Structure of 884494-73-9
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CAS No. : | 884494-73-9 |
Formula : | C7H6FNO2 |
M.W : | 155.13 |
SMILES Code : | O=CC1=CN=C(OC)C(F)=C1 |
MDL No. : | MFCD04112587 |
InChI Key : | BKATVSAQJLGKJC-UHFFFAOYSA-N |
Pubchem ID : | 44754784 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-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 |
---|---|---|
6 g | With Dess-Martin periodane; In dichloromethane; at 0 - 23℃; for 16h; | DMP (27.37g, 64.4 immol) was added portion wise to a stirred solution of (5-fluoro-6-methoxypyridin-3-yl)methanol (6.8g, 43.83mmol) in DCM (l5OmL) at 0C and stirred for 16 h at RT. The RM was filteredthrough celite and washed with DCM (3x5OmL).The filtrate was washed with aq. NaHCO3 (200mL), water (lOOmL), brine(l5OmL), dried(Na2504), filtered, concentrated under reduced pressure to give crude. The crude was purified by CC (silica-gel 60-l20mesh, 0-15% EtOAc in PE) to give 5-fluoro-6- methoxynicotinaldehyde (6.Og, 89%) as a white solid. |
With manganese(IV) oxide; In dichloromethane; at 20℃; for 6.5h; | To a solution of 0.54 g of (5-fluoro-6-methoxypyridin-3-yl)methanol in 5 mL of dichloromethane, 1.5 g of manganese dioxide was added. The mixture was stirred at room temperature for 3 hours, thereto were then added 0.89 g of manganese dioxide and 4 mL of dichloromethane, and the mixture was stirred for 1 hour. Thereto were further added 1.5 g of manganese dioxide and 2 mL of dichloromethane, and the mixture was stirred at room temperature for 2 hours 30 minutes. After leaving overnight, the insoluble substance was filtered off, and the filtration residue was washed with chloroform. The solvent was distilled off under reduced pressure to obtain 0.48 g of 5-fluoro-6-methoxynicotinaldehyde as a yellow solid. 1H-NMR (CDCl3) delta: 4.13 (3H, s), 7.78 (1H, dd, J = 9.8, 1.8 Hz), 8.42 (1H, d, J = 1.8 Hz), 9.97 (1H, d, J = 2.7 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of 0.10 g of 1-(2-(4-(aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride in 2 mL of methanol, 0.15 g of a 28% sodium methoxide/methanol solution, 39 mg of (5-fluoro-6-methoxy)nicotinaldehyde and 14 muL of acetic acid were added. Thereto was added 31 mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 3 hours. After leaving for overnight, the mixture was stirred at room temperature for 35 minutes, 31 mg of sodium cyanoborohydride was added, and the mixture was stirred at the same temperature for 1 hour 40 minutes. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, 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. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol = 95:5 to 92:8 to obtain 43 mg of 7-fluoro-1-(2-(4-(((5-fluoro-6-methoxypyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one as a white solid. 1H-NMR (CDCl3) delta: 1.32-1.46 (2H, m), 1.85-1.94 (2H, m), 2.13-2.22 (2H, m), 2.45-2.55 (1H, m), 2.62-2.68 (2H, m), 2.91-2.99 (2H, m), 3.75 (2H, s), 4.01 (3H, m), 4.28-4.34 (2H, m), 6.86 (1H, d, J = 9.8 Hz), 7.38 (1H, dd, J = 10.9, 2.0 Hz), 7.50-7.55 (1H, m), 7.83 (1H, d, J = 2.0 Hz), 7.88 (1H, d, J = 9.8 Hz), 8.42 (1H, d, 2.4 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 2 mL of methanol, 0.28 g of a 28% sodium methoxide/methanol solution and 28 muL of acetic acid were added. Thereto was added 75 mg of <strong>[884494-73-9]5-fluoro-6-methoxynicotinaldehyde</strong>, then, 61 mg of sodium cyanoborohydride was added thereto, and the mixture was stirred at room temperature for 1 hour 20 minutes. Thereto was further added 62 mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 1 hour 30 minutes, and then stirred at 30 to 35C for 1 hour. