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【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information