Structure of 959616-64-9
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CAS No. : | 959616-64-9 |
Formula : | C8H7ClFNO3 |
M.W : | 219.60 |
SMILES Code : | O=C(OC)C1=C(Cl)N=C(OC)C(F)=C1 |
MDL No. : | MFCD12025844 |
InChI Key : | KGWMUWXJNVKKCF-UHFFFAOYSA-N |
Pubchem ID : | 40148026 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
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 |
---|---|---|
74% | To a solution of 2-chloro-5-fluoro-6-oxo-l,6- dihydropyridine-3-carboxylic acid (6.37 g, 33.26 mmol) in DMF (250 mL) at 0 C was added LiH (95%, 0.661 g, 83.14 mmol). The reaction mixture was stirred for 45 minutes, and then iodomethane (4.56 mL, 73.16 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then quenched with 2 M HCl until the pH of the reaction mixture was 6-7. The reaction mixture was diluted with EtOAc and saturated NaCl and the layers separated. The aqueous layer was back extracted with EtOAc (Ix). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield a crude yellow oil. HPLC analysis showed two products in a 5:1 ratio that were separated by flash column chromatography (methylene chloride/EtOAc, 15:1) to give the desired product (5.40 g, 74%) as a pale yellow solid. The minor product was also isolated as a pale yellow crystalline solid and identified as the regioisomer methyl 2-chloro-5-fluoro-6- methoxynicotinate . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With tetrakis(triphenylphosphine) palladium(0); formic acid; triethylamine; In N,N-dimethyl-formamide; at 100℃; for 4h; | [00672] Intermediate 73c: methyl 5-fluoro-6-methoxy-pyridine-3-carboxylate[00673] Triethylamine (1 .62mL, 11.61 mmol), tetrakis(triphenylphosphine)palladium(0) (0.45g, 0.3gmmol) and formic acid (0.44mL, 11 .61 mmol) were added to a flask containing a stirring solutionof <strong>[959616-64-9]methyl 2-chloro-5-fluoro-6-methoxy-pyridine-3-carboxylate</strong> (1 .7g, 7.74mmol) in DMF (1 7mL). The reaction mixture was then heated to 100 C and left to stir for 4 hours. The reaction mixture was left to cool before being filtered through celite and the solvent removed in vacuo. The residue was taken up in EtOAc (5OmL), water (5OmL) added and the organics extracted with further EtOAc (3 x 5OmL). The organic layers were combined, dried over Na2504, filtered and concentrated in vacuo. Theresidue was purified by column chromatography using an eluent of 0-50% EtOAc in heptane) toafford the desired product methyl 5-fluoro-6-methoxy-pyridine-3-carboxylate (590mg, 3.1 9mmol,41% yield) as a white solid.1H NMR (CDCI3,400MHz) O/ppm: 8.61 (1H, d, J= 1.9Hz), 7.88 (1H, dd, J= 10.4Hz, 1.9Hz), 4.09(3H, 5), 3.92 (3H, 5),MS Method 3: RT: 5.10 mm, 186.1 m/z [M+H] |
With formic acid; triethylamine;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 20 - 100℃; for 4.33333h; | To a solution of 1.5 g of <strong>[959616-64-9]methyl 2-chloro-5-fluoro-6-methoxynicotinate</strong> in 15 mL of N,N-dimethylformamide, 0.38 g of tetrakis(triphenylphosphine)palladium(0), 1.4 mL of triethylamine, and 0.38 mL of formic acid were added at room temperature, and the mixture was stirred at 50 to 60C for 1 hour under a nitrogen atmosphere, and then stirred at 90 to 100C for 2 hours 20 minutes. Thereto were further added 1.4 mL of triethylamine, 0.38 g of tetrakis(triphenylphosphine)palladium(0) and 0.38 mL of formic acid at room temperature, and the mixture was stirred at 90 to 100C for 1 hour. After cooling to room temperature, the reaction mixture was charged with ethyl acetate and water, and adjusted to pH 4.8 with 2 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with a saturated aqueous sodium chloride solution. A mixed solvent of chloroform:methanol was added to the organic layer to dissolve the insoluble substance, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resultant residue, and the solid was filtered off to obtain 0.30 g of methyl 5-fluoro-6-methoxynicotinate as a yellow solid. 1H-NMR (CDCl3) delta: 3.92 (3H, s), 4.09 (3H, s), 7.88 (1H, dd, J = 10.5, 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In methanol; at 20℃; for 1h; | [00670] Intermediate 73b: methyl 2-chloro-5-fluoro-6-methoxy-pyridine-3-carboxylate[00671] Sodium methoxide (1 .86mL, 11.91 mmol) was added to methyl 2,6-dichloro-5-fluoro-pyridine-3-carboxylate (1 .8g, 8.O3mmol) in Methanol (9mL) and the resultant mixture was left to stir for 1 hour. To the mixture was added EtOAc (20 mL) and water (20 mL), the layers were separated and the organ ics extracted using EtOAc (3 x 20 mL). Organic fractions were collected, dried (Na2SO4), filtered and reduced in vacuo to afford the desired product methyl 2-chloro-5-fluoro-6- methoxy-pyridine-3-carboxylate (1 .72g, 7.83mmol, 97% yield) as an orange solid.1H NMR (CDCI3,400MHZ) Olppm: 7.92 (1H, d, J= 9.6 Hz), 4.09 (3H, 5), 3.92 (3H, 5). MS Method 2: RT: 1.71 mm, 220.0 mlz [M+H] |
With methanol; at 20℃; for 0.666667h; | To a solution of 1.5 g of methyl 2,6-dichloro-5-fluoronicotinate in 12 mL of methanol, a solution of 1.3 g of 28% sodium methoxide/methanol in 3 mL of methanol was dropped, and the mixture was stirred at room temperature for 40 minutes. Thereto were added water and ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.2 g of methyl 2-chloro-5-fluoro-6-methoxynicotinate as a white solid. 1H-NMR (CDCl3) delta: 3.92 (3H, s), 4.09 (3H, s), 7.92 (1H, d, J = 9.8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.9% | With caesium carbonate; In acetonitrile; at 60℃; for 3h; | A mixture of <strong>[959616-64-9]methyl 2-chloro-5-fluoro-6-methoxy-pyridine-3-carboxylate</strong> (200 mg, 0.911 mmol), 4-fluoro-2-methoxyphenol (114 pL, 1.00 mmol) and cesium carbonate (742 mg, 2.28 mmol) in MeCN (8 mL) was stirred at 80 C for 3 h, then allowed to cool to room temperature with stirring. Water (30 mL) and methanol (5 mL) were added and the resulting mixture was sonicated briefly then stirred for 4 h. The precipitate was collected by filtration, washed with water and dried under vacuum to give methyl 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy- pyridine-3-carboxylate (237 mg, 0.727 mmol, 79.9% yield) as a beige solid. MS, ES+m/z 326.0 [M+H]+. -NMR (400 MHz, DMSO-rie) d 8.12 (d, J=l0.11 Hz, 1 H), 7.18 (dd, J=8.72, 5.94 Hz, 1 H), 7.09 (dd, J=l0.74, 2.91 Hz, 1 H), 6.81 (td, J=8.46, 2.78 Hz, 1 H), 3.83 (s, 3 H), 3.72 (s, 3 H), 3.57 (s, 3 H). |
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