl2 and sodium azide in a modified Curtius reaction to obtain the urethane (XVIII). Lastly trimethylsilyl iodide is used to effect both N- and O-deprotection.
| 【1】 Xia, Y.; Kozikowski, A.P.; A practical synthesis of the Chinese "nootropic" agent huperzine A: A possible lead in the treatment of Alzheimer's disease. J Am Chem Soc 1989, 111, 11, 4116. |
| 【2】 Qian, L.; Ji, R.; A total synthesis of (±)-huperzine A. Tetrahedron Lett 1989, 30, 16, 2089. |
| 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) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (II) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (III) | 11378 | 1-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)pyrrolidine | C12H19NO2 | 详情 | 详情 | |
| (IV) | 11379 | 3-Butenamide | C4H7NO | 详情 | 详情 | |
| (V) | 11380 | 1',2',3',4',5',6',7',8'-Octahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C11H15NO3 | 详情 | 详情 | |
| (VI) | 11381 | 1'-Benzyl-1',2',3',4',5',6',7',8'-Octahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C18H21NO3 | 详情 | 详情 | |
| (VII) | 11382 | 1'-Benzyl-1',2',5',6',7',8'-Hexahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C18H19NO3 | 详情 | 详情 | |
| (VIII) | 11383 | 1',2',5',6',7',8'-Hexahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C11H13NO3 | 详情 | 详情 | |
| (IX) | 11384 | 2'-Methoxy-5',6',7',8'-tetrahydrospiro[1,3-dioxlane-2,6'-quinoline] | C12H15NO3 | 详情 | 详情 | |
| (X) | 11385 | 2-Methoxy-7,8-dihydro-6(5H)-quinolinone | C10H11NO2 | 详情 | 详情 | |
| (XI) | 11386 | methyl 2-methoxy-6-oxo-5,6,7,8-tetrahydro-5-quinolinecarboxylate | C12H13NO4 | 详情 | 详情 | |
| (XII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (XIII) | 11388 | methyl (1S)-10-hydroxy-5-methoxy-11-methyl-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C16H19NO5 | 详情 | 详情 | |
| (XIV) | 11389 | methyl (1S)-5-methoxy-11-methyl-10-[(methylsulfonyl)oxy]-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C17H21NO7S | 详情 | 详情 | |
| (XV) | 11390 | methyl (1S)-5-methoxy-11-methyl-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylate | C16H17NO4 | 详情 | 详情 | |
| (XVI) | 11391 | methyl (1R)-13-[(E)ethylidene]-5-methoxy-11-methyl-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylate | C18H21NO3 | 详情 | 详情 | |
| (XVII) | 11392 | (1R)-13-[(E)Ethylidene]-5-methoxy-11-methyl-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylic acid | C17H19NO3 | 详情 | 详情 | |
| (XVIII) | 11393 | ethyl 13-[(E)ethylidene]-5-methoxy-11-methyl-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraen-1-ylcarbamate | C19H24N2O3 | 详情 | 详情 | |
| (XIX) | 11394 | ethyl 13-[(E)ethylidene]-11-methyl-5-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2(7),3,10-trien-1-ylcarbamate | C18H22N2O3 | 详情 | 详情 |
合成路线2
A synthesis for optically pure (-)-huperzine A, through modification of the previously reported synthesis of (±)-huperzine A, has been described: Intermediate methyl ester (XI) of this synthesis [Drugs Fut 1990, 15(6): 616] is transesterified with (-)-8-phenylmenthol (A) in refluxing benzene to give the optical ester (XIa), suitable for a stereocontrolled cyclization. The cyclization of (XIa) with 2-methylacrolein, as in the previous synthesis, yields the tricyclic compound (XIIa) [an analogue of the previously reported (XII), but with the adequate absolute configuration]. The following step is dehydration to (XIVa), in the same way as in the case of (XIV) of the previous synthesis. From here, the previously reported synthetic route is repeated, finally yielding optically pure (-)-huperzine A. In some steps, separation of undesirable minor amounts of other enantiomers must be performed.
