Journal of Medicinal Chemistry p. 366 - 374 (1987)
Update date:2022-08-11
Topics:
Boyd, Victoria L.
Summers, Michael F.
Ludeman, Susan Marie
Egan, William
Zon, Gerald
Regan, Judith B.
4-Hydroxy-5,5-dimethylcyclophosphamide (6) was synthesized as a stable (to fragmentation) analogue of 4-hydroxycyclophosphamide (1).In anhydrous Me2SO-d6 (<*>0.03 mol percent water), cis- and trans-6 were observed by multinuclear NMR spectroscopy to equlibrate with α,α-dimethylaldophosphamide (7) and 5,5-dimethyliminocyclophosphamide (8).Identification of 8 was based on 1H, 13C, and 31P chemical shifts, selective INEPT and two-dimensional NMR correlation experiments, and temperature-dependent equilibria data.The interconversion of cis-/trans-6 and -7 was also observed in lutidine buffer; 8 was not detected under the aqueous conditions.In Me2SO-d6, hydroxy metabolite 1 underwent dehydration to give iminocyclophosphamide (5), as evidenced by chemical shift data and a selective INEPT experiment.Concentrations of cis-/trans-1, aldophosphamide (2), and 5 were found to be temperature-dependent with higher temperatures favoring 2 and 5 in a reversible manner, thus indicating that 1/2/5 were interconverting.The addition of small amount of water to Me2SO-d6 solutions of imine 5 resulted in the immediate disappearance of its NMR signals.The role of imine 5 in the conversion of 1 to C-4 substituted analogues of 1 was elucidated for the formation of 4-cyanocyclophosphamide (3a) from 1 and sodium cyanate in lutidine buffer.
View MoreContact:+86-25-52346955
Address:199,JIANYE ROAD,NANJING,CHINA
Shanghai Maxchemco Chemical Industry Co., Ltd.
Contact:(86)21-51079223
Address:No.1305-8, B241, the Ecust Park, Huajing Road, Xuhui District, Shanghai
Contact:0512-62706911
Address:No.289 Yinzhong South Road Wuzhong Economic Development District,Suzhou,China
Beyond Pharmaceutical Co., Ltd
Contact:+86-571-8195-3185
Address:No. 13-1, Liansheng Road, Yuhang District
Contact:(86) 731 88718666
Address:Room 1222, Unit 4, Building B, Shangcheng, No.47, Kaiyuan East Road.
Doi:10.1002/chem.201700333
(2017)Doi:10.1016/S0040-4039(00)76214-9
(1994)Doi:10.1007/s10562-020-03417-3
(2021)Doi:10.1016/S0040-4020(02)00901-8
(2002)Doi:10.1016/j.jmmm.2009.08.028
(2010)Doi:10.1039/DT9960000899
(1996)