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【结 构 式】

【药物名称】LUCITANIB HYDROCHLORIDE

【化学名称】6-([7-[(1-Aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy)-N-methylnaphthalene-1-carboxamide hydrochloride

【CA登记号】1058137-84-0; 1058137-23-7 (as free base)

【 分 子 式 】C26H25N3O4

【 分 子 量 】479.955

【开发单位】　

【药理作用】Dual FGFR/VEGFR inhibitor;Treatment of NSCLC and breast cancer
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7

合成路线1

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
【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

Condensation of 4-hydroxy-3-methoxyacetophenone (XIII) with mesylate (XIV) by means of K2CO3 in DMF at 100 °C yields the aryl ether (XV), which by nitration using HNO3 in AcOH gives the corresponding o-nitroaryl ketone (XVI). Reduction of the nitro group in compound (XVI) using Fe and NH4Cl in refluxing EtOH/H2O gives amine (XVII). Friedlaender cyclization of the o-aminoaryl ketone (XVII) with ethyl formate (XVIII) and NaOMe in DME affords a 4-hydroxyquinoline derivative, which without isolation is chlorinated using POCl3 to produce the corresponding chloride (XIX). Condensation of the aryl chloride (XIX) with 6-hydroxy-N-methyl-1-naphthamide (V) in the presence of DMAP in refluxing dioxane gives adduct (XX), whose methyl ester is hydrolyzed with NaOH in refluxing MeOH to afford acid (XXI). Activation of acid (XXI) with i-BuOCOCl in the presence of DIEA in acetone and subsequent substitution of the obtained mixed anhydride with NaN3 produces azide (XXII), which is finally treated with PhCH2OH in refluxing toluene .

参考文献 中间体
【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
(V) 67629 6-hydroxy-N-methyl-1-naphthamide 　 C12H11NO2 详情 详情
(XIII) 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
(XIV) 67637 1-(4-hydroxy-3-methoxyphenyl)ethanone 　 C7H12O5S 详情 详情
(XV) 67638 methyl 1-((4-acetyl-2-methoxyphenoxy)methyl)cyclopropanecarboxylate 　 C15H18O5 详情 详情
(XVI) 67639 methyl 1-((4-acetyl-2-methoxy-5-nitrophenoxy)methyl)cyclopropanecarboxylate 　 C15H17NO7 详情 详情
(XVII) 67640 methyl 1-((4-acetyl-5-amino-2-methoxyphenoxy)methyl)cyclopropanecarboxylate 　 C15H19NO5 详情 详情
(XVIII) 16602 ethyl formate 109-94-4 C3H6O2 详情 详情
(XIX) 67641 methyl 1-(((4-chloro-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropanecarboxylate 　 C16H16ClNO4 详情 详情
(XX) 67642 methyl 1-(((6-methoxy-4-((5-(methylcarbamoyl)naphthalen-1-yl)oxy)quinolin-7-yl)oxy)methyl)cyclopropanecarboxylate C28H26N2O6 详情 详情
(XXI) 67643 1-(((6-methoxy-4-((5-(methylcarbamoyl)naphthalen-1-yl)oxy)quinolin-7-yl)oxy)methyl)cyclopropanecarboxylic acid 　 C27H24N2O6 详情 详情
(XXII) 67644 1-(((6-methoxy-4-((5-(methylcarbamoyl)naphthalen-1-yl)oxy)quinolin-7-yl)oxy)methyl)cyclopropanecarbonyl azide 　 C27H23N5O5 详情 详情

合成路线3

Intermediate (XIV) is obtained by selective hydrolysis of dimethyl 1,1-cyclopropanedicarboxylate (XXIII) using NaOH in MeOH/H2O to afford acid-ester (XXIV), which by treatment with ClCO2Et in THF gives the mixed anhydride (XXV). Reduction of carboxylic anhydride (XXV) using NaBH4 in MeOH gives the primary alcohol (XXVI), which is finally activated as mesylate (XIV) by means of MsCl in the presence of DIEA in CH2Cl2 at 0 °C .

参考文献 中间体
【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
(XIV) 67637 1-(4-hydroxy-3-methoxyphenyl)ethanone 　 C7H12O5S 详情 详情
(XXIII) 58458 dimethyl 1,1-cyclopropanedicarboxylate; cyclopropane-1,1-dicarboxylic acid dimethyl ester; 1,1-cyclopropanedicarboxylic acid dimethyl ester 6914-71-2 C7H10O4 详情 详情
(XXIV) 58459 1-(methoxycarbonyl)cyclopropanecarboxylic acid 113020-21-6 C6H8O4 详情 详情
(XXV) 67645 (ethyl carbonic) 1-(methoxycarbonyl)cyclopropanecarboxylic anhydride 　 C9H12O6 详情 详情
(XXVI) 67646 methyl 1-(hydroxymethyl)cyclopropanecarboxylate 　　 C6H10O3 详情 详情

