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【结 构 式】 
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【分子编号】67632 【品名】6-((7-(benzyloxy)-6-methoxyquinolin-4-yl)oxy)-N-methyl-1-naphthamide 【CA登记号】 |
【 分 子 式 】C29H24N2O4 【 分 子 量 】464.521 【元素组成】C 74.98% H 5.21% N 6.03% O 13.78% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Activation of 6-hydroxy-1-naphthoic acid (I) using CDI, followed by coupling with methylamine hydrochloride (III) in DMF at 90 °C gives amide (V). Condensation of compound (V) with the aryl chloride (VI) using DMAP in 2,6-lutidine or i-PrOH at 130 °C or by means of Cs2CO3, CuI and picolinic acid or acetylacetone (Ullmann reaction) in DMF at 120 °C affords the diaryl ether (VIII), whose benzyl group is finally cleaved using TFA at 90 °C .
Esterification naphthoic acid (I) with EtOH and H2SO4 at reflux yields ethyl 6-hydroxy-1-naphthoic acid (XLIII), which then couples with aryl chloride (VI) in the presence of DMAP in 2,6-lutidine or i-PrOH at 130°C or by means of Cs2CO3, CuI and picolinic acid or acetylacetone in DMF at 120 °C (Ullmann reaction) to give diayl ether (XLIV). Finally, this compound is debenzylated with TFA at 90 °C .
| 【1】 Chen, G.P. (Advenchen Laboratories, LLC). Process for preparing the antitumor agent 6-(7-((1-aminocyclopropyl) methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide and its crystalline. WO 2014113616. |
| 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 |
| (III) | 67627 | methanamine hydrochloride | CH5N.HCl | 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 | |
| (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 | |
| (XL) | 67670 | ethyl 6-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)-1-naphthoate | C23H19NO5 | 详情 | 详情 | |
| (XLIII) | 67674 | ethyl 6-hydroxy-1-naphthoate | C13H12O3 | 详情 | 详情 | |
| (XLIV) | 67675 | ethyl 6-((7-(benzyloxy)-6-methoxyquinolin-4-yl)oxy)-1-naphthoate | C30H25NO5 | 详情 | 详情 |