| 【1】 Yamada, F.; Kozikowski, A.P.; Reddy, E.R.; Pang, Y.P.; Miller, J.H.; McKinney, M.; A route to optically pure (-)-huperzine-A - Molecular modeling and invitro pharmacology. J Am Chem Soc 1991, 113, 12, 4695. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 | |
| (A) | 11396 | (1S,2S,4R)-4-Methyl-2-(1-methyl-1-phenylethyl)cyclohexanol | C16H24O | 详情 | 详情 | |
| (XIa) | 11397 | (1S,2S,4R)-4-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl 2-methoxy-6-oxo-5,6,7,8-tetrahydro-5-quinolinecarboxylate | C27H33NO4 | 详情 | 详情 | |
| (XIIa) | 11398 | (1S,2S,4R)-4-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (1S,9R)-10-hydroxy-5-methoxy-11-methyl-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C31H39NO5 | 详情 | 详情 | |
| (XIVa) | 11399 | (1S,2S,4R)-4-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (1S,9R)-5-methoxy-11-methyl-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylate | C31H37NO4 | 详情 | 详情 | |
| (XI) | 11386 | methyl 2-methoxy-6-oxo-5,6,7,8-tetrahydro-5-quinolinecarboxylate | C12H13NO4 | 详情 | 详情 |
合成路线3
A new synthesis of huperzine A has been described: The cyclization of 6-hydroxy-2-methoxy-7,8-dihydroquinoline-5-carboxylic acid methyl ester (I) with 2-methylene-1,3-propanediol diacetate (II) by means of palladium diacetate and triphenylphosphine in dioxane gives the tricyclic ketone (III), which is treated with ethyl triphenylphosphonium bromide and butyllithium in THF to yield the corresponding (Z)-ethylidene derivative (IV). Isomerization of (IV) with AIBN and thiophenol in hot toluene affords the (E)-isomer (V), which is hydrolyzed with NaOH to the free acid (VI). The reaction of acid (VI) with diphenyl phosphorazidate and triethylamine gives the carbamic acid ester (VII), which is finally deprotected and isomerized to huperzine A with trimethylsilyl bromide in refluxing CHCl3, followed by a treatment with trifluoromethanesulfonic acid in hot dioxane.
| 【1】 Sun, L.Q.; Kozikowski, A.P.; Campiani, G.; Aagaard, P.; McKinney, M.; A palladium-catalyzed route to huperzine-A and its analogues and their anticholinesterase activity. J Org Chem 1993, 58, 27, 7660. |
| 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) | 11400 | methyl 6-hydroxy-2-methoxy-7,8-dihydro-5-quinolinecarboxylate | C12H13NO4 | 详情 | 详情 | |
| (II) | 11401 | 2-[(acetoxy)methyl]-2-propenyl acetate | C8H12O4 | 详情 | 详情 | |
| (III) | 11402 | methyl (1S,9S)-5-methoxy-11-methylene-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C16H17NO4 | 详情 | 详情 | |
| (IV) | 11403 | methyl (1R,9S)-13-[(Z)ethylidene]-5-methoxy-11-methylene-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C18H21NO3 | 详情 | 详情 | |
| (V) | 11404 | methyl (1R,9S)-13-[(E)ethylidene]-5-methoxy-11-methylene-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C18H21NO3 | 详情 | 详情 | |
| (VI) | 11405 | (1R,9S)-13-[(E)Ethylidene]-5-methoxy-11-methylene-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylic acid | C17H19NO3 | 详情 | 详情 | |
| (VII) | 11406 | methyl N-[(9S)-13-[(E)ethylidene]-5-methoxy-11-methylene-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-1-yl]carbamate | C18H22N2O3 | 详情 | 详情 |