* 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] Journal of the Chemical Society, 1952, p. 2042,2044
[2] Journal of the Chemical Society, 1952, p. 2042,2044
2
[ 15862-37-0 ]
[ 588729-99-1 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 2042,2044
[2] Journal of the Chemical Society, 1952, p. 2042,2044
3
[ 15862-37-0 ]
[ 90902-84-4 ]
Yield
Reaction Conditions
Operation in experiment
76%
at 80℃; for 15 h;
(b) 2,5-Dibromo-3-aminopyridine; 2,5-Dibromo-3-nitropyridine (2.5 g, 8.87 mmol) was stirred in acetic acid (10 mL). Powdered iron (2.476 g, 44.3 mmol) was added and the solution heated at 800C for 15 minutes with vigorous stirring. The reaction mixture was filtered through Celite washed with ether and EtOAc. The resulting organic layer was washed with water and brine, dried over magnesium sulfate and filtered. The solvent was removed to give the crude product. Crude product was purified on silica eluting with 0-30percent EtOAc :hexane to give the title compound (1.7 g, 6.75 mmol, 76 percent yield) as white solid. MS (ES+) m/z 252(MH+).
67.39%
at 80℃; for 2 h;
To the solution of 2,5-Dibromo-3-nitro-pyridine (10.30 g, 35.47 mmol) in the 100 ml of ethanol was added SnCI2 (24.0 g, 106.42 mmol) slowly. The reaction mixture was heated at 800C for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (250 ml_) was added, white solid separated out, then, basified the reaction mixture with NaOH Solution. To this added the 250 ml of ethyl acetate. Filtered it and washed the residue with ethyl acetate, layers are separated, dried (Na2SO4), filtered, concentrated to give the desired product (6.2Og, 67.39percent).
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 1, p. 51 - 54
[2] Patent: WO2008/128961, 2008, A1, . Location in patent: Page/Page column 37; 73
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 3927 - 3936
[4] Patent: WO2007/107758, 2007, A1, . Location in patent: Page/Page column 125
[5] Journal of the Chemical Society, 1952, p. 2042,2044
[6] Patent: US2010/331293, 2010, A1, . Location in patent: Page/Page column 70
[7] Patent: WO2015/95795, 2015, A1, . Location in patent: Paragraph 0628
4
[ 15862-37-0 ]
[ 7440-44-0 ]
[ 90902-84-4 ]
Reference：
[1] Patent: US5445763, 1995, A,
5
[ 15862-37-0 ]
[ 573675-27-1 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 2042,2044
6
[ 15862-37-0 ]
[ 669066-89-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3608 - 3612
7
[ 15862-34-7 ]
[ 15862-37-0 ]
Yield
Reaction Conditions
Operation in experiment
97%
With phosphorus(V) oxybromide In N,N-dimethyl-formamide; toluene at 90℃; for 16 h;
Intermediate 12; N-[(R)-1-(5-Bromo-3-fluoro-pyridin-2-yl)-ethyl]-acetamide Step A: 2,5-Dibromo-3-nitro-pyridine To a suspension 5-bromo-3-nitro-pyridin-2-ol (20 g, 91.32 mmol) in toluene (100 ml) was added DMF (0.7 ml, 9.13 mmol) and the mixture was heated to 90° C. (the reaction mixture was protected from light). A solution of POBr3 (31.41 g, 109.51 mmol) in toluene (40 ml) was added dropwise at 90° C. and the reaction mixture was stirred at that temperature for 16 h. The mixture was allowed to cool to room temperature and toluene (50 ml) and water (50 ml) were added. The organic layer was separated, washed successively with aqueous 1N NaOH (60 ml), water (60 ml) and brine (30 ml), dried with Na2SO4 and evaporated obtain the title compound as yellow solid (25.2 g, 97percent).
97%
Stage #1: With phosphorus(V) oxybromide In N,N-dimethyl-formamide; toluene at 90℃; for 16 h; Darkness Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide; toluene
Step A: 2,5-Dibromo-3-nitro-pyridineTo a suspension 5-bromo-3-nitro-pyridin-2-ol (20 g, 91.32 mmol) in toluene (100 ml) was added DMF (0.7 ml, 9.13 mmol) and the mixture was heated to 90°C (the reaction mixture was protected from light). A solution of POBr3 (31.41 g,109.51 mmol) in toluene (40 ml) was added dropwise at 90°C and the reaction mixture was stirred at that temperature for 16 h. The mixture was allowed to cool to room temperature and toluene (50 ml) and water (50 ml) were added. The organic layer was separated, washed successively with aqueous IN NaOH (60 ml), water (60 ml) and brine (30 ml), dried with Na2S04 and evaporated obtain the title compound as yellow solid (25.2 g, 97percent).
80.03%
With phosphorus tribromide In N,N-dimethyl-formamide at 120℃; for 0.333333 h;
To a solution of 5-Bromo-3-nitro-pyridin-2-ol (10.0 g, 45.66 mmol) in 70 ml of toluene and 7 ml of DMF was added PBr3 (6.60 ml, 68.49 mmol) and the reaction mixture was heated at 12O0C for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3 x 200 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (10.30 g, 80.03percent).
Reference：
[1] Patent: US2012/165338, 2012, A1, . Location in patent: Page/Page column 2
[2] Patent: WO2012/89601, 2012, A1, . Location in patent: Page/Page column 53
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 3927 - 3936
[4] Patent: WO2007/107758, 2007, A1, . Location in patent: Page/Page column 124
[5] Journal of the Chemical Society, 1952, p. 2042,2044
[6] Journal of the American Chemical Society, 1955, vol. 77, p. 6053
[7] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3608 - 3612
[8] Patent: WO2005/63690, 2005, A1, . Location in patent: Page/Page column 28
[9] Journal of Organic Chemistry, 2009, vol. 74, # 12, p. 4547 - 4553
[10] Patent: WO2006/52514, 2006, A1, . Location in patent: Page/Page column 7
[11] Patent: WO2006/132837, 2006, A1, . Location in patent: Page/Page column 19
8
[ 6945-68-2 ]
[ 15862-37-0 ]
Yield
Reaction Conditions
Operation in experiment
58.9%
Stage #1: With hydrogen bromide In water at 0 - 5℃; Stage #2: at 0℃; for 0.75 h; Stage #3: With sodium hydroxide In water at 20℃; for 1 h;
(1) Production of 2,5-dibromo-3-nitropyridine: Hydrogen bromide (48 percent in H2O, 13 mL) was stirred at 0°C, to which 5-bromo-3-nitropyridin-2-amine (5.0 g, 22.9 mmol) was dropwise added with its inner temperature kept at 5°C or lower. After the addition, bromine (4.69 mL) and sodium sulfite (6.32 g) were added to it in that order. After stirred at 0°C for 45 minutes, aqueous sodium hydroxide (9.16 g) solution (10 mL) was added thereto and stirred at room temperature for 1 hour. The resulting solid was taken out through filtration, washed with water and dried to obtain the intended compound (3.80 g, 58.9 percent).
35%
Stage #1: With hydrogen bromide; bromine In water at 0℃; Stage #2: With sodium nitrite In water at 0℃; Stage #3: With sodium hydroxide In waterCooling with ice
Synthesis Example 2; Synthesis of N-ethyl-N-methyl-N'[2,5-dimethyl-6-(4-t-butylphenyl)pyridin-3- y 1] formamidine (Compound No .11); (1); Bromine (68.81 mmol, 3.5 ml) was gradually added dropwise to an aqueous solution of 48percent hydrobromic acid (120 ml) of 2-amino-5-bromo-3-nitropyridine (22.93 mmol, 5.0 g) at 0°C, followed by stirring at the same temperature for 1 hour. An aqueous solution prepared by dissolving sodium nitrite (57.34 mmol, 4.0 g) in 60 ml of water was gradually added dropwise, followed by stirring at the same temperature for1.5 hours. To the resulting reaction mixture, 10 mol/liter sodium hydroxide aqueous solution was added on ice to neutralize, and an aqueous layer was extracted with ethyl acetate. An organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered, followed by distilling away a solvent under reduced pressure. The resulting crude product was purified with column chromatography to obtain 2.24 g of 2,5-dibromo-3-nitropyridine (yield 35percent). 1H NMR δ ppm (300 MHz, CDCl3) data of this compound are 8.66 (d, 2H, J=2.4Hz), 8.27 (d, 2H, J=2.1Hz).
Reference：
[1] Patent: EP1757594, 2007, A1, . Location in patent: Page/Page column 76
[2] Patent: WO2009/88103, 2009, A1, . Location in patent: Page/Page column 16
[3] Tetrahedron, 2003, vol. 59, # 43, p. 8555 - 8570
[4] Journal of the Chemical Society, 1952, p. 2042,2044
[5] Patent: US2009/69319, 2009, A1, . Location in patent: Page/Page column 31
9
[ 15862-34-7 ]
[ 15862-37-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With pyridine; phosphorus(V) oxybromide In toluene at 90℃; for 15.5 h;
Example 15; 4-{7- [(2,3-dihydro [1 ,4] dioxino [2,3-c] pyridin-7-ylmethyl)amino] -5- methyl-6-oxo-5,6,7,8-tetrahydro-l,5-naphthyridin-3-yl}-6-(methyloxy)pyrido[2,3- b]pyrazin-3(4H)-one; <n="74"/>(a) 2,5-Dibromo-3-nitropyridine; 5-Bromo-3-nitro-2(lH)-pyridinone (5g, 22.83 mmol) was suspended in toluene (50 ml). DMF (0.177 ml, 2.283 mmol) was added and the mixture was protected from light. A solution of phoshorous oxybromide (7.85 g, 27.4 mmol) in toluene (50 ml) was added to the pyridine mixture over 1.5h at 90 0C. The reaction mixture was heated at 90 0C for 14h, cooled down and extracted with water. The organic layer was washed with IN NaOH and brine and dried over MgSOφ The solvent was removed to give title compound (6.45 g, 22.88 mmol, 100 percent yield) as yellow solid. MS (ES+) m/z 282(MH+).
