【结 构 式】 |
【分子编号】67626 【品名】6-acetoxy-1-naphthoic acid 【CA登记号】 |
【 分 子 式 】C13H10O4 【 分 子 量 】230.22 【元素组成】C 67.82% H 4.38% O 27.80% |
合成路线1
该中间体在本合成路线中的序号:(II)O-Protection of 6-hydroxy-1-naphthoic acid (I) with Ac2O in the presence of H2SO4 at reflux affords 6-acetoxy-1-naphthoic acid (II), which then is condensed with methylamine hydrochloride (III) in the presence of EDC, HOBt and DIEA in CH2Cl2 to give 6-acetoxy-N-methyl-1-naphthamide (IV). Hydrolysis of acetate (IV) with KOH in MeOH provides 6-hydroxy-N-methyl-1-naphthamide (V). Condensation of naphthamide (V) with the aryl chloride (VI)—obtained by chlorination of 7-benzyloxy-6-methoxyquinolin-4-ol (VII) with POCl3 in CH2Cl2 using DMAP in refluxing dioxane yields the diaryl ether (VIII), whose benzyl group is reductively cleaved using HCOONH4 over Pd/C in refluxing EtOH to produce the 7-hydroxyquinoline derivative (IX). Condensation of intermediate (IX) with the mesylate (X) —produced by activation of the primary alcohol (XI) using MsCl and DIEA in CH2Cl2 at 0 °C by means of Cs2CO3 in DMA at 100 °C gives compound (XII), which is finally deprotected by means of H2 over Pd/C in EtOH and treated with HCl in EtOAc . See Scheme 1 at the end of this article. Also, intermediate (VIII) can be prepared by condensation of 6-hydroxy-1-naphthoic acid (I) with 7-benzyloxy-6-methoxy-4-chloroquinoline (VI) using KOH in DMSO at 130 °C and subsequent coupling of the obtained adduct with methylamine hydrochloride (III) using EDC, HOBt and DIEA in CH2Cl2 .
【1】 Chen, G.P. (Advenchen Laboratories, LLC). Spiro substituted compounds as angiogenesis inhibitors. KR 2015039889; US 8163923; EP 2125777; JP 2010521474; WO 2008112408; US 2008227812. |
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) | 67625 | 6-hydroxy-1-naphthoic acid;6-Hydroxy-1-naphthalenecarboxylic acid | 2437-17-4 | C11H8O3 | 详情 | 详情 |
(II) | 67626 | 6-acetoxy-1-naphthoic acid | C13H10O4 | 详情 | 详情 | |
(III) | 67627 | methanamine hydrochloride | CH5N.HCl | 详情 | 详情 | |
(IV) | 67628 | 6-acetoxy-N-methyl-1-naphthamide | C14H13NO3 | 详情 | 详情 | |
(V) | 67629 | 6-hydroxy-N-methyl-1-naphthamide | C12H11NO2 | 详情 | 详情 | |
(VI) | 67630 | 7-benzyloxy-6-methoxy-4-chloroquinoline | C17H14ClNO2 | 详情 | 详情 | |
(VII) | 67631 | 7-(benzyloxy)-6-methoxyquinolin-4-ol | C17H15NO3 | 详情 | 详情 | |
(VIII) | 67632 | 6-((7-(benzyloxy)-6-methoxyquinolin-4-yl)oxy)-N-methyl-1-naphthamide | C29H24N2O4 | 详情 | 详情 | |
(IX) | 67633 | 6-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)-N-methyl-1-naphthamide | C22H18N2O4 | 详情 | 详情 | |
(X) | 67634 | (1-(((benzyloxy)carbonyl)amino)cyclopropyl)methyl methanesulfonate | C13H17NO5S | 详情 | 详情 | |
(XI) | 67635 | benzyl (1-(hydroxymethyl)cyclopropyl)carbamate | C12H15NO3 | 详情 | 详情 | |
(XII) | 67636 | benzyl (1-(((3-methoxy-5-((5-(methylcarbamoyl)naphthalen-1-yl)oxy)naphthalen-2-yl)oxy)methyl)cyclopropyl)carbamate | C34H31N3O6 | 详情 | 详情 |