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【结 构 式】 
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【分子编号】67633 【品名】6-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)-N-methyl-1-naphthamide 【CA登记号】 |
【 分 子 式 】C22H18N2O4 【 分 子 量 】374.396 【元素组成】C 70.58% H 4.85% N 7.48% O 17.09% |
合成路线1
该中间体在本合成路线中的序号：(IX)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：(IX)Treatment of acid (XXXIV) with Pmb-OH in the presence of DPPA and Et3N (through Curtius rearrangement) in refluxing toluene produces carbamate (XXXV), which is reduced at the ethyl ester group to alcohol (XXXVI) by means of NaBH4 in THF/MeOH. Activation of primary alcohol (XXXVI) using MsCl and DIEA in CH2Cl2 at 5 °C gives mesylate (XXXVII), which by treatment with KI in refluxing acetone affords its corresponding iodide (XXXVIII). Condensation of the 7-hydroxyquinoline derivative (IX) with either, mesylate (XXXVII) using K2CO3 in the presence of KI or NaI or with iodide (XXXVIII) using K2CO3 in refluxing acetone yields ether (XXXIX), which is finally deprotected by cleavement of the PMB group by treatment with TFA or p-TsOH in CH2Cl2 or acetonitrile .
Condensation of mesylate (XXXVII) with the 7-hydroxyquinoline derivative (XL) by means of K2CO3 and NaI in refluxing acetone gives ether (XLI), whose ethyl ester group is hydrolyzed with NaOH in EtOH to give acid (XLII). Finally, preactivation of acid (XLII) with CDI, followed by coupling with methylamine hydrochloride (III) in DMF at 80 °C affords amide (XXXIX) .
| 【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 |
|---|---|---|---|---|---|---|
| (IX) | 67633 | 6-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)-N-methyl-1-naphthamide | C22H18N2O4 | 详情 | 详情 | |
| (XXXIV) | 67665 | 1-(ethoxycarbonyl)cyclopropanecarboxylic acid | C7H10O4 | 详情 | 详情 | |
| (XXXV) | 67666 | ethyl 1-((((4-methoxybenzyl)oxy)carbonyl)amino)cyclopropanecarboxylate | C15H19NO5 | 详情 | 详情 | |
| (XXXVI) | 67667 | 4-methoxybenzyl (1-(hydroxymethyl)cyclopropyl)carbamate | C13H17NO4 | 详情 | 详情 | |
| (XXXVII) | 67668 | (1-((((4-methoxybenzyl)oxy)carbonyl)amino)cyclopropyl)methyl methanesulfonate | C14H19NO6S | 详情 | 详情 | |
| (XXXVIII) | 67669 | 4-methoxybenzyl (1-(iodomethyl)cyclopropyl)carbamate | C13H16INO3 | 详情 | 详情 | |
| (XXXIX) | 67671 | 4-methoxybenzyl (1-(((6-methoxy-4-((5-(methylcarbamoyl)naphthalen-2-yl)oxy)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate | C35H33N3O7 | 详情 | 详情 | |
| (XL) | 67670 | ethyl 6-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)-1-naphthoate | C23H19NO5 | 详情 | 详情 | |
| (XLI) | 67672 | ethyl 6-((6-methoxy-7-((1-((((4-methoxybenzyl)oxy)carbonyl)amino)cyclopropyl)methoxy)quinolin-4-yl)oxy)-1-naphthoate | C36H34N2O8 | 详情 | 详情 | |
| (XLII) | 67673 | 6-((6-methoxy-7-((1-((((4-methoxybenzyl)oxy)carbonyl)amino)cyclopropyl)methoxy)quinolin-4-yl)oxy)-1-naphthoic acid | C34H30N2O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)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 |