Step B: 5-Bromo-3-nitro-pyridine-2-carbonitrile To a stirred solution of 2,5-dibromo-3-nitro-pyridine (25 g, 88.68 mmol) in propionitrile (100 ml) was added CuCN (8.7 g, 97.55 mmol) and the mixture was heated to 90° C. for 17 h. Then it was allowed to cool to room temperature, diluted with EtOAc, washed twice with brine, dried with Na2SO4 and concentrated. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 95:5-85:15) to obtain the title compound as yellow solid (17.5 g, 68percent).
68%
at 90℃; for 17 h;
Step B: 5-Bromo-3-nitro-pyridine-2-carbonitrile OTo a stirred solution of 2,5-dibromo-3-nitro-pyridine (25 g, 88.68 mmol) in propionitrile (100 ml) was added CuCN (8.7 g, 97.55 mmol) and the mixture was heated to 90°C for 17 h. Then it was allowed to cool to room temperature, diluted with EtOAc, washed twice with brine, dried with Na2S04 and concentrated. The remaining residue was purified by chromatography (silica gel; DCM / MeOH 95:5-85: 15) to obtain the title compound as yellow solid (17.5 g, 68percent).
Reference：
[1] Patent: US2012/165338, 2012, A1, . Location in patent: Page/Page column 22
[2] Patent: WO2012/89601, 2012, A1, . Location in patent: Page/Page column 53-54
[3] Journal of Organic Chemistry, 2009, vol. 74, # 12, p. 4547 - 4553
14
[ 15862-37-0 ]
[ 544-92-3 ]
[ 573675-25-9 ]
Yield
Reaction Conditions
Operation in experiment
59%
at 150℃; for 2 h;
(2) Production of 5-bromo-2-cyano-3-nitropyridine: 2,5-Dibromo-3-nitropyridine (3.80 g, 13.4 mmol) and copper cyanide (2.42 g, 26.8 mmol) were mixed, and stirred under heat at 150°C for 2 hours. After cooled to room temperature, the contents were filtered, and the residue was washed with acetone. The mother liquid was concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate = 9/1 to 3/1) to obtain the intended compound (1.80 g, 59 percent) as a yellow solid.
(b) 2,5-Dibromo-3-aminopyridine; 2,5-Dibromo-3-nitropyridine (2.5 g, 8.87 mmol) was stirred in acetic acid (10 mL). Powdered iron (2.476 g, 44.3 mmol) was added and the solution heated at 800C for 15 minutes with vigorous stirring. The reaction mixture was filtered through Celite washed with ether and EtOAc. The resulting organic layer was washed with water and brine, dried over magnesium sulfate and filtered. The solvent was removed to give the crude product. Crude product was purified on silica eluting with 0-30% EtOAc :hexane to give the title compound (1.7 g, 6.75 mmol, 76 % yield) as white solid. MS (ES+) m/z 252(MH+).
67.39%
tin(ll) chloride; In ethanol; at 80℃; for 2h;
To the solution of 2,5-Dibromo-3-nitro-pyridine (10.30 g, 35.47 mmol) in the 100 ml of ethanol was added SnCI2 (24.0 g, 106.42 mmol) slowly. The reaction mixture was heated at 800C for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (250 ml_) was added, white solid separated out, then, basified the reaction mixture with NaOH Solution. To this added the 250 ml of ethyl acetate. Filtered it and washed the residue with ethyl acetate, layers are separated, dried (Na2SO4), filtered, concentrated to give the desired product (6.2Og, 67.39%).
With tin(II) chloride dihdyrate; In ethyl acetate; at 90℃; for 2h;
2,5-Dibromopyridin-3-amine To a stirred mixture of 2,5-dibromo-3-nitropyridine (0.99 g, 3.50 mmol) in EtOAc (30.0 mL) was added tin(II) chloride dihydrate (4.02 g, 17.80 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 90 C. After 2 h, the reaction was cooled to rt and diluted with ethyl acetate, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as 2,5-dibromopyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.65 (1H, d, J=2.5 Hz), 7.27 (1H, d, J=2.5 Hz), 5.82 (2H, br, s).
With ammonium chloride; zinc; In acetone; at 20℃; for 5h;Inert atmosphere;
EXAMPLE 120: Preparation of (R or 5)-l,l,l-trifluoro-2-methylpropan-2-yl (6-methyl-8- oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-l,5-naphthyridin-3- yl)carbamate (Example 120) [0628] To a solution of 2,5-dibromo-3-nitropyridine (13.00 g, 46.1 mmol) in acetone (150 mL) was added ammonium chloride (24.67 g, 461 mmol) and zinc dust (15.08 g, 231 mmol) and the resulting mixture was stirred at room temperature for 5 h under N2. Water (100 mL) was next added and the aqueous layer was extracted with EtOAc (3x200 mL). The combined organic layers were concentrated in vacuo and the crude product was purified by flash chromatography (0-30% EtOAc in petroleum ether) to afford the title compound as a white solid. 1H NMR (400 MHz, MeOD) delta 7.67 (d, J= 2.0 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H).
With phosphorus(V) oxybromide; In N,N-dimethyl-formamide; toluene; at 90℃; for 16h;
Intermediate 12; N-[(R)-1-(5-Bromo-3-fluoro-pyridin-2-yl)-ethyl]-acetamide Step A: 2,5-Dibromo-3-nitro-pyridine To a suspension 5-bromo-3-nitro-pyridin-2-ol (20 g, 91.32 mmol) in toluene (100 ml) was added DMF (0.7 ml, 9.13 mmol) and the mixture was heated to 90 C. (the reaction mixture was protected from light). A solution of POBr3 (31.41 g, 109.51 mmol) in toluene (40 ml) was added dropwise at 90 C. and the reaction mixture was stirred at that temperature for 16 h. The mixture was allowed to cool to room temperature and toluene (50 ml) and water (50 ml) were added. The organic layer was separated, washed successively with aqueous 1N NaOH (60 ml), water (60 ml) and brine (30 ml), dried with Na2SO4 and evaporated obtain the title compound as yellow solid (25.2 g, 97%).
97%
Step A: 2,5-Dibromo-3-nitro-pyridineTo a suspension 5-bromo-3-nitro-pyridin-2-ol (20 g, 91.32 mmol) in toluene (100 ml) was added DMF (0.7 ml, 9.13 mmol) and the mixture was heated to 90C (the reaction mixture was protected from light). A solution of POBr3 (31.41 g,109.51 mmol) in toluene (40 ml) was added dropwise at 90C and the reaction mixture was stirred at that temperature for 16 h. The mixture was allowed to cool to room temperature and toluene (50 ml) and water (50 ml) were added. The organic layer was separated, washed successively with aqueous IN NaOH (60 ml), water (60 ml) and brine (30 ml), dried with Na2S04 and evaporated obtain the title compound as yellow solid (25.2 g, 97%).
80.03%
With phosphorus tribromide; In N,N-dimethyl-formamide; at 120℃; for 0.333333h;
To a solution of 5-Bromo-3-nitro-pyridin-2-ol (10.0 g, 45.66 mmol) in 70 ml of toluene and 7 ml of DMF was added PBr3 (6.60 ml, 68.49 mmol) and the reaction mixture was heated at 12O0C for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3 x 200 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (10.30 g, 80.03%).
With N,N-dimethyl-formamide; phosphorus(V) oxybromide; In toluene; at 90℃; for 15.5h;
2-Hydroxy-3-nitro-5-bromopyridine (1 eq) was suspended in toluene (3 vol) and N, N- dimethylformamide (0.1 eq) was added. The mixture was protected from light. A solution of phosphorus oxybromide (1. 2 eq) in toluene (2 vol) was added to the pyridine mixture over 1.5 h at about 90 C and the reaction was aged for about 14 h at 90 C. The reaction mixture was cooled to room temperature and water (10 vol) and toluene (5 vol) were added. The layers were cut and the organic layer was washed with 1N NaOH (2 x 10 vol) and H20 (5 vol). The batch was concentrated under reduced pressure to yield the desired product.
With N,N-dimethyl-formamide; phosphorus(V) oxybromide; In toluene; at 90℃; for 15.5h;
REFERENCE EXAMPLE1. N-[I -(5-Bromo-3 -fluoropyridin-2-yl)vinyl] acetamideStep 1. 2,5-Dibromo-3-nitropyridine.2-Hydroxy-3-nitro-5-bromopyridine (1 eq) was suspended in toluene (3 vol) and N1N- dimethylformamide (DMF, 0.1 eq) was added. The mixture was protected from light. A solution of phosphorus oxybromide (1.2 eq) in toluene (2 vol) was added to the pyridine mixture over 1.5 h at about 90 0C and the reaction was aged for about 14 h at 90 0C. The reaction mixture was cooled to room temperature and water (10 vol) and toluene (5 vol) were added. The layers were cut and the organic layer was washed with IN NaOH (2 x 10 vol) and H2O (5 vol). The batch was concentrated under reduced pressure to yield the desired product.
