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【结 构 式】

【分子编号】48482

【品名】methyl (13R,15S)-17-(2-methoxyethyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9,17-pentaene-13-carboxylate

【CA登记号】

【 分 子 式 】C22H28N2O3

【 分 子 量 】368.476

【元素组成】C 71.71% H 7.66% N 7.6% O 13.03%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VII)

Condensation of the indoloazepine (I) bearing a chiral N-(1-naphthylethyl) substituent with 4-(1,3-dioxolan-2-yl)-6-methoxyhexanal (II) through a secodine-type intramolecular Diels-Alder reaction generated the epimeric mixture of pyrrolocarbazoles (III) along with minor amounts of their diastereoisomers (IV). The subsequent reductive ring cleavage of this mixture yielded the corresponding mixture of tricyclic compounds (V). Hydrogenolysis of the N-naphthylethyl group of (V), followed by chromatographic separation, gave the enantiomerically enriched secondary amines (VI). Acetal hydrolysis of (VI) with simultaneous cyclization of a transient aminoaldehyde provided the tetracyclic enamine (VII). Rearrangement of this enamine in refluxing toluene furnished the desired compound in 76% ee, which was further enriched to >98% ee by fractional crystallization.

1 Kuehne, M.E.; et al.; Enantioselective syntheses of coronaridine and 18-methoxycoronaridine. Tetrahedron 2001, 57, 11, 2085.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIIa) 48475 methyl (3aS,4R,11bR)-4-[(2S)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1R)-1-(1-naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate C36H42N2O5 详情 详情
(IIIb) 48476 methyl (3aS,4R,11bR)-4-[(2R)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1R)-1-(1-naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate C36H42N2O5 详情 详情
(IVa) 48477 methyl (3aR,4S,11bS)-4-[(2S)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1R)-1-(1-naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate C36H42N2O5 详情 详情
(IVb) 48478 methyl (3aR,4S,11bS)-4-[(2R)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1R)-1-(1-naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate C36H42N2O5 详情 详情
(VIa) 48480 methyl (5R,7S)-5-[(2R)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate C24H34N2O5 详情 详情
(VIb) 48481 methyl (5R,7S)-5-[(2S)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate C24H34N2O5 详情 详情
(I) 48473 methyl 3-[(1R)-1-(1-naphthyl)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate C26H26N2O2 详情 详情
(II) 48474 4-(1,3-dioxolan-2-yl)-6-methoxyhexanal C10H18O4 详情 详情
(V) 48479 methyl 5-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1R)-1-(1-naphthyl)ethyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate C36H44N2O5 详情 详情
(VII) 48482 methyl (13R,15S)-17-(2-methoxyethyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9,17-pentaene-13-carboxylate C22H28N2O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XV)

The condensation of allylmalonic acid diethyl ester (I) with 2-methoxyethyl bromide (II) by means of NaOEt in ethanol gives 2-allyl-2-(2-methoxyethyl)malonic acid diethyl ester (III), which is monodecarboxylated with LiCl in DMSO/DMF at 170 C to yield the pentenoic ester (IV). The reduction of the ester group of (IV) with LiAlH4 in dry ether affords the alcohol (V), which is oxidized to the corresponding aldehyde (VI) with (COCl)2 in dichloromethane. The protection of the aldehyde group of (VI) with ethyleneglycol (VII) and Ts-OH affords the cyclic ketal (VIII), which is treated with BH3/Me2S in dichloromethane to provide the primary alcohol (IX). The oxidation of (IX) with (COCl)2 as before gives the corresponding aldehyde (X), which is condensed with the indoloazepine (XI) in refluxing toluene, yielding the pyrrolocarbazole derivative (XII). The reductive ring opening of (XII) with NaBH4 in hot acetic acid affords the tricyclic intermediate (XIII), which is debenzylated with H2 over Pd/C in acetic acid to provide the secondary amine (XIV). The deprotection of the cyclic ketal group of (XIV) with HCl and HOAc, followed by treatment with NaOH, induces cyclization to the tetracyclic compound (XV), which is finally cyclized to the target compound in refluxing toluene.

1 Bandarage, U.K.; et al.; Total syntheses of racemic albifloranine and its anti-addictive congeners, including 18-methoxycoronaridine. Tetrahedron 1999, 55, 31, 9405.
2 Glick, S.D.; Kuehne, M.E. (Albany Medical College; University of Vermont); Ibogamine congeners. US 6211360; WO 9705869 .
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) 51458 Allylmalonic acid diethyl ester; Allyl malonic acid; Diethyl allylmalonate 2049-80-1 C10H16O4 详情 详情
(II) 51459 2-Methoxyethyl bromide; 2-Bromoethyl methyl ether; 1-Bromo-2-methoxyethane; Methyl 2-bromoethyl ether 6482-24-2 C3H7BrO 详情 详情
(III) 51460 diethyl 2-allyl-2-(2-methoxyethyl)malonate C13H22O5 详情 详情
(IV) 51461 ethyl 2-(2-methoxyethyl)-4-pentenoate C10H18O3 详情 详情
(V) 51462 2-(2-methoxyethyl)-4-penten-1-ol C8H16O2 详情 详情
(VI) 51463 2-(2-methoxyethyl)-4-pentenal C8H14O2 详情 详情
(VII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(VIII) 51464 2-[1-(2-methoxyethyl)-3-butenyl]-1,3-dioxolane; 3-(1,3-dioxolan-2-yl)-5-hexenyl methyl ether C10H18O3 详情 详情
(IX) 51465 4-(1,3-dioxolan-2-yl)-6-methoxy-1-hexanol C10H20O4 详情 详情
(X) 48474 4-(1,3-dioxolan-2-yl)-6-methoxyhexanal C10H18O4 详情 详情
(XI) 51466 methyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate C21H22N2O2 详情 详情
(XII) 51468 methyl (3aS,4R,11bR)-3-benzyl-4-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate C31H38N2O5 详情 详情
(XIII) 51467 methyl (5R)-3-benzyl-5-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate C31H40N2O5 详情 详情
(XIV) 51469 methyl (5R)-5-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate C24H34N2O5 详情 详情
(XV) 48482 methyl (13R,15S)-17-(2-methoxyethyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9,17-pentaene-13-carboxylate C22H28N2O3 详情 详情
Extended Information