* 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.
Stage #1: With hydrogen bromide; sodium nitrite In water at -10 - 20℃; for 16.5 h;
4-Bromo-2-methylpyridine (153)A stirred solution of amino-pyridine 152 (10.1 g, 93.4 mmol) in 48percent aqueous HBr (165 mL) at -10"C is treated with a pre-cooled (0°C) solution of sodium nitrite (7.04 g, 0.102 mol) in water (165 mL) dropwise over 0.5 h. The solution is then warmed to RT and stirred 16 h. It is then diluted with 4 M NaOH (400 mL) and extracted into TBME (4 x 150 mL). The TBME phases are combined, dried (MgSO4) and reduced in vacuo to afford the title compound. Yield: 14.8 g (92percent). LC/MS tτ 0.57 min. MS(ES+) m/z 174, 172 (M+H).
92%
With hydrogen bromide; sodium nitrite In water at -10 - 20℃; for 16.5 h;
4-Bromo-2-methylpyridine (153)A stirred solution of amino-pyridine 152 (10.1 g, 93.4 mmol) in 48percent aqueous HBr (165 mL) at -10°C was treated with a pre-cooled (0°C) solution of sodium nitrite <n="205"/>(7.04 g, 0.102 mol) in water (165 mL) dropwise over 0.5 h. The solution was then warmed to RT and stirred 16 h. It was then diluted with 4 M NaOH (400 mL) and extracted into TBME (4 x 150 mL). The TBME phases were combined, dried(MgSO4) and reduced in vacuo to afford the title compound.Yield: 14.8 g (92percent).LC/MS tr 0.57 rain.MS(ES+) m/z 174, 172 (M+H).
92%
Stage #1: With hydrogen bromide; sodium nitrite In water at -10 - 20℃; for 16.5 h;
4-Bromo-2-methylpyridine (153); A stirred solution of amino-pyridine 152 (10.1 g, 93.4 mmol) in 48percent aqueous HBr (165 mL) at -10°C is treated with a pre-cooled (0°C) solution of sodium nitrite (7.04 g, 0.102 mol) in water (165 mL) dropwise over 0.5 h. The solution is then warmed to RT and stirred 16 h. It is then diluted with 4 M NaOH (400 mL) and extracted into TBME (4 x 150 mL). The TBME phases are combined, dried (MgSO4) and reduced in vacuo to afford the title compound. Yield: 14.8 g (92percent). LC/MS U 0.57 min. MS(ES+) m/z 174, 172 (M+H).
92%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0 - 20℃; for 16.5 h; Stage #2: With sodium hydroxide In water
4-Bromo-2-methylpyridine (153); A stirred solution of amino-pyridine 152 (10.1 g, 93.4 mmol) in 48percent aqueous HBr(165 mL) at -10°C is treated with a pre-cooled (0°C) solution of sodium nitrite (7.04 g, 0.102 mol) in water (165 mL) dropwise over 0.5 h. The solution is then warmed toRT and stirred 16 h. It is then diluted with 4 M NaOH (400 mL) and extracted into TBME (4 x 150 mL). The TBME phases are combined, dried (MgSO4) and reduced in vacuo to afford the title compound.Yield: 14.8 g (92percent).LC/MS /, 0.57 min.MS(ES+) m/z 174, 172 (M+H).
89%
Stage #1: With hydrogen bromide; sodium nitrite In water at -15 - 15℃; Stage #2: With copper(I) bromide In water at -15 - 20℃; for 12 h;
-Methyl-4-aminopyridine (3. 86 g, 35.69 mmol) in [48percent] aqueous HBr (24 [ML)] was cooled to -15°C and [NAN02] (4.9 g, 71.4 mmol) in water (34 mL) was added slowly. (Note: The temperature was maintained between-10 to [15 °C] during the addition. ) CuBr [(510 MG,] 3.6 mmol) was added to the above reaction mixture at-15° C and slowly allowed to warm to room temperature over 12 hours. The pH of the reaction mixture was adjusted to [PH =10,] by addition [OF NAOH (11 G] in 21 mL water). The reaction mixture was filtered through celite and washed with ether/water. The layers were separated and the aqueous layer was extracted twice with ether. The combined organic extracts were dried [(NA2SO4),] concentrated under vacuum, and purified by silica gel chromatography (50percent ether in hexanes) to afford [4-BROMO-2-METHYLPYRIDINE] [(5.] 48 g, 89percent yield).
