6-hydroxy-1-naphthoic acid；6-Hydroxy-1-naphthalenecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】67625

【品名】6-hydroxy-1-naphthoic acid；6-Hydroxy-1-naphthalenecarboxylic acid

【CA登记号】2437-17-4

【分子式】C₁₁H₈O₃

【分子量】188.18272

【元素组成】C 70.21% H 4.28% O 25.51%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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 .

参考文献中间体

合成目标

【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：(I)

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 .

参考文献中间体

合成目标

【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

Extended Information