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CAS No. : | 849217-60-3 | MDL No. : | MFCD22045581 |
Formula : | C17H15FN2O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FSFMBVMXIPQPMJ-UHFFFAOYSA-N |
M.W : | 314.31 | Pubchem ID : | 57810197 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; | will1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride(5.15 g, 26.9 mmol)Aminophenol (2.93 g, 26.9 mmol) and1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (5.00 g, 22.4 mmol)In N, N-dimethylacetamide (30 mL).The reaction was stirred until the reaction was complete and the mixture was poured into saturated aqueous sodium bicarbonate(200 ml) and stirred for 1 hour.The residue was filtered, washed with water (50 ml) and then with chloroform (50 ml)Drying tooN- (4-fluorophenyl) -N'-(4-hydroxyphenyl) -cyclopropane-1,1-dicarboxamide(6.22 g, yield: 88%). |
88% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In ISOPROPYLAMIDE; at 20℃; for 3h; | To a solution of 4-aminophenol (2.93 g, 26.9 mmol) and 1- (4-FLUORO-PHENYLCARBAMOYL)-CYCLOPROPANECARBOXYLIC acid (5.00 g, 22.4 mmol) in DMA (30 mL) was added EDCI (5.15 g, 26.9 mmol). The mixture was stirred vigorously until the reaction was complete (-3 h). With vigorous stirring, the reaction mixture was then poured into a flask containing sat. aqueous NAHCO3 solution (200 mL). The stirring was continued for 1 h. The resulting suspension was then filtered. The solid was washed with water (50 mL), chloroform (50 ML) and dried under vacuum, affording 1- (4-FLUORO- phenylcarbamoyl) -cyclopropanecarboxylic acid (6.22g, 88% yield) as a powder (>95% purity by HPLC AND 1H NMR). |
87.9% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h; | General procedure: To a solution of the intermediate 9 (1.0g, 4.48mmol) and substituted aminophenol (5.38mmol) in DMF (15mL) was added EDCI (1.03g, 5.38mmol). The solution was stirred at room temperature for 3h. Then water (50mL) was added to precipitate white solid, adjusting pH to 4.0-5.0 by 1M HCl. The white solid was filtered off, washed and dried in vacuum to afford 10a-b [45]. 5.3.1 N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (10a) Yield: 87.9%; MS (ESI) m/z: 315.4 [M+H]+. 1H NMR (400MHz, DMSO-d6) delta: 10.17 (s, 1H, CONH), 9.73 (s, 1H, CONH), 9.23 (s, 1H, OH), 7.83-6.68 (m, 8H, Ar-H), 1.48 (s, 4H, CH2CH2). |
85% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 20℃; for 4h; | General procedure: To a solution of 3a-k (6.40 mmol) in MeOH/H2O (30 mL,1:1=V:V), lithium hydroxide (230 mg, 9.6 mmol) was added, whichwas stirredat room temperature for 2 h. The pH value was then adjustedto 3 with dilute hydrochloric acid, and a large amount of solid wasprecipitated, which was filtered and dried to give an off-white solid (4a-k). The next step was carried out without purification of these products.A mixture of 4a-k (1 mmol), aminophenol (1 mmol), and 3-(ethyliminomethyleneamino)-N,N- dimethyl-propan-1-amine (1 mmol) in 10 mLDMA, was stirred at room temperature for 4 h. The reaction mixturewas monitored by TLC. After the starting material disappeared, thewater was added and the product was extracted with ethyl acetate andthe solvent was then evaporated. Finally, the product was separated bycolumn chromatography to give a pure product (5a-k). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With 2,6-dimethylpyridine; at 165℃; for 18h;Sealed tube; | 6,7-Dimethoxyquinolin-4-yl trifluoromethanesulfonate (5 g, 14.8 mmol) was added to a solution ofN- (4-fluorophenyl) -N '- (4-hydroxyphenyl) -cyclopropane-1,1-dicarboxamide (6.98 g, 22.2 mmol)2,6-lutidine (50 ml).The reaction mixture was stirred in a borning jar at 165 C for 18 hours.The reaction mixture was evaporated to dryness under reduced pressure and the remaining solid was dissolved in dichloromethane (250 ml)Wash twice with aqueous sodium hydroxide (1 N).The crude product was passed through a column of solid N- [4 - [(6,7-dimethoxy-Quinolyl) oxy] phenyl] -N '- (4-fluorophenyl) -1,1- cyclopropane dicarboxamide (3.2 g, yield: 44%),Captopinib |
44% | With 2,6-dimethylpyridine; at 165℃; for 18h; | To a solution of cyclopropane-l, L-DICARBOXYLIC acid (4- fluoro-phenyl) -amide (4-hydroxy-phenyl) -amide (6.98 g, 22.2 mmol) in anhydrous 2,6- lutidine (50 mL) was added trifluoromethanesulfonic acid 6,7-dimethoxy-quinolin-4-yl ester (5 g, 14.8 mmol). The reaction mixture was heated at 165C in a sealed pressure tube with stirring for 18 h. The reaction mixture was concentrated on high vacuum to completely remove lutidine. The resulting solid material was dissolved in DCM (250 mL), and washed several times with 1 N sodium hydroxide to remove the excess phenol. The crude mixture was loaded on a silica gel flash column and eluted with 75% EtOAc- hexanes, affording N- (4- { [6,7-bis (methyloxy) quinolin-4-yl] OXY} PHENYL)-N- (4- fluorophenyl) cyclopropane-l, L-DICARBOXAMIDE (3.2 g, 44%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With cyclohexa-1,4-diene;palladium 10% on activated carbon; In ethanol; for 2 - 5h;Heating / reflux; | To a refluxing mixture of cyclopropane-l, L-DICARBOXYLIC acid (4-benzyloxy- phenyl) -amide (4-fluoro-phenyl) -amide (46 g, 113 mmol), 10% Pd/C (2 g) in EtOH (400 mL) was added dropwise 1,4-cyclohexadiene (62.7 mL, 678 mmol). Stirring was continued for 2-5 h until the reaction was complete. The mixture was cooled to rt, filtered through celite, and washed with EtOH. The solution was then concentrated under reduced pressure. To the flask containing the crude product was added CHC13 (200 mL). The resulting suspension was stirred for 15 min at rt. The solid was filtered, and dried in the air to give cyclopropane-l, L-DICARBOXYLIC acid (4-fluoro-phenyl) -amide (4-hydroxy- phenyl) -amide (34.4 g, 95%, yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.3% | With copper; caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.166667h;Microwave irradiation; | Intermediate M-4 (0.26g, 1mmol) and intermediate M-1' (0.47g, 1.5mmol) dissolved in DMF 3mL was added Cu powder (6.1mg, 0.1mmol) and Cs2CO3 (0.98g, 3mmol). It was placed in a microwave reactor setting power at 60W. The reaction was stirred at 100C for 10min. After completion of the reaction, it was filtered. The solvent was evaporated to dryness. Water 10mL was slowly added dropwise with stirring. Solid precipitated. Column chromatography, eluted with petroleum ether: ethyl acetate (V / V, 1: 1), to give the desired product 0.45g I-4, yield: 83.3%. |
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