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 1, p. 263 - 266[2] Angew. Chem., 2015, vol. 127, # 01, p. 265 - 268,4
12
[ 22282-99-1 ]
[ 68-12-2 ]
[ 63875-01-4 ]
Yield
Reaction Conditions
Operation in experiment
85%
With n-butyllithium In tetrahydrofuran; hexane; N,N-dimethyl-formamide at -78℃; for 1.58333 h;
Example 117 Preparation of 2-(2-methylpyridin-4-yl)-6-(morpholinomethyl)quinazolin-4(3H)-one A solution of n-butyllithium (1.6 M solution in hexanes, 6.32 mL, 12.6 mmol) in THF (50 mL) was cooled to -78° C. A solution of 4-bromo-2-methyl-pyridine (2.00 g, 11.6 mmol.) in anhydrous THF (5 mL) was added. The resulting mixture was stirred for 5 minutes, then anhydrous N,N dimethylformamide (3.39 g, 46.4 mmol,) was added. The solution was stirred for 90 min at -78° C. and quenched with saturated aqueous NH4Cl solution (30 mL). The reaction mixture was warmed to room temperature. The mixture was extracted with ethyl acetate (3*100 mL), and the combined organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give 2-methyl-pyridine-4-carbaldehyde. Yield: 1.20 g, (85percent).
30%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 0.25 h; Inert atmosphere Stage #2: at 0℃; for 0.5 h;
To a stirred solution of 4-bromo-2-methylpyridine (1.00 g, 5.81 mmol) in anhydrous diethyl ether (70 mL) was added n-BuLi (2.5 M, 2.56 mL, 6.39 mmol) at -78 °C under N2. After stirring at -78 °C for 15 mi DMF (0.54 mL, 6.92 mmol) was added slowly. The mixture was stirred for another 30 mm and warmed to 0 °C. The mixture was quenched with 20 mL of aq. NaHCO3, extracted with EA (50 mL x 2). The combined organics was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The resulted residue was purified by column chromatography eluted with PE/EA (5:1) to give the title product (210 mg, 30percent) as a light yellow solid. ‘HNMR (400 MHz, CDCl) 10.05 (s, 1H),8.76 (d, J=4.8 Hz, 1H),7.56 (s, 1H),7.51 (d, J=4.8 Hz, 1H), 2.68 (s, 3H)
1 g
Stage #1: With tert.-butyl lithium In diethyl ether at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78℃; for 0.5 h; Inert atmosphere
Intermediate H: Preparation of 2-methylisonicotinaldehyde Under a nitrogen atmosphere, to a solution of 4-bromo-2-methylpyridine (2.00 g, 11.63 mmol) in anhydrous Et20 (150 mL) was added t-butyllithium (0.82 g, 12.79 mmol) at -78 °C. The reaction was kept at that temperature for 30 min. Anhydrous DMF (0.85 g, 11.63 mmol) was added and the mixture was stirred at -78 °C for an additional 30 min. Saturated aqueous NH4C1 (50 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were washed with Et20 (6 x 50 mL). The combined organics were washed with saturated NaCl (2 x 50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo to provide 2-methylisonicotinaldehyde (lg, 8.3 mmol). GCMS [M] = 121
4.1.12 5-Bromopyridine-2-carboxylic acid (16) In a 250 mL three-necked flask equipped with a stirrer, a thermometer, and a condenser, 100 mL water and 4-bromo-2-methylpyridine (15) (4.0 g, 23 mmol) was added to it and stirring until the temperature was raised to 80 °C, then KMnO4 (16.6 g, 105 mmol) was added in three batches at intervals of 1 h. The mixture was stirred at the same temperature for 3-4 h. Suction filtration to give a clear solution, the solution was adjusted to pH 4-5 with concentrated HCl, some white solid precipitated, the filter cake is a small amount of the product (16). After filtration and concentration in vacuo, an appropriate amount of ethanol was added to the residues to dissolve the residue compound (16), a lot of white solid precipitated, discarded it after subjected to suction filtration again, finally the filtrate was concentrated in vacuo, total yielding (16) (1.70 g, 33percent) as light yellow solid.
