* 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.
Reference：
[1] Organic Process Research and Development, 2007, vol. 11, # 4, p. 716 - 720
3
[ 695-37-4 ]
[ 7677-24-9 ]
[ 97509-75-6 ]
Yield
Reaction Conditions
Operation in experiment
84%
at 20℃; for 10 h; Heating / reflux
To solution of intermediate A (2. 85 g, 25.2 mmol) in dichloromethane (25 ml) at rt was added trimethylsilylcyanide (10.0 mL, 75.6 mmol) and the mixture was refluxed for 10h. After cooling to rt, saturated aqueous sodium bicarbonate solution (30 mL) was added and the reulting mixture was extracted with dichloromethane (3 x 150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provided a light brown oil (4.60 g) as the crude product. This material was purified by flash column chromatography on silicas gel eluting with 30percent ethyl acetate in hexane to provide a light tan oil which solidified upon standing to give product B as a light tan solid (2.48 g, 84). HPLC Ret. Time: 1.03 min.
Reference：
[1] Patent: WO2003/90912, 2003, A1, . Location in patent: Page/Page column 65
[2] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 2, p. 565 - 571
[3] Patent: WO2006/12374, 2006, A1, . Location in patent: Page/Page column 213
[4] Patent: US2004/77605, 2004, A1,
[5] Patent: US2003/232842, 2003, A1, . Location in patent: Page 7-8
[6] Patent: US2007/3539, 2007, A1, . Location in patent: Page/Page column 72
4
[ 152126-32-4 ]
[ 97509-75-6 ]
Reference：
[1] Organic Process Research and Development, 2004, vol. 8, # 2, p. 192 - 200
[2] Patent: US2011/105753, 2011, A1, . Location in patent: Page/Page column 5
[3] Patent: WO2011/56806, 2011, A1, . Location in patent: Page/Page column 10; 11
With potassium fluoride In 1-methyl-pyrrolidin-2-one
A solution of 2-cyano-3-chloropyridine (1 g, 7.22 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was treated with potassium fluoride (1.26 g, 21.68 mmol) and heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 442 mg (50percent) of 2-cyano-3-fluoropyridine.
Reference：
[1] Patent: US2003/55085, 2003, A1,
8
[ 372-47-4 ]
[ 97509-75-6 ]
Reference：
[1] Patent: US2011/105753, 2011, A1,
[2] Patent: WO2011/56806, 2011, A1,
[3] Organic Process Research and Development, 2004, vol. 8, # 2, p. 192 - 200
[4] Patent: WO2003/90912, 2003, A1,
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 28, p. 9499 - 9502
11
[ 929568-98-9 ]
[ 97509-75-6 ]
Reference：
[1] Organic Process Research and Development, 2004, vol. 8, # 2, p. 192 - 200
12
[ 97509-75-6 ]
[ 114080-93-2 ]
Reference：
[1] Green Chemistry, 2016, vol. 18, # 18, p. 4941 - 4946
13
[ 546-88-3 ]
[ 97509-75-6 ]
[ 114080-93-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 14, p. 3142 - 3145
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 14, p. 3142 - 3145
14
[ 97509-75-6 ]
[ 669066-35-7 ]
Yield
Reaction Conditions
Operation in experiment
55.2%
Stage #1: With n-butyllithium; diisopropylamine; lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.583333 h; Stage #2: With iodine In tetrahydrofuran for 0.75 h;
Pre aration 86A: 3-Fluoro-4-iodopicolinonitrile[00297] To a solution of diisopropylamine (2.80 ml, 19.66 mmol) in THF (Volume: 201 ml) cooled to -78 °C was added n-butyllithium (7.86 ml, 19.66 mmol) dropwise. The dry ice/acetone bath was replaced with an ice water bath and reaction mixture was stirred at 0 °C for 25 min, and then re-cooled to -78 °C. In a separate flask, a solution of 3- fluoropicolinonitrile (1.5 g, 12.29 mmol) in THF (50 mL) was cooled to -78 °C, and then LDA (130 mL, 1.0 equiv) was added. The solution turned dark red. After 35 min, iodine (3.43 g, 13.51 mmol) was added rapidly. The reaction mixture was stirred for 45 min, then quenched with H20. Layers were separated and the aqueous phase extracted with CH2CI2 (2X). Organics combined, dried over Na2S04, filtered, and concentrated to afford a brown residue. The crude material was dissolved in a minimal amount of CH2CI2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-20percent EtOAc in hexanes over 23 min, tr = 18 min) gave the title compound (1.7 g, 6.79 mmol, 55.2percent yield) as a brown solid.
31.5%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.416667 h; Stage #2: With iodine In tetrahydrofuran; hexane at -78℃; for 0.666667 h;
[0088] Preparation 1 : 7-iodo-lH-pyrazolo[4,3-b]pyridine [0089] Diisopropylamine (50.9 mL, 360 mmol) was added to THF (1600 mL), and the mixture was cooled to 0 °C in an ice bath and then n-butyllithium (137.6 ml, 2.5 M in hexane) was added drop wise at 0 °C, and stirred for another 30 minutes. The mixture was then cooled to -78 °C, and a solution of 2-cyano-3-fluoropyridine (40 g, 328 mmol) in 300 mL of THF was added. After 25 minutes, a solution of I2 (83.2 g, 328 mmol) in THF (80mL) was added and the reaction was stirred for 40 minutes at -78 °C. The reaction was removed from the cooling bath and quenched with 400 mL sodium thiosulfate solution (10percent aq.) followed by water (400 mL). The reaction mixture was diluted with ether (400 mL), and the layers were separated. The organic layer were washed with brine, dried over sodium sulfate, filtered and concentrated to a brown solid. The solid was purified with silica column chromatography eluted with 95:5 hexanes: ethyl acetate to give 3-fluoro-4- iodopicolinonitrile (25.6 g, 31.5 percent yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25 - 8.26 (m, 1 H) 8.35 (t, J=5.05 Hz, 1 H). MS [M+H] found 249.0.
In dichloromethane; at 20℃; for 10h;Heating / reflux;
To solution of intermediate A (2. 85 g, 25.2 mmol) in dichloromethane (25 ml) at rt was added trimethylsilylcyanide (10.0 mL, 75.6 mmol) and the mixture was refluxed for 10h. After cooling to rt, saturated aqueous sodium bicarbonate solution (30 mL) was added and the reulting mixture was extracted with dichloromethane (3 x 150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provided a light brown oil (4.60 g) as the crude product. This material was purified by flash column chromatography on silicas gel eluting with 30percent ethyl acetate in hexane to provide a light tan oil which solidified upon standing to give product B as a light tan solid (2.48 g, 84). HPLC Ret. Time: 1.03 min.
With triethylamine; In acetonitrile;Heating / reflux;
The mixture of 3-fluoro-pyridine 1-oxide (0.99 g, 8.75mrnol), trimethylsilyl cyanide (4.80 ml, 35.0 mmol), andtriethyl amine (1.84 ml, 13.2 mmol) in 100 ml of CH3CN washeated at reflux overnight. The solvents were removed, underreduced pressure and the residue was partitioned betweenEtOAc and saturated NaHC03. The organic portion wasseparated, dried with Na2S04, filtered, condensed, the crudecompound as purified by flash column chromatography (10 to20percent of EtOAc in hexanes). The titled compound was obtainedas a light yellowish solid. MS (ES+) : 123.1 (M+H) + . Calc'dfor C6H3FN2 - 122.10.
