4-methoxybenzyl (1-(((6-methoxy-4-((5-(methylcarbamoyl)naphthalen-2-yl)oxy)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate -Drug Synthesis Database

【结构式】

【分子编号】67671

【品名】4-methoxybenzyl (1-(((6-methoxy-4-((5-(methylcarbamoyl)naphthalen-2-yl)oxy)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate

【CA登记号】　

【分子式】C₃₅H₃₃N₃O₇

【分子量】607.663

【元素组成】C 69.18% H 5.47% N 6.92% O 18.43%

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：(XXXIX)

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) .

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	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2

该中间体在本合成路线中的序号：(XXXIX)

Mitsunobu reaction of 4-chloro-6-methoxyquinolin-7-ol (XXXIII) with alcohol (XXXVI) using DEAD and PPh3 in THF yields adduct (XLV), which by Ullmann reaction with 6-hydroxy-N-methyl-1-naphthamide (V) 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 gives diaryl ether (XXXIX). This compound is alternatively obtained by Curtius rearrangement of azide (XLVI) with Pmb-OH in refluxing toluene .

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	分子式	供应商	用于合成
(XXXIII)	67664	4-chloro-6-methoxyquinolin-7-ol	C₁₀H₈ClNO₂	详情	详情
(XXXVI)	67667	4-methoxybenzyl (1-(hydroxymethyl)cyclopropyl)carbamate	C₁₃H₁₇NO₄	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
(XLV)	67676	4-methoxybenzyl (1-(((4-chloro-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate	C₂₃H₂₃ClN₂O₅	详情	详情
(XLVI)	67677	1-(((6-methoxy-4-((5-(methylcarbamoyl)naphthalen-2-yl)oxy)quinolin-7-yl)oxy)methyl)cyclopropanecarbonyl azide	C₂₇H₂₃N₅O₅	详情	详情

Extended Information