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【结 构 式】

【分子编号】54142

【品名】diethyl 2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethylphosphonate

【CA登记号】n/a

【 分 子 式 】C13H21N2O5P

【 分 子 量 】316.293982

【元素组成】C 49.37% H 6.69% N 8.86% O 25.29% P 9.79%

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:(IV)

Combining (3-aminopropyl)carbamic acid benzyl ester (CBZ-protected propylene diamine) (I) with 2-oxoethylphosphonic acid diethyl ester under reductive amination conditions in the presence of sodium cyanoborohydride gives the CBZ-protected phosphonoethyl-substituted propylene diamine (II). The condensation of (II) with 3,4-diethoxy-3-cyclobutene-1,2-dione at room temperature in ethanol leads to the squaric acid analog (III). Removal of the CBZ protecting group under catalytic transfer hydrogenation conditions followed by spontaneous cyclization provides the penultimate diethylphosphonate ester (IV), which is hydrolyzed in the presence of bromotrimethylsilane in refluxing 1,2-dichloroethane to yield the final product in 15% overall yield.

1 Zaleska, M.M.; Childers, W.E. Jr.; Abou-Gharbia, M.A.; Moyer, J.A.; EAA-090. Drugs Fut 2002, 27, 7, 633.
2 Kowal, D.M.; Abou-Gharbia, M.; Schmid, J.; Bramlett, D.R.; Miller, T.L.; Tasse, R.P.; Zaleska, M.M.; Moyer, J.A.; Garrison, D.T.; Kinney, W.A.; Design and synthesis of [2-(8,9-dioxo-2, 6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-cyclobutene-1,2-dione as an achiral alpha-amino acid bioisostere. J Med Chem 1998, 41, 2, 236.
3 Kinney, W.A.; Garrison, D.C. (Wyeth); [[(2-Amino-3, 4-dioxo-1-cyclo-buten-1-yl)amino]alkyl]-acid derivs.. EP 0496561; JP 1992321654; US 5168103 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
30975 3,4-diethoxy-3-cyclobutene-1,2-dione 5231-87-8 C8H10O4 详情 详情
31516 1,4-cyclohexadiene 628-41-1 C6H8 详情 详情
54139 Diethyl (formylmethyl)phosphonate 1606-75-3 C6H13O4P 详情 详情
(I) 54138 ethyl 3-aminopropylcarbamate n/a C6H14N2O2 详情 详情
(II) 54140 diethyl 2-({3-[(ethoxycarbonyl)amino]propyl}amino)ethylphosphonate n/a C12H27N2O5P 详情 详情
(III) 54141 diethyl 2-[{3-[(ethoxycarbonyl)amino]propyl}(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]ethylphosphonate n/a C18H31N2O8P 详情 详情
(IV) 54142 diethyl 2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethylphosphonate n/a C13H21N2O5P 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VII)

The monoprotection of propane-1,3-diamine (I) with Boc2O in dichloromethane gives the N-(3-aminopropyl)carbamic acid tert-butyl ester (II), which is condensed with vinylphosphonic acid diethyl ester (III) to yield the aminoethylphosphonic ester derivative (IV). The condensation of (IV) with 3,4-diethoxycyclobutene-1,2-dione (V) in ethanol affords the disubstituted 2-aminoethylphosphonic ester derivative (VI), which is cyclized by means of trifluoroacetic acid in dichloromethane to provide the bicyclic phosphonic ester (VII). Finally, the phosphonic ester group of (VII) is hydrolyzed by means of trimethylsilyl bromide in dichloromethane to furnish the target phosphonic acid.

1 Kinney, W.A.; Schmid, J.; Asselin, A.A. (Wyeth); Process for the preparation of [2-((8.9)-dioxo-2,6-diazabicyclo[5.2.0]-non-1(7)-en-2-yl)ethyl]phosphonic acid. US 5990307 .
2 Kinney, W.A.; Schmid, J.; Asselin, A.A. (Wyeth); Process for the preparation of [2-((8,9)-dioxo-2,6-diazabicyclo[5.2.0]-non-1(7)-en-2-yl)-ethyl]phosphonic acid. WO 9906417 .
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) 19331 3-aminopropylamine; 1,3-propanediamine 109-76-2 C3H10N2 详情 详情
(II) 52474 1,1-dimethylethyl 3-aminopropylcarbamate C8H18N2O2 详情 详情
(III) 54644 diethyl vinylphosphonate C6H13O3P 详情 详情
(IV) 54645 diethyl 2-({3-[(tert-butoxycarbonyl)amino]propyl}amino)ethylphosphonate C14H31N2O5P 详情 详情
(V) 30975 3,4-diethoxy-3-cyclobutene-1,2-dione 5231-87-8 C8H10O4 详情 详情
(VI) 54646 diethyl 2-[{3-[(tert-butoxycarbonyl)amino]propyl}(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]ethylphosphonate C20H35N2O8P 详情 详情
(VII) 54142 diethyl 2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethylphosphonate n/a C13H21N2O5P 详情 详情
Extended Information