With N,N-dimethyl-formamide; phosphorus(V) oxybromide; In toluene; at 90℃; for 15.5h;
REFERENCE EXAMPLES; 1. Lambda^[l-(5-Bromo-3-fluoropyridin-2-yl)vinyI]acetamide; Step 1; 2,5-Dibromo-3-nitropyridine; 2-Hydroxy-3-nitro-5-bromopyridine (1 eq) was suspended in toluene (3 vol) and N;N-dimethylformamide (0.1 eq) was added. The mixture was protected from light. A solution of phosphorus oxybromide (1.2 eq) in toluene (2 vol) was added to the pyridine mixture over 1.5 h at about 90 0C and the reaction was aged for about 14 h at 90 0C. The reaction mixture was cooled to room temperature and water (10 vol) and toluene (5 vol) were added. The layers were cut and the organic layer was washed with IN NaOH (2 x 10 vol) and H2O (5 vol). The batch was concentrated under reduced pressure to yield the desired product.
(1) Production of 2,5-dibromo-3-nitropyridine: Hydrogen bromide (48 % in H2O, 13 mL) was stirred at 0C, to which <strong>[6945-68-2]5-bromo-3-nitropyridin-2-amine</strong> (5.0 g, 22.9 mmol) was dropwise added with its inner temperature kept at 5C or lower. After the addition, bromine (4.69 mL) and sodium sulfite (6.32 g) were added to it in that order. After stirred at 0C for 45 minutes, aqueous sodium hydroxide (9.16 g) solution (10 mL) was added thereto and stirred at room temperature for 1 hour. The resulting solid was taken out through filtration, washed with water and dried to obtain the intended compound (3.80 g, 58.9 %).
35%
Synthesis Example 2; Synthesis of N-ethyl-N-methyl-N'[2,5-dimethyl-6-(4-t-butylphenyl)pyridin-3- y 1] formamidine (Compound No .11); (1); Bromine (68.81 mmol, 3.5 ml) was gradually added dropwise to an aqueous solution of 48% hydrobromic acid (120 ml) of <strong>[6945-68-2]2-amino-5-bromo-3-nitropyridine</strong> (22.93 mmol, 5.0 g) at 0C, followed by stirring at the same temperature for 1 hour. An aqueous solution prepared by dissolving sodium nitrite (57.34 mmol, 4.0 g) in 60 ml of water was gradually added dropwise, followed by stirring at the same temperature for1.5 hours. To the resulting reaction mixture, 10 mol/liter sodium hydroxide aqueous solution was added on ice to neutralize, and an aqueous layer was extracted with ethyl acetate. An organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered, followed by distilling away a solvent under reduced pressure. The resulting crude product was purified with column chromatography to obtain 2.24 g of 2,5-dibromo-3-nitropyridine (yield 35%). 1H NMR delta ppm (300 MHz, CDCl3) data of this compound are 8.66 (d, 2H, J=2.4Hz), 8.27 (d, 2H, J=2.1Hz).
With hydrogen bromide; bromine; sodium nitrite; In water; at 0 - 20℃;
Example 156 4-[6-(2-naphthyl)-3-piperidin-4-yl-3H-imidazo[4,5-b]pyridin-2-yl]phenol 2,5-dibromo-3-nitropyridine. <strong>[6945-68-2]2-Amino-5-bromo-3-nitropyridine</strong> (4.70 g, 21.5 mmol) was suspended in hydrobromic acid and cooled in an ice bath. Bromice (3.85 mL, 75.3 mmol) was carefully added dropwise, followed by sodium nitrite (4.45 g, 64.5 mmol) portionwise with stirring. After 45 min., the mixture was warmed to rt. An additional portion of sodium nitrite (10.0 g, 144.9 mmol) was added, followed by an additional 10 mL of hydrobromic acid and water (20 mL.) Stirring was continued at rt. until no additional effervescence was observed. The mixture was poured into an Erlenmeyer flask and carefully basified with aq. sodium carbonate followed by addition of excess aq. sodium thiosulfate. The mixture was extracted with dichloromethane (3*100 mL). The organic layers were washed with water, brine and 5% sodium thiosulfate, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the title compound. 4.58 g (75%). HPLC (method A): Rt=8.6 min. MS: [M]+=280.
(2) Production of 5-bromo-2-cyano-3-nitropyridine: 2,5-Dibromo-3-nitropyridine (3.80 g, 13.4 mmol) and copper cyanide (2.42 g, 26.8 mmol) were mixed, and stirred under heat at 150C for 2 hours. After cooled to room temperature, the contents were filtered, and the residue was washed with acetone. The mother liquid was concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate = 9/1 to 3/1) to obtain the intended compound (1.80 g, 59 %) as a yellow solid.
In N,N-dimethyl acetamide; at 100℃; for 72h;
B. (7-BROMO-PYRIDO [3, 2-D] PYRIMIDIN-4-YL-4-TERT-BUTYL-ISOXAZOLE)-AMINE (COMPOUND 2) 1. 5-bromo-3-nitropyridine-2-carbonitrile Heat a solution of 2, 5-dibromo-3-nitropyridine (1.77g, 6.3 mmol; Malinowski (1988) Bull. Soc. Chim. Belg 97 : 51 ; see also US 5, 801, 183) and cuprous cyanide (0.60 g, 6.69 mmol) in N, N-dimethylacetamide (25 mL) at 100C for 72 hours. After cooling, dilute the mixture with water (25 mL) and extract twice with EtOAc (25 mL each), then wash twice with water (25 mL each). The combined EtOAc extracts are dried (Na2SO4), evaporated, and purified by flash chromatography (50% EtOAc-hexane) to obtain 5-bromo-3-nitropyridine-2- carbonitrile as a pale solid.
In propiononitrile; at 90℃; for 17h;
Step 2. 5-Bromo-3-nitropyridine-2-carbonitrile.The compound of Step 1 (1 eq) was suspended in propionitrile (3 vol). Copper cyanide (1.1 eq) was added and the mixture was heated to 90 0C and aged for about 17 h. The reaction mixture was cooled to room temperature and isopropyl acetate (12 vol) and saturated brine (8 vol) were added. EPO <DP n="9"/>The mixture was stirred for 15 min and the layers were cut. The top organic layer was washed with brine (4 x 6 vol). The batch concentrated under reduced pressure to yield the desired product
In propiononitrile; at 90℃; for 17h;
Step 2; 5-Bromo-3-nitropyridine-2-carbonitrile; The compound of Step 1 (1 eq) was suspended in propionitrile (3 vol). Copper cyanide (1.1 eq) was added and the mixture was heated to 90 0C and aged for about 17 h. The reaction mixture was cooled to room temperature and isopropyl acetate (12 vol) and saturated brine (8 vol) were added. The mixture was stirred for 15 min and the layers were cut. The top organic layer was washed with brine (4 x 6 vol). The batch concentrated under reduced pressure to yield the desired product.
43.00 g (152.52 mol) of 2,5-dibromo-3-nitropyridine are hydrogenated in 1.5 g of Pd (10%) on activated charcoal in 450 ml of methanol until the calculated mount of hydrogen has been consumed, the catalyst is filtered off, and the filtrate is freed from solvent, giving 37.56 g of 3-amino-2,5-dibromopyridine. STR12
77.11 g (354.4 mmol) of 5-bromo-2-hydroxy-3-nitropyridine are heated at 120 C. for 3 hours together with 101.61 g (354.4 mmol) of <strong>[7789-59-5]phosphorus oxytribromide</strong> and 33.7 ml (354.4 mmol) of phosphorus tribromide. The reaction mixture is subsequently poured carefully, in small portions, into ice water, stirred for 1 hour and extracted three times with dichloromethane. The organic phase is washed twice with water, dried over sodium sulfate, filtered and freed from the solvent. Chromatographic purification (silica gel/dichloromethane) gives 43.05 g of 2,5-dibromo-3-nitropyridine. STR11
Step B: 5-Bromo-3-nitro-pyridine-2-carbonitrile To a stirred solution of 2,5-dibromo-3-nitro-pyridine (25 g, 88.68 mmol) in propionitrile (100 ml) was added CuCN (8.7 g, 97.55 mmol) and the mixture was heated to 90 C. for 17 h. Then it was allowed to cool to room temperature, diluted with EtOAc, washed twice with brine, dried with Na2SO4 and concentrated. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 95:5-85:15) to obtain the title compound as yellow solid (17.5 g, 68%).
68%
In propiononitrile; at 90℃; for 17h;
Step B: 5-Bromo-3-nitro-pyridine-2-carbonitrile OTo a stirred solution of 2,5-dibromo-3-nitro-pyridine (25 g, 88.68 mmol) in propionitrile (100 ml) was added CuCN (8.7 g, 97.55 mmol) and the mixture was heated to 90C for 17 h. Then it was allowed to cool to room temperature, diluted with EtOAc, washed twice with brine, dried with Na2S04 and concentrated. The remaining residue was purified by chromatography (silica gel; DCM / MeOH 95:5-85: 15) to obtain the title compound as yellow solid (17.5 g, 68%).
