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CAS No. : | 1009-35-4 |
Formula : | C7H3FN2O2 |
M.W : | 166.11 |
SMILES Code : | N#CC1=CC=C(F)C([N+]([O-])=O)=C1 |
MDL No. : | MFCD01632197 |
InChI Key : | LKOWKPGBAZVHOF-UHFFFAOYSA-N |
Pubchem ID : | 2774654 |
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 |
---|---|---|
97% | With 5%-palladium/activated carbon; hydrogen; In ethanol; under 12001.2 Torr;Flow reactor; | General procedure: Before each run, the system (see Fig.4) was allowed to equilibrate by pumping solvent through for 30min with the Tube-in-Tube device at 16bar of hydrogen. An omnifit cartridge (20.0mm OD, 15.0mm ID) containing 1g of Pd-C catalyst was used. To avoid an overpressure of the system in the event of blockage, the upper pressure cut-off limit on the Knauer pump was set to 25bar. With the injection loop disconnected from the flow line, the loop was opened and filled manually (using a syringe) with 3.6mL of a 0.076M solution of starting material in ethanol (excess starting material solution exiting the loop was recovered for reuse). The injection loop was then closed off and switched into the flow stream. The outlet from the system (downstream of the back-pressure regulator) was collected for 120min. The solvent was removed under reduced pressure (using a rotary evaporator followed by a 2-stage rotary vane pump) to afford the product. |
91% | Step A 3-amino-4-fluorobenzonitrile Using 4-fluoro-3-nitrobenzonitrile (13.64 g, 82.11 mmol) and according to the method of Reference Example 68, step A, the title compound (10.16 g, yield 91%) was obtained as a pale-yellow solid. 1H-NMR (300 MHz, CDCl3); delta(ppm) 3.94 (brs, 2H), 7.00-7.09 (m, 3H). | |
87% | With iron; ammonium chloride; In water; isopropyl alcohol; for 4h;Reflux; | Intermediate 1: 3-Amino-4-fluoro benzonitrile; A solution of 4-fluoro-3-nitro benzonitrile (Combi-Blocks; 5.0 g; 30 mmol) and saturated solution of ammonium chloride (16 g; 0.3 mol in 20ml of water) in iPrOH (100 ml) was treated with iron powder (8.4 g; 0.15 mol) and refluxed for 4h. The mixture was cooled and diluted with ethyl acetate (200ml) and the organic phase was washed with water, brine and dried on MgSO^ The solvents were evaporated under reduced pressure and the residue was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the Title compound (3.5 g, 87%) as a solid.1H NMR (300MHz, DMSO-dg) delta [ppm] 7.21-7.17 (m, IH), 7.10-7.07 (m, IH), 6.98-6.94 (m, IH), 5.70 (bs, 2H). MS (ESI+): 136.9. |
With hydrogen;5%-palladium/activated carbon; In methanol; under 1500.15 Torr; for 2h; | 4-fluoro-3-nitrobenzonitrile (5 g, 30 mmol) is first of all subjected to catalytic hydrogenation with 5% palladium on activated charcoal (0.4 g) in 300 mL methanol (2 h at 2 bar hydrogen pressure), whereupon the 3-amino-4-fluorobenzonitrile formed is obtained as a solid after filtration and evaporation of the solvent. Yield: 4.1 g. | |
With iron; acetic acid; at 80℃; for 1h;Inert atmosphere; | A mixture of 4-fluoro-3-nitrobenzonitrile (5.0 g, 30.1 mmol) and Fe powder (5.05 g, 90.3 mmol) in AcOH (100 mL) was heated at 80 C. for 1 hour under N2. Then the solvent was removed under vacuum and water (200 mL) was added to the residue. The solution was adjusted to pH 6 by addition of Na2CO3 and extracted with DCM (2×200 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to yield 3-amino-4-fluorobenzonitrile (48), which was used without further purification. MS m/z 137.0 (M+1)+.; To a stirring suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (3.0 g, 18.5 mmol) in anhydrous dichloromethane (50 mL) at 0 C. was added dropwise oxalyl chloride (4.84 mL, 55.5 mmol). Then, three drops of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 15 minutes. The solvent was concentrated and the crude solid was added to a stirring solution of 3-amino-4-fluorobenzonitrile (48) (2.5 g, 18.5 mmol) in anhydrous pyridine (50 mL) at room temperature. The reaction was stirred for 20 minutes and quenched with water (200 mL) with stirring for another 10 minutes. Then the precipitate was filtered and dried in air to yield N-(5-cyano-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (49). 