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【结 构 式】

【分子编号】32457

【品名】methyl (2S)-2-[(11R)-11-hydroxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate

【CA登记号】

【 分 子 式 】C22H29NO7

【 分 子 量 】419.4748

【元素组成】C 62.99% H 6.97% N 3.34% O 26.7%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

The methylation of N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (I) with methyl iodide and KOH gives the protected 4-O-methyl-L-tyrosine methyl ester (II), which is deprotected with TFA yielding (III). The Grundke oxidation of (III) affords the N-hydroxy derivative (IV), which is cyclocondensed with cyclohexane-1,4-dione monoethylene ketal (V) and ethyl acrylate (VI) in refluxing toluene to afford the spiroisoxazolidinone (VII). The reductive rearrangement of (VII) with H2 over Pd/C in acetic acid provides the spiropyrrolidinone (VIII), which is treated successively with tosyl chloride and with sodium azide to obtain the azido derivative (IX). The reduction of (IX) with H2 over Pd/C, protection of the resulting amine with Boc2O, and methylation of the resulting carbamate with NaH and methyl iodide affords the N-methylcarbamate (X). The reduction of the methoxycarbonyl group of (X) with LiBH4 in THF gives the carbinol (XI), which is oxidized with Dess-Martin periodinane to the aldehyde (XII). The rearrangement of (XII) by means of potassium tert-butoxide, followed by deprotection of the carbamate group yields the 7,10a-methanopyrrolo[1,2-a]azocin-8-one derivative (XIII), which is reduced at the carbonyl group with LiAlH4 in THF affords the 8(R)-hydroxy derivative (XIV). The protection of the amino group of (XIV) with benzyloxycarbonyl chloride and triethylamine yields the carbamate (XV).

1 Snider, B.B.; et al.; Total synthesis of (-)-FR901483. J Am Chem Soc 1999, 121, 34, 7778.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 19875 methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate 4326-36-7 C15H21NO5 详情 详情
(II) 32453 methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate C16H23NO5 详情 详情
(III) 32454 methyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate C11H15NO3 详情 详情
(IV) 32455 methyl (2S)-2-(hydroxyamino)-3-(4-methoxyphenyl)propanoate C11H15NO4 详情 详情
(V) 11377 1,4-Dioxaspiro[4.5]decan-8-one 4746-97-8 C8H12O3 详情 详情
(VI) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(VII) 32456 ethyl (3R)-1-[(1S)-2-methoxy-1-(4-methoxybenzyl)-2-oxoethyl]-2,9,12-trioxa-1-azadispiro[4.2.4.2]tetradecane-3-carboxylate C24H33NO8 详情 详情
(VIII) 32457 methyl (2S)-2-[(11R)-11-hydroxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate C22H29NO7 详情 详情
(IX) 32458 methyl (2S)-2-[(11S)-11-azido-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate C22H28N4O6 详情 详情
(X) 32459 methyl (2S)-2-[(11S)-11-[(tert-butoxycarbonyl)(methyl)amino]-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate C28H40N2O8 详情 详情
(XI) 32460 tert-butyl (3S)-1-[(1S)-2-hydroxy-1-(4-methoxybenzyl)ethyl]-2,8-dioxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate C25H36N2O6 详情 详情
(XII) 32461 tert-butyl (3S)-1-[(1S)-1-formyl-2-(4-methoxyphenyl)ethyl]-2,8-dioxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate C25H34N2O6 详情 详情
(XIII) 32462 (1S,3S,6S,7S,8S)-7-hydroxy-6-(4-methoxybenzyl)-3-(methylamino)-5-azatricyclo[6.3.1.0(1,5)]dodecan-9-one C20H28N2O3 详情 详情
(XIV) 32463 (1S,3S,6S,7S,8R,9R)-6-(4-methoxybenzyl)-3-(methylamino)-5-azatricyclo[6.3.1.0(1,5)]dodecane-7,9-diol C20H30N2O3 详情 详情
(XV) 32464 benzyl (1S,3S,6S,7S,8R,9R)-7,9-dihydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate C28H36N2O5 详情 详情
Extended Information