【结 构 式】 ![]() |
【药物名称】Palifosfamide tromethamine, IPM-tris, Isophosphoramide tromethamine salt, Palifosfamide-tris, ZIO-201, Zymafos 【化学名称】Phosphorodiamidic acid, N,N'-bis(2-chloroethyl)-, compd. with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1) 【CA登记号】1070409-31-2;31645-39-3 (free acid) 【 分 子 式 】C4H11Cl2N2O2P.C4H11NO3 【 分 子 量 】342.1570 |
【开发单位】ZIOPHARM Oncology, Inc. (US). 【药理作用】DNA-Alkylating Agent, Oncolytic |
合成路线1
The condensation of phenyl dichlorophosphonate (I) with 2-chloroethylamine hydrochloride (II) in the presence of Et3N in cold CH2Cl2 provides phenyl N,N ’-bis(2-chloroethyl)phosphorodiamidate (III), which is finally converted to the corresponding phosphorodiamidic acid by catalytic hydrogenation over PtO2 in EtOH . In an alternative method, acylation of benzyl alcohol (IV) with POCl3 in the presence of Et3N in cold acetonitrile gives benzyl dichlorophosphonate (V), which is further condensed with 2-chloroethylamine hydrochloride (II) in the presence of Et3N to yield benzyl N,N’-bis(2-chloroethyl)phosphorodiamidate (VI). Finally, benzyl ester (VI) is then submitted to hydrogenolysis over Pd/C in acetonitrile .
【1】 Morgan, L. (Dekk-Tec, Inc.). Salts of isophosphoramide mustard and analogs thereof as anti-tumor agents. EP 1805192, JP 2008517929, US 2006089333, US 2008267945, WO 2006047575. |
【2】 Amedio, J.C., Wallner, B.P., Komarnitsky, P.B. (ZIOPHARM Oncology, Inc.). Salts of isophosphoramide mustard and analogs thereof. EP 2155682, JP 2010523571, US 2008255056, WO 2008124097. |
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) | 39640 | Phenyl dichlorophosphate;phenyl phosphorodichloridate | 770-12-7 | C6H5Cl2O2P | 详情 | 详情 |
(II) | 21411 | 2-chloro-1-ethanamine hydrochloride | 870-24-6 | C2H7Cl2N | 详情 | 详情 |
(III) | 39641 | Phenyl N,N'-Bis(2-Chloroethyl)Phosphorodiamidate; 2-Chloroethyl-[(2-Chloroethylamino)-(Phenoxy)Phosphoryl]Amine; Nsc318225 | 70772-68-8 | C10H15Cl2N2O2P | 详情 | 详情 |
(IV) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
(V) | 66026 | Dichlorophosphoryloxymethylbenzene; Phosphorodichloridic acid, phenylmethyl ester | 52692-02-1 | C7H7Cl2O2P | 详情 | 详情 |
(VI) | 66027 | Benzyl N,N'-Bis(2-Chloroethyl)Phosphorodiamidate; 2-Chloroethyl-[(2-Chloroethylamino)-(Benzyloxy)Phosphoryl]Amine | C11H17Cl2N2O2P | 详情 | 详情 |