22%
Stage #1: at 20℃; for 6.5 h; Heating / reflux
4-Bromopyridine-2-carboxylic acid (154) EPO <DP n="294"/>A stirred solution of pyridyl bromide 153 (5.03 g, 29.0 mmol) in water (130 mL) is treated at RT with KMnO4 (4.72 g, 29.5 mmol) in one portion then heated to reflux 1.5 h. At this juncture more KMnO4 is added (4.72 g, 29.5 mmol) and the solution heated at reflux a further 2 h. Another portion of KMnO4 is then added (9.43 g, 59 mmol), the reaction heated at reflux a further 3 h then filtered whilst still hot, washing the isolated solids with boiling water (200 mL). The aqueous filtrate is then concentrated in vacuo to approximately 40 mL, acidified to pH 4 by careful addition of 1 M HCl and the resultant white precipitate isolated by filtration. The filtrate is then reduced in vacuo to approximately 10 mL and the forthcoming precipitate also isolated by filtration. Combining these two isolated precipitates gives the title compound. Yield: 1.28 g (22percent). LC/MS U 0.67 min. MS(ES+) m/z 204, 202 (M+H).
22%
Stage #1: for 6.5 h; Heating / reflux Stage #2: With hydrogenchloride In water
4-Bromopyridine-2-carboxylic acid (154)A stirred solution of pyridyl bromide 153 (5.03 g, 29.0 mmol) in water (130 mL) was treated at RT with KMnO4 (4.72 g, 29.5 mmol) in one portion then heated to reflux 1.5 h. At this juncture more KMnO4 was added (4.72 g, 29.5 mmol) and the solution heated at reflux a further 2 h. Another portion OfKMnO4 was then added (9.43 g, 59 mmol), the reaction heated at reflux a further 3 h then filtered whilst still hot, washing the isolated solids with boiling water (200 mL). The aqueous filtrate was then concentrated in vacuo to approximately 40 mL, acidified to pH 4 by careful addition of 1 M HCl and the resultant white precipitate isolated by filtration. The filtrate was then reduced in vacuo to approximately 10 mL and the forthcoming precipitate also isolated by filtration. Combining these two isolated precipitates gave the title compound. Yield: 1.28 g (22percent). LC/MS tr 0.67 min. MS(ES+) m/z 204, 202 (M+H).
22%
Stage #1: With potassium permanganate In water at 20℃; for 6.5 h; Heating / reflux
4-Bromopyridine-2-carboxylic acid (154); EPO <DP n="294"/>A stirred solution of pyridyl bromide 153 (5.03 g, 29.0 mmol) in water (130 mL) is treated at RT with KMnO4 (4.72 g, 29.5 mmol) in one portion then heated to reflux 1.5 h. At this juncture more KMnO4 is added (4.72 g, 29.5 mmol) and the solution heated at reflux a further 2 h. Another portion OfKMnO4 is then added (9.43 g, 59 mmol), the reaction heated at reflux a further 3 h then filtered whilst still hot, washing the isolated solids with boiling water (200 mL). The aqueous filtrate is then concentrated in vacuo to approximately 40 mL, acidified to pH 4 by careful addition of 1 M HCl and the resultant white precipitate isolated by filtration. The filtrate is then reduced in vacuo to approximately 10 mL and the forthcoming precipitate also isolated by filtration. Combining these two isolated precipitates gives the title compound. Yield: 1.28 g (22percent). LC/MS ty 0.67 min. MS(ES+) m/z 204, 202 (M+H).
