Structure of 1256808-59-9
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CAS No. : | 1256808-59-9 |
Formula : | C7H6FNO2 |
M.W : | 155.13 |
SMILES Code : | O=C(O)C1=NC=C(F)C=C1C |
MDL No. : | MFCD18256735 |
InChI Key : | AJTJGMWIBKBTRW-UHFFFAOYSA-N |
Pubchem ID : | 58224628 |
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 |
---|---|---|
To a solution of <strong>[1346148-32-0]5-fluoro-3-methyl-pyridine-2-carboxylic acid methyl ester</strong> (1.28 g) inMeOH (6 ml) was added at 22C a solution of lithium hydroxide mono hydrate (636 mg) in water (3 ml) and stiring was continued for 16 h. The mixture was diluted with water, the MeOH was evaporated at reduced pressure and the pH was adjusted to 1 using 1 N aqueous HC1. The aqueous layer was extracted with AcOEt, the organic layer was dried, evaporated and the residue was crystallized from AcOEt/n-heptane to give the title compound (1.02 g) as a pale yellow solid. MS: m/z = 153.7 [M-H] | ||
b) 5-Fluoro-3-methyl-pyridine-2-carboxylic acid To a solution of <strong>[1346148-32-0]5-fluoro-3-methyl-pyridine-2-carboxylic acid methyl ester</strong> (1.28 g) in MeOH (6 ml) was added at 22 C. a solution of lithium hydroxide mono hydrate (636 mg) in water (3 ml) and stiring was continued for 16 h. The mixture was diluted with water, the MeOH was evaporated at reduced pressure and the pH was adjusted to 1 using 1 N aqueous HCl. The aqueous layer was extracted with AcOEt, the organic layer was dried, evaporated and the residue was crystallized from AcOEt/n-heptane to give the title compound (1.02 g) as a pale yellow solid. MS: m/z=153.7 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
b) 5-Fluoro-3-methyl-pyridine-2-carboxylic acid; 5-Fluoro-3-methyl-pyridine-2-carbonitrile (254 mg, 1.866 mmol) in cone. aq. HCI (1.5 ml) was stirred in a sealed glass vial at 120C for 2 h. The reaction mixture was basified with solid NaOH and extracted twice with TBME. The combined org. phases were washed with H20. The combined aq. phases were acidified to pH 2 with 2M aq. HCI, and were three times extracted with TMBE, dried over Na2S04, filtered and concentrated. The crude product was used in the next step without further purification.HPLC: RtH12= 0.48 min; ESIMS [M+H]+ = 156; 1H NMR (400 MHz, CD3OD): delta 8.37 (d, 1 H), 7.63 (dd, 1 H), 2.64 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.1% | To a solution of <strong>[1256808-59-9]5-fluoro-3-methylpicolinic acid</strong> (40.0 mg, 258 mumol, Eq: 1.2) in methanol (3.00 ml) was added at 0 C 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (83.3 mg, 301 mumol, Eq: 1.4), the colorless solution was stirred at 0 C for 30 min, then a solution of (3R,4aS)-3-(5-amino-2-fluoro-phenyl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4alambda6-thia-2,5,9a-triaza-benzocyclohepten-1-ylamine (70 mg, 215 mumol, Eq: 1.00) in methanol (5.00 ml) was added dropwise via syringe and the reaction mixture was stirred at 23 C for 4 h. Extracted with ethyl acetate and sat. NaHCO3-sol. plus brine, dried organic layer over Na2SO4. Filtration and removal of the solvent in vacuum left a brown foam which was purified by flash chromatography (NH2-silica gel, 20 g, 0% to 100% EtOAc in heptane) to give the <strong>[1256808-59-9]5-fluoro-3-methyl-pyridine-2-carboxylic acid</strong> [3-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4alambda6-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-4-fluoro-phenyl]-amide (29 mg, 62.7 mumol, 29.1 % yield) as a white solid. MS (ISP): m/z = 463.2 [(M+H)+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 49 N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-fluoro-3-methylpicolinamide Prepared from (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione and <strong>[1256808-59-9]5-fluoro-3-methylpicolinic acid</strong> LC-MS (m/z) 427.1 (MH+) tR=0.54 minutes (Method A) 1H NMR (600 MHz, DMSO-d6) delta 10.51 (s, 1H), 8.53 (dd, J=2.7, 0.4 Hz, 1H), 7.89-7.84 (m, 1H), 7.81 (ddd, J=9.8, 2.7, 0.6 Hz, 1H), 7.75 (dd, J=7.2, 2.7 Hz, 1H), 7.12 (dd, J=12.0, 8.8 Hz, 1H), 6.22 (s, 2H), 2.75-2.61 (m, 1H), 2.58 (s, 3H), 2.49-2.37 (m, 1H), 1.67 (d, J=22.7 Hz, 3H), 1.62 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