With triethylamine; In acetonitrile;
B. 2-Cyano-3-fluoropyridine (771B) 3-Fluoropyridine-1-oxide (10.0 g, 88.4 mmol), trimethylsilylcyanide (26.32 g, 265.3 mmol), and triethylamine (17.89 g, 177 mmol) were reacted in 90 mL of acetonitrile utilizing the procedure described in example 762B. Purification of the crude by silica gel chomatography using CH2Cl2 as eluent gives compound 771B (7.5 g, 70percent) as a light yellow solid.
With triethylamine; In acetonitrile;Heating / reflux;
[0157] 5.20 g (45.980 mmol) of the compound from Example I are dissolved in 50 ml of acetonitrile. Under argon, 13.70 g (138.092 mmol) of trimethylsilylnitrile are added and 12.80 ml of triethylamine are slowly run in. The solution is stirred under reflux for 7 hours and then at room temperature overnight. Concentration using a waterpump is followed by taking up in dichloromethane, shaking twice with 50 ml of 2N aqueous sodium carbonate solution, washing with water, drying and concentrating. [0158] Yield (crude): 5.3 g (oil) [0159] Column chromatography: methylene chloride to methylene chloride/ethyl acetate (10:1)
In dichloromethane; for 16h;Heating / reflux;
To 72A (4.4 g, 39 mmol) in CH2Cl2 (150 mL) was added trimethylsilyl cyanide (8.3 mL, 62 mmol). The mixture was heated at reflux for 6 h. Additional trimethylsilyl cyanide (16 mL) was added and refluxed for additional 10 h. After cooled to rt, the reaction was quenched by addition of 100 mL of sat. NaHCO3. The organic layer was collected and dried over Na2SO4. The crude product was purified by column chromatography (EtOAc:hexanes=6:9) to give 72B (2.5 g) as a solid. 1H NMR (400 MHz, CDCl3) delta ppm 8.57 (m, 1 H), 7.61 (m, 2 H).
With ammonium hydroxide; caesium carbonate; In methanol; dichloromethane; N,N-dimethyl-formamide;
Step A Preparation of 3-[1,2,4]Triazol-1-yl-pyridine-2-carbonitrile To a solution of <strong>[97509-75-6]2-cyano-3-fluoro-pyridine</strong> (2.99 g, 24.49 mmol, preparation described in Sakamoto et.al., Chem. Pharm. Bull. 1985, 33(2), 565-571) in DMF (30 ml) is added cesium carbonate (2.03 g, 29.39 mmol) and 1,2,4-triazole (2.03 g, 29.39 mmol) and the reaction mixture is stirred at 65° C. for 4 h. After cooling to room temperature, the mixture is diluted with water and extracted with EtOAc 3 times. The aqueous layer is saturated with LiCl and further extracted with EtOAc. The combined organic layer is dried on sodium sulfate, concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 2percent MeOH containing 10percent NH4OH in CH2Cl2 to 6percent) to give 3-[1,2,4]triazol-1-yl-pyridine-2-carbonitrile. 1H NMR (CDCl3, 400 MHz) delta 8.95 ((s, 1H); 8.8 (d, J=4 Hz, 1H); 8.24 (s, 1H); 8.22 (d, J=8.5 Hz, 1H); 7.75 (dd, J=4, 8.5 Hz, 1H).
With ammonium hydroxide; caesium carbonate; In methanol; dichloromethane; N,N-dimethyl-formamide;
Step A. 3-[1,2,4]Triazol-1-yl-pyridine-2-carbonitrile To a solution of <strong>[97509-75-6]2-cyano-3-fluoro-pyridine</strong> (2.99 g, 24.49 mmol) in DMF (30 ml) is added cesium carbonate (2.03 g, 29.39 mmol) and 1,2,4-triazole (2.03 g, 29.39 mmol) and the reaction mixture is stirred at 65° C. for 4 h. After cooling to room temperature, the mixture is diluted with water and extracted with EtOAc 3 times. The aqueous layer is saturated with LiCl and further extracted with EtOAc. The combined organic layer is dried on sodium sulfate, concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 2percent MeOH containing 10percent NH4OH in CH2Cl2 to 6percent) to give 3-[1,2,4]Triazol-1-yl-pyridine-2-carbonitrile. 1H NMR (CDCl3, 400 MHz) delta8.95 (s, 1H); 8.8 (d, J=4 Hz, 1 H); 8.24 (s, 1H); 8.22 (d, J=8.5 Hz, 1H); 7.75 (dd, J=4, 8.5 Hz, 1 H).
2-aminomethyl-3-fluoropyridine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; hydrogen;10% palladium on activated carbon; In ethanol; under 2068.65 Torr; for 16h;
A stirred solution of 6.11 g (50.1 mmol) of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> in 250 mL of ethanol and 12.5 mL (150 mmol) of conc. HCl was hydrogenated over 1.90 g of 10percent palladium on carbon at 40 psi for 16 h. The catalyst was removed by filtration and the solvents removed at reduced pressure. The resulting solid was diluted with acetonitrile and filtered to give 8.0 g of the title compound as an off-white solid: 1H NMR (CD3OD) delta8.48 (d, 1H, 4.8 Hz), 7.69 (td,1H, 9.2, 1.1 Hz), 7.68 (ddd, 1H, 8.8, 4.4, 4.4 Hz), 4.34 (s, 2 H).
Step 4:1-(3-fluoropyridin-2-yl)methanamine dihydrochloride salt (K1)3 g of <strong>[97509-75-6]3-fluoropyridine-2-carbonitrile</strong> (D) (crude), 50 mL of acetic acid and 0.75 g of Raney Ni were taken in a par shaker vessel.The reaction mass was hydrogenated for 4 hours under 6 kg hydrogen pressure at RT.After completion of the reaction, the catalyst was filtered off and the bed was washed with 30 mL of isopropyl alcohol (IPA).The combined filtrate was concentrated under vacuum.To this mass, 30 mL of toluene was added and distilled off to a minimum volume.To the above residue, 20 mL of toluene and 13 mL of IPA.HCl was added dropwise at RT with stirring.After 30 minutes, the RM temperature was brought to 10 to 15° C. and maintained for 30 minutes.The RM was filtered, and the solid was washed with 5 mL of cold IPA, and dried under vacuum at 40° C., resulting in 3.8 g of 1-(3-fluoropyridin-2-yl)methanamine dihydrochloride salt (K1).
3g of 3-Fluoropyridine-2-carbonitrile (D) (crude), 50 mL of acetic acid and 0.75 g of Raney Ni were taken in a par shaker vessel. The reaction mass was hydrogenated for 4 hours under 6 kg hydrogen pressure at RT. After completion of the reaction, the catalyst was filtered off and the bed was washed with 30 mL of isopropyl alcohol (IPA). The combined filtrate was concentrated under vacuum. To this mass, 30 mL of toluene was added and distilled off to a minimum volume. To the above residue, 20 mL of toluene and 13 mL of IPA.HC1 was added dropwise at RT with stirring. After 30 minutes, the RM temperature was brought to 10 to 15 C and maintained for 30 minutes. The RM was filtered, and the solid was washed with 5 mL of cold IPA, and dried under vacuum at 40 C, resulting in 3.8 g of l-(3-fluoropyridin-2-yl)methanamine dihydrochloride salt (Kl).
With hydrogenchloride; C23H28N6O3;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 20h;
To intermediate B (1.40 g) in ethanol (50 ml) were successively added 10percent palladium on carbon (500 mg) and concentrated hydrogen chloride (2.9 ml) and the resulting mixture was shaken under hydrogen (40 psi) for 20 h. The solution was filtered through a bed of celite and the filtrate was concentrated in vacuo to give 1.80 g of product C as a white solid. HPLC Ret. Time: 0.19 min.
