【结 构 式】 |
【分子编号】39641 【品名】Phenyl N,N'-Bis(2-Chloroethyl)Phosphorodiamidate; 2-Chloroethyl-[(2-Chloroethylamino)-(Phenoxy)Phosphoryl]Amine; Nsc318225 【CA登记号】70772-68-8 |
【 分 子 式 】C10H15Cl2N2O2P 【 分 子 量 】297.120542 【元素组成】C 40.42% H 5.09% Cl 23.86% N 9.43% O 10.77% P 10.42% |
合成路线1
该中间体在本合成路线中的序号:(II)In the first reaction step phenyl phosphate dichloride (I) and 2-chloroethylamine hydrochloride are reacted in dichloromethane with triethylamine as base to give phenyl N,N'-di-(2-chloroethyl)phosphoric acid diamide (II). Hydrogenation of compound (II) with platinic oxide/hydrogen in methanol yields N,N'-di-(2-chloroethyl)phosphoric acid diamide (III), which directly crystallizes in the methanolic solution. 2,3,4,6-6-Tetra-O-benzyl-alpha-D-glucopyranose (IV) and trichloroacetonitrile react in ethyl acetate with sodium hydride as catalyst to yield O-(2,3,4,6-tetra-O-benzyl-alpha-D-glucopyranosyl) trichloroacetimidate (V). A mixture of the imidate (V) and compound (III) in ethyl acetate is warmed up to 60 C. After filtration and concentration, 2,3,4,6-tetra-O-benzyl-beta-D-glucopyranosyl N,N'-di-(2-chloroethyl)phosphoric acid diamide (VI) crystallizes. Finally, compound (VI) is hydrogenated with palladium catalyst in acetone/water (80:20) to give beta-D-glucopyranosyl N,N'-di-(2-chloroethyl)phosphoric acid diamide. The solution is filtered and concentrated. The residual water is lyophilisated and the lyophilisate is crystallized in acetone/water.
【1】 Niemeyer, U.; Peter, G.; Schuessler, M.; Voss, A.; Schupke, H.; Klenner, T.; Wiessler, M.; Engel, J.; Glufosfamide. Drugs Fut 2000, 25, 8, 791. |
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) | 39641 | Phenyl N,N'-Bis(2-Chloroethyl)Phosphorodiamidate; 2-Chloroethyl-[(2-Chloroethylamino)-(Phenoxy)Phosphoryl]Amine; Nsc318225 | 70772-68-8 | C10H15Cl2N2O2P | 详情 | 详情 |
(III) | 39642 | N,N'-bis(2-chloroethyl)phosphorodiamidic acid | C4H11Cl2N2O2P | 详情 | 详情 | |
(IV) | 30843 | (2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-ol | C34H36O6 | 详情 | 详情 | |
(V) | 39643 | (2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl 2,2,2-trichloroethanimidoate | C36H36Cl3NO6 | 详情 | 详情 | |
(VI) | 39644 | C38H45Cl2N2O7P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(III)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 |