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【结 构 式】 
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【分子编号】67635 【品名】benzyl (1-(hydroxymethyl)cyclopropyl)carbamate 【CA登记号】 |
【 分 子 式 】C12H15NO3 【 分 子 量 】221.25604 【元素组成】C 65.14% H 6.83% N 6.33% O 21.69% |
合成路线1
该中间体在本合成路线中的序号：(XI)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：（XIa）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 |