5-bromo-N-4-(ethoxybenzyl)-3-nitropyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With triethylamine; In ethanol; at 20℃; for 18h;
Synthesis of 5-Bromo-N- (4-ethoxybenzyl) -3-nitropyridin-2-amine (compound 62-2)[0000214] To a stirred solution of 2,5-dibromo-3- nitropyridine (1 g, 3.5 mmol, 1 equiv) in ethanol (10 mL) was added a <strong>[6850-60-8](4-ethoxyphenyl)methanamine</strong> (580 IlL, 3.9 mmol, 1.1 equiv) and triethylamine (1 mL, 7.1 mmol, 2 equiv) . The reaction mixture was allowed to stir at room temperature for 18 hours, at which time LC-MS indicated the reaction was complete. The suspension was filtered and the solid washed with ethanol (2 x 5 mL) to produce compound 62-2 as a yellow solid (1.1 g, 92% yield)
methyl 3-(5-bromo-3-nitropyridin-2-yl)-4-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 80.0℃; for 3.0h;Inert atmosphere;
Step 1: Methyl 3-(5-bromo-3-nitropyridin-2-yl)-4-fluorobenzoate A mixture of 2,5-dibromo-3-nitropyridine (705 mg, 2.50 mmol) and <strong>[850568-04-6](2-fluoro-5-(methoxycarbonyl)phenyl)boronic acid</strong> (495 mg, 2.50 mmol) in tetrahydrofuran (10 mL) in a 20 mL vial was purged under a stream of nitrogen and then treated with 2 M aqueous tripotassium phosphate (3.75 mL, 7.50 mmol) (solids formed) and then with PdC12(dppf)- CH2C12 adduct (204 mg, 0.250 mmol). The vial was capped with a septum, evacuated, and purged with nitrogen 3 times before the reaction mixture was heated in a heating block to 80 C. Note - the solids gradually dissolved on heating. After 3 h, the mixture was cooled to room temperature, diluted with water, and extracted into ethyl acetate. The organics were washed with water, and the volatiles were removed under reduced pressure to give a dark residue. The material was purified using silica gel colunm chromatographywith an ISCO Companion (80 g silica gel column) and eluted with EtOAc/hexane gradient (10-40%) to give methyl 3 -(5 -bromo-3 -nitropyridin-2-yl)-4-fluorobenzoate (507 mg, 1.43 mmol, 57 %) as a white crystalline solid. LCMS: Waters Acquity SDS. Column:BEH C 18 2.1 x5 0 mm 1 .7u (1 .6 mm grad) 2-98 % B. Flow Rate = 0.8 mL/min. SolventA: H20 -0.1 % TFA. Solvent B: Acetonitrile - 0.1 % TFA. LCMS: RT = 0.99 mm; (ES):mlz (M+H) = 355.0, 356.9. ?H NMR (400MHz, CDC13) oe 8.99 (d, J2.1 Hz, 1H), 8.52 (d, J2.1 Hz, 1H), 8.39 (dd, J7.0, 2.2 Hz, 1H), 8.18 (ddd, J8.7, 5.1, 2.3 Hz, 1H), 7.18 (dd, J=9.7, 8.8 Hz, 1H), 3.94 (s, 3H).
57%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 80.0℃; for 3.0h;Inert atmosphere;
A mixture of 2,5-dibromo-3-nitropyridine (705 mg, 2.50 mmol) and <strong>[850568-04-6](2-fluoro-5-(methoxycarbonyl)phenyl)boronic acid</strong> (495 mg, 2.50 mmol) in tetrahydrofuran (10 mL) in a 20 mL vial was purged under a stream of nitrogen and then treated with 2 M aqueous tripotassium phosphate (3.75 mL, 7.50 mmol) (solids formed) and then with PdCl2(dppf)-CH2Cl2 adduct (204 mg, 0.250 mmol). The vial was capped with a septum, evacuated, and purged with nitrogen 3 times before the reaction mixture was heated in a heating block to 80 C. Note-the solids gradually dissolved on heating. After 3 h, the mixture was cooled to room temperature, diluted with water, and extracted into ethyl acetate. The organics were washed with water, and the volatiles were removed under reduced pressure to give a dark residue. The material was purified using silica gel column chromatography with an ISCO Companion (80 g silica gel column) and eluted with EtOAc/hexane gradient (10-40%) to give methyl 3-(5-bromo-3-nitropyridin-2-yl)-4-fluorobenzoate (507 mg, 1.43 mmol, 57%) as a white crystalline solid. LCMS: Waters Acquity SDS. Column: BEH C18 2.1×50 mm 1.7 u (1.6 min grad) 2-98% B. Flow Rate=0.8 mL/min. Solvent A: H2O-0.1% TFA. Solvent B: Acetonitrile-0.1% TFA. LCMS: RT=0.99 min; (ES): m/z (M+H)+=355.0, 356.9. 1H NMR (400 MHz, CDCl3) delta 8.99 (d, J=2.1 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.39 (dd, J=7.0, 2.2 Hz, 1H), 8.18 (ddd, J=8.7, 5.1, 2.3 Hz, 1H), 7.18 (dd, J=9.7, 8.8 Hz, 1H), 3.94 (s, 3H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In tetrahydrofuran; water at 80℃; for 3h; Inert atmosphere;
181.1 Step 1: 5-Bromo-2-(2-fluoro-5-methanesulfonylphenyl)-3-nitropyridine
Step 1: Methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoate To a mixture of 2,5-dibromo-3-nitropyridine (2.00 g, 7.09 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (1.28 g, 7.09 mmol) Pd(dppf)C12 (0.36 g, 0.50 mmol) in THF (30 mL) was added tripotassium phosphate (3M in water) (7.09 mL, 21.3 mmol). The reaction mixture was purged with N2 (3x) and then stirred at 80 °C for 3 h. The aqueous layer was separated. The organic layer dried with Na2SO4, filtered through a small plug of Celite washing with EtOAc and concentrated. The crude residue waspurified using ISCO silica gel chromatography (120 g column, gradient from 0% to 50% EtOAc/CH2C12) to give the title compound (1.64 g, 69%) as a white solid. Step 1: 5-Bromo-2-(2-fluoro-5-methanesulfonylphenyl)-3-nitropyridineFollowing procedures analogous to those described for methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoate, 2-(2-fluoro-5 -methanesulfonylphenyl)-4,4,5 ,5 -tetramethyl1,3 ,2-dioxaborolane (500 mg, 1.66 mmol) was converted to the title compound (325 mg,52%). ‘H NMR (500MHz, CDC13) ö 9.02 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.34(dd, J6.5, 2.4 Hz, 1H), 8.10 (ddd, J8.7, 4.7, 2.4 Hz, 1H), 7.34 (dd, J=9.4, 8.8 Hz, 1H),3.15 (s, 3H); LCMS (M+H) = 375; HPLC RT = 1.977 mm (Column: Chromolith ODS S54.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B:90:10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 mm; Flow: 4 mL/min).
ethyl 2-(4-(5-bromo-3-nitropyridin-2-yl)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 70℃; for 4h;Inert atmosphere;
Step 2: Ethyl 2-(4-(5-bromo-3-nitropyridin-2-yl)phenyl)acetate To a solution of ethyl 2-(4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenyl)acetate (460 mg, 1.59 mmol) and 2,5-dibromo-3-nitropyridine (447 mg, 1.59mmol) in THF (5 mL) was added tripotassium phosphate (2M) (1.50 mL, 3.17 mmol).The reaction was degassed with bubbling nitrogen followed by the addition of PdC12(dppf)-CH2C12 adduct (64.7 mg, 0.0790 mmol). The reaction was heated to 70 C for 4 h. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (25 mL). The aqueous layer was extracted with ethyl acetate (3x 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (24 g column, gradient from 0% to 20% EtOAc/hexanes) to give the title compound (265 mg, 46%) as a colorless oil. LCMS (M+H) = 365.2; HPLC RT = 0.98 mm (Column: BEH C18 2.1 x 50 mm; Mobile Phase A: Water with 0.05% TFA; MobilePhase B: Acetonitrile with 0.05% TFA; Gradient: 2-98% B over 1.6 mm; Flow: 0.8 mL/min).
