Structure of 135838-04-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 135838-04-9 |
Formula : | C9H6FNO |
M.W : | 163.15 |
SMILES Code : | OC1=C2N=CC=CC2=CC(F)=C1 |
MDL No. : | MFCD18414597 |
InChI Key : | SCUWALYGODIPCH-UHFFFAOYSA-N |
Pubchem ID : | 384160 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
100% | With sodium hydroxide; In methanol; water; | 2.06 g of sodium hydroxide in pellet form are dissolved in 2.5 ml of water. 150 ml of methanol and 8.39 g of <strong>[135838-04-9]6-fluoro-8-hydroxyquinoline</strong> are added. The whole is stirred until dissolved, then concentrated to dryness and dried at 50 C. under 0.5 Torr. 9.54 g of the sodium salt of <strong>[135838-04-9]6-fluoro-8-hydroxyquinoline</strong> are obtained in a yield of 100%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | Intermediate 14 6-Fluoro-8-q uinolinol 2-Amino-5-fluorophenol (for example, as prepared for Intermediate 13) (602 mg, 4.74 mmol) was dissolved in 5M hydrochloric acid (21 ml). Toluene (6.5 ml) and acrolein (1 ml, 14 mmol) were added to the solution and the mixture was stirred at 1000C overnight. The aqueous layer was removed and 10M sodium hydroxide was added until the solution was neutral. The compound which precipitated was extracted with dichloromethane and the organic phase was washed with water and brine, then it was dried with sodium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified by Flashmaster (50 g cartridge, 0-50% ethyl acetate- dichloromethane, 60 min). Pure fractions were combined and evaporated to give the title compound (96 mg, 12%). LCMS RT=1.97 min, ES+ve m/z 164 (M+H)+. RT=2.85 min, ES+ve m/z 176 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere; | Intermediate 32 1,1-Dimethylethyl 4-[(6-fluoro-8-quinolinyl)oxy]-l-piperidinecarboxylate 6-Fluoro-8-quinolinol (for example, as prepared for Intermediate 14) (96 mg, 0.59 mmol) was dissolved in tetrahydrofuran (2.5 ml) and then 1 ,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Aldrich) (120 mg, 0.59 mmol) and triphenylphosphine (310 mg, 1.18 mmol) were added. The mixture was stirred under nitrogen for ten minutes, and then diisopropyl azodicarboxylate (0.232 ml, 1.18 mmol) was added. The reaction mixture was stirred overnight at room temperature under nitrogen, and then the solvent was evaporated. The residue was dissolved in dichloromethane and purified by Flash-MS (50 g cartridge, eluting with 0- 100% ethyl acetate-cyclohexane over 30 min). Pure fractions were combined and evaporated to give the title compound (159 mg, 78%). LCMS RT=3.12 min, ES+ve m/z 347 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With hydrogenchloride; In water; at 111℃; for 24.0h; | General procedure: A 1N HCl solution (82.5 mL) was added to the aniline (~1 mmol) in a round bottom flask. To this was added acrolein diethyl acetal (2.5 mmol). The resulting solution was refluxed at 111 C for 24 hours. After cooling to room temperature, the solution was neutralized (pH 7-8) by addition of solid Na2CO3. The product was then extracted into dichloromethane (3 x 100 mL), and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was then purified by column chromatography (elution mixture of hexane with ethyl acetate or 15% ethyl acetate/cyclohexane with methanol) to give the desired quinoline product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 72.0h; | 8-0I (Intermediate 126A) (380 mg, 2.23 mmol) in tetrahydrofuran (10 mL). The reaction mixture was cooled to 0 C, and methyl 3-hydroxycyclobutanecarboxylate (0.37 mL, 3.5 mmol) was added, followed by DIAD (0.68 mL, 3.5 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2X). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-1 00% EtOAc-hexanes gradient to give a mixture of cis and trans isomers which were separated on an IC 30 X 250 mm column eluting with 50% EtOH in hexanes to give the title compound (137 mg, 21 %). 1H NMR (400 MHz, CD3SOCD3) delta 2.48- 2.59 (m, 2 H), 2.82 (ddd, J = 14, 7, 5 Hz, 2 H), 3.22-3.32 (m, 1 H), 3.31 (s, 3 H), 5.07 (t, J = 7 Hz, 1 H), 6.91 (dd, J = 1 1 , 3 Hz, 1 H), 7.31 (dd, J = 9, 3 Hz, 1 H), 7.59 (dd, J = 8, 4 Hz, 1 H), 8.30 (dd, J = 8, 2 Hz, 1 H), 8.83 (dd, J = 4, 2 Hz, 1 H); LC-MS (LC-ES) M+H = 276. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminum (III) chloride; In 1,2-dichloro-ethane; at 50℃; for 3.0h; | Aluminium chloride (4.52 g, 33.9 mmol) was added to a solution of 6-fluoro-8- methoxyquinoline (2.00 g, 1 1 .3 mmol) in 1 ,2-dichloroethane (20 mL), and the reaction mixture was heated to 50 C. After 3 h, the mixture was cooled to 0 C, quenched with saturated aqueous NaHC03 until pH neutral and filtered. The collected solid was retained. The aqueous layer of the filtrate was extracted with DCM (3X), and the combined organics were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified on silica gel using 0%-100% EtOAc: EtOH (3:1 ) in hexanes to afford 186 mg of the title compound. The previously retained solid was stirred in THF (20 mL) overnight, and the mixture was filtered through Celite. The filtrate was concentrated and dried under vacuum to afford an additional 500 mg the title compound (37% total yield). LC-MS (LC-ES) peak at T = 0.37 min; M+H = 164. |