7-(benzyloxy)-6-methoxyquinolin-4-ol -Drug Synthesis Database

【结构式】

【分子编号】67631

【品名】7-(benzyloxy)-6-methoxyquinolin-4-ol

【CA登记号】　

【分子式】C₁₇H₁₅NO₃

【分子量】281.31104

【元素组成】C 72.58% H 5.37% N 4.98% O 17.06%

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：(VII)

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：(XXII)

Treatment of cyclopropane-1,1-dicarboxylic acid (IX) with one equivalent of SOCl2 in the presence of Et3N in THF at 0 °C, followed by condensation of the activated intermediate with 4-fluoroaniline (X), provides the monoamide (XI) , which is optionally chlorinated to (VIII) by treatment with oxalyl chloride in cold THF .
Reaction of 3,4-difluoronitrobenzene (XII) with sodium benzylate prepared from benzyl alcohol and NaH in dimethylacetamide gives 1-benzyloxy-2-fluoro-4-nitrobenzene (XIII) as the main product. Subsequent reduction of compound (XIII) by means of iron and ammonium formate in refluxing toluene leads to the corresponding aniline (XIV), which is subsequently coupled with carboxylic acid (XI) using EDC in CH2Cl2 to afford the diamide (XV). Finally, debenzylation of diamide (XV) by transfer hydrogenation with 1,4-cyclohexadiene and Pd/C in boiling EtOH provides the target intermediate (I) . Scheme 2. Alternatively, acid chloride (VIII) can be directly condensed with 4-amino-2-fluorophenol (XVI) in the presence of 2,6-lutidine in cold THF to give diamide (I) .

参考文献中间体

合成目标

【1】 Bannen, L.C., Chan, D.S.-M., Chen, J. (Exelixis, Inc.). c-Met modulators and methods of use. EP 1673085, EP 2210607, EP 2213661, JP 2007506777, JP 2010235631, JP 2010235632, WO 2005030140.
【2】 Forsyth, T.P., Mac, M.B., Leahy, J.W., Nuss, J.M., Xu, W.(Exelixis, Inc.). c-Met modulators and methods of use. EP 1874759, JP 2008537748, US 2008161305, WO 2006108059.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	69103	7-(benzyloxy)-6-methoxyquinolin-4-yl trifluoromethanesulfonate		C₁₈H₁₄F₃NO₅S	详情	详情
(XVII)	22604	1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone	498-02-2	C₉H₁₀O₃	详情	详情
(XVIII)	69112	1-(4-(benzyloxy)-3-methoxyphenyl)ethanone;3'-Methoxy-4'-(benzyloxy)acetophenone;4'-(Benzyloxy)-3'-methoxyacetophenone;Acetovanillone benzyl ether;1-(3-Methoxy-4-phenylmethoxyphenyl)ethanone	1835-11-6	C₁₆H₁₆O₃	详情	详情
(XIX)	69113	1-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)ethanone;4’-benzyloxy-5’-methoxy-2’-nitroacetophenone		C₁₆H₁₅NO₅	详情	详情
(XX)	69114	1-(2-amino-4-(benzyloxy)-5-methoxyphenyl)ethanone		C₁₆H₁₇NO₃	详情	详情
(XXI)	16602	ethyl formate	109-94-4	C₃H₆O₂	详情	详情
(XXII)	67631	7-(benzyloxy)-6-methoxyquinolin-4-ol		C₁₇H₁₅NO₃	详情	详情

Extended Information