46%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 70℃; for 4h;Inert atmosphere;
To a solution of <strong>[859169-20-3]ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate</strong> (460 mg, 1.59 mmol) and 2,5-dibromo-3-nitropyridine (447 mg, 1.59 mmol) in THF (5 mL) was added tripotassium phosphate (2M) (1.50 mL, 3.17 mmol). The reaction was degassed with bubbling nitrogen followed by the addition of PdCl2(dppf)-CH2Cl2 adduct (64.7 mg, 0.0790 mmol). The reaction was heated to 70 C. for 4 h. The reaction mixture was transferred to a reparatory funnel containing saturated aqueous NaHCO3 solution (25 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (24 g column, gradient from 0% to 20% EtOAc/hexanes) to give the title compound (265 mg, 46%) as a colorless oil. LCMS (M+H)=365.2; HPLC RT=0.98 min (Column: BEH C18 2.1×50 mm; Mobile Phase A: Water with 0.05% TFA; Mobile Phase B: Acetonitrile with 0.05% TFA; Gradient: 2-98% B over 1.6 min; Flow: 0.8 mL/min).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In tetrahydrofuran; water; at 75℃; for 0.5h;Inert atmosphere;
To a stirred solution of methyl 2-methoxy-4-(4 ,4,5 ,5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)benzoate (1.30 g, 4.43 mmol), 2,5-dibromo-3-nitropyridine (1.04 g, 3.69 mmol), and PdC12(dppf) (0.140 g, 0.191 mmol) in THF (37 mL) was added tripotassium phosphate (3M in H20, 3.7 mL, 11.1 mmol), purged with N2 (g), and thereaction was heated to 75 C with stirring for 30 mm, cooled to room temperature, partially concentrated, diluted with EtOAc, washed with H20, sat. aq. NaC1, and dried over sodium sulfate. The solids were filtered away, and the volatiles were concentrated in vacuo. The residue was purified by silica gel column chromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 100% using solvent A/B=CH2C12/EtOAc over 15column volumes, RediSep 5i02 120 g, loaded as DCM solution) to afford a mixture of the mono- and bis-coupled products (1.04 g) as a pale-yellow solid: HPLC for major product:RT=1.212 mm (Waters Acquity BEH C,8 1.7 urn 2.0 x 50mm, CH3CN/H20/0.1% TFA, 1 .5mm gradient, wavelength=254nm); MS (ES): mlz= 367/369 Br79/Br8? [M+1].
methyl 3-bromo-6-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate[ No CAS ]
methyl 3-bromo-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%; 34%
Step 2: Methyl 3-bromo-6-methoxy-5H-pyrido [3,2-bj indole-7-carboxylate andmethyl 3-bromo-8-methoxy-5H-pyrido [3,2-bj indole-7-carboxylateTo a stirred solution of methyl 2-methoxy-4-(4 ,4,5 ,5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)benzoate (1.30 g, 4.43 mmol), 2,5-dibromo-3-nitropyridine (1.04 g, 3.69 mmol), and PdC12(dppf) (0.140 g, 0.191 mmol) in THF (37 mL) was added tripotassium phosphate (3M in H20, 3.7 mL, 11.1 mmol), purged with N2 (g), and thereaction was heated to 75 C with stirring for 30 mm, cooled to room temperature, partially concentrated, diluted with EtOAc, washed with H20, sat. aq. NaC1, and dried over sodium sulfate. The solids were filtered away, and the volatiles were concentrated in vacuo. The residue was purified by silica gel column chromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 100% using solvent A/B=CH2C12/EtOAc over 15column volumes, RediSep 5i02 120 g, loaded as DCM solution) to afford a mixture of the mono- and bis-coupled products (1.04 g) as a pale-yellow solid: HPLC for major product:RT=1.212 mm (Waters Acquity BEH C,8 1.7 urn 2.0 x 50mm, CH3CN/H20/0.1% TFA, 1 .5mm gradient, wavelength=254nm); MS (ES): mlz= 367/369 Br79/Br8? [M+1].In a 100 mL RB flask was added the mixture above (1.04 g) and 1,2-bis(diphenylphosphino)ethane (1.27 g, 3.19 mmol) in 1 ,2-dichlorobenzene (12 mL), and the flask was heated in a pre-heated heating block at 170 C for 90 mm, then cooled to room temperature. The mixture was poured into 150 mL hexanes, the solid was collected by filtration, washed with hexanes, and air dried. The residue was purified by silica gel column chromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 100% usingsolvent A/B=hexanes/EtOAc over 15 column volumes, RediSep 5i02 220 g Gold). The clean fractions were set aside, and the mixed fractions resubjected to flash chromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 30% using solvent A/B=CH2C12/EtOAc over 19 column volumes, RediSep 5i02 12g Gold). Two regioisomers were obtained: (methyl 3 -bromo-6-methoxy-5H-pyrido [3 ,2-b]indole-7-carboxylate (339.7 mg, 36 %)) as a cream solid: ?H NMR (400 MHz, DMSO-d6) oe 12.04 (s, 1 H), 8.59 (d,J=2.0 Hz, 1 H), 8.12 (d,J2.0 Hz, 1 H), 7.98 (d,J8.1 Hz, 1 H), 7.61 (d, J8.1 Hz, 1 H), 4.01 (s, 3 H), 3.90 (s, 3 H); HPLC: RT=0.97 mm (Waters Acquity BEH C18 1.7 urn 2.0 x 50mm, CH3CN/H20/0.05% TFA, 1 mill gradient, wavelength=220 nm); MS (ES): mlz= 335/337 Br79/Br8? [M+1] and (methyl 3-bromo-8- methoxy-5H-pyrido[3,2-b]indole-7-carboxylate (322 mg, 0.962 mmol, 34 %)) as a yellow solid: ?H NMR (400 MHz, DMSO-d6) oe 11.55 (s, 1 H), 8.53 (d, J=2.0 Hz, 1 H), 8.20 (d,J=2.0 Hz, 1 H), 7.87 (s, 1 H), 7.80 (s, 1 H), 3.92 (s, 3 H), 3.85 (s, 3 H); HPLC: RT=0.90 mm (Waters Acquity BEH C,8 1.7 urn 2.0 x 50 mm, CH3CN/H20/0.05% TFA, 1 mm gradient, wavelength=220 nm); MS (ES): mlz= 335/337 Br79/Br8? [M+1].
5-(5-bromo-3-nitropyridin-2-yl)-1,3-dihydro-2-benzofuran-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In tetrahydrofuran; water at 80℃; for 3h; Inert atmosphere;
356.2 Step 2: 5-(5-Bromo-3-nitropyridin-2-yl)- 1,3-dihydro-2-benzofuran- 1-one
Step 1: Methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoate To a mixture of 2,5-dibromo-3-nitropyridine (2.00 g, 7.09 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (1.28 g, 7.09 mmol) Pd(dppf)C12 (0.36 g, 0.50 mmol) in THF (30 mL) was added tripotassium phosphate (3M in water) (7.09 mL, 21.3 mmol). The reaction mixture was purged with N2 (3x) and then stirred at 80 °C for 3 h. The aqueous layer was separated. The organic layer dried with Na2SO4, filtered through a small plug of Celite washing with EtOAc and concentrated. The crude residue waspurified using ISCO silica gel chromatography (120 g column, gradient from 0% to 50% EtOAc/CH2C12) to give the title compound (1.64 g, 69%) as a white solid. Step 2: 5-(5-Bromo-3-nitropyridin-2-yl)- 1,3-dihydro-2-benzofuran- 1-one Following a procedure analogous to that described for methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoate, 5 -(tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1,3 -dihydro-2- benzofuran- 1-one (695 mg, 2.67 mmol) was converted to the title compound, which waspurified using ISCO silica gel chromatography (24 g column, gradient from 0% to 100%EtOAc/hexanes) to give 568 mg (70%). ‘H NMR (400MHz, DMSO-d6) ö 9.17 (d, J2.0Hz, 1H), 8.91 (d, J=2.0 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.90-7.86 (m, 1H), 7.75-7.69 (m,1H), 5.50 (s, 2H). LCMS (M+H) = 335; HPLC RT = 1.12 mm (Column: Waters AcquityBEH C 182.0 x 50 mm; Mobile Phase A: 10:90 ACN:water with 0.1% TFA; Mobile PhaseB: 90:10 ACN:water with 0.1% TFA; Temperature: 40°C; Gradient: 0-100% B over 1.5mm; Flow: 1 mL/min).
methyl 4-(5-bromo-3-nitropyridin-2-yl)-3-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 70℃; for 2h;Inert atmosphere;
Step 1: Methyl 4-(5-bromo-3-nitropyridin-2-yl)-3-fluorobenzoateTo a solution of <strong>[603122-84-5](2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid</strong> (0.5 00 g, 2.53mmol) and 2,5-dibromo-3-nitropyridine (0.7 12 g, 2.53 mmol) in THF (8.42 mL) wasadded aq. tripotassium phosphate (2M, 2.53 ml, 5.05 mmol). The reaction was degassedwith bubbling nitrogen, then PdC12(dppf)-CH2C12 adduct (0.124 g, 0.152 mmol) wasadded and the reaction was heated to 70 C for 2 h. The reaction was cooled, diluted withwater, and extracted 3 times with EtOAc. The combined organics were concentrated.The residue was purified via ISCO silica gel chromatography (40 g column; Hex/EtOAc;0 to 100%) to give methyl 4-(5-bromo-3-nitropyridin-2-yl)-3-fluorobenzoate (0.6 10 g,68%). ?H NMR (400MHz, CDC13) oe 9.01 (d, J2.1 Hz, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.02(dd, J8.0, 1.5 Hz, 1H), 7.84-7.73 (m, 2H), 3.97 (s, 3H); LCMS (M+H) = 355.1; HPLC RT = 1.15 mm. Analytical HPLC Method 1.
methyl 4-(5-bromo-3-nitropyridin-2-yl)-2-chlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In tetrahydrofuran; water; at 75℃; for 2h;Inert atmosphere;
Step 1: Methyl 4-(5-bromo-3-nitropyridin-2-yl)-2-chlorobenzoate A flask was charged with 2,5-dibromo-3-nitropyridine (6.55 g, 23.24 mmol) and (3 -chloro-4-(methoxycarbonyl)phenyl)boronic acid (4.98 g, 23.24 mmol), flushed with nitrogen, and treated with tetrahydrofuran (65 mL), followed by 2M aqueous tripotassium phosphate (23.24 mL, 46.5 mmol). The resulting mixture was stirred while bubblingnitrogen through the mixture for 30 mm. To this was added PdC12(dppf) (0.595 g, 0.8 13 mmol) and heated at 75 C for 2 h. The reaction was cooled to room temperature and poured into a stirred mixture of water and ethyl acetate. The layers were separated, the organics washed with water (2X), then brine, dried over magnesium sulfate, filtered and concentrated. It was purified by silica gel column chromatography (100% DCM) to give5.76 g product (67%) as white solid. ?H NMR (400 MHz, CDC13) oe 8.97(m, 1H), 8.40(m,1H), 7.94(m, 1H), 7.71(m, 1H), 7.44(m, 1H), 3.99(s, 3H), LCMS (M+H) = 373.2.