2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2<i>H</i>-pyrazin-1-yl]-<i>N</i>-(3-[1,2,4]triazol-1-yl-pyridin-2-ylmethyl)-acetamide[ No CAS ]
2-[3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-6-trifluoromethyl-2<i>H</i>-pyrazin-1-yl]-<i>N</i>-(3-fluoro-pyridin-2-ylmethyl)-acetamide[ No CAS ]
2-{3-[2,2-difluoro-2-(1-oxy-pyridin-2-yl)-ethylamino]-2-oxo-6-trifluoromethyl-2<i>H</i>-pyrazin-1-yl}-<i>N</i>-(3-fluoro-pyridin-2-ylmethyl)-acetamide[ No CAS ]
With trimethylsilyl cyanide; triethylamine; In acetonitrile;Heating / reflux;
The mixture of 3-fluoro-pyridine 1-oxide (0.99 g, 8.75 mmol), trimethylsilyl cyanide (4.80 ml, 35.0 mmol), and Et3N (1.84 ml, 13.2 mmol) in 100 ml of CH3CN was heated at reflux overnight. The solvents were removed, under reduced pressure and the residue was partitioned between EtOAc and saturated NaHCO3. The organic portion was separated, dried with Na2SO4, filtered, condensed, the crude compound was purified by flash column chromatography (10 to 20percent of EtOAc in hexanes). [1971] The titled compound was obtained as a light yellowish solid. MS (ES+): 123.1 (M+H)+. Calc'd for C6H3FN2 - 122.10.
With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 4h;
The mixture of <strong>[97509-75-6]3-fluoro-pyridine-2-carbonitrile</strong> (0.81 g,6.63 mmol) and Pd/C (0.20 g, 10percent wt) in 10 ml of MeOH and2.7 ml of concentrated HC1 was placed under H2 which wasprovided by a balloon and stirred at RT for 4 h, filteredthrough Celite.(R)., condensed, the residue was purified byflash column chromatography, 0.13 g of the titled compoundwas obtained as a light yellowish oil. MS(ES+): 127.1(M+H)+. Calc'd for C6H7PN2 - 126.13.
With hydrogenchloride;palladium; In ethanol;
2-Aminomethyl-3-fluoropyridine as a dihydrochloride salt A stirred solution of 6.11 g (50.1 mmol) of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> in 250 mL of ethanol and 12.5 mL (150 mmol) of conc. HCl was hydrogenated over 1.90 g of 10percent palladium on carbon at 40 psi for 16 h. The catalyst was removed by filtration and the solvents removed at reduced pressure. The resulting solid was diluted with acetonitrile and filtered to give 8.0 g of the title compound as an off-white solid: 1H NMR (CD3OD) delta8.48 (d, 1H, 4.8 Hz), 7.69 (td,1H, 9.2, 1.1 Hz), 7.68 (ddd, 1H, 8.8, 4.4, 4.4 Hz), 4.34 (s, 2 H).
With hydrogenchloride;palladium; In ethanol;
Step A 2-Aminomethyl-3-fluoropyridine (B) as a dihydrochloride salt A stirred solution of 6.11 g (50.1 mmol) of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> in 250 mL of ethanol and 12.5 mL (150 mmol) of conc. HCl was hydrogenated over 1.90 g of 10percent palladium on carbon at 40 psi for 16 h. The catalyst was removed by filtration and the solvents removed at reduced pressure. The resulting solid was diluted with acetonitrile and filtered to give the title compound as an off-white solid: 1H NMR (CD3OD) delta8.48 (d, 1H, 4.8 Hz), 7.69 (td,1H, 9.2, 1.1 Hz), 7.68 (ddd, 1H, 8.8, 4.4, 4.4 Hz), 4.34 (s, 2H).
With hydrogenchloride;palladium 10% on activated carbon; In methanol; water;
The mixture of <strong>[97509-75-6]3-fluoro-pyridine-2-carbonitrile</strong> (0.81 g, 6.63 mmol) and Pd/C (0.20 g, 10percent wt) in 10 ml of MeOH and 2.7 ml of concentrated HCl was placed under H2 which was provided by a balloon and stirred at RT for 4 h, filtered through Celite.(R)., condensed, the residue was purified by flash column chromatography. The titled compound was obtained as a light yellowish oil. MS (ES+): 127.1 (M+H)+. Calc'd for C6H7FN2 - 126.13.
A sodium methoxide solution made from 0.40 g (17.391 mmol) of sodium and 65 ml of methanol is added to a solution of 10.30 g (84.355 mmol) of the compound from Example II in 30 ml of methanol, and the mixture is stirred at 20° C. for 72 hours. 5.44 g (101.682 mmol) of ammonium chloride (powdered) and 17.39 mmol (1.04 ml) of acetic acid are added, and the mixture is stirred at 40° C. for 28 hours and cooled. Insoluble salt is filtered off with suction (1.78 g), and the filtrate is concentrated, concentrated with acetone and then stirred with acetone, filtered off with suction and washed. Yield: 10.6 g. Melting point: 150° C. decomposition.
1.15 g
With diisobutylaluminum hydride; ammonium chloride; In toluene; at 80℃;
To a mixture of ammonium chloride (1.34 g) and toluene (15 mL) was added a solution (1.5 M, 15.3 mL) of diisobutylaluminum hydride in toluene at 0°C, and the mixture was stirred at 80°C for 20 min. To the reaction mixture was added <strong>[97509-75-6]3-fluoropyridine-2-carbonitrile</strong> (0.6 g), and the mixture was stirred at 80°C overnight. To the reaction mixture was added methanol at 0°C, and the mixture was stirred at room temperature for 3 hr, filtered, and insoluble material was washed with methanol. The obtained filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (1.15 g). MS: [M+H]+ 140.1.
With triethylamine; In N,N-dimethyl acetamide; at 80℃; for 4h;
2, 4-DIMETHOXYBENZYLAMINE (3.29 g, 19. 7 mmol) and triethylamine (1.99 g, 19.7 mmol) were added sequentially to a solution of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> (2.0 g, 16.4 mmol) (Sakamoto et. AL., Chem. PHARM. Bull., 1985, 33, 565-71) in N, N-DIMETHYLACETAMIDE (29 mL). The reaction was heated at 80 oC for 4 h, quenched with water and extracted with diethyl ether (3x). The combined organic extracts were washed water, saturated brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 0- 12percent ethyl acetate (with 0.1 triethylamine) in dichloromethane gradient elution) to produce the title compound (3.25 g). MS 270.3 (M + 1).
Pre aration 86A: 3-Fluoro-4-iodopicolinonitrile[00297] To a solution of diisopropylamine (2.80 ml, 19.66 mmol) in THF (Volume: 201 ml) cooled to -78 C was added n-butyllithium (7.86 ml, 19.66 mmol) dropwise. The dry ice/acetone bath was replaced with an ice water bath and reaction mixture was stirred at 0 C for 25 min, and then re-cooled to -78 C. In a separate flask, a solution of 3- fluoropicolinonitrile (1.5 g, 12.29 mmol) in THF (50 mL) was cooled to -78 C, and then LDA (130 mL, 1.0 equiv) was added. The solution turned dark red. After 35 min, iodine (3.43 g, 13.51 mmol) was added rapidly. The reaction mixture was stirred for 45 min, then quenched with H20. Layers were separated and the aqueous phase extracted with CH2CI2 (2X). Organics combined, dried over Na2S04, filtered, and concentrated to afford a brown residue. The crude material was dissolved in a minimal amount of CH2CI2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-20% EtOAc in hexanes over 23 min, tr = 18 min) gave the title compound (1.7 g, 6.79 mmol, 55.2% yield) as a brown solid.
