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【结 构 式】 
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【分子编号】45833 【品名】4-Bromobenzonitrile 【CA登记号】623-00-7 |
【 分 子 式 】C7H4BrN 【 分 子 量 】182.0195 【元素组成】C 46.19% H 2.22% Br 43.9% N 7.7% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(VI)Methylation of (4-bromophenyl)acetonitrile (I) to afford 2-(4-bromophenyl)propionitrile (III) was carried out by heating with K2CO3 and dimethyl carbonate at 180 C in a sealed vessel. Alternatively, nitrile (III) was obtained by treatment of 4'-bromoacetophenone (II) with tosylmethyl isocyanide and potassium tert-butoxide. Nitrile (III) was reduced to amine (IV) using borane-dimethyl sulfide complex. Condensation of this amine with isopropylsulfonyl chloride furnished the corresponding sulfonamide (V). 4-Cyanophenylboronic acid (VII) was obtained by lithiation of 4-bromobenzonitrile (VI), followed by treatment with triisopropyl borate. Then, Suzuki coupling of boronic acid (VII) with bromide (V) furnished the title compound.
| 【1】 Nakamura, J.; Kuwana, Y.; Kitamura, S.; Ichikawa, S.; Yamada, K.; Ornstein, P.L.; Biarylpropylsulfonamides as novel, potent potentiators of 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)-propanoic acid (AMPA) receptors. J Med Chem 2000, 43, 23, 4354. |
| 【3】 Ornstein, P.L.; Jones, W.D.; Zarrinmayeh, H.; Zimmerman, D.M.; Arnold, M.B. (Eli Lilly and Company); N-Substd. sulfonamide derivs.. WO 0006537 . |
| 【2】 Arnold, M.B.; Bleakman, D.; Simon, R.L.; Cantrell, B.E.; Ornstein, P.L.; McKennon, T.E.; Tizzano, J.P.; Bleisch, T.J.; Zimmerman, D.M.; Baker, S.R.; Smith, E.; Zarrinmayeh, H.; Matsumoto, K.; Escribano, A.M. (Eli Lilly and Company); Sulphonamide derivs.. EP 0860428; WO 9833496 . |
| 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) | 45829 | 2-(4-bromophenyl)acetonitrile; 4-Bromobenzyl cyanide | 16532-79-9 | C8H6BrN | 详情 | 详情 |
| (II) | 25421 | 1-(4-bromophenyl)-1-ethanone | 99-90-1 | C8H7BrO | 详情 | 详情 |
| (III) | 45830 | 2-(4-bromophenyl)propanenitrile | C9H8BrN | 详情 | 详情 | |
| (IV) | 45831 | 2-(4-bromophenyl)propylamine; 2-(4-bromophenyl)-1-propanamine | C9H12BrN | 详情 | 详情 | |
| (V) | 45832 | N-[2-(4-bromophenyl)propyl]-2-propanesulfonamide | C12H18BrNO2S | 详情 | 详情 | |
| (VI) | 45833 | 4-Bromobenzonitrile | 623-00-7 | C7H4BrN | 详情 | 详情 |
| (VII) | 38835 | 4-cyanophenylboronic acid | 126747-14-6 | C7H6BNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Suzuki coupling between 2-methoxy-5-formylphenylboronic acid (VI) and 4-bromobenzonitrile (VII) affords the biphenyl aldehyde (VIII). This is then reductively condensed with amine (V) in the presence of NaBH(OAc)3 to furnish (IX). Acylation of amine (IX) with 3-chlorobenzo[b]thiophene-2-carbonyl chloride (X) leads to amide (XI). The N-Boc protecting group of (XI) is finally removed with ethanolic HCl to provide the title compound. (1,2)
| 【1】 Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Porter, J.; Rubin, L.E. (Curis, Inc.); Small organic molecule regulators of cell proliferation. US 6613798; US 6683108; WO 0174344 . |
| 【2】 Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Porter, J.; Rubin, L.; Stibbard, J.H.A. (Curis, Inc.); Small organic molecule regulators of cell proliferation. US 2002198236; WO 0327234 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 63697 | 1,1-dimethylethyl 4-aminocyclohexyl(methyl)carbamate | C12H24N2O2 | 详情 | 详情 | |
| (VI) | 63698 | 5-formyl-2-(methyloxy)phenylboronic acid | C8H9BO4 | 详情 | 详情 | |
| (VII) | 45833 | 4-Bromobenzonitrile | 623-00-7 | C7H4BrN | 详情 | 详情 |
| (VIII) | 63699 | 3'-formyl-6'-(methyloxy)[1,1'-biphenyl]-4-carbonitrile | C15H11NO2 | 详情 | 详情 | |
| (IX) | 63700 | C27H35N3O3 | 详情 | 详情 | ||
| (X) | 63701 | 3-chloro-1-benzothiophene-2-carbonyl chloride | C9H4Cl2OS | 详情 | 详情 | |
| (XI) | 63702 | 1,1-dimethylethyl 4-([(3-chloro-1-benzothiophen-2-yl)carbonyl]{[4'-cyano-6-(methyloxy)[1,1'-biphenyl]-3-yl]methyl}amino)cyclohexyl(methyl)carbamate | C36H38ClN3O4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Iniparib can be prepared from 4-iodo-3-nitrobenzoic acid (I) by activation as the corresponding acid chloride (II) with SOCl2 in DMF, followed by quenching with concentrated ammonium hydroxide .
Alternatively, by reaction of 4-bromobenzonitrile (III) with KNO3 in the presence of H2SO4 to give 4-bromo-3-nitrobenzamide (IV) and finally Ni-catalyzed iodination using NaI, NiBr2 and Bu3P in NMP at 140 °C
| 【1】 Mendeleyev, J., Kun, E., Kirsten, E. (Octamer, Inc.). Novel aromatic and nitroso compounds and their metabolites useful as anti-viral and antitumor agents. WO 1994026730. |
| 【2】 Cant, A.A., Bhalla, R., Pimlott, S.L., Sutherland, A. Nickel-catalysed aromatic Finkelstein reaction of aryl and heteroaryl bromides. Chem Commun (London) 2012, 48(33): 3993-5. |