67%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In tetrahydrofuran; water; at 75℃; for 2h;Inert atmosphere;
A flask was charged with 2,5-dibromo-3-nitropyridine (6.55 g, 23.24 mmol) and <strong>[603122-82-3](3-chloro-4-(methoxycarbonyl)phenyl)boronic acid</strong> (4.98 g, 23.24 mmol), flushed with nitrogen, and treated with tetrahydrofuran (65 mL), followed by 2M aqueous tripotassium phosphate (23.24 mL, 46.5 mmol). The resulting mixture was stirred while bubbling nitrogen through the mixture for 30 min. To this was added PdCl2(dppf) (0.595 g, 0.813 mmol) and heated at 75 C. for 2 h. The reaction was cooled to room temperature and poured into a stirred mixture of water and ethyl acetate. The layers were separated, the organics washed with water (2×), then brine, dried over magnesium sulfate, filtered and concentrated. It was purified by silica gel column chromatography (100% DCM) to give 5.76 g product (67%) as white solid. 1H NMR (400 MHz, CDCl3) delta 8.97 (m, 1H), 8.40 (m, 1H), 7.94 (m, 1H), 7.71 (m, 1H), 7.44 (m, 1H), 3.99 (s, 3H), LCMS (M+H)=373.2.
methyl 3-bromo-6-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.04 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In tetrahydrofuran; at 75℃; for 0.5h;Inert atmosphere;
To a stirred solution of <strong>[603122-40-3]methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate</strong> (1.30 g, 4.43 mmol), 2,5-dibromo-3-nitropyridine (1.04 g, 3.69 mmol), and PdCl2(dppf) (0.140 g, 0.191 mmol) in THF (37 mL) was added tripotassium phosphate (3M in H2O, 3.7 mL, 11.1 mmol), purged with N2 (g), and the reaction was heated to 75 C. with stirring for 30 min, cooled to room temperature, partially concentrated, diluted with EtOAc, washed with H2O, sat. aq. NaCl, and dried over sodium sulfate. The solids were filtered away, and the volatiles were concentrated in vacuo. The residue was purified by silica gel column chromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 100% using solvent A/B=CH2Cl2/EtOAc over 15 column volumes, RediSep SiO2 120 g, loaded as DCM solution) to afford a mixture of the mono- and bis-coupled products (1.04 g) as a pale-yellow solid: HPLC for major product: RT=1.212 min (Waters Acquity BEH C18 1.7 um 2.0×50 mm, CH3CN/H2O/0.1% TFA, 1.5 min gradient, wavelength=254 nm); MS (ES): m/z=367/369 Br79/Br81 [M+1]+.
methyl 3-bromo-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With 1,2-bis-(diphenylphosphino)ethane; In 1,2-dichloro-benzene; at 170℃; for 1.5h;
In a 100 mL RB flask was added the mixture above (1.04 g) and 1,2-bis(diphenylphosphino)ethane (1.27 g, 3.19 mmol) in 1,2-dichlorobenzene (12 mL), and the flask was heated in a pre-heated heating block at 170 C. for 90 min, then cooled to room temperature. The mixture was poured into 150 mL hexanes, the solid was collected by filtration, washed with hexanes, and air dried. The residue was purified by silica gel column chromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 100% using solvent A/B=hexanes/EtOAc over 15 column volumes, RediSep SiO2 220 g Gold). The clean fractions were set aside, and the mixed fractions resubjected to flash chromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 30% using solvent A/B=CH2Cl2/EtOAc over 19 column volumes, RediSep SiO2 12 g Gold). Two regioisomers were obtained: (methyl 3-bromo-6-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate (339.7 mg, 36%)) as a cream solid: 1H NMR (400 MHz, DMSO-d6) delta 12.04 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 4.01 (s, 3H), 3.90 (s, 3H); HPLC: RT=0.97 min (Waters Acquity BEH C18 1.7 um 2.0×50 mm, CH3CN/H2O/0.05% TFA, 1 min gradient, wavelength=220 nm); MS (ES): m/z=335/337 Br79/Br81 [M+1]+ and (methyl 3-bromo-8-methoxy-5H-pyrido[3,2-b]indole-7-carboxylate (322 mg, 0.962 mmol, 34%)) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) delta 11.55 (s, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H); HPLC: RT=0.90 min (Waters Acquity BEH C18 1.7 um 2.0×50 mm, CH3CN/H2O/0.05% TFA, 1 min gradient, wavelength=220 nm); MS (ES): m/z=335/337 Br79/Br81 [M+1]+.
methyl 4-(5-bromo-3-nitropyridin-2-yl)-3-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 70.0℃; for 2.0h;Inert atmosphere;
To a solution of (2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (0.500 g, 2.53 mmol) and 2,5-dibromo-3-nitropyridine (0.712 g, 2.53 mmol) in THF (8.42 mL) was added aq. tripotassium phosphate (2M, 2.53 ml, 5.05 mmol). The reaction was degassed with bubbling nitrogen, then PdCl2(dppf)-CH2Cl2 adduct (0.124 g, 0.152 mmol) was added and the reaction was heated to 70 C. for 2 h. The reaction was cooled, diluted with water, and extracted 3 times with EtOAc. The combined organics were concentrated. The residue was purified via ISCO silica gel chromatography (40 g column; Hex/EtOAc; 0 to 100%) to give methyl 4-(5-bromo-3-nitropyridin-2-yl)-3-fluorobenzoate (0.610 g, 68%). 1H NMR (400 MHz, CDCl3) delta 9.01 (d, J=2.1 Hz, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.02 (dd, J=8.0, 1.5 Hz, 1H), 7.84-7.73 (m, 2H), 3.97 (s, 3H); LCMS (M+H)=355.1; HPLC RT=1.15 min. Analytical HPLC Method 1.
5-bromo-2-(4-(methylthio)phenyl)-3-nitropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In tetrahydrofuran; water at 70℃; for 1.5h; Inert atmosphere;
371.1 5-Bromo-2-(4-(methylthio)phenyl)-3-nitropyridine
To a solution of (4-(methylthio)phenyl)boronic acid (0.500 g, 2.98 mmol) and (4-(methylthio)phenyl)boronic acid (0.500 g, 2.98 mmol) in THF (9.92 ml) was added aq. tripotassium phosphate (2M, 2.98 ml, 5.95 mmol). The reaction was degassed with bubbling nitrogen, then PdCl2(dppf)-DCM adduct (0.146 g, 0.179 mmol) was added, and the reaction was heated to 70° C. After ca. 1.5 h, the reaction was cooled, diluted with water, and extracted 3 times with EtOAc. The organic layer was concentrated. The residue was purified via ISCO silica gel column chromatography (40 g column; Hex/EtOAc; 0 to 50% gradient) to give 5-bromo-2-(4-(methylthio)phenyl)-3-nitropyridine (0.684 g, 71%). 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J=2.1 Hz, 1H), 8.92-8.86 (m, 1H), 8.26 (d, J=2.1 Hz, 1H), 7.51-7.45 (m, 2H), 7.36-7.29 (m, 2H), 2.53 (s, 3H).
5-bromo-2’-chloro-3-nitro-2,4’-bipyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; for 2.5h;Inert atmosphere; Reflux;
In a RB flask was added a mixture of 2,5-dibromo-3-nitropyridine (8.78 g, 31.1 mmol) and <strong>[458532-96-2](2-chloropyridin-4-yl)boronic acid</strong> (5 g, 31.8 mmol) in tetrahydrofuran (60 mL) and the solution was purged under a stream of nitrogen. Added 2 M aqueous potassium phosphate (39.7 mL, 79 mmol) and continued purging with nitrogen and then added PdCl2(dppf)-CH2Cl2Adduct (1.297 g, 1.59 mmol) and the mixture was then heated to reflux under nitrogen for 2.5 h. Let cool to room temperature and diluted with water and extracted into ethyl acetate. Washed with water and concentrated. The material was dissolved in DCM and chromatographed on an ISCO Companion 120 g silica gel column and eluted with EtOAc/Hexane gradient (20-50%) to give 5-bromo-2'-chloro-3-nitro-2,4'- bipyridine (5 g, 15.9 mmol, 50.0 % yield). LCMS: RT = 0.92 min; (ES): m/z (M+H)+ = 314.0, 316.0. (Waters Acquity SDS. Column: BEH C18 2.1x50mm 1.7u (1.6 min grad) 2- 98 % B. Flow Rate = 0.8 mL/min. Solvent A: H2O -0.1 %TFA. Solvent B: Acetonitrile - 0.1 %TFA).