31.5%
[0088] Preparation 1 : 7-iodo-lH-pyrazolo[4,3-b]pyridine [0089] Diisopropylamine (50.9 mL, 360 mmol) was added to THF (1600 mL), and the mixture was cooled to 0 C in an ice bath and then n-butyllithium (137.6 ml, 2.5 M in hexane) was added drop wise at 0 C, and stirred for another 30 minutes. The mixture was then cooled to -78 C, and a solution of 2-cyano-3-fluoropyridine (40 g, 328 mmol) in 300 mL of THF was added. After 25 minutes, a solution of I2 (83.2 g, 328 mmol) in THF (80mL) was added and the reaction was stirred for 40 minutes at -78 C. The reaction was removed from the cooling bath and quenched with 400 mL sodium thiosulfate solution (10% aq.) followed by water (400 mL). The reaction mixture was diluted with ether (400 mL), and the layers were separated. The organic layer were washed with brine, dried over sodium sulfate, filtered and concentrated to a brown solid. The solid was purified with silica column chromatography eluted with 95:5 hexanes: ethyl acetate to give 3-fluoro-4- iodopicolinonitrile (25.6 g, 31.5 % yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.25 - 8.26 (m, 1 H) 8.35 (t, J=5.05 Hz, 1 H). MS [M+H] found 249.0.
A solution of LDA (40.9 mmol, prepared from 11.4 mL of diisopropylamine and 16.4 mL of 2.5 M n-butyl lithium in hexanes) in 200 mL THE at-78C was treated with 2-cyano-3-fluoropyridine (5.0 g, 40.9 mmol) in 50 mL of THF drop-wise. After 10 minutes a solution of iodine (10.4 g, 40.9 mmol) in 10 mL of THF was added. After 30 minutes the reaction was quenched with 40 mL of water followed by workup with aqueous sodium thiosulfate. The mixture was diluted with ether, washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-20% ethyl acetate in hexanes to provide 3-fluoro-4-iodopyridine-2- carbonitrile that gave proton NMR spectra consistent with theory
With n-butyllithium; diisopropylamine; In tetrahydrofuran; water; ethyl acetate;
To a cold (0 C.) solution of diisopropylamine (4.84 mL, 32 mmol) in THF (82.3 mL) was added n-butyllithium (12.8 mL, 2.5 M in hexanes, 32 mmol) dropwise. The resultant solution was stirred at 0 C. for 15 minutes to give a 0.32 M stock solution of LDA. To a cold (-78 C.) solution of LDA (74 mL, 0.32 M in THF, 23.7 mmol) in THF (50 mL) was added 3-fluoro-2-pyridinecarbonitrile (2.4 g, 19.7 mmol) (Sakamoto et. al. Chem. Pharm. Bull. 1985, 33, 565) as a solution in THF (20 mL). After 15 minutes, a solution of I2 (5.49 g, 21.6 mmol) in THF (20 mL) was added rapidly and the resultant suspension was stirred for 20 minutes at -78 C. The reaction mixture was quenched by the addition of water and warmed to ambient temperature. Ethyl acetate was added and the organic layer was washed successively with sodium thiosulfate, and brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulphate. Filtration and concentration followed by purification by silica gel chromatography provided 3-fluoro-4-iodo-2-pyridinecarbonitrile (3.6 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.14 (d, J=4.8 Hz, 1H), 7.98 (t, J=4.8 Hz, 1H).
With sodium hydroxide; hydroxylamine hydrochloride; In ethanol;
Using the general procedure for the synthesis of amidoximes, <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> (442 mg, 3.62 mmol), a solution of hydroxylamine hydrochloride (0.82 mL of 5 M, 4.1 mmol) in ethanol (5 mL), and sodium hydroxide (0.415 ml of 10N, 4.15 mmol) were heated at reflux for 24 hours. Standard work up afforded 368 mg (66percent) of 3-fluoropyrid-2-ylamidoxime.
With potassium fluoride; In 1-methyl-pyrrolidin-2-one;
A solution of <strong>[38180-46-0]2-cyano-3-chloropyridine</strong> (1 g, 7.22 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was treated with potassium fluoride (1.26 g, 21.68 mmol) and heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 442 mg (50%) of 2-cyano-3-fluoropyridine.
With 1H-tetrazole; In ethyl acetate; N,N-dimethyl-formamide;
Step A. 3-(tetrazol-1-yl)cyanopyridine To a stirred solution of tetrazole (1.0 g; 14 mmol) in DMF (150 mL) was added 40percent aqueous tetrabutylammonium hydroxide (7.8 g; 12 mmol). The solvent was removed under reduced pressure. To ensure removal of all the water from the tetrabutylammonium hydroxide solution, the residue was redissolved in DMF and the solution was evaporated under reduced pressure. This procedure was repeated a total of three times. The residue was then dissolved in DMF (60 mL) and 3-fluoro-2-cyanopyridine (1.5 g; 12 mmol) was added. The reaction was stirred at ambient temperature under inert atmosphere for four days, at which time hplc analysis indicated about 65percent conversion of the 3-fluoro-2-cyanopyridine to new products. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a gradient elution of 1:4 to 100:0 EtOAc:hexanes to give 3-(tetrazol-1-yl)cyanopyridine as a white crystalline solid (TLC Rf=0.5, 1:1 EtOAc-hexanes; hplc retention time=2.04 min, method X; 1H NMR (CDCl3) delta9.42 (s, 1H), 8.94 (dd, J=1.3, 4.6 Hz, 1H), 8.31 (dd, J=1.3, 8.4 Hz, 1H), 7.87 (dd, J=4.6, 8.4 Hz, 1H).
Step A 2-Cyano-3-(2-hydroxy-2-methylpropanethio)pyridine A stirred solution of 2.44 g (20.0 mmol) of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong>, 2.34 g (22.0 mmol) of 2-hydroxy-2-methylpropanethiol, and 1.68 g (20.0 mmol) of sodium hydrogencarbonate in 50 ml of methanol was heated to reflux for 3 hours. The reaction was cooled to room temperature and partitioned between water (200 mL) and methylene chloride (3*150 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. This residue was chromatographed on SiO2 using 3:97 methanol-chloroform, yielding a white solid: 1H NMR (CDCl3): delta1.39 (s, 6H), 3.18 (s, 2H), 7.42 (dd, 1H), 7.94 (dd, 1H), 8.49 (dd, 1H).
Step C 2-Cyano-3-(2-methyl-2-trifluoroacetamidopropanethio)-pyridine A solution of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> (0.20 g, 1.64 mmol), 2-methyl-2-trifluroacetamidopropanethiol (330 mg, 1.64 mmol) and sodium hydrogen carbonate (0.138 g, 1.64 mmol) in methanol (16 mL) was stirred at room temperature for 64 h. The reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography on silica (eluding with chloroform) to give the title compound: 1H NMR (CDCl3) delta1H NMR (CDCl3) delta1.55 (s, 6H), 3.56 (s, 2H), 6.17 (br s, 1H), 7.44 (dd, 4.6, 8.2 Hz, 1H), 7.88 (dd, J=1.5 and 8.2 Hz, 1H), 8.46 (dd, J=1.5 and 4.6 Hz, 1H).
