4-Benzyloxyindole; 4-(benzyloxy)-1H-indole; benzyl 1H-indol-4-yl ether -Drug Synthesis Database

【结构式】

【分子编号】31535

【品名】4-Benzyloxyindole; 4-(benzyloxy)-1H-indole; benzyl 1H-indol-4-yl ether

【CA登记号】20289-26-3

【分子式】C₁₅H₁₃NO

【分子量】223.27436

【元素组成】C 80.69% H 5.87% N 6.27% O 7.17%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

This compound can be prepared by two related ways: 1) The condensation of methoxyacetaldehyde (I) with isopropylamine (II) gives methoxyacetaldehyde isopropylimine (III), which is treated with 4-benzyloxyindole (IV) in acetic acid yielding 4-benzyloxy-3-(1-isopropylamino-2-ethoxyethyl)indole (V). The reaction of (V) with ethyl nitroacetate (VI) in hot toluene affords ethyl 3-(4-benzyloxyindol-3-yl)-2-nitro-5-oxahexanoate (VII), which is reduced with H2 over Raney-Ni in ethanol giving ethyl 3-(4-benzyloxyindol-3-yl)-2-amino-5-oxahexanoate (VIII). Finally, this compound is cyclized with paraformaldehyde (IX) in refluxing benzene. 2) Compound (VIII) can also be cyclized with glyoxylic acid (X) yielding a mixture of the tetrahydrocarboline (XI) and the dihydrocarboline (XII), which, without separation, are decarboxylated and dehydrogenated with sulfur at 140 C.

参考文献中间体

合成目标

【1】 Neef, G.; Schmiechen, R.; Huth, A.; Eder, U.; Rathz, D.; Seidelmann, D.; Synthesis of 4-sibstituted beta-carbolines. Heterocycles 1983, 20, 7, 1295-1313.
【2】 Neef, G.; Eder, U.; Schmiechen, R.; Huth, A.; Rathz, D.; Seidelmonn, D.; Kehr, W.; Palenschat, D.; Braestrup, C.T.; et al. (Schering AG); Pharmacologically active 3-substituted beta-carbolines. DD 161210; EP 0054507; ES 8301984; US 4435403; US 4596808 .
【3】 Castaner, J.; Serradell, M.N.; ZK-91296. Drugs Fut 1984, 9, 10, 761.

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)	34354	2-methoxyacetaldehyde	10312-83-1	C₃H₆O₂	详情	详情
(II)	23933	2-Propanamine; Isopropylamine	75-31-0	C₃H₉N	详情	详情
(III)	34355	N-[(E)-2-methoxyethylidene]-2-propanamine; N-isopropyl-N-[(E)-2-methoxyethylidene]amine		C₆H₁₃NO	详情	详情
(IV)	31535	4-Benzyloxyindole; 4-(benzyloxy)-1H-indole; benzyl 1H-indol-4-yl ether	20289-26-3	C₁₅H₁₃NO	详情	详情
(V)	34356	N-[1-[4-(benzyloxy)-1H-indol-3-yl]-2-methoxyethyl]-2-propanamine; N-[1-[4-(benzyloxy)-1H-indol-3-yl]-2-methoxyethyl]-N-isopropylamine		C₂₁H₂₆N₂O₂	详情	详情
(VI)	15050	ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester	626-35-7	C₄H₇NO₄	详情	详情
(VII)	34357	ethyl 3-[4-(benzyloxy)-1H-indol-3-yl]-4-methoxy-2-nitrobutanoate		C₂₂H₂₄N₂O₆	详情	详情
(VIII)	34358	ethyl 2-amino-3-[4-(benzyloxy)-1H-indol-3-yl]-4-methoxybutanoate		C₂₂H₂₆N₂O₄	详情	详情
(X)	15618	2-Oxoacetic acid; Glyoxylic Acid	298-12-4	C₂H₂O₃	详情	详情
(XI)	34359	5-(benzyloxy)-3-(ethoxycarbonyl)-4-(methoxymethyl)-2,3,4,9-tetrahydro-1H-beta-carboline-1-carboxylic acid		C₂₄H₂₆N₂O₆	详情	详情
(XII)	34360	5-(benzyloxy)-3-(ethoxycarbonyl)-4-(methoxymethyl)-2,4a,9,9a-tetrahydro-1H-beta-carboline-1-carboxylic acid		C₂₄H₂₆N₂O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Silylation of 4-benzyloxyindole (I) employing tert-butyldimethylsilyl chloride and NaH gave the N-silyl derivative (II), which was brominated with N-bromosuccinimide at -78 C to afford the 3-bromoindole (III). After lithium-bromine exchange with n-BuLi at -78 C, the 3-lithio compound was condensed with N-methyl-D-proline methyl ester (IV) to give the indolyl ketone (V). The ketone function of (V) was finally reduced employing LiAlH4 in boiling dioxan, with concomitant cleavage of the benzyl ether to furnish the title compound.

参考文献中间体

合成目标

【1】 Qandil, A.M.; Marona-Lewicka, D.; Gerasimov, M.; Kurrasch-Orbaugh, D.M.; Nichols, D.E.; Further studies on oxygenated tryptamines with LSD-like activity incorporating a chiral pyrrolidine moiety into the side chain. J Med Chem 1999, 42, 20, 4257.

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)	31535	4-Benzyloxyindole; 4-(benzyloxy)-1H-indole; benzyl 1H-indol-4-yl ether	20289-26-3	C₁₅H₁₃NO	详情	详情
(II)	31536	4-(benzyloxy)-1-[tert-butyl(dimethyl)silyl]-1H-indole; benzyl 1-[tert-butyl(dimethyl)silyl]-1H-indol-4-yl ether		C₂₁H₂₇NOSi	详情	详情
(III)	31537	benzyl 3-bromo-1-[tert-butyl(dimethyl)silyl]-1H-indol-4-yl ether; 4-(benzyloxy)-3-bromo-1-[tert-butyl(dimethyl)silyl]-1H-indole		C₂₁H₂₆BrNOSi	详情	详情
(IV)	31538	methyl (2R)-1-methyl-2-pyrrolidinecarboxylate		C₇H₁₃NO₂	详情	详情
(V)	31539	[4-(benzyloxy)-1H-indol-3-yl][(2R)-1-methylpyrrolidinyl]methanone		C₂₁H₂₂N₂O₂	详情	详情

Extended Information