Perzinfotel, WAY-126090, EAA-090, -Drug Synthesis Database

【结构式】

【药物名称】Perzinfotel, WAY-126090, EAA-090

【化学名称】2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethylphosphonic acid

【CA登记号】144912-63-0

【分子式】C₉H₁₃N₂O₅P

【分子量】260.18816

【开发单位】Wyeth Pharmaceuticals (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Cerebrovascular Diseases, Treatment of, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Neuropathic Pain, Treatment of, Stroke, Treatment of, NMDA Antagonists

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

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.

参考文献中间体

【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

Drug NewChemical Entity Original Patent(1)