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【结 构 式】 
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【药物名称】Dendroamide A 【化学名称】(4R,11R,18R)-11-Isopropyl-4,7,18-trimethyl-6-oxa-13,20-dithia-3,10,17,22,23,24-hexaazatetracyclo[17.2.1.1(5,8).1(12,15)]tetracosa-1(21),5(24),7,12(23),14,19(22)-hexaene-2,9,16-trione 【CA登记号】176666-84-5 【 分 子 式 】C21H24N6O4S2 【 分 子 量 】488.59123 |
【开发单位】Fox Chase Cancer Center (Originator) 【药理作用】Modulators of the Therapeutic Activity of Antineoplastic Agents, Multidrug Resistance Modulators, ONCOLYTIC DRUGS |
合成路线1
The heterocyclic amino acid precursor (VI) was synthesized as follows. Coupling between N-Boc-D-alanine (I) and L-threonine methyl ester (II) in the presence of DCC and HOBt gave dipeptide (III). Cyclization of (III) using Burgess reagent provided the oxazoline (IV) as a mixture of diastereoisomers. Subsequent dehydrogenation of (IV) by means of bromotrichloromethane and DBU afforded the protected oxazole amino acid (V). Basic hydrolysis of the ethyl ester group then yielded the intermediate acid (VI).
| 【1】 Xia, Z.; Smith, C.D.; Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J Org Chem 2001, 66, 10, 3459. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 48360 | methyl (4S,5R)-2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C13H22N2O5 | 详情 | 详情 | |
| (IVb) | 48361 | methyl (4S,5S)-2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C13H22N2O5 | 详情 | 详情 | |
| (I) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (II) | 42026 | methyl (2S,3R)-2-amino-3-hydroxybutanoate | C5H11NO3 | 详情 | 详情 | |
| (III) | 48359 | methyl (2S,3R)-2-([(2R)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-3-hydroxybutanoate | C13H24N2O6 | 详情 | 详情 | |
| (V) | 48362 | methyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-1,3-oxazole-4-carboxylate | C13H20N2O5 | 详情 | 详情 | |
| (VI) | 48363 | 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-1,3-oxazole-4-carboxylic acid | C12H18N2O5 | 详情 | 详情 |
合成路线2
N-Boc-D-alanine (VII) was converted into amide (VIII) via activation as the corresponding mixed anhydride with isobutyl chloroformate. Treatment of amide (VIII) with Lawesson’s reagent gave thioamide (IX). Coupling of (IX) with ethyl bromopyruvate (X) produced the intermediate hydroxythiazoline (XI), which was further dehydrated using trifluoroacetic anhydride to afford the fully protected thiazole amino acid (XII). Removal of the Boc protecting group of (XII) to give (XIII) was achieved by treatment with either trifluoroacetic acid or acetyl chloride in EtOH.
| 【1】 Xia, Z.; Smith, C.D.; Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J Org Chem 2001, 66, 10, 3459. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (VIII) | 46750 | tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate | C8H16N2O3 | 详情 | 详情 | |
| (IX) | 48364 | tert-butyl (1R)-2-amino-1-methyl-2-thioxoethylcarbamate | C8H16N2O2S | 详情 | 详情 | |
| (X) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (XI) | 48365 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-4-hydroxy-4,5-dihydro-1,3-thiazole-4-carboxylate | C13H22N2O5S | 详情 | 详情 | |
| (XII) | 48366 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-1,3-thiazole-4-carboxylate | C13H20N2O4S | 详情 | 详情 | |
| (XIII) | 48367 | ethyl 2-[(1R)-1-aminoethyl]-1,3-thiazole-4-carboxylate | C8H12N2O2S | 详情 | 详情 |
合成路线3
The thiazole amino acid (XIX) was prepared by a similar method as above, consisting of conversion of N-Boc-D-valine (XIV) to the corresponding amide (XV) followed by thionation to (XVI). Condensation of thioamide (XVI) with ethyl bromopyruvate (X) and subsequent acid dehydration gave thiazole (XVIII). Basic hydrolysis of the ethyl ester group of (XVIII) then gave acid (XIX). Coupling of the N-Boc-amino acid (XIX) with aminoester (XIII) produced the corresponding amide (XX). Further acid cleavage of the Boc protecting group gave (XXI).