22%
Stage #1: With potassium permanganate In water at 20℃; for 6.5 h; Heating / reflux Stage #2: With hydrogenchloride In water
4-Bromopyridine-2-carboxylic acid (154); A stirred solution of pyridyl bromide 153 (5.03 g, 29.0 mmol) in water (130 mL) is treated at RT with KMnO4 (4.72 g, 29.5 mmol) in one portion then heated to reflux 1.5 h. At this juncture more KMnO4 is added (4.72 g, 29.5 mmol) and the solution heated at reflux a further 2 h. Another portion Of KMnO4 is then added (9.43 g, 59 mmol), the reaction heated at reflux a further 3 h then filtered whilst still hot, washing the isolated solids with boiling water (200 mL). The aqueous filtrate is then concentrated in vacuo to approximately 40 mL, acidified to pH 4 by careful addition of 1 M HCl and the resultant white precipitate isolated by filtration. The filtrate is then reduced in vacuo to approximately 10 mL and the forthcoming precipitate also isolated by filtration. Combining these two isolated precipitates gives the title compound. Yield: 1.28 g (22percent). LC/MS tτ 0.67 min. MS(ES+) m/z 204, 202 (M+H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3228 - 3236
[2] Patent: WO2008/57497, 2008, A2, . Location in patent: Page/Page column 292-293
[3] Patent: WO2007/89669, 2007, A2, . Location in patent: Page/Page column 204
[4] Patent: WO2008/57469, 2008, A1, . Location in patent: Page/Page column 292-293
[5] Patent: WO2008/57468, 2008, A1, . Location in patent: Page/Page column 292-293
[6] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
18
[ 22282-99-1 ]
[ 55218-73-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4721 - 4734
19
[ 22282-99-1 ]
[ 97674-02-7 ]
[ 2732-28-7 ]
Yield
Reaction Conditions
Operation in experiment
44%
With tetrakis(triphenylphosphine) palladium(0) In toluene at 80℃; Inert atmosphere
To a solution of 4-bromo-2-methylpyridine (10.0 g, 58 mmol) in toluene (100 mL) was added tributyl(l-ethoxyvinyl)stannane (39.7 g, 110 mmol) and Pd(PPh3)4 (5.8 g, 5 mmol). The mixture was stirred at 80 °C under a nitrogen atmosphere overnight. IM HCl was added at 0 °C until the pH of the mixture was adjusted to 1-2. The mixture was stirred for 0.5 h. The pH was adjusted to 6-7 by adding IM NaOH. The mixture was extracted with ethyl acetate (150 mL*3). The organics layer was washed with brine and dried over sodium sulfate. Concentration and purification by column chromatography on silica gel (petroleum ether/ethyl acetate = 30/1-4/1) afforded l-(2-methylpyridin-4-yl)ethanone as light yellow solid (3.0 g, 44percent).
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6427 - 6439
25
[ 22282-99-1 ]
[ 73183-34-3 ]
[ 660867-80-1 ]
Yield
Reaction Conditions
Operation in experiment
39%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 4 h; Inert atmosphere; Sealed tube
To a previously degassed solution of 4-bromo-2-methylpidine (0.500 g, 2.906 mmol),4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi( 1 ,3,2-dioxaborolane) (0.812 g, 3.997 mmol),potassium acetate (0.854 g, 8.720 mmol) in 1,4-dioxane (5mL) in 50 mL sealed tube was added [1,1 ‘-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.021 g, 0.029 mmol) and stirred at 80°C 4 h. Evaporated off the solvent and purified column chromatography on silica gel (ethyl acetate pet ether = 3070) to give the titledcompound (0.250 g, 39percent) as a off white solid .LCMS: mlz 220.1 [M+H] .