1H NMR (400 MHz, d6-DMSO) delta 10.40 (s, 1H), 9.43 (td, J=1.2, 6.8 Hz, 1H), 8.63 (s, 1H), 8.21 (dd, J=2.0, 7.2 Hz, 1H), 7.78-7.84 (m, 2H), 7.54-7.63 (m, 2H), 7.22 (dt, J=1.2, 6.8, 1H). MS m/z 281.1 (M+1)+.; NH2OH (10 mL, 32.1 mmol) was added in one portion to a stirred suspension of N-(5-cyano-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (49) (3.6 g, 12.85 mmol) in EtOH (100 mL). The resulting suspension was heated at 70 C. for 3 hours and then the solvent was removed to yield N-(2-fluoro-5-(N?-hydroxycarbamimidoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (50). 1H NMR (400 MHz, d6-DMSO) delta 10.21 (s, 1H), 9.70 (s, 1H), 9.45 (td, J=1.2, 7.2 Hz, 1H), 8.61 (s, 1H), 7.95 (dd, J=2.4, 7.6 Hz, 1H), 7.79 (td, J=1.2, 8.8 Hz, 1H), 7.51-7.60 (m, 2H), 7.31-7.37 (m, 1H), 7.19 (dt, J=1.2, 6.8, 1H), 5.88 (s, 2H). MS m/z 314.1 (M+1)+. | |
A mixture of 4-fluoro-3-nitrobenzonitrile (5.0 g, 30.1 mmol) and Fe powder (5.05 g, 90.3 mmol) in AcOH (100 mL) was heated at 80 C for 1 hour under N2. Then the solvent was removed under vacuum and water (200 mL) was added to the residue. The solution was adjusted to pH 6 by addition of Na2C03 and extracted with DCM (2 x 200 mL). The organic layers were combined, dried over Na2S04, filtered and concentrated to yield 3- amino-4-fluorobenzonitrile (48), which was used without further purification. MS m/z 137.0 (M+1 ) +. | ||
A mixture of 4-fluoro-3-nitrobenzonitrile (5.0 g, 30.1 mmol) and Fe powder (5.05 g, 90.3 mmol) in AcOH (100 mL) was heated at 80 C. for 1 hour under N2. Then the solvent was removed under vacuum and water (200 mL) was added to the residue. The solution was adjusted to pH 6 by addition of Na2CO3 and extracted with DCM (2×200 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to yield 3-amino-4-fluorobenzonitrile (48), which was used without further purification. MS m/z 137.0 (M+1)+. | ||
With iron; acetic acid; at 80℃; for 1h;Inert atmosphere; | A mixture of 4-fluoro-3-nitrobenzonitrile (5.0 g, 30.1 mmol) and Fe powder (5.05 g, 90.3 mmol) in AcOH (100 mL) was heated at 80 C for 1 hour under N2. Then the solvent was removed under vacuum and water (200 mL) was added to the residue. The solution was adjusted to pH 6 by addition of Na2C03 and extracted with DCM (2 x 200 mL). The organic layers were combined, dried over Na2S04, filtered and concentrated to yield 3- amino-4-fluorobenzonitrile (48), which was used without further purification. MS m/z 137.0 (M+1 ) +. To a stirring suspension of imidazo[1 ,2-a]pyridine-3-carboxylic acid (1 ) (3.0 g, 18.5 mmol) in anhydrous dichloromethane (50 mL) at 0 C was added dropwise oxalyl chloride (4.84 mL, 55.5 mmol). Then, three drops of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 15 minutes. The solvent was concentrated and the crude solid was added to a stirring solution of 3-amino-4- fluorobenzonitrile (48) (2.5 g, 18.5 mmol) in anhydrous pyridine (50 mL) at room temperature. The reaction was stirred for 20 minutes and quenched with water (200 mL) with stirring for another 10 minutes. Then the precipitate was filtered and dried in air to yield N-(5-cyano-2-fluorophenyl)imidazo[1 ,2-a]pyridine-3-carboxamide (49). 1 H NMR (400MHz, c/6-DMSO) delta 10.40 (s, 1 H), 9.43 (td, J = 1 .2, 6.8 Hz, 1 H), 8.63 (s, 1 H), 8.21(dd, J = 2.0, 7.2 Hz, 1 H), 7.78-7.84 (m , 2H), 7.54-7.63 (m , 2H), 7.22 (dt, J = 1 .2, 6.8, 1 H). MS m/z 281 .1 (M+1 ) +. NH2OH (10 mL, 32.1 mmol) was added in one portion to a stirred suspension of N-(5- cyano-2-fluorophenyl)imidazo[1 ,2-a]pyridine-3-carboxamide (49) (3.6 g, 12.85 mmol) in EtOH (100 mL). The resulting suspension was heated at 70 C for 3 hours and then the solvent was removed to yield N-(2-fluoro-5-(N'- hydroxycarbamimidoyl)phenyl)imidazo[1 ,2-a]pyridine-3-carboxamide (50). 1 H NMR (400MHz, c/6-DMSO) delta 10.21 (s, 1 H), 9.70 (s, 1 H), 9.45 (td, J = 1 .2, 7.2 Hz, 1 H), 8.61 (s, 1 H), 7.95 (dd, J = 2.4, 7.6 Hz, 1 H), 7.79 (td, J = 1 .2, 8.8 Hz, 1 H), 7.51 -7.60 (m , 2H), 7.31 -7.37 (m, 1 H), 7.19 (dt, J = 1 .2, 6.8, 1 H), 5.88 (s, 2H). MS m/z 314.1 (M+1 ) +. | |
