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【结 构 式】 
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【药物名称】ANG-615 【化学名称】N-[5-[4-(L-Alanylamino)phenylsulfanyl]-1H-benzimidazol-2-yl]carbamic acid methyl ester 【CA登记号】284019-34-7 【 分 子 式 】C18H19N5O3S 【 分 子 量 】385.44783 |
【开发单位】Angiogene Pharmaceuticals (Originator) 【药理作用】ONCOLYTIC DRUGS, Angiogenesis Inhibitors |
合成路线1
The condensation between 4-(acetylamino)thiophenol (I) and 5-chloro-2-nitroaniline (II) produced the diaryl sulfide (III). Nitro group reduction in (III) employing SnCl2 gave the phenylenediamine (IV), which was cyclized to the benzimidazole (VI) upon treatment with N,N'-bis(methoxycarbonyl)-S-methylisothiourea (V). Hydrolysis of the acetamido group of (VI) with HCl in MeOH afforded aniline (VII). This was acylated with N-Boc-alanine (VIII) in the presence of EDC to yield amide (IX). The N-Boc protecting group of (IX) was finally removed by treatment with trifluoroacetic acid.
| 【1】 Lewis, G.S.; Nolan, J.; Davis, P.D.; Naylor, M.A.; Thomson, P.; Hill, S.A.; Benzimidazole carbamates: A new structural class of vascular targeting agents. Proc Amer Assoc Cancer Res 2001, 42, Abst 2000. |
| 【2】 Davis, P.D. (Angiogene Pharmaceuticals Ltd.); Benzimidazole vascular damaging agents. EP 1140078; WO 0041669 . |
| 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) | 34329 | N-(4-sulfanylphenyl)acetamide | 1126-81-4 | C8H9NOS | 详情 | 详情 |
| (II) | 15709 | 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline | 1635-61-6 | C6H5ClN2O2 | 详情 | 详情 |
| (III) | 51869 | N-[4-[(3-amino-4-nitrophenyl)sulfanyl]phenyl]acetamide | C14H13N3O3S | 详情 | 详情 | |
| (IV) | 51870 | N-[4-[(3,4-diaminophenyl)sulfanyl]phenyl]acetamide | C14H15N3OS | 详情 | 详情 | |
| (V) | 28696 | methyl (Z)-[(methoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C6H10N2O4S | 详情 | 详情 | |
| (VI) | 51871 | methyl 5-[[4-(acetamido)phenyl]sulfanyl]-1H-benzimidazol-2-ylcarbamate | C17H16N4O3S | 详情 | 详情 | |
| (VII) | 51872 | methyl 5-[(4-aminophenyl)sulfanyl]-1H-benzimidazol-2-ylcarbamate | C15H14N4O2S | 详情 | 详情 | |
| (VIII) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (IX) | 51873 | methyl 5-[[4-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)phenyl]sulfanyl]-1H-benzimidazol-2-ylcarbamate | C23H27N5O5S | 详情 | 详情 |