Step A 2-Cyano-3-(2,2,2-trifluoroethoxy)pyridine A stirred solution of 680 mg (6.80 mmol) of 2,2,2-trifluoroethanol in 25 mL of THF was added 273 mg (6.83 mmol) of sodium hydride (60percent dispersion). After 30 min at room temperature, 822 mg (6.73 mmol) of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> in 5 mL THF was added via syringe. The reaction was quenched after 1 h, by the addition of 15percent K2CO3 aqueous solution. Concentration gave an oil that was partitioned between water and EtOAc. The layers were separated, the aqueous phase was backwashed with EtOAc (2*), and the combined organic layers were dried (MgSO4) and concentrated to an orange oil. The resultant crude residue was chromatographed on SiO2 using 25:75 EtOAc-hexanes to afford the title compound as a yellow oil: 1H NMR (CDCl3) delta8.43 (d,1H, 4.6 Hz), 7.55 (dd, 1H, 4.6, 8.7 Hz), 7.42 (d, 1H, 8.7 Hz), 4.55 (q, 2H, 7.8 Hz).
Step A 2-Cyano-3-methylthiopyridine A stirred solution of 1.00 g (8.19 mmol) of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> and 0.631 g (9.01 mmol) of sodium thiomethoxide in 8 mL of DMF was stirred at room temperature for 1 h. The reaction mixture was diluted with water (80 mL) and stirred for 5 min. The resulting solid was filtered and dried on a high vacuum line to give the product as an off-white solid: 1H NMR (CDCl3) delta8.46 (d,1H, 4.6 Hz), 7.66 (d, 1H, 8.3 Hz), 7.44 (dd, 1H, 4.6, 8.3 Hz), 2.58 (s, 3H).
In N,N-dimethyl-formamide;
2-Cyano-3-methylthiopyridine (3-1) A stirred solution of 1.00 g (8.19 mmol) of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> and 0.631g (9.01 mmol) of sodium thiomethoxide in 8 mL of DMF was stirred at room temperature for 1 h. The reaction mixture was diluted with water (80 mL) and stirred for 5 min. The resulting solid was filtered and dried on a high vacuum line to give 3-1 as an off-white solid: 1H NMR (CDCl3) delta 8.46 (d, 1H, 4.6 Hz), 7.66 (d, 1H, 8.3 Hz), 7.44 (dd, 1H, 4.6, 8.3 Hz), 2.58 (s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 18h;
To a solution of 72B (246 mg, 2.0 mmol) in DMF (5.0 mL) was added K2CO3 (484 mg, 3.5 mmol) and propane-2-thiol (0.33 mL, 3.5 mmol). The reaction was heated at 40° C. for 18 h. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4. After evaporation of solvent, 72C (300 mg) was obtained as viscous oil. It was used for next step without further purification. 1H NMR (400 MHz, CDCl3) delta ppm 1.36 (d, J=6.59 Hz, 6 H) 3.45-3.70 (m, 1 H) 7.43 (dd, J=8.13, 4.61 Hz, 1 H) 8.42-8.66 (m, 1 H).
With trifluoroacetic anhydride; In dichloromethane;
C. 2-Cyano-3-fluoro-5-nitropyridine (771C) 2-Cyano-3-fluoropyridine (6.5 g, 53.2 mmol), tetrabutylammonium nitrate (21.07 g, 69.2 mmol), and trifluoroacetic anhydride (14.53 g, 69.2 mmol) were reacted in 245 mL of CH2Cl2 utilizing the procedure described in example 762C. Purification of the crude by silica gel chomatography using 20percent hexanes/CH2Cl2 gave compound 771C (0.12 g, 1.3percent) as a yellow oil.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 15h;
To a solution of 1,1-dimethylethyl (35)-3-pyrrolidinylcarbamate (0.763 g, 4.10 mmol) and <strong>[97509-75-6]3-fluoro-2-pyridinecarbonitrile</strong> (0.500 g, 4.10 mmol) in DMF (5.0 mL) was added K2CO3 (1.132 g, 8.19 mmol). The reaction mixture was heated to 100 0C for 15 h. Upon cooling, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (3 x 30 mL) and concentrated in vacuo. Purification via flash column chromatography (30-100percent EtOAc/hexanes) afforded the title compound (1.36 g, >100percent, contained some residual solvent) as a colorless oil. LC-MS m/z 289 (M+H)+, 1.36 min (ret time).
With triethylamine; trifluoroacetic anhydride; In tetrahydrofuran; at 0 - 10℃; for 3h;
Step 3:3-fluoropyridine-2-carbonitrile (D)30 g of 3-fluoropyridine-2-carboxamide (C), 120 mL of THF and 768.5 mL of TEA were taken in a reaction flask and cooled to 0-5° C.To this mixture, 72.2 mL of trifluoroacetic anhydride (in 30 mL of THF) was added dropwise over a period of 30 minutes keeping the reaction temperature below 5° C. (0° C. to 5° C.) and the RM was stirred for 2 hours 30 minutes at a temperature below 10° C. (5° C. to 10° C.).After completion of the reaction, 150 mL of 20percent Na2CO3 solution was added dropwise to the RM while maintaining the temperature below 10° C. (5° C. to 5° C.), followed by addition of 360 mL of purified water.The RM was brought to room temperature (RT) and extracted with dichloromethane (MDC) and the organic layer was washed with 300 mL purified water, 150 mL of 2percent dil HCl, followed by purified water and brine.The organic layer was dried over Na2SO4 and distilled under vacuum, resulting in the titled compound as a dark brown viscous oily mass.Crude Yield: 22-24 g.
30 g of 3-Fluoropyridine-2-carboxamide (C), 120 mL of THF and 768.5 mL of TEA were taken in a reaction flask and cooled to 0-5 C. To this mixture, 72.2 mL of Trifluoroacetic anhydride (in 30 mL of THF) was added dropwise over a period of 30 minutes keeping the reaction temperature below 5 C (0 C to 5 C) and the RM was stirred for 2 hours 30 minutes at a temperature below 10 C (5 C to 10 C). After completion of the reaction, 150 mL of 20percent Na2C03 solution was added dropwise to the RM while maintaining the temperature below 10 C (5 C to 5 C), followed by addition of 360 mL of purified water. The RM was brought to room temperature (RT) and extracted with dichloromethane (MDC) and the organic layer was washed with 300 mL purified water, 150 mL of 2percent dil HC1, followed by purified water and brine. The organic layer was dried over Na2S04 and distilled under vacuum, resulting in the titled compound as a dark brown viscous oily mass. Crude Yield: 22-24 g.
With potassium nitrate; trifluoroacetic acid; trifluoroacetic anhydride; for 48h;Inert atmosphere;
TFA (12.2 ml_, 164 mmol, 18.7 g, 2 eq) was added to KN03 (16.6 g, 164 mmol, 2 eq) under nitrogen atmosphere, followed by trifluoroacetic anhydride (11.4 mL, 17.2 g, 82 mmol, 1 eq). After 15 minutes <strong>[97509-75-6]3-fluoropicolinonitrile</strong> (10.0 g, 82 mmol) was added at once as an oil. After stirring for 48 h it was poured into saturated aq. NaHC03 (aq) (400 mL) and the mixture was extracted with ethyl acetate (3 * 300 mL). The combined organic layers were dried over sodium sulphate and concentrated to give a yellow oil. The crude product consisted of -20 percent of product and starting material according to H NMR. The oil was adsorbed on silica (100 g) using dichloromethane. The adsorbed silica was placed on top of a 10 cm pad of silica (-1 L) and the product was eluted with 20 percent ethyl acetate in heptane. The product-containing fractions were pooled to give 3-fluoro-5-nitropicolinonitrile as a white solid (2.1 g, 15 percent).
