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【结 构 式】 
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【分子编号】67654 【品名】ethyl (1-((4-acetyl-2-methoxy-5-nitrophenoxy)methyl)cyclopropyl)carbamate 【CA登记号】 |
【 分 子 式 】C16H20N2O7 【 分 子 量 】352.34408 【元素组成】C 54.54% H 5.72% N 7.95% O 31.79% |
合成路线1
该中间体在本合成路线中的序号：(XXVIIIb)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 |