5-(5-bromo-3-nitropyridin-2-yl)pyrimidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In tetrahydrofuran; water at 65℃; Inert atmosphere; Sealed tube;
143.1 Step 1: 5-(5-Bromo-3-nitropyridin-2-yl)pyrimidine-2-carbonitrile
To a 250 mL round bottom flask was added 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidine-2-carbonitrile (0.65 g, 2.81 mmol),2,5-dibromo-3- nitropyridine (0.793 g, 2.81 mmol) and 50 mL of THF. To this mixture was added 2M aqueous tripotassium phosphate (2.81 ml, 5.63 mmol) and PdCi2(dppf) CH2Ci2 (0.230 g, 0.281 mmol). The resulting solution was degassed by bubbling through argon gas while sonicating for 1 min. The flask was sealed and heated in an oil bath at 65°C overnight. The reaction mixture was concentrated to give a black residue. This material was purified on SiC (40 g) loaded on dry column in DCM and eluted using hexane (51 mL), 20% EtOAc/hexane (252 mL) , 20 to 50% EtOAc/hexane (357 mL, linear gradient). The product fractions gave the title compound (251 mg, 29%) as a white fluffy solid. NMR (400MHz, CDCh) δ 9.08 (d, J=2.0 Hz, 1H), 9.01 (s, 2H), 8.64 (d, J=2.0 Hz, 1H). LC/MS (306, [M+H]+). LCMS: Rt = 1.28 min; (ES): m/z (M+H)+ 306: (Waters Acquity SDS; Column Type: ACQUITY UPLC BEH C18 1.7μιη 2.1 x 50 mm; Run Time: 2.20 min; 0-100%B; Solvent A: 100% water /0.05%TFA; Solvent B: 100% ACN w/0.05%TFA; Flow: 0.8 mL/min;Detection: UV = 220 nm).
5-bromo-6’-(methylsulfonyl)-3-nitro-2,3’-bipyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 80℃; for 3h; Inert atmosphere; Sealed tube;
144.1 Step 1: 5-Bromo-6'-(methylsulfonyl)-3-nitro-2,3'-bipyridine
(6-(methylsulfonyl)pyridin-3-yl)boronic acid (1 g, 4.97 mmol), 2,5-dibromo-3- nitropyridine (1.402 g, 4.97 mmol), potassium carbonate (2.063 g, 14.9 mmol) and PdCl2(dppf)-CH2Cl2Adduct (0.406 g, 0.497 mmol) were taken up in 50 mL of dioxane. 2 mL of water was added. The reaction mixture was bubbled in argon for 5 min while sonicating. The flask was capped and heated at 80 °C for 3 h. Concentrated and took up thick black residue in methylene chloride and purified on a 120 g ISCO (silica gel) column, eluting with 5% EtOAc/methylene chloride to 80% EtOAc/methylene chloride over 1200 mL. Concentrated fractions containing product to afford 0.43 g of the title compound (24%). LC/MS: RT = 0.96 min (Column: Waters Acquity SDS; Mobile Phase A: 100% Water, 0.1% TFA; Mobile Phase B: 100% ACN, 0.1% TFA; Temperature 50 °C; Gradient 2% B to 98 % B over 2.2 min; Flow 0.8 mL/min; Detection: UV at 220 nm). NMR (400MHz, DMSO-de) δ 9.25 (d, J=2.3 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.99 (dd, J=2.3, 0.8 Hz, 1H), 8.41 - 8.34 (m, 1H), 8.21 (dd, J=8.2, 0.9 Hz, 1H), 3.39 (s, 3H).
5-(5-bromo-3-nitropyridin-2-yl)-2-chloropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 65℃;Inert atmosphere; Sealed tube;
In a 250 mL thick-walled flask was added <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (1 g, 6.32 mmol),2,5-dibromo-3-nitropyridine (1.780 g, 6.32 mmol) in 90 mL of THF. Added tripotassium phosphate (2.68 g, 12.6 mmol)and PdChidppO-CLhChAdduct (0.103 g, 0.126 mmol) . Bubbled in argon through the mixture while sonicating for 1 min. Capped flask and heated in an oil bath at 65 C overnight. Concentrated to afford a brown solid. The crude material was purified on a 120 g ISCO column, eluting with 20% EtOAc/hexanes to 50% EtOAc/hexanes over 20 column volumes. The fractions containing the title compound were concentrated to afford 0.72 g (36% yield) of a yellow solid. NMR (400MHz, CDCh) delta 9.04 (d, J=2.0 Hz, 1H), 8.83 (s, 2H), 8.58 (d, J=2.0 Hz, 1H).
5-bromo-6’-chloro-3-nitro-2,3’-bipyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 80℃; for 2h;Inert atmosphere; Sealed tube;
Step 1: 5-Bromo-6'-chloro-3-nitro-2,3'-bipyridine In a 75 mL pressure flask equipped with a magnetic stirring bar was added (6- chloropyridin-3-yl)boronic acid (1 g, 6.35 mmol), 2,5-dibromo-3-nitropyridine (1.791 g, 6.35 mmol). The solids were suspended in THF (30 mL). The mixture was treated with PdCl2(dppf)-CH2Cl2 adduct (0.259 g, 0.318 mmol) and K3P04 (9.53 mL, 19.1 mmol) (25g K3PO4/6O mL water = 2M solution). Argon was bubbled through the mixture for 5 min while sonicating. The flask was capped and heated to 80C within a preheated oil bath for 2 h. The reaction vessel was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated to remove the organic solvent. The remaining aqueous layer was diluted with water and was extracted with ethyl acetate (emulsion formed, brine added). The organic layer was dried over MgS04, filtered and concentrated to give a solid. The material was taken up in DCM and ethyl acetate. The solution was purified by flash column chromatography (80g silica gel ISCO, 0-50% ethyl acetate/hexanes over 600 mL total solvent, then 50-100% over 300 mL solvent; TLC Rf = 0.88 (50% ethyl acetate/hexanes)). Like fractions were concentrated to give 660 mg (33%) of a pale yellow solid with 99% purity by LC/MS. LC/MS (M+H) = 315.9; HPLC conditions: Rt = 3.43 min (Phenomenex LUNA C 18 2 x 50 mm (4 min grad) eluting with 10-90% aq MeOH containing 0.1% TFA, 0.8 mL/min, monitoring at 254 nm); Temperature: 40C).
5-bromo-6’-chloro-2’-methoxy-3-nitro-2,3’-bipyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 80℃;Inert atmosphere; Sealed tube;
A 150 mL pressure flask was charged with (6-chloro-2-methoxypyridin-3- yl)boronic acid (2.5 g, 13.3 mmol) and 2,5-dibromo-3-nitropyridine (3.38 g, 12.01 mmol). The solids were suspended in THF (60 mL). The mixture was treated with PdCl2(dppf)-CH2Cl2 adduct (0.545 g, 0.667 mmol) and K3P04 (2M, 20 mL, 40 mmol). Argon was bubbled through the mixture for 5 min while sonicating. The flask was capped and heated to 80C in a preheated oil bath. The reaction was cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated to remove THF. The remaining water layer was diluted further with water and was extracted with ethyl acetate. The organic layer was dried over MgS04, filtered and concentrated under vacuum to give a solid. The material was taken up in DCM and a minimum of ethyl acetate and purified by flash column chromatography (80g ISCO column, 0-30% ethyl acetate/hexanes over 600 mL, then 50-100% over 300 mL). Like fractions were concentrated to give 4.5g (78%). NMR (400MHz, CDCh) delta 8.94 (d, J=2.0 Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 3.89 (s, 3H). LC/MS (M+H) = 345.95
5-bromo-5’-chloro-3-nitro-2,3’-bipyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 80℃; for 2h;Inert atmosphere; Sealed tube;
A pressure flask was charged with <strong>[872041-85-5](5-chloropyridin-3-yl)boronic acid</strong> (5 g, 31.8 mmol) and 2,5-dibromo-3-nitropyridine (8.06 g, 28.6 mmol). The solids were suspended in THF (100 mL). The mixture was treated with PdCl2(dppf)-CH2Cl2 adduct (1.297 g, 1.589 mmol) and K3PO4 (2M, 47.7 mL, 95 mmol). Argon was bubbled through the mixture for 5 min while sonicating. The flask was capped and heated to 80C in a preheated oil bath for 2 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated to remove THF. The remaining water layer was diluted further with water and extracted with ethyl acetate. The organic layer was dried over MgS04, filtered and concentrated under vacuum to give a solid. The material was triturated with ethanol and the remaining brown solid (6.8g, 68%) dried under vacuum. LC/MS (M+H) = 315.97; HPLC conditions: TR = 3.73 min. : Column: Phenomenex LUNA C 18 2 x 50 mm (4 min grad) eluting with 10-90% aqueous methanol containing 0.1 %TFA, 0.8 mL/min, monitoring at 254 nm); Temperature: 40C.
methyl 5-bromo-3-nitro-[2,3’-bipyridine]-5’-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In tetrahydrofuran at 80℃; for 2h; Inert atmosphere; Sealed tube;
348.1 Step 1: Methyl 5-bromo-3-nitro-[2,3'-bipyridine]-5'-carboxylate
A pressure flask was charged with methyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)nicotinate (1.4 g, 5.32 mmol) and 2,5-dibromo-3-nitropyridine (1.35 g, 4.79 mmol). The solids were suspended in THF (40 mL). The mixture was treated with PdCl2(dppf)-CH2Cl2 adduct (0.217 g, 0.266 mmol) and K3P04 (2 M, 8 mL, 16 mmol). Argon was bubbled throught the mixture for 5 min with sonication. The flask was capped and placed in a preheated oil bath at 80°C. After 2 h, the vessel was cooled to room temperature and the reaction mixture was filtered. The filtrate was concentrated under vacuum to near dryness. The remaining water layer was diluted with water and was extracted with ethyl acetate. Brine was added and the organic layer was removed, dried over MgS04, filtered and concentrated under vacuum to give 2.14g (95%). NMR (400MHz, CDCh) δ 9.35 (d, J=2.0 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.57 - 8.43 (m, 2H), 4.01 (s, 3H). LC/MS (M+H) = 348.10.