合成路线4

Mitsunobu reaction of apocynin (XIII) with the cyclopropylmethanol derivatives (XIa-c) in the presence of DEAD, PPh3 and DIEA in THF affords the aryl ethers (XXVIIa-c), which by nitration with HNO3 in Ac2O yields the 6-nitrophenyl derivatives (XXVIIIa-c). Condensation of ketones (XXVIIIa-c) with dimethylformamide dimethylacetal (XXIX) in DMF at 100 °C furnishes keto-enamines (XXXa-c), which upon Leimgruber-Batcho reaction using Fe in AcOH at 80 °C produces quinoline derivatives (XXXIa-c). Chlorination of 4-hydroxyquinolines (XXXIa-c) with POCl3 at 85 °C gives their corresponding chlorides (XXXIIa-c). These compounds are alternatively obtained by Mitsunobu condensation of 4-chloro-7-hydroxy-6-methoxyquinoline (XXXIII) with alcohols (Xia-c) using DEAD and PPh3 in CH2Cl2 at 0 °C. Condensation of chlorides (XXXIIa-c) with 6-hydroxy-N-methyl-1-naphthamide (V) by means of DMAP in 2,6-lutidine at 140 °C yields ethers (XIIa-c), whose N-carbamates are cleaved by means of HBr in AcOH .

参考文献 中间体
【1】 Spinelli, S., Livi, V. (EOS SpA). A process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide and synthetic intermediates thereof. US 9012645; US 2014114075; CN 102356063; US 8642767; US 2012010415; EP 2408739; US 2015191429; WO 2010105761; EP 2641897; JP 2012520332.
【2】 Spinelli, S., Livi, V. (EOS SpA). Preparation method of compound and a synthesis intermediate. CN 104193676.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
（XIa） 67635 benzyl (1-(hydroxymethyl)cyclopropyl)carbamate C12H15NO3 详情 详情
（XIb） 67647 ethyl (1-(hydroxymethyl)cyclopropyl)carbamate C7H13NO3 详情 详情
（XIc） 67648 tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate 107017-73-2 C9H17NO3 详情 详情
(XXVIIa) 67649 benzyl (1-((4-acetyl-2-methoxyphenoxy)methyl)cyclopropyl)carbamate 　 C21H23NO5 详情 详情
(XXVIIb) 67650 ethyl (1-((4-acetyl-2-methoxyphenoxy)methyl)cyclopropyl)carbamate 　 C16H21NO5 详情 详情
(XXVIIc) 67651 tert-butyl (1-((4-acetyl-2-methoxyphenoxy)methyl)cyclopropyl)carbamate 　 C18H25NO5 详情 详情
(XXVIIIa) 67653 benzyl (1-((4-acetyl-2-methoxy-5-nitrophenoxy)methyl)cyclopropyl)carbamate C21H22N2O7 详情 详情
(XXVIIIb) 67654 ethyl (1-((4-acetyl-2-methoxy-5-nitrophenoxy)methyl)cyclopropyl)carbamate 　 C16H20N2O7 详情 详情
(XXVIIIc) 67652 tert-butyl (1-((4-acetyl-2-methoxy-5-nitrophenoxy)methyl)cyclopropyl)carbamate 　 C18H24N2O7 详情 详情
(XXXa) 67656 (E)-benzyl (1-((4-(3-(dimethylamino)acryloyl)-2-methoxy-5-nitrophenoxy)methyl)cyclopropyl)carbamate 　 C24H27N3O7 详情 详情
(XXXb) 67655 (E)-ethyl (1-((4-(3-(dimethylamino)acryloyl)-2-methoxy-5-nitrophenoxy)methyl)cyclopropyl)carbamate 　 C19H25N3O7 详情 详情
(XXXc) 67657 (E)-tert-butyl (1-((4-(3-(dimethylamino)acryloyl)-2-methoxy-5-nitrophenoxy)methyl)cyclopropyl)carbamate 　 C21H29N3O7 详情 详情
(XXXIa) 67658 benzyl (1-(((4-hydroxy-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate 　 C22H22N2O5 详情 详情
(XXXIb) 67659 ethyl (1-(((4-hydroxy-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate C17H20N2O5 详情 详情
(XXXIc) 67660 tert-butyl (1-(((4-hydroxy-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate 　 C19H24N2O5 详情 详情
(XXXIIa) 67663 benzyl (1-(((4-chloro-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate 　 C22H21ClN2O4 详情 详情
(XXXIIb) 67662 ethyl (1-(((4-chloro-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate 　 C17H19ClN2O4 详情 详情
(XXXIIc) 67661 tert-butyl (1-(((4-chloro-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate 　 C19H23ClN2O4 详情 详情
(V) 67629 6-hydroxy-N-methyl-1-naphthamide 　 C12H11NO2 详情 详情
(XIII) 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
(XXIX) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(XXXIII) 67664 4-chloro-6-methoxyquinolin-7-ol 　 C10H8ClNO2 详情 详情

合成路线5

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
【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6

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
【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

合成路线7

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
【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
(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
Drug NewChemical Entity Original Patent(1)