| 【1】 Xia, Z.; Smith, C.D.; Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J Org Chem 2001, 66, 10, 3459. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (XIII) | 48367 | ethyl 2-[(1R)-1-aminoethyl]-1,3-thiazole-4-carboxylate | C8H12N2O2S | 详情 | 详情 | |
| (XIV) | 48375 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XV) | 48368 | tert-butyl (1R)-1-(aminocarbonyl)-2-methylpropylcarbamate | C10H20N2O3 | 详情 | 详情 | |
| (XVI) | 48369 | tert-butyl (1R)-1-(aminocarbothioyl)-2-methylpropylcarbamate | C10H20N2O2S | 详情 | 详情 | |
| (XVII) | 48370 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-4-hydroxy-4,5-dihydro-1,3-thiazole-4-carboxylate | C15H26N2O5S | 详情 | 详情 | |
| (XVIII) | 48371 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-1,3-thiazole-4-carboxylate | C15H24N2O4S | 详情 | 详情 | |
| (XIX) | 48372 | 2-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-1,3-thiazole-4-carboxylic acid | C13H20N2O4S | 详情 | 详情 | |
| (XX) | 48373 | ethyl 2-((1R)-1-[[(2-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-1,3-thiazol-4-yl)carbonyl]amino]ethyl)-1,3-thiazole-4-carboxylate | C21H30N4O5S2 | 详情 | 详情 | |
| (XXI) | 48374 | ethyl 2-[(1R)-1-[([2-[(1R)-1-amino-2-methylpropyl]-1,3-thiazol-4-yl]carbonyl)amino]ethyl]-1,3-thiazole-4-carboxylate | C16H22N4O3S2 | 详情 | 详情 |
合成路线4
The intermediate acid (VI) was then coupled to amine (XXI) to furnish (XXII). Sequential deprotection of the ethyl ester and the N-Boc protecting groups of (XXII) produced the linear precursor (XXIV). This was finally cyclized to the title compound using DPPA.
| 【1】 Xia, Z.; Smith, C.D.; Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J Org Chem 2001, 66, 10, 3459. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 48363 | 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-1,3-oxazole-4-carboxylic acid | C12H18N2O5 | 详情 | 详情 | |
| (XXI) | 48374 | ethyl 2-[(1R)-1-[([2-[(1R)-1-amino-2-methylpropyl]-1,3-thiazol-4-yl]carbonyl)amino]ethyl]-1,3-thiazole-4-carboxylate | C16H22N4O3S2 | 详情 | 详情 | |
| (XXII) | 48376 | ethyl 2-[(1R)-1-([[2-((1R)-1-[[(2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-1,3-oxazol-4-yl)carbonyl]amino]-2-methylpropyl)-1,3-thiazol-4-yl]carbonyl]amino)ethyl]-1,3-thiazole-4-carboxylate | C28H38N6O7S2 | 详情 | 详情 | |
| (XXIII) | 48377 | 2-[(1R)-1-([[2-((1R)-1-[[(2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-1,3-oxazol-4-yl)carbonyl]amino]-2-methylpropyl)-1,3-thiazol-4-yl]carbonyl]amino)ethyl]-1,3-thiazole-4-carboxylic acid | C26H34N6O7S2 | 详情 | 详情 | |
| (XXIV) | 48378 | 2-((1R)-1-[[(2-[(1R)-1-[([2-[(1R)-1-aminoethyl]-5-methyl-1,3-oxazol-4-yl]carbonyl)amino]-2-methylpropyl]-1,3-thiazol-4-yl)carbonyl]amino]ethyl)-1,3-thiazole-4-carboxylic acid | C21H26N6O5S2 | 详情 | 详情 |