15%
With potassium nitrate; trifluoroacetic acid; trifluoroacetic anhydride; for 48h;Inert atmosphere;
Step 1 TFA (12.2 mL, 164 mmol, 18.7 g, 2 eq) was added to KNO3 (16.6 g, 164 mmol, 2 eq) under nitrogen atmosphere, followed by trifluoroacetic anhydride (11.4 mL, 17.2 g, 82 mmol, 1 eq). After 15 minutes <strong>[97509-75-6]3-fluoropicolinonitrile</strong> (10.0 g, 82 mmol) was added at once as an oil. After stirring for 48 h it was poured into saturated aq. NaHCO3 (aq) (400 mL) and the mixture was extracted with ethyl acetate (3*300 mL). The combined organic layers were dried over sodium sulfate and concentrated to give a yellow oil. The crude product consisted of ?20percent of product and starting material according to H NMR. The oil was adsorbed on silica (100 g) using dichloromethane. The adsorbed silica was placed on top of a 10 cm pad of silica (?1 L) and the product was eluted with 20percent ethyl acetate in heptane. The product-containing fractions were pooled to give 3-fluoro-5-nitropicolinonitrile as a white solid (2.1 g, 15percent).
With tetrabutylammonium nitrate; trifluoroacetic anhydride; In dichloromethane; at 0 - 20℃; for 72h;Inert atmosphere;
Step A: 3-Fluoro-5-nitropicolinonitrile A solution of tetrabutylammonium nitrate (11.14 g, 36.6 mmol) and trifiuoroacetic anhydride (5.16 mL, 36.6 mmol) in dry CH2C12 (43.2 mL) was added via cannula to a stirred solution of 2-cyano-3-fiuoropyridine (3.4376 g, 28.2 mmol) in dry CH2C12 (86 mL) at 0 °C under N2. The reaction was warmed to room temperature and stirred for 3 days. The reaction was quenched with satd aq. NaHC03 and extracted with CH2C12 (3 x). The combined extracts were dried (Na2S04) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Isco Combiflash Rf, RediSep Silica 80 g, 60 mL/min, loaded using solid loading cartridge after dissolving in CH2C12, 100percent hexanes for 3 min, gradient to 50percent EtOAc in hexanes over 24 min, isocratic at 50percent EtOAc in hexanes for 23 min) to afford in order of elution desired product 3-fluoro-5-nitropicolinonitrile, a as colorless solid. LCMS calc. = 168.02; found = 168.02 (M+H)+. NMR (500 MHz, CHCl3-d): 5 9.36 (d, J - 2.1 Hz, 1 H); 8.44 (dd, 7= 7.4, 2.1 Hz, 1 H).
In 1-methyl-pyrrolidin-2-one; at 250℃; for 0.166667h;Microwave irradiation;
General procedure: (R)-4-N-Boc-2-methylpiperazine (665 mg, 3.32 mmol), 1-adamantoyl chloride (990 mg, 4.98 mmol), and DIEA (1.15 mL, 6.64 mmol) were dissolved in 2.0 mL of dichloromethane, and the reaction was monitored by LCMS. Upon completion, 5.0 mL of MeOH was added, and the mixture was concentrated in vacuo. The residue was purified by flash chromatography. The purified product was immediately dissolved in 1.0 mL of MeOH and excess 4 N HCl in dioxanes (4.0 mL, 16 mmol). Once the protecting group had cleaved as judged by LCMS, an aqueous solution of saturated sodium bicarbonate was added until the pH was basic. The mixture was extracted with dichloromethane, and the organic layers were concentrated in vacuo to afford 814 mg (94percent yield) of adamantan-1-yl((R)-2-methylpiperazin-1-yl)methanone as a white solid. Adamantan-1-yl((R)-2-methylpiperazin-1-yl)methanone (355 mg, 1.35 mmol) and <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> (1.42 mL, 5.41 mmol) were dissolved in 4.0 mL of NMP in a microwave reaction vial and heated in the microwave for 10 min at 250 °C. The reaction mixture was purified via reverse phase chromatography (0.1percent TFA in H2O/MeCN). The fractions containing the product were combined and neutralized by the addition of aqueous saturated sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic layers were combined and concentrated in vacuo. The residue was dissolved in 1.0 mL of MeOH and 4 N HCl in dioxanes (3.0 mL, 12 mmol) and stirred for 2 h. The mixture was concentrated in vacuo to afford 212 mgs (39percent yield) of the HCl salt as a yellow solid.
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 16h;
General procedure: 4.3.1. Ethyl 5-amino-2-methylpyrazolo[1,5-a]quinoline-3-carboxylate (7a). Condition C: A mixture of 2-fluorobenzonitrile6a (121 mg, 1.00 mmol), 1H-pyrazole 4 (202 mg, 1.20 mmol) andCs2CO3 (980 mg, 3.00 mmol) in DMF (5.0 mL) was stirred at 120 Cfor 16 h. After monitoring the end of the reaction on TLC, themixture was cooled to room temperature and diluted with water.The resulting mixture was extracted with ethyl acetate twice. Thecombined organic layers werewashed with water twice, dried overMgSO4 and the solvent was removed in vacuo to afford a residue.The residue was purified by flash column chromatography(hexane:EtOAc1:1) on silica gel to afford 7a (124 mg, 46% yield).Condition D: The reaction was carried out in DMSO instead of DMFunder the same conditions as that of condition C to afford 7a (175 mg, 65% yield).
With N-acetylcystein; ammonium acetate; In methanol; at 50℃; for 14h;
3-Fluoro-2-pyridinecarbonitrile (500 mg, 4.1 mmol) and N-acetyl-L-cysteine (75 mg, 0.45 mmol) were dissolved in 4 mL methanol. Ammonium acetate (380 mg, 4.9 mmol) was added and the reaction stirred at 50°C for 14 hours. The solution was evaporated under reduced pressure and purified by flash chromatography. The product was recovered as a tan solid (170 mg, 30percent). LCMS (M/Z): 140 (M + H).
7-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)isoindolin-1-one[ No CAS ]
[ 97509-75-6 ]
3-((2-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl)oxy)pyridine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.022 g
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 5h;
To a solution of 7-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl}benzyl)isoindolin-1-one (0.10 g) obtained in Reference Example 6 in DMF (5 mL) were added <strong>[97509-75-6]3-fluoropicolinonitrile</strong> (0.15 g) and potassium carbonate (0.17 g), and the mixture was stirred at 90°C for 5 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by NH silica gel chromatography (hexane-ethyl acetate) to give the title compound (0.022 g). MS: [M+H]+ 422.2 1H NMR (300 MHz, DMSO-d6) delta 3.85 (3H, s), 4.41 (2H, s), 4.58 (2H, s), 7.21 (2H, d, J = 8.3 Hz), 7.26-7.41 (2H, m), 7.47-7.57 (3H, m), 7.59-7.66 (1H, m), 7.68-7.76 (1H, m), 7.82 (1H, s), 8.10 (1H, s), 8.44 (1H, dd, J = 4.5, 1.1 Hz).