A Step A: 5-Bromo-N-methyl-3-nitropyridin-2-amine.
Into a 20 L four-necked flask were charged with EtOH (10.5 L) and 2,5-dibromo-3-nitropyridine (1500 g, 5.32 mol). The mixture was heated to 50 °C followed by addition of aq. MeNH2 (40% w/w, 1032.5 g, 13.3 mol) during 1 h. After stirring at 55 to 65 °C for 2 h, the reaction mixture was cooled 20 °C and filtered. The cake was washed with EtOH/H2O (V/V = 1/1, 1 L) followed by slurring in water (8 L) at room temperature for 1.5 h. Then the suspension was filtered and the cake was washed with water (1 L). The cake was collected and dried at room temperature overnight to give the title compound (1198 g, 97%).1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.20 (bs, 1H), 3.18 (d, J = 8.0 Hz, 3H).
To a mixed solution of compound 2b (5 g, 22 mmol), bisboronic acid pinacol (8.5 g, 33 mmol) and KOAc (3.2g, 33 mmol) in 1,4 dioxane (50 ml) was added Pd(dppf)2Cl2 (1g), and flushed with nitrogen. The reaction flask wassealed and the reaction was stirred overnight at 85C. After cooling to room temperature, an aqueous Na2CO3 solution(2.5M, 10ml), Pd(dppf)2Cl2 (1g) and 2,5-dibromo-3-nitropyridine (9 g, 33 mmol) were added. After flushed with nitrogenfor 10 minutes, the reaction flask was sealed and the mixture was stirred overnight at 85C. The reaction was pouredinto water and extracted with ethyl acetate. The organic phase mixture was dried over Na2SO4, dried by suction andpurified by silica gel column chromatography (PE:EA=10:1 to 1:1) to provide compound 2c as a yellow solid.HNMR(DMSO),9.1(s,1H),8.8(s,1H),7.7-7.8(m,3H),4.5(s,2H),3.1(s,3H).MS(ESI)m/z:347.9(M +H)+.
To a mixed solution of compound 3b (5 g, 22 mmol), bisboronic acid pinacol (8.5 g, 33 mmol) and KOAc (3.2g, 33 mmol) in 1,4-dioxane (50 ml) was added Pd(dppf)2Cl2 (1g), and flushed with nitrogen. The reaction flask wassealed and the reaction was stirred overnight at 85C. After cooled to room temperature, an aqueous Na2CO3 solution (2.5M, 10ml), Pd(dppf)2Cl2 (1g) and 2,5-dibromo-3-nitropyridine (9 g, 33 mmol) were added. After flushed with nitrogenfor 10 minutes, the reaction flask was sealed and the mixture was stirred overnight at 85C. The reaction was pouredinto water and extracted with ethyl acetate. The organic phase mixture was dried over Na2SO4, dried by suction andpurified by silica gel column chromatography (PE:EA=10:2 to 1:1) to provide compound 3c as a yellow solid.MS(ESI)m/z:347.9(M+H)+.
To a mixed solution of compound 4a (10.5g, 50mmol), bisboronic acid pinacol (19g, 75mmol) and KOAc (7.5g,75mmol) in 1,4-dioxane (150ml) was added Pd(dppf)2Cl2 (1g), and flushed with nitrogen. The reaction flask was sealedand the reaction was stirred overnight at 85°C. After cooling to room temperature, an aqueous Na2CO3 solution (2.5M,30ml), Pd(dppf)2Cl2 (1g) and 2,5-dibromo-3-nitropyridine (21g, 75mmol) were added. After flushed with nitrogen for 10minutes, the reaction flask was sealed and the mixture was stirred overnight at 85°C. The reaction was poured into waterand extracted with ethyl acetate. The organic phase mixture was dried over Na2SO4, dried by suction and purified bysilica gel column chromatography (PE:EA=10:1 to 1:1) to provide compound 4b as a yellow solid.HNMR(CDCl3),8.9(s,1H),8.3(s,1H),8.0(s,1H),7.8(m,1H),7.7(m,1H),7.2(m,1H),4.1(s,3H).MS( ESI)m/z:332.8(M+H)+.
To a mixed solution of compound 5a (10.5g, 50mmol), bisboronic acid pinacol (19g, 75mmol) and KOAc (7.5g,75mmol) in 1,4-dioxane (150ml) was added Pd(dppf)2Cl2 (1g), and flushed with nitrogen. The reaction flask was sealedand the reaction was stirred overnight at 85C. After cooling to room temperature, an aqueous Na2CO3 solution (2.5M,30ml), Pd(dppf)2Cl2 (1g) and 2,5-dibromo-3-nitropyridine (21g, 75mmol) were added. After flushed with nitrogen for 10minutes, the reaction flask was sealed and the mixture was stirred overnight at 85C. The reaction was poured into waterand extracted with ethyl acetate. The mixed organic phase was dried over Na2SO4, dried by suction and purified bysilica gel column chromatography (PE:EA=10:1 to 1:1) to provide compound 5b as a yellow solid.HNMR(CDCl3),8.9(d,1H),8.3(d,1H),8.0(s,1H),7.9(s,1H),7.5(m,1H),7.4(m,1H),4.1(s,3H).MS( ESI)m/z:332.8(M+H)+.
To a mixed solution of compound 6a (10.5g, 50mmol), bisboronic acid pinacol (19g, 75mmol) and KOAc (7.5g,75mmol) in 1,4-dioxane (150ml) was added Pd(dppf)2Cl2 (1g), and flushed with nitrogen. The reaction flask was sealedand the reaction was stirred overnight at 85C. After cooling to room temperature, an aqueous Na2CO3 solution (2.5M,30ml), Pd(dppf)2Cl2 (1g) and 2,5-dibromo-3-nitropyridine (21g, 75mmol) were added. After flushed with nitrogen for 10minutes, the reaction flask was sealed and the mixture was stirred overnight at 85C. The reaction was poured into waterand extracted with ethyl acetate. The mixed organic phase was dried over Na2SO4, dried by suction purified by silicagel column chromatography (PE:EA=10:1 to 1:1) to provide compound 6b as a yellow solid.HNMR(CDCl3),8.99(s,1H),8.39(s,1H),7.9(s,1H),7.52(m,1H),7.45(m,1H),7.2(m,1H),4.1(s,3H).MS(ESI)m/z:332.8(M+H)+.
To a mixed solution of compound 1b (5 g, 22 mmol), bisboronic acid pinacol (8.5 g, 33 mmol) and KOAc (3.2g, 33 mmol) in 1,4 dioxane (50 ml) was added Pd(dppf)2Cl2 (1g), and flushed with nitrogen. The reaction flask wassealed and the reaction was stirred overnight at 85°C. After cooling to room temperature, an aqueous Na2CO3 solution(2.5M, 10ml), Pd(dppf)2Cl2 (1g) and 2,5-dibromo-3-nitropyridine (9 g, 33 mmol) were added. After flushed with nitrogenfor 10 minutes, the reaction flask was sealed and the mixture was stirred overnight at 85°C. The reaction was pouredinto water and extracted with ethyl acetate. The organic phase mixture was dried over Na2SO4, dried by suction andpurified by silica gel column chromatography (PE:EA=10:1 to 1:1) to provide compound 1c as a yellow solid.HNMR(CDCl3),9.0(s,1H),8.4(s,1H),8.0(d,1H),7.6-7.7(m,2H),4.5(s,2H),3.3(s,3H).MS(ESI)m/z :347.9(M+H)+.
Stage #1: 4-bromo-1-methyl-1H-indole With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; bis(pinacol)diborane In 1,4-dioxane at 85℃; Inert atmosphere; Sealed tube;
Stage #2: 2,5-dibromo-3-nitro-pyridine With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In 1,4-dioxane; water at 85℃; Inert atmosphere; Sealed tube;
9.A Step A
To a mixed solution of compound 9a (5g, 24mmol), bisboronic acid pinacol (7.6g, 30mmol) and KOAc(5g,48mmol) in 1,4-dioxane (150ml) was added Pd(dppf)2Cl2 (1g), and flushed with nitrogen. The reaction flask wassealed and the reaction was stirred overnight at 85°C. After cooling to room temperature, an aqueous Na2CO3 solution(2.5M, 20ml), Pd(dppf)2Cl2 (1g) and 2,5-dibromo-3-nitropyridine (8g, 30mmol) were added. After flushed with nitrogenfor 10 minutes, the reaction flask was sealed and the mixture was stirred overnight at 85°C. The reaction was pouredinto water and extracted with ethyl acetate. The mixed organic phase was dried over Na2SO4, dried by suction andpurified by silica gel column chromatography (PE:EA=10:1 to 1:1) to provide compound 9b as a yellow solid.HNMR(DMSO),9.0(s,1H),8.8(s,1H),7.5(m,1H),7.4(m,1H),7.2-7.3(m,2H),7.1-7.2(m,1H),3.8(s,3H).MS(ESI)m/z:332.4(M+H)+.
Chemistry
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Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
