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【结 构 式】 
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【药物名称】 【化学名称】1-beta-D-Arabinofuranosyl-N4-[2-[2-[2-[4-[2-[2-[2-(1-beta-D-arabinofuranosylcytosin-N4-yl)-2-oxoethoxy]ethoxy]ethylamino]-2-[4-[1,2-bis[N-[2-[2-[2-[1-beta-D-arabinofuranosylcytosin-N4-yl]-2-oxoethoxy]ethoxy]ethyl]carbamoyl]ethylamino]-3-[2-(polyethylene glycol)acetamido]succinamido]succinamido]ethoxy]ethoxy]acetyl]cytosine 【CA登记号】 【 分 子 式 】C76H110N19O40 【 分 子 量 】1929.8274 |
【开发单位】Enzon (Originator) 【药理作用】Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, ONCOLYTIC DRUGS, Antimetabolites |
合成路线1
Coupling between N-Boc-aspartic acid (I) and dimethyl aspartate (II) using EDC and DMAP affords tripeptide (III). Subsequent Boc group deprotection in (III) employing trifluoroacetic acid leads to amine (IV).This is then coupled to the polyethyleneglycol-acid (V) producing amide (VI). Basic hydrolysis of the ester groups of (VI) then gives the tetra-carboxylic acid scaffold (VII).
| 【1】 Choe, Y.H.; et al.; Anticancer drug delivery systems: multi-loaded N-4-acyl poly(ethylene glycol) prodrugs of ara-C. II. Efficacy in ascites and solid tumors. J Control Release 2002, 79, 1-3, 55. |
| 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) | 57571 | N-(tert-butoxycarbonyl)aspartic acid | C9H15NO6 | 详情 | 详情 | |
| (II) | 39047 | dimethyl 2-aminosuccinate | C6H11NO4 | 详情 | 详情 | |
| (III) | 57572 | dimethyl 2-[(2-[(tert-butoxycarbonyl)amino]-4-{[3-methoxy-1-(methoxycarbonyl)-3-oxopropyl]amino}-4-oxobutanoyl)amino]succinate | C21H33N3O12 | 详情 | 详情 | |
| (IV) | 57573 | dimethyl 2-[(2-amino-4-{[3-methoxy-1-(methoxycarbonyl)-3-oxopropyl]amino}-4-oxobutanoyl)amino]succinate | C16H25N3O10 | 详情 | 详情 | |
| (V) | 65175 | C4H7O3 | 详情 | 详情 | ||
| (VI) | 65176 | C20H30N3O12 | 详情 | 详情 | ||
| (VII) | 65177 | C16H22N3O12 | 详情 | 详情 |
合成路线2
The Boc-protected amino alcohol (VIII) is condensed with ethyl bromoacetate (IX) in the presence of potassium tert-butoxide to afford ether (X). After alkaline hydrolysis of the ethyl ester group of (X), the resultant carboxylic acid (XI) is activated as the thioimide (XIII) upon treatment with thiazolidine-2-thione (XII) and EDC. Coupling of the acyl thiazolidinone (XIII) with cytosine arabinoside (XIV) leads to the N-acyl cytosine derivative (XV). The Boc protecting group of (XV) is then removed under acidic conditions to furnish amine (XVI).
| 【1】 Choe, Y.H.; et al.; Anticancer drug delivery systems: multi-loaded N-4-acyl poly(ethylene glycol) prodrugs of ara-C. II. Efficacy in ascites and solid tumors. J Control Release 2002, 79, 1-3, 55. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 57574 | tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate | C9H19NO4 | 详情 | 详情 | |
| (IX) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (X) | 57575 | ethyl 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-oate | C13H25NO6 | 详情 | 详情 | |
| (XI) | 57576 | 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-oic acid | C11H21NO6 | 详情 | 详情 | |
| (XII) | 54751 | Thiazolidine-2-thione | C3H5NS2 | 详情 | 详情 | |
| (XIII) | 57577 | tert-butyl 2-{2-[2-oxo-2-(2-thioxo-1,3-thiazolidin-3-yl)ethoxy]ethoxy}ethylcarbamate | C14H24N2O5S2 | 详情 | 详情 | |
| (XIV) | 32709 | Cytarabine; Cytosine Beta-D-Arabinofuranoside; 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 147-94-4 | C9H13N3O5 | 详情 | 详情 |
| (XV) | 57578 | tert-butyl 2-{2-[2-({1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}amino)-2-oxoethoxy]ethoxy}ethylcarbamate | C20H32N4O10 | 详情 | 详情 | |
| (XVI) | 57579 | 2-[2-(2-aminoethoxy)ethoxy]-N-{1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}acetamide | C15H24N4O8 | 详情 | 详情 |
合成路线3
Finally, condensation of the tetra-acid scaffold (VII) with the aminoacyl cytosine prodrug (XVI) gives rise to the title tetra-amide adduct.
| 【1】 Choe, Y.H.; et al.; Anticancer drug delivery systems: multi-loaded N-4-acyl poly(ethylene glycol) prodrugs of ara-C. II. Efficacy in ascites and solid tumors. J Control Release 2002, 79, 1-3, 55. |