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere;
General procedure: Under an argon atmosphere, cyclotriguaiacylene 1 (1.63 g, 4.0 mmol) in a 200 mL twoneckflask was totally dissolved in DMF (40 mL). To the flask was added ortho-substitutedfluorobenzene (24 mmol) and K2CO3 (2.76 g, 20 mmol), and the mixture was conducted at150 C (pre-heated oil bath was used) for appropriate reaction time with TLC monitoring.Allowed to cool to ambient temperature, the reaction mixture was filtered through a pad ofcelite (eluent; toluene) and the filtrate was evaporated off. The resultant stuff wasdissolved in CH2Cl2 (ca. 120 mL), and washed with water and brine, and dried overNa2SO4, filtered, and concentrated in vacuo to give a crude product. Purification protocolsand analytical data are listed in the section below. d) Data for novel compounds 2-7.For the nitro 2 ((±)2,7,12-Tris-(2-nitrophenoxy)-3,8,13-trimethoxy-10,15-dihydro-5Htribenzo[a,d,g]-cyclononene): The crude product was rinsed with acetonitrile (8.6 mL/g)afforded 2 in 93percent yield (2.87 g) as a pure form of white solid material
tert-butyl (5-(7-amino-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)carbamate[ No CAS ]
[ 97509-75-6 ]
C27H27N9O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium t-butanolate; In N,N-dimethyl-formamide; at 0 - 20℃;
To a solution of intermediate 15 (105 mg, 0.25 mmol) and sodium tert-butoxide (48 mg, 0.5 mmol) in 5 mL DMF was added <strong>[97509-75-6]3-fluoropicolinonitrile</strong> (37 mg, 0.3 mmol) at 0 °C. The mixture was stirred at room temperature for 1.5 h. The Boc-protected product was purified by column chromatography on silica gel. Then the Boc-protected product was mixed with CF3COOH (3 mL) and CH2Cl2 (3 mL), the reaction was stirred for 2 h. Then the organic solvent was removed, saturated solution was added to neutralize the solution. Then MeOH/CH2Cl2 (1:9) was added, the organic layer was separated and concentrated. The residue was purified by silica gel chromatography with 1:20 MeOH/CH2Cl2 to give product 17f (48 mg, 37percent yield, Rf = 0.28 in 1:20 MeOH/CH2Cl2).
5 g (40.9 mmol) of <strong>[97509-75-6]3-fluoropyridine-2-carbonitrile</strong> were dissolved in 40 ml of N,N-dimethylformamide. 3.2 g (45 mmol) of sodium thiomethoxide were then added slowly at room temperature. The mixture was stirred at room temperature for 2 h and then poured onto 500 ml of water. This resulted in the precipitation of a solid which was filtered off and washed with water. Drying under high vacuum gave 5.1 g (79percent of theory) of the intermediate 3-(methylsulphanyl)pyridine-2-carbonitrile.
In N,N-dimethyl-formamide; at 20℃; for 2h;
5 g (40.9 mmol) of <strong>[97509-75-6]3-fluoropyridine-2-carbonitrile</strong> were dissolved in 40 ml of N,N-dimethylformamide. 3.2 g (45 mmol) of sodium thiomethoxide were then added slowly at room temperature. The mixture was stirred at room temperature for 2 h and then poured onto 500 ml of water. This resulted in the precipitation of a solid which was filtered off and washed with watet Drying under high vacuum gave 5.1 g (79percent of theory) of the intermediate 3-(methylsulphanyl)py- ridine-2-carbonitrile.
5-aminobenzimidazo[1,2-a][1,5]naphthyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 16h;
General procedure: To verify the validity of the proposed cascade reaction for the synthesis of5-aminobenzimidazo[1,2-a]quinoline, first, we chose 2-fluoroarynitriles 2a?2f as one of the substrates in our cascade reaction from 2-methyl-1H-benzo[d]imidazole (1a). In our previous studies onSNAr/Dieckmann?Thorpe cyclization cascade reaction from 2-fluoroarylnitriles and 3,5-disubstituted1H-pyrazoles, Cs2CO3 was found to be the best base promoting this reaction in DMF or DMSO at120 °C.10a, With these findings in mind, the reaction of 1a with 2-fluoroarylnitriles 2a?2f was examinedunder the two representative conditions. The results are summarized in Table 1. Initially, a mixture of 2-fluorobenzonitrile (2a) and 2-methyl-1H-benzo[d]imidazole (1a) was heated at120 °C in DMF in the presence of Cs2CO3 for 16 h as a model reaction (entry 1). This reaction gave theexpected cascade product 4aa in a very low yield (7percent). In this reaction, a large amount of unidentifiedproducts were produced though the starting two substrates were almost consumed. Resubmission of theisolated 4aa to the same conditions (Cs2CO3, DMF, 120 °C, 16 h) gave an insoluble unidentifiedcompound. This suggested to us that DMF may react with the amino group of the cascade product 4aaunder the conditions to suppress a good yield.13 The yield significantly increased to 63percent, upon switchingthe solvent to DMSO (entry 1). In this reaction, by-product 5aa, which was produced by concomitantSNAr reaction between 4a and 2a under the conditions, was isolated in a 26percent yield. In an effort to surveythe scope of the present cascade reaction, several 2-fluorobenzonitriles 2b?2f were reacted with 1a in thepresence of Cs2CO3 in DMSO. As expected, almost all of the tested combinations successfully producedthe desired cascade products 4ab?4af, though the yields varied depending on the electron nature of thesubstituents. 2-Fluorobenzonitriles 2b?2d bearing an electron-withdrawing group were found to be the better substrate than 2-fluorobenzonitriels 2e and 2f having an electron-donating group (entries 2, 3, 4 vs.5, 6). In these reactions, trace amounts of by-products 5ab?5af were detected in the crude NMR spectrumFluoropyridinylnitriles were also available to the SNAr/Dieckmann?Thorpe cyclization cascade reaction.As shown in Scheme 3, 2-fluoronicotinonitrile (6a) reacted with 1a to give naphthyridine derivative 7aain an 81percent yield, while a modest yield (59percent) was observed with <strong>[97509-75-6]3-fluoropicolinonitrile</strong> (6b) under thesame conditions (Cs2CO3, DMSO, 120 °C).
tert-butyl N-[(3-fluoropyridin-2-yl)methyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With palladium 10% on activated carbon; hydrogen; triethylamine; In ethanol; for 16h;
A suspension of <strong>[97509-75-6]3-fluoropyridine-2-carbonitrile</strong> (8.0 g, 6.55 mmol), dhtert-butyl dicarbonate (15.7 g, 72.07 mmol), TEA (10.05 ml, 72.07 mmol) in EtOH (300 ml) was purged with N>.Pd/C (10percent wt. , 0.7g , 6.55 mmol) was added and the reaction mixture was stirred under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered through celite, rinsed with MeOH (100 ml) and the filtrates were re moved under vacuum to afford the crude product. Purification by flash column chromatography (gradient elution 0-70percent EtOAc / heptane) afforded the title compound (1 1 .3 g , 72percent) as an off-white solid .1 H-NMR (DMSO-d6, 250 MHz): d[ppm]= 8.41 - 8.31 (m, 1 H), 7.65 (ddd, J = 10.1 , 8.3, 1 .3 Hz, 1 H), 7.38 (dt, J = 8.5, 4.4 Hz, 1 H), 7.18 (s, 1 H), 4.30 (d, J = 5.4 Hz, 2H), 1 .37 (s, 9H)HPLCMS (Method A): [m/z]: 226.9 [M+H]+
With caesium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 65℃;
To a solution of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> (200 mg, 1.64 mmol, 1.00 equiv) in 5.12 mL DMF were added cesium carbonate (640 mg, 1.97 mmol, 1.20 equiv.) and methylamine (1.97 mL, 3.94 mmol, 2.0M in THF, 2.4 equiv.). The reaction mixture was stirred at 65°C overnight. After the reaction, DMF was removed via a high vacuum rotary evaporator. The mixture was diluted with 15 mL Brine solution and extract with 15 mL ethyl acetate for three times. The organic layers were combined and dried over MgS04. Purification by flash chromatography(35percent EA/Hexane) gave 3- (methylamino)picolinonitrile (211 mg, 97percent) as a white solid.