220 mg | With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 1h; | 5-Fluoro-3-methylpicolinic acid (200 mg, 1.29 mmol) was suspended in dichloromethane (4 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (435 mg, 300 mu, 3.43 mmol) as well as a drop of a mixture of dimethylformamide and toluene (1 :3, v/v) were added. The mixture was stirred for 1 h at room temperature. Then, it was concentrated in vacuo at 40C, the residue was treated with n-heptane (4 mL) and again concentrated and dried in vacuo (40C, 5 mbar) to afford 5-fluoro-3-methylpicolinoyl chloride as dark brown oil (220 mg). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-5,8,8-trimethyl- 9-oxido-2,3 ,4,4a,5 ,8-hexahydro- [ 1 ,4] thiazino [2, 1 -f] [ 1 ,2] thiazin-7-yl)carbamate (Int- 17 A A, 100 mg, 228 muiotaetaomicron) was dissolved in dichloromethane (4 mL), the solution cooled to 0-5C (ice bath) and N,N-diisopropylethylamine (75.5 mg, 100 mu, 584 muiotaetaomicron) was added, followed by a solution of 5-fluoro-3-methylpicolinoyl chloride (vide supra, 50 mg, 288 muiotaetaomicron) in dichloromethane (1 mL). The reaction mixture was stirred at 0-5C for 1.5 h. Then, ethanol (100 mu) was added, the mixture was stirred for 45 min at room temperature, poured onto a saturated aqueous solution of sodium hydrogencarbonate (15 mL) and extracted with dichloromethane (1 x 30 mL, 2 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 50 g, eluting with ethyl acetate / n-heptane, gradient 60:40 to 80:20) to afford, after drying in vacuo (50C, 5 mbar), the title compound as a white foam (115 mg, 88% yield). HPLC (method LCMS_gradient) tR = 3.2 min. 1H NMR (CDC13, 400 MHz): delta 1.48 (s, 9 H), 1.79 (s, 3 H), 1.80-2.01 (m, 3 H), 1.85 (s, 3 H), 1.96 (d, J = 1.2 Hz, 3 H), 2.31-2.48 (m, 1 H), 2.83 (s, 3 H), 3.35-3.45 (m, 1 H), 3.56-3.68 (m, 1 H), 4.07-4.14 (m, 1 H), 7.40 (ddd, J = 0.6, 2.7, 8.8 Hz, 1 H), 7.55 (dd, J = 8.9, 10.9 Hz, 1 H), 8.38 (d, J = 2.6 Hz, 1 H), 8.41 (dd, / = 3.0, 8.9 Hz, 1 H), 10.41 (br s, 1 H), 11.23 (br s, 1 H, exch). MS (ES+) m/z 577.3 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 70℃; for 4h; | To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int- 39AB, 150 mg, 0.35 mmol) in THF (20 mL) was added <strong>[1256808-59-9]5-fluoro-3-methylpicolinic acid</strong> (82 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (130 mg, 66% yield). XH NMR (CDC13, 400 MHz): delta 1.50-1.59 (m, 1 H), 1.66 (s, 9 H), 1.86 (s, 3 H), 1.97 (s, 3 H), 2.06-2.12 (m, 1 H), 2.14 (s, 3 H), 2.84 (s, 3 H), 3.54 (dd, J = 7.7, 10.7 Hz, 1 H), 3.69 (ddd, J = 4.8, 10.7, 10.7 Hz, 1 H), 4.30 (ddd, / = 2.1, 7.1, 12.0 Hz, 1 H), 7.40 (dd, J = 2.1, 8.9 Hz, 1 H), 7.58 (dd, = 9.1, 10.0 Hz, 1 H), 8.31 (d, J = 2.6 Hz, 1 H), 8.49 (dd, / = 3.1, 8.9 Hz, 1 H), 10.78 (s, 1 H), 12.54 (s, 1 H). MS (ES+) m/z 563.2 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 70℃; for 4h; | To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added <strong>[1256808-59-9]5-fluoro-3-methylpicolinic acid</strong> (82 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1: 1) to yield, after drying in vacuo, the title compound as a yellow solid (130 mg, 66% yield). XH NMR (CDC13, 400 MHz): delta 0.81-0.91 (m, 3 H), 1.49-1.59 (m, 9 H), 1.67- 1.76 (m, 6 H), 2.08-2.22 (m, 1 H), 2.52-2.64 (m, 1 H), 2.76-2.87 (m, 3 H), 3.71-3.87 (m, 2 H), 5.21 (dd, / = 7.1, 11.0 Hz, 1 H), 7.37 (dd, / = 2.3, 8.8 Hz, 1 H), 7.48-7.57 (m, 1 H), 8.37 (d, / = 2.5 Hz, 1 H), 8.44 (dd, / = 3.0, 8.9 Hz, 1 H), 10.46 (s, 1 H), 11.00 (br s, 1 H). MS (ES+) mJz 563.2 [M+H] . |
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