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【结 构 式】 
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【药物名称】Ambamustine hydrochloride, PTT-119 【化学名称】3-(4-Fluorophenyl)-L-alanyl-3-[3-bis(2-chloroethyl)aminophenyl]-L-alanyl-L-methionine ethyl ester hydrochloride 【CA登记号】83996-50-3, 85754-59-2 (free base) 【 分 子 式 】C29H40Cl3FN4O4S 【 分 子 量 】666.08795 |
【开发单位】Proter (Originator) 【药理作用】ONCOLYTIC DRUGS |
合成路线1
The condensation of N-formyl-4-fluorophenylalanine (I) with 3-[bis(2-chloroethyl)amino]phenylalanine ethyl ester (II) by means of dicyclohexylcarbodiimide in THF gives N-formyl-4-fluoro-L-phenylalanyl-3-[bis(2-chloroethyl)amino]-L-phenylalanine ethyl ester (III), which is saponified with NaOH in DMF water yielding the free acid (IV). The condensation of (IV) with L-methionine ethyl ester (V) by means of N-hydroxysuccinimide and dicyclohexylcarbodiimide in DMF affords N-formyl-4-fluoro-L-phenylalanyl-3-[bis(2-chloroethyl)amino]phenylalanyl-L-methionine ethyl ester (VI), which is finally deprotected by elimination of the formyl group in ethanolic HCl.
| 【1】 De Barbieri, A.; et al.; Synthesis, acute toxicity and chemotherapeutic anti-cancer activities of a new tripeptidic mustard. Farm Sci Ed 1983, 38, 4, 205-218. |
| 【2】 De Barbieri, A.; Compounds of dichlorodiethylaminophenylalanine with anti-tumor activity. EP 0056565; ES 8206449; IT 1134503; JP 57120559; US 4428875 . |
| 【3】 Castaner, J.; Serradell, M.N.; PTT-119. Drugs Fut 1984, 9, 10, 753. |
| 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) | 34301 | (2S)-3-(4-fluorophenyl)-2-(formylamino)propionic acid | C10H10FNO3 | 详情 | 详情 | |
| (II) | 34302 | ethyl (2S)-2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoate | C15H22Cl2N2O2 | 详情 | 详情 | |
| (III) | 34303 | ethyl (2S)-3-[3-[bis(2-chloroethyl)amino]phenyl]-2-[[(2S)-3-(4-fluorophenyl)-2-(formylamino)propanoyl]amino]propanoate | C25H30Cl2FN3O4 | 详情 | 详情 | |
| (IV) | 34304 | (2S)-3-[3-[bis(2-chloroethyl)amino]phenyl]-2-[[(2S)-3-(4-fluorophenyl)-2-(formylamino)propanoyl]amino]propionic acid | C23H26Cl2FN3O4 | 详情 | 详情 | |
| (V) | 34305 | ethyl (2S)-2-amino-4-(methylsulfanyl)butanoate | C7H15NO2S | 详情 | 详情 | |
| (VI) | 34306 | ethyl (2S)-2-[((2S)-3-[3-[bis(2-chloroethyl)amino]phenyl]-2-[[(2S)-3-(4-fluorophenyl)-2-(formylamino)propanoyl]amino]propanoyl)amino]-4-(methylsulfanyl)butanoate | C30H39Cl2FN4O5S | 详情 | 详情 |