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【结 构 式】 
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【分子编号】35815 【品名】ethyl 4-(5-[4-[ethoxy(imino)methyl]phenyl]-2-furyl)benzenecarboximidoate 【CA登记号】 |
【 分 子 式 】C22H22N2O3 【 分 子 量 】362.42836 【元素组成】C 72.91% H 6.12% N 7.73% O 13.24% |
合成路线1
该中间体在本合成路线中的序号：(V)The reaction of furan (I) with BuLi and Bu3Sn-Cl gives the bis tributyltin derivative (II), which is condensed with 4-bromobenzonitrile (III) by means of Pd(PPh3)4 in dioxane to yield 4,4'-(furan-2,5-diyl)-bis(benzonitrile) (IV). The reaction of (IV) with HCl and ethanol affords 4,4'-(furan-2,5-diyl)bis(ethyl benzimidate) (V), which is finally treated with O-methylhydroxylamine in ethanol to provide the target bis-O-methyl benzamidoxime.
| 【1】 McChesney-Harris, L.; et al.; Synthesis, characterization, and formulation of DB289, a novel dication prodrug for the treatment of African sleeping sickness and Pneumocystis carinii pneumonia (PCP). 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-2162. |
| 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) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (II) | 51325 | 2-[3-(3,4-dichlorophenyl)-1-[2-(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl methanesulfonate | C25H31Cl2NO5S | 详情 | 详情 | |
| (III) | 45833 | 4-Bromobenzonitrile | 623-00-7 | C7H4BrN | 详情 | 详情 |
| (IV) | 35814 | 4-[5-(4-cyanophenyl)-2-furyl]benzonitrile | C18H10N2O | 详情 | 详情 | |
| (V) | 35815 | ethyl 4-(5-[4-[ethoxy(imino)methyl]phenyl]-2-furyl)benzenecarboximidoate | C22H22N2O3 | 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 Friedel Crafts condensation of fumaryl chloride (I) with bromobenzene (II) gives 1,2-bis(4-bromobenzoyl)ethylene (III), which is reduced with Zn and Ac-OH to yield 1,4-bis(4-bromophenyl)butane-1,4-dione (IV). The cyclization of (IV) in refluxing Ac2O affords 2,5-bis(4-bromophenyl)furan (V), which is treated with CNCu in refluxing quinoline to provide 2,5-bis(4-cyanophenyl)furan (VI). The reaction of (VI) with HCl in ethanol gives the bis imidate (VII), which is finally treated with O-methylhydroxylamine to yield the target bis O-methylamidooxime.
| 【3】 Tidwell, R.R.; Hall, J.E.; Kumar, A.; Dykstra, C.C.; Boykin, D.W.; Wilson, W.D.; Blagburn, B.L. (Auburn University; Georgia State University; University of North Carolina); Furan derivs. for inhibiting Pneumocystis carinii pneumonia, Giardia lamblia and Cryptosporidium parvum. WO 9615126 . |
| 【1】 Boykin, D.W.; et al.; Anti-pneumocystis activity of bis-amidoximes and bis-O-alkylamidoximes prodrugs. Bioorg Med Chem Lett 1996, 6, 24, 3017. |
| 【2】 Boykin, D.W.; et al.; 2,5-Bis[4-(N-alkylamidino)phenyl]furans as anti-Pneumocystis carinii agents. J Med Chem 1998, 41, 1, 124. |
| 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) | 57909 | Fumaryl chloride | 627-63-4 | C4H2Cl2O2 | 详情 | 详情 |
| (II) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (III) | 57910 | (E)-1,4-bis(4-bromophenyl)-2-butene-1,4-dione | C16H10Br2O2 | 详情 | 详情 | |
| (IV) | 35811 | 1,4-bis(4-bromophenyl)-1,4-butanedione | C16H12Br2O2 | 详情 | 详情 | |
| (V) | 35812 | 2,5-bis(4-bromophenyl)furan | C16H10Br2O | 详情 | 详情 | |
| (VI) | 35814 | 4-[5-(4-cyanophenyl)-2-furyl]benzonitrile | C18H10N2O | 详情 | 详情 | |
| (VII) | 35815 | ethyl 4-(5-[4-[ethoxy(imino)methyl]phenyl]-2-furyl)benzenecarboximidoate | C22H22N2O3 | 详情 | 详情 | |
| (VIII) | 15455 | (aminooxy)methane; O-methylhydroxylamine | 67-62-9 | CH5NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The Friedel Crafts condensation of fumaryl chloride (I) with bromobenzene (II) gives 1,2-bis(4-bromobenzoyl)ethylene (III), which is reduced with Zn and Ac-OH to yield 1,4-bis(4-bromophenyl)butane-1,4-dione (IV). The cyclization of (IV) in refluxing Ac2O affords 2,5-bis(4-bromophenyl)furan (V) which is treated with CNCu in refluxing quinoline to provide 2,5-bis(4-cyanophenyl)furan (VI). The reaction of (VI) with HCl in ethanol gives the bis imidate (VII), which is finally treated with ammonia in ethanol to yield the target bis benzamidine.
