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【结 构 式】 
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【药物名称】AN-2728 【化学名称】4-(1-Hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yloxy)benzonitrile 【CA登记号】906673-24-3 【 分 子 式 】C14H10BNO3 【 分 子 量 】251.0451 |
【开发单位】Anacor Pharmaceuticals, Inc. (US). 【药理作用】Phosphodiesterase PDE4 inhibitor;Treatment of atopic dermatitis;Treatment of psoriasis |
合成路线1
Protection of 2-bromo-5-hydroxybenzaldehyde (I) as the corresponding ethylene ketal (III) by means of ethylene glycol (II) and p-TsOH in refluxing toluene, followed by coupling with 4-fluorobenzonitrile (IV) in the presence of K2CO3 in DMF and subsequent acetal hydrolysis with HCl in refluxing H2O/THF provides 4-(4-bromo-3-formylphenoxy) benzonitrile (V). Reduction of aldehyde (V) with NaBH4 in MeOH affords the benzylic alcohol (VI), which is then protected with DHP in the presence of CSA in CH2Cl2 to give the tetrahydropyranyl ether (VII). Finally, aryl bromide (VII) is submitted to halogen-metal exchange by treatment with BuLi, followed by borylation with (i-PrO)3B in THF and then treatment with HCl in refluxing H2O/THF .
| 【1】 Akama, T., Baker, S.J., Zhang, Y.K. et al. Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett 2009, 19(8): 2129-32. |
| 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) | 67826 | 2-bromo-5-hydroxybenzaldehyde | C7H5BrO2 | 详情 | 详情 | |
| (II) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (III) | 67827 | 4-bromo-3-(1,3-dioxolan-2-yl)phenol | C9H9BrO3 | 详情 | 详情 | |
| (IV) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (V) | 67828 | 4-(4-bromo-3-formylphenoxy)benzonitrile | C14H8BrNO2 | 详情 | 详情 | |
| (VI) | 67829 | 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile | C14H10BrNO2 | 详情 | 详情 | |
| (VII) | 67830 | 4-(4-bromo-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenoxy)benzonitrile | C19H18BrNO3 | 详情 | 详情 |
合成路线2
Alternatively, benzylic alcohol (VI) can be protected as the methoxymethyl ether (IX) by treatment with chloromethyl methyl ether (VIII) and DIEA in CH2Cl2. Finally, aryl bromide (IX) is metalated with t-BuLi or n-BuLi, followed by borylation with B(OMe)3 in THF and subsequent treatment with HCl in H2O/MeOH .
| 【1】 Baker, S.J., AkamA, T., Bellinger-Kawahara, C. et al. (Anacor Pharmaceuticals, Inc.). Boron-containing small molecules. CN 101914109, EP 1853251, EP 2343304, JP 2008535781, JP 2010248265, KR 2010105869, KR 2013095330, KR 2013100019, US 20062334981, US 7582621, US 8039451, US 2011319361, US 2012289686, US 2013059802, US 2013059803, US 2013064783, US 8440642, US 2013210770, US 2013244980, US 8722917, US 2014142064, WO 2013210770. |
| 【2】 Baker, S.J., Sanders, V. Akama, T. et al. (Anacor Pharmaceuticals, Inc.). Boron-containing small molecules as anti-inflammatory agents. CN 103479654, EP 2719388, JP 2009531292, KR 2013120552, KR 2014082842, US 8168614, US 2012264714, US 8501712, US 2013316979, WO 2007095638. |
| 【3】 Akama, T., Zhang, Y.-K., Ding, C.Z. et al. (Anacor Pharmaceuticals, Inc.). Boron-containing small molecules as anti-inflammatory agents. US 2009291917, US 8039450. |