With sodium hydrogencarbonate; tin(ll) chloride; In ethyl acetate; | 4-Fluoro-3-nitrobenzonitrile (1) (2 g, 0.012 mol) in ethyl acetate(50 mL) was supplemented with stannous chloride (11.4 g,0.06 mol). The reaction mixture was stirred for 30 min and then a saturated solution of sodium hydrogenocarbonate (100 mL) was added. This mixture was treated with ethyl acetate (300 mL) andthe aqueous layer was separated. The ethyl acetate layer was evaporated under reduced pressure. The crude product was dissolved in methanol, and ice was added; the resulting precipitate was collected by filtration (Yield: 30e60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | Step A 2-(4-Cyano-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile To a suspension of sodium hydride (60%, 0.58 g) in THF (2 mL), was added 4-fluoro-3-nitro-benzonitrile (1.33 g, 8.0 mmol) and <strong>[138564-58-6]2-amino-5-methyl-thiophene-3-carbonitrile</strong> (1.10 g, 8.0 mmol) in THF (10 mL), dropwise. The mixture was stirred at room temperature overnight. Two more batches of sodium hydride (60%, 0.50 g and 0.4 g) were added over the next 6 hours. After stirring for 3 days, the mixture was poured into ice-water (20 mL) and acidified to pH 3 with 6N hydrochloric acid (7 mL). The precipitate was filtered and washed with water. The solid was extracted with dichloromethane (35 mL). The solution was concentrated to a solid, and used in the next step without additional purification. LC-MS: m/z 285 (M+1), 307 (M+23). 1H NMR (CDCl3, 400 MHz): delta (ppm) 9.76 (s, 1H), 8.59 (s, 1H), 7.70 (d, 1H), 7.14 (d, 1H), 6.87 (s, 1H), 2.52 (s, 1H). | |
With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; | To a suspension of sodium hydride (60'Yo, 0.58 g) in THF (2 ml), wasadded 4-fluoro-3-nitro-benzonitrile (1.33 g, 8.0 rnmol) and 2-arnino-5-methylthiophene-3-carbonitrile (1. i 0 g, 8.0 rnmol) in THF (1 0 ml), dropwise. The mixture was stirred at room temperature overnight. Two more batches of sodium hydride(60%, 0.50 g and OA g) were added over the next 6 hours. After stirring for 3 days,the mixture was poured into ice-water (20 ml) and acidified to pH 3 with 6Nhydrochloric acid (7 ml). The precipitate was filtered and washed with water. Thesolid was extracted with dichloromethane (35 ml). The solution was concentrated toa solid, and used in the next step without additional purification. LC-MS: rn/z 285(M+1 ), 307 (M+23). 1H NMR (CDCb, 400 MHz): i5 (ppm) 9.76 (s, 1 H), 8.59 (s, 1 H),7.70 (d, 1H), 7.14 (d, 1H), 6.87 (s, 1H), 2.52 (s, 1H). | |
With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 72h; | To a suspension of sodium hydride (60%, 0.58 g) in THF (2 rnL), was added 4-fluoro-3-nitro-benzonitrile (1 .33 g, 8.0 mmol) and 2-amino-5-methy1-thiophene-3-carbonitrile (1.10 g, 8.0 rmnol) in THF (10 mL), dropwise. The mixture was stirred at room temperature overnight. Two more batches of sodium hydride (60%, 0.50 g and 0.4 g)were added over the next 6 hours. After stirring for 3 days, the mixture was poured into ice-water (20 mL) and acidified to pH 3 with 6N hydrochloric acid (7 mL). The precipitate was filtered and washed with water. The solid was extracted with dichloromethane (35 mL). The solution was concentrated to a solid, and used in the next step without additional purification. LC-MS: rn/z 285 (M+ 1), 307 (M+23). 1H NMR (CDCl3, 400 MHz): delta (ppm) 9.76 (s, 1H), 8.59 (s, 1H), 7.70 (d, 1H), 7.14 (d, 1H), 6.87 (s, 1H), 2.52 (s, 1H). |
Tags: 4-Fluoro-3-nitrobenzonitrile | Fluorinated Building Blocks | Nitriles | Nitroes | Aryls | Organic Building Blocks | 1009-35-4
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H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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