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. 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. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol = 19:1 to 9:1, diethyl ether was added to the resultant light yellow oily substance, and the solid was filtered off to obtain 97 mg of 1-(2-(4-(((5-fluoro-6-methoxypyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a slightly yellow solid. 1H-NMR (CDCl3) delta: 1.35-1.46 (2H, m), 1.86-1.95 (2H, m), 2.15-2.23 (2H, m), 2.47-2.58 (1H, m), 2.62-2.68 (2H, m), 2.92-3.02 (2H, m), 3.75 (2H, m), 3.98 (3H, s), 4.01 (3H, s), 4.33-4.40 (2H, m), 6.74 (1H, d, J = 9.8 Hz), 7.23 (1H, d, J = 2.3 Hz), 7.38 (1H, dd, J = 11.0, 2.0 Hz), 7.82-7.86 (2H, m), 8.28 (1H, d, J = 2.3 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylsilane; trifluoroacetic acid; In acetonitrile; at 80℃; for 4h; | To 6-fluoro-pyridin-2ylamine (14, 1.50 g, 13.4 mmol) in 52.9 mL of acetonitrile, <strong>[884494-73-9]5-fluoro-6-methoxy-pyridine-3-carbaldehyde</strong> (23, 2.00 g, 12.9 mmol), triethylsilane (10.6 mL, 66.3 mmol), and trifluoroacetic acid (5.3 mL, 69.0 mmol) were added. The reaction was stirred at 80 C. overnight, then concentrated under vacuum, combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as white solid (24, 3.21 g). | |
3.21 g | With triethylsilane; trifluoroacetic acid; In acetonitrile; at 80℃; | To 6-fluoro-pyridin-2-ylamine (43, 1.50 g, 13.4 mmol) in 52.9 mL of acetonitrile, <strong>[884494-73-9]5-fluoro-6-methoxy-pyridine-3-carbaldehyde</strong> (57, 2.00 g, 12.9 mmol), triethylsilane (10.6 mL, 66.3 mmol), and trifluoroacetic acid (5.3 mL, 69.0 mmol) were added. The reaction was stirred at 80 C. overnight, then concentrated under vacuum, combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as white solid (58, 3.21 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | A suspension of 6-(i -methyl- iH-pyrazol-4-yl)-4-(6-(piperazin- 1 -yl)pyridin-3 - yl)pyrazolo[i,5-a]pyridine-3-carbonitrile dihydrochloride (Example 2; 100 mg, 0.219 mmol) in DCM (3 mL) was treated with DIEA (95.5 tL, 0.547 mmol). After stirring for 5 mm at ambient temperature, the mixture was treated sequentially with <strong>[884494-73-9]5-fluoro-6-methoxynicotinaldehyde</strong> (37.3 mg, 0.241 mmol) and NaBH(AcO)3 (92.7 mg, 0.437 mmol). After stirring for 12 h at room temperature, the reaction mixture was diluted with DCM and washed with 10% Na2CO3(aq). The organic extracts were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica chromatography (10% MeOHIDCM with 1% NH4OH as the eluent) to afford the title compound (85 mg, 74% yield). MS (apci) m/z = 524.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 1h; | A solution of 4-(5-(3 ,6-diazabicyclo[3. 1.1 ]heptan-3 -yl)pyrazin-2-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[ 1,5 -a]pyridine-3 -carbonitrile bi s(2,2,2-trifluoroacetate) (Intermediate P90; 25 mg, 0.0395 mmol) in DCE (197 tL) was treated sequentially with 5-fluoro-6- methoxynicotinaldehyde (12.2 mg, 0.0789 mmol) and NaBH(AcO)3 (25.1 mg, 0.118 mmol). Afterstirring for 1 h at ambient temperature, the reaction mixture was purified directly by silica chromatography (using 0-100% DCM in Hexanes then 0-60% (2% NH4OHI2O% MeOHI78% DCM) in DCM as the gradient eluent) to afford the title compound (8.17 mg, 38% yield). MS (apci) m/z = 545.