Reference：
[1] Patent: WO2014/111871, 2014, A1, . Location in patent: Page/Page column 199
[2] Patent: WO2004/14913, 2004, A2, . Location in patent: Page 82
[3] Patent: US2011/190269, 2011, A1, . Location in patent: Page/Page column 36
[4] Patent: WO2011/92272, 2011, A1, . Location in patent: Page/Page column 73
[5] Patent: WO2011/119518, 2011, A1, . Location in patent: Page/Page column 47-48
[6] Patent: WO2012/3189, 2012, A1, . Location in patent: Page/Page column 109-111
[7] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6855 - 6868
[8] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 154 - 165
[9] Patent: CN105254613, 2016, A, . Location in patent: Paragraph 0046;0047; 0048; 0049; 0050; 0051
[10] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5861 - 5872
[11] Patent: WO2017/31325, 2017, A1, . Location in patent: Paragraph 0569
[12] Organometallics, 2017, vol. 36, # 17, p. 3429 - 3434
26
[ 22282-99-1 ]
[ 865156-50-9 ]
Reference：
[1] Chemical Science, 2013, vol. 4, # 8, p. 3269 - 3274
[2] Patent: WO2015/181797, 2015, A1,
With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -70℃; for 2 h;
Intermediate 331 -(4-Bromo-pyridin-2-yl)-cvclopropanecarboxylic acid ethyl esterStep 1 : (4-bromo-pyridin-2-yl)-acetic acid ethyl ester; Lithium diisopropylamide (2 mol/L in tetrahydrofuran/heptane/ethylbenzene, 3.00 mL) was added to a solution of 4-bromo-2-methylpyridine (2.00 g) and diethyl carbonate (1 .8 mL) in tetrahydrofuran (30 mL) cooled to -70 'C. The solution was stirred for 1 h prior to the addition of another portion of lithium diisopropylamide (2 mol/L in tetrahydrofuran/heptane/ ethylbenzene, 3.00 mL). Stirring was continued at -70 °C for one more hour and then the reaction was quenched by the addition of water. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (Na2S04). The solvent was evaporated and the residue was chromatographed on silica gel(cyclohexane/ethyl acetate 95:5-->1 :1 ) to give the title compound. Yield: 2.35 g (83percent of theory); LC (method 3): tR = 2.86 min; Mass spectrum (ESI+): m/z = 244/246 (Br) [M+H]+.
46%
With lithium diisopropyl amide In tetrahydrofuran at -60℃; for 2 h;
To a solution of 4-bromo-2-methyl-pyridine (2.00 g, 11.6 mmol, CAS 22282-99- 1) and diethyl carbonate (1.65 g, 13.9 mmol, 1.68 mL) in THF (15.0 mL) was added LDA (2 M, 11.63 mL) at -60 °C dropwise. Then the mixture was stirred at -60 °C for 2 hours. On completion, the reaction mixture was quenched by addition of saturated ammonium chloride solution 30 mL at 0 °C, and extracted with ethyl acetate 60 mL (3 X 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 8:1) to give the title compound (1.30 g, 46percent yield) as a yellow oil.1H NMR (400MHz, CDCl3) δ = 8.40 (d, J = 5.2 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 1.6, 5.2 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.83 (s, 2H), 1.29 (t, J = 7.2 Hz, 3H).
2-Methyl-4-aminopyridine (10.8 g, 0.1 mol) was added to 48% HBr (46 ml, 0.4 mol) with ice-cooling.After the addition is completed, the mixture is cooled to -5 C, and liquid bromine (15 ml, 0.3 mol) is slowly added dropwise, and the addition is completed in 30-35 minutes.Then, 42% of a 40% sodium nitrite solution was added dropwise at 0 C or less, and the addition was completed in 1-1.1 h.After the addition is completed, the mixture is stirred at 0 C for 30 min, and then slowly added with 50% sodium hydroxide solution below 20 C to adjust the pH of the solution to 9,The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate grassroots, suction filtered, and concentrated2-Methyl-4-bromopyridine was obtained in a molar yield of 95%.
95%
Under ice salt bath cooling,Add 2-methyl-4-aminopyridine (10.8g, 0.1mol) to 48% HBr (46ml, 0.4mol). After the addition, cool to -5 C and slowly add liquid bromine (15ml, 0.3mol) , Add 30-35min, then add 42g of 40% sodium nitrite solution dropwise below 0 C , add within 1-1.1h,After the addition, continue stirring at 0 C for 30min,Then slowly add 50% sodium hydroxide solution below 20 C to adjust the solution pH to 9,The reaction solution was extracted with ethyl acetate, the basic layer was dried over anhydrous sodium sulfate, filtered with suction, and concentrated.2-Methyl-4-bromopyridine was obtained with a molar yield of 95%.
