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【结 构 式】 
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【药物名称】Tryprostatin B, TPS-B 【化学名称】(3S,8aS)-3-[2-(3-Methyl-2-butenyl)-1H-indol-3-ylmethyl]perhydropyrrolo[1,2-a]pyrazine-1,4-dione 【CA登记号】 【 分 子 式 】C21H25N3O2 【 分 子 量 】351.4523 |
【开发单位】 【药理作用】ONCOLYTIC DRUGS |
合成路线1
The compound was originally isolated from Aspergillus fumigatus. The synthesis of this compound was further described. Treatment of N-phthaloyltryptophan methyl ester (I) with tert-butyl hypochlorite and triethylamine at -78 C led to the formation of the intermediate 3-chloroindolenine (II). Reaction of tributyl prenyl stannane (III) with boron trichloride generated in situ the transient boron reagent (IV), which after condensation with chloroindolenine (II) produced the 3-prenylindole (V). Subsequent removal of the phthalimide protecting group of (V) by hydrazinolysis provided aminoester (VI). Coupling of (VI) with acid fluoride (VIII), (generated from N-Boc-L-proline (VII) and cyanuric fluoride), gave rise to amide (IX). The Boc protecting group of (IX) was cleaved employing iodotrimethylsilane, and the resulting aminoester (X) was then cyclized with methanolic ammonia to produce the target diketopiperazine.
| 【1】 Schkeryantz, J.M.; et al.; Total synthesis of gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin B: Novel constructions of 2,3-disubstituted indoles. J Am Chem Soc 1999, 121, 51, 11964. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 26782 | Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine | 675-14-9 | C3F3N3 | 详情 | 详情 |
| (I) | 31493 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(1H-indol-3-yl)propanoate | C20H16N2O4 | 详情 | 详情 | |
| (II) | 31494 | methyl (2S)-3-(3-chloro-3H-indol-3-yl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate | C20H15ClN2O4 | 详情 | 详情 | |
| (III) | 31502 | tributyl(3-methyl-2-butenyl)stannane | C17H36Sn | 详情 | 详情 | |
| (IV) | 31503 | dichloro(1,1-dimethyl-2-propenyl)borane | C5H9BCl2 | 详情 | 详情 | |
| (V) | 31504 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate | C25H24N2O4 | 详情 | 详情 | |
| (VI) | 31505 | methyl (2S)-2-amino-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate | C17H22N2O2 | 详情 | 详情 | |
| (VII) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (VIII) | 31506 | tert-butyl (2S)-2-(fluorocarbonyl)-1-pyrrolidinecarboxylate | C10H16FNO3 | 详情 | 详情 | |
| (IX) | 31507 | tert-butyl (2S)-2-[[((1S)-2-methoxy-1-[[2-(3-methyl-2-butenyl)-1H-indol-3-yl]methyl]-2-oxoethyl)amino]carbonyl]-1-pyrrolidinecarboxylate | C27H37N3O5 | 详情 | 详情 | |
| (X) | 31508 | methyl (2S)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoate | C22H29N3O3 | 详情 | 详情 |
合成路线2
The esterification of the silylated resin (II) with the prenyltryptophan derivative (I) by means of HATU, OBT and DIEA in DMF gives the resin-bonded ester (III), which is treated with hydrazine in methanol/dichloromethane to eliminate the protecting phthalimido group and yield the resin-bonded tryptophan ester derivative (IV). The condensation of (IV) with N-(Fmoc)-L-proline (V) by means of HATU, HOBT and DIEA in DMF affords the dipeptide (VI), which is treated with piperidine in N-methylpyrrolidine to eliminate the Fmoc protecting group and yield dipeptide ester (VII). Finally, this compound is submitted to an acid-induced cyclization by means of HOAc in refluxing methanol to afford the target bicyclic diketopiperazine.
| 【1】 Wang, B.B.; et al.; Preparation of novel 2-(trialkylsilyl)ethyl linkers and first synthesis of Tryprostatin B on solid phase. Tetrahedron Lett 2001, 42, 8, 1463. |
| 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) | 50024 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propionic acid | C24H22N2O4 | 详情 | 详情 | |
| (II) | 50025 | 2-[dimethyl(phenyl)silyl]-1-ethanol | C10H16OSi | 详情 | 详情 | |
| (III) | 50026 | 2-[dimethyl(phenyl)silyl]ethyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate | C34H36N2O4Si | 详情 | 详情 | |
| (IV) | 50027 | 2-[dimethyl(phenyl)silyl]ethyl (2S)-2-amino-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate | C26H34N2O2Si | 详情 | 详情 | |
| (V) | 34762 | (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid | 71989-31-6 | C20H19NO4 | 详情 | 详情 |
| (VI) | 50028 | 9H-fluoren-9-ylmethyl (2S)-2-[[((1S)-2-[2-[dimethyl(phenyl)silyl]ethoxy]-1-[[2-(3-methyl-2-butenyl)-1H-indol-3-yl]methyl]-2-oxoethyl)amino]carbonyl]-1-pyrrolidinecarboxylate | C46H51N3O5Si | 详情 | 详情 | |
| (VII) | 50029 | 2-[dimethyl(phenyl)silyl]ethyl (2S)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoate | C31H41N3O3Si | 详情 | 详情 |