With caesium carbonate; In N,N-dimethyl-formamide; at 65℃;
To a solution of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> (200 mg, 1.64 mmol, 1.00 equiv) in 5.10 mL DMF were added cesium carbonate (640 mg, 1.97 mmol, 1.20 equiv.) and butylamine (0.195 mL, 1.97 mmol, 1.20 equiv.). The reaction mixture was stirred at 65°C overnight. After the reaction, DMF was removed via a high vacuum rotary evaporator. The mixture was diluted with 15 mL Brine solution and extract with 15 mL ethyl acetate for three times. The organic layers were combined and dried over MgS04. Purification by flash chromatography (20percent EA/Hexane) gave 3-(butylamino)picolinonitrile (257 mg, 90percent) as a colorless oil.
3-[(2-hydroxyethyl)amino]pyridine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With caesium carbonate; In N,N-dimethyl-formamide; at 65℃; for 8h;
To a solution of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> (500 mg, 4.10 mmol, 1.00 equiv) in 12.8 mL DMF were added cesium carbonate (1.60 g, 4.91 mmol, 1.20 equiv.) and ethanolamine (0.295 mL, 4.91 mmol, 1.20 equiv.). The reaction mixture was stirred at 65°C for 8 hours. After the reaction, DMF was removed via a high vacuum rotary evaporator. The mixture was diluted with 15 mL Brine solution and extract with 15 mL ethyl acetate for three times. The organic layers were combined and dried over MgS04. Purification by flash chromatography(lpercent-5percent methanol/dcm) gave 3-((2- hydroxyethyl)amino)picolinonitrile (177 mg, 27percent) as a white solid.
With hydrazine hydrate; In butan-1-ol; for 12h;Reflux; Inert atmosphere;
A mixture of <strong>[97509-75-6]3-fluoropicolinonitrile</strong> (40 g, 327.8 mmol, 1.0 eq) and hydrazine hydrate (49 g, 980 mmol, 1.2 eq) in n-butanol (400 mL) was heated at reflux under nitrogen for 12 h. The reaction mixture was allowed to cool to rt and the solid was collected by filtration and washed with ethyl acetate (100 mL), dried to give 3-aminopyrazolo[4,3-b]pyridine (32 g, 73percent). 1HNMR (300 MHz, DMSO-d6): delta 11.57 (br, 1 H), 8.28- 8.27 (m, 1 H), 7.71- 7.68 (m, 1 H), 7.26- 7.22 (m, 1 H), 5.37 (s, 2 H).
3-Fluoropyridine-2-carbonitrile (216 pi, 2.05 mmol) and piperazine (1.75 g, 20.0 mmol) were suspended in toluene (1 ml) in a sealed reaction tube. The reaction was heated at 110°C for 3 hours. The reaction was then partitioned between DCM and water. The DCM was washed with water (x 2). The organics were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a light brown solid (421 mg, 79 percent).1HNIVIR (250 IVIHz, Chloroform-d) 8.40 (dd, J = 4.0, 1.8 Hz, 1H), 7.50?7.41 (m, 2H), 3.97 (d, J = 23.5 Hz, 1H), 3.59?3.36 (m, 8H).LCMS Method 2 - Tr = 2.81 mm (ES+) (M+H)+ 189.0
(Z)-N'-hydroxy-3-fluoropyridine-2-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With hydroxylamine hydrochloride; potassium carbonate; In ethanol; for 12h;Reflux;
General procedure: 2-cyanopyridine (2.5g, 24.01mmol) was dissolved in EtOH (60mL) treated with K2CO3 (5.97g; 43.22mmol; 1.8 equiv) and H2NOH·HCl (3.0g; 43.22mmol; 1.8 equiv) and heated to reflux for 12h. The mixture was diluted with diethyl ether when it was cooled to room temperature. The product was collected by filtration, washed with water, and dried under an infrared lamp. The compound was used without further purification. Yield: 1.5g (45.5percent).
With ammonia; In dimethyl sulfoxide; at 70℃; for 6h;
To a solution of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> (5.0 g, 41 mmol, 1.0 eq) in DMSO (50 mL) at 70 °C was bubbled ammonia gas for 6 h. After completion and cooling to room temperature, water (80 mL) was added, extracted with EA (100 mL chi 3), the combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated to give a crude residue, which was purified by silica column to give 3-amino-2-cyanopyridine (3.0 g, 6 percent)._ NMR (300 MHz, DMSO-tfc): delta 7.85 (d, J= 3.0 Hz, 1H), 7.33-7.30 (m, 1H), 7.21-7.19 (m, 1H), 6.30 (br, 2H).
With hydrazine hydrate; In butan-1-ol;Reflux; Inert atmosphere;
A mixture of <strong>[97509-75-6]2-cyano-3-fluoropyridine</strong> (40 g, 328 mmol, 1.0 eq) and hydrazine hydrate (47.8 mL, 984 mmol, 3.0 eq) in n-butanol (400 mL) was heated to reflux under nitrogen overnight. The reaction mixture was allowed to cool to roomtemperature, water (300 mL) was added, the phases were separated, and the organic phase was concentrated under reduced pressure. The residual solid was collected by filtration and washed with water, dried to give 3-amino-1H- pyrazolo[4,3-bjpyridine as a yellow solid (31 g, 73percent). ?H NMR (300 MHz, CDC13): 5 11.64 (s, 1H), 8.27 (sl br s, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.25- 7.22 (m, 1H), 5.37 (br, 2H). ESI-MS (mlz): 135.0 (M+H).
With caesium carbonate; In N,N-dimethyl-formamide; at 70℃;
The solution of 3- fluoropicolinonitrile (10 g, 82 mmol), (4-methoxyphenyl)methanamine (16.8 g, 123 mmol) and CS2CO3(40 g, 123 mmol) in DMF (50 mL) was stirred at 70°C overnight. The reaction mixture was concentrated, diluted with ethyl acetate (50 mL) and washed with saturated brine solution (20 mL x 3). The organic layer was dried over Na2S04, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to give the desired product (11 g, 56percent) as a yellow solid. H NMR (400 MHz, CDC13) delta 7.98 (s, 1H), 7.28- 7.18 (m, 3H), 7.00 (d, / = 8.8 Hz, 1H), 6.90 (d, / = 8.0 Hz, 2H), 5.05 (s, 1H), 4.36 (d, / = 5.6 Hz, 2H), 3.81 (s, 3H).
With caesium carbonate; In N,N-dimethyl acetamide; at 80℃; for 5h;
To a solution of compound B96 (4.00 g, 32.8 mmol) in DMA (50 mL) was added 1H- pyrazole (2.68 g, 39.3 mmol) and Cs2C03 (10.7 g, 32.8 mmol). The reaction mixture was stirred at 80 C for 5 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between water (250 mL) and EtOAc (250 mL). The organic layer was washed with water (100 mL x 2), brine (10 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure to give a residue. The residue was purified by Combi Flash to give compound B97 (4.76 g) as a white powder.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 90℃; for 4h;Green chemistry;
General procedure: To a mixture of substituted alcohol 1 (1 mmol) and substituted nitrile 2 (1 mmol), T3P 50 wt% in ethyl acetate (50 mol%) was added and stirred at 90 C. After the reactant disappeared (monitored by TLC), the reaction mixture was cooled to room temperature, excess of water was added and extracted with ethyl acetate and combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by recrystallization using DCM: pet ether (1:9) mixture to get pure compound 3.
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