| 【1】 Dann, O.; et al.; Trypanocidal diamidines with three isolated ring systems. Liebigs Ann Chem 1975, 1, 160. |
| 【2】 Das, B.P.; Boykin, D.W.; Synthesis and antiprotozoal activity of 2,5-bis (4-guanylphenyl) furans. J Med Chem 1977, 20, 4, 531-536. |
| 【3】 Boykin, D.W.; et al.; 2,5-Bis[4-(N-alkylamidino)phenyl]furans as anti-Pneumocystis carinii agents. J Med Chem 1998, 41, 1, 124. |
| 【4】 Boykin, D.W.; et al.; Anti-pneumocystis activity of bis-amidoximes and bis-O-alkylamidoximes prodrugs. Bioorg Med Chem Lett 1996, 6, 24, 3017. |
| 【5】 Niigata, K.; Murakami, M.; Kagami, S.; Fujikura, S.; Kojima, A.; Tachikawa, S.; Nozaki, J.; Takahashi, K. (Yamanouchi Pharmaceutical Co., Ltd.); Novel indene derivs. or their salts. JP 1977111580 . |
| 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) | 57909 | Fumaryl chloride | 627-63-4 | C4H2Cl2O2 | 详情 | 详情 |
| (II) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (III) | 57910 | (E)-1,4-bis(4-bromophenyl)-2-butene-1,4-dione | C16H10Br2O2 | 详情 | 详情 | |
| (IV) | 35811 | 1,4-bis(4-bromophenyl)-1,4-butanedione | C16H12Br2O2 | 详情 | 详情 | |
| (V) | 35812 | 2,5-bis(4-bromophenyl)furan | C16H10Br2O | 详情 | 详情 | |
| (VI) | 56856 | Copper (I) cyanide; Cuprous cyanide | 544-92-3 | CCuN | 详情 | 详情 |
| (VII) | 35814 | 4-[5-(4-cyanophenyl)-2-furyl]benzonitrile | C18H10N2O | 详情 | 详情 | |
| (VIII) | 35815 | ethyl 4-(5-[4-[ethoxy(imino)methyl]phenyl]-2-furyl)benzenecarboximidoate | C22H22N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)2,5-Bis(p-bromophenyl)furan (II) was prepared by cyclodehydration of diketone (I) in refluxing acetic anhydride. Displacement of both bromine atoms by copper(I) cyanide in boiling quinoline generated the dicyano derivative (V). Alternatively, furan (V) was prepared by addition of p-cyanobenzaldehyde (III) to divinyl sulfone (IV) in the presence of a thiazolium catalyst. After conversion of the cyano groups of (V) into bis-imidate (VI), reaccion with ethanolic ammonia furnished amidine (VII). The stable symmetrical carbonate (X) was obtained by reaction of p-fluorophenyl chloroformate (VIII) with p-fluorophenol (IX) in the presence of pyridine. Finally, reaction of the bis(amidine) compound (VII) with carbonate (X) yielded the title compound.
| 【1】 Kawada, A.; Aragane, Y.; Maeda, A.; Tezuka, T.; Heterocycl Commun 1996, 2, 2, 135-140. |
| 【2】 Das, B.P.; Boykin, D.W.; Synthesis and antiprotozoal activity of 2,5-bis (4-guanylphenyl) furans. J Med Chem 1977, 20, 4, 531-536. |
| 【3】 Rahmathullah, S.M.; et al.; Prodrugs for amidines: Synthesis and anti-Pneumocystis carinii activity of carbamates of 2,5-bis(4-amidinophenyl)furan. J Med Chem 1999, 42, 19, 3994. |
| 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) | 35811 | 1,4-bis(4-bromophenyl)-1,4-butanedione | C16H12Br2O2 | 详情 | 详情 | |
| (II) | 35812 | 2,5-bis(4-bromophenyl)furan | C16H10Br2O | 详情 | 详情 | |
| (III) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
| (IV) | 35813 | divinyl sulfone; dioxo(divinyl)-lambda(6)-sulfane | 77-77-0 | C4H6O2S | 详情 | 详情 |
| (V) | 35814 | 4-[5-(4-cyanophenyl)-2-furyl]benzonitrile | C18H10N2O | 详情 | 详情 | |
| (VI) | 35815 | ethyl 4-(5-[4-[ethoxy(imino)methyl]phenyl]-2-furyl)benzenecarboximidoate | C22H22N2O3 | 详情 | 详情 | |
| (VII) | 35816 | 4-(5-[4-[amino(imino)methyl]phenyl]-2-furyl)benzenecarboximidamide | C18H16N4O | 详情 | 详情 | |
| (VIII) | 35817 | 1-[(chlorocarbonyl)oxy]-4-fluorobenzene | 38377-38-7 | C7H4ClFO2 | 详情 | 详情 |
| (IX) | 19639 | 4-fluorophenol | 371-41-5 | C6H5FO | 详情 | 详情 |
| (X) | 35818 | bis(4-fluorophenyl) carbonate | C13H8F2O3 | 详情 | 详情 |