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium tris(acetoxy)borohydride; triethylamine; In N,N-dimethyl acetamide; at 20℃; | A solution of 4-(6-(1,4-diazepan-1-yl)pyridin-3-yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[ 1,5 -a]pyridine-3 -carbonitrile bis(2,2,2-trifluoroacetate) (Intermediate P98; 50 mg, 0. 0788 mmol) in DMA (500 tL) was treated with 5-fluoro-6- methoxynicotininaldehyde (36.7 mg, 0.237 mmol), TEA (77 tL, 0.55 mmol) and (NaBH(AcO)3 (50 mg, 0.237 mmol), then stirred overnight at ambient temperature. The reaction mixture wastreated with additional TEA (77 tL, 0.55 mmol), NaBH(AcO)3 (50 mg, 0.237 mmol) and 5-fluoro- 6-methoxynicotininaldehyde (36.7 mg, 0.237 mmol), and then stirred at ambient temperature until LCMS indicated complete consumption of starting material. The reaction mixture was purified directly by silica chromatography (using 0-25% EtOAc/MeOH as the gradient eluent) and again by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as the gradient eluent) to afford impure title compound as the TFA salt. The TFA salt was neutralized with 1 M NaOH and brine, and then extracted with EtOAc. The organic extracts then were dried over anhydrous Na2SO4(), filtered and concentrated in vacuo to cleanly afford the title compound (30 mg, 70% yield). MS (apci) m/z = 546.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; | A mixture of 4-(5-(3 ,6-diazabicyclo[3. 1.1 ]heptan-3 -yl)pyrazin-2-yl)-6-ethoxypyrazolo[ 1,5 -a]pyridine-3 -carbonitrile bi s(2,2,2-trifluoroacetate) (Intermediate P103; 20 mg, 0.034 mmol) in DCM (679 tL) was treated with 5-fluoro-6-methoxynicotininaldehyde (16 mg, 0.10 mmol) and NaBH(AcO)3 (36 mg, 0.17 mmol), then stirred overnight at ambient temperature. The reaction mixture was purified directly by silica chromatography (using 0-10% MeOH in DCM with 0.1% NH4OH as the gradient eluent) to cleanly afford the title compound (14 mg, 82% yield). MS (apci) m/z = 501.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution of 4-(6-(3 ,6-diazabicyclo[3. 1.1 ]heptan-3 -yl)pyridin-3 -yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[ 1,5 -a]pyridine-3 -carbonitrile dihydrochloride (Intermediate P43; 30mg, 0.063 mmol), in DCM (1 mL) was treated with DIEA (27 tL, 0.16 mmol) and stirred for 5 mm at ambient temperature. The resulting mixture was treated sequentially with 5-chloro- 6-methoxynicotinaldehyde (11 mg, 0.063 mmol) and NaBH(AcO)3 (27 mg, 0.13 mmol). After stirring 12 h at ambient temperature, the reaction mixture was diluted with DCM and washed with 10% Na2CO3(aq). The combined organic extracts were dried over anhydrous MgSO4(), filtered, and concentrated in vacuo. The residue was purified by silica chromatography (10% MeOHI DCM with 1% NH4OH as the eluent) to cleanly provide the title compound (22 mg, 63% yield). MS (apci) m/z = 560.3 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of intermediate 3 (0.10 g, 0.49 mmol) in anhydrous DCM (2 mL), 5- fluoro-6-methoxynicotinaldehyde (CAS 884494-73-9, 0.83 g, 0.54 mmol) and titanium(IV)isopropoxide (0.21 mL, 0.73 mmol) were added and the reaction mixture was stirred at rt for 24 h. Then the reaction was cooled to 0 C and 1 4M solution of methyl magnesium bromide in THF doluene (1.75 mL, 2.44 mmol) was added dropwise and the reaction mixture was stirred at 0 C for 5 min and at rt for 3.5 h. Then saturated solution of NH4Cl was added and the product extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7M solution of ammonia in MeOH in DCM 0/100 to 2/98). The desired fractions were collected and the solvents evaporated in vacuo to yield product 45 as a yellow oil. |
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