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【结 构 式】 
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【分子编号】67629 【品名】6-hydroxy-N-methyl-1-naphthamide 【CA登记号】 |
【 分 子 式 】C12H11NO2 【 分 子 量 】201.22488 【元素组成】C 71.63% H 5.51% N 6.96% O 15.9% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(V)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 .
| 【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
该中间体在本合成路线中的序号：(V)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 .
| 【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4
该中间体在本合成路线中的序号：(V)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 |