92%
4-Bromo-2-methylpyridine (153)A stirred solution of amino-pyridine 152 (10.1 g, 93.4 mmol) in 48% aqueous HBr (165 mL) at -10"C is treated with a pre-cooled (0C) solution of sodium nitrite (7.04 g, 0.102 mol) in water (165 mL) dropwise over 0.5 h. The solution is then warmed to RT and stirred 16 h. It is then diluted with 4 M NaOH (400 mL) and extracted into TBME (4 x 150 mL). The TBME phases are combined, dried (MgSO4) and reduced in vacuo to afford the title compound. Yield: 14.8 g (92%). LC/MS ttau 0.57 min. MS(ES+) m/z 174, 172 (M+H).
92%
With hydrogen bromide; sodium nitrite; In water; at -10 - 20℃; for 16.5h;
4-Bromo-2-methylpyridine (153)A stirred solution of amino-pyridine 152 (10.1 g, 93.4 mmol) in 48% aqueous HBr (165 mL) at -10C was treated with a pre-cooled (0C) solution of sodium nitrite <n="205"/>(7.04 g, 0.102 mol) in water (165 mL) dropwise over 0.5 h. The solution was then warmed to RT and stirred 16 h. It was then diluted with 4 M NaOH (400 mL) and extracted into TBME (4 x 150 mL). The TBME phases were combined, dried(MgSO4) and reduced in vacuo to afford the title compound.Yield: 14.8 g (92%).LC/MS tr 0.57 rain.MS(ES+) m/z 174, 172 (M+H).
92%
4-Bromo-2-methylpyridine (153); A stirred solution of amino-pyridine 152 (10.1 g, 93.4 mmol) in 48% aqueous HBr (165 mL) at -10C is treated with a pre-cooled (0C) solution of sodium nitrite (7.04 g, 0.102 mol) in water (165 mL) dropwise over 0.5 h. The solution is then warmed to RT and stirred 16 h. It is then diluted with 4 M NaOH (400 mL) and extracted into TBME (4 x 150 mL). The TBME phases are combined, dried (MgSO4) and reduced in vacuo to afford the title compound. Yield: 14.8 g (92%). LC/MS U 0.57 min. MS(ES+) m/z 174, 172 (M+H).
92%
4-Bromo-2-methylpyridine (153); A stirred solution of amino-pyridine 152 (10.1 g, 93.4 mmol) in 48% aqueous HBr(165 mL) at -10C is treated with a pre-cooled (0C) solution of sodium nitrite (7.04 g, 0.102 mol) in water (165 mL) dropwise over 0.5 h. The solution is then warmed toRT and stirred 16 h. It is then diluted with 4 M NaOH (400 mL) and extracted into TBME (4 x 150 mL). The TBME phases are combined, dried (MgSO4) and reduced in vacuo to afford the title compound.Yield: 14.8 g (92%).LC/MS /, 0.57 min.MS(ES+) m/z 174, 172 (M+H).
89%
-Methyl-4-aminopyridine (3. 86 g, 35.69 mmol) in [48%] aqueous HBr (24 [ML)] was cooled to -15C and [NAN02] (4.9 g, 71.4 mmol) in water (34 mL) was added slowly. (Note: The temperature was maintained between-10 to [15 C] during the addition. ) CuBr [(510 MG,] 3.6 mmol) was added to the above reaction mixture at-15 C and slowly allowed to warm to room temperature over 12 hours. The pH of the reaction mixture was adjusted to [PH =10,] by addition [OF NAOH (11 G] in 21 mL water). The reaction mixture was filtered through celite and washed with ether/water. The layers were separated and the aqueous layer was extracted twice with ether. The combined organic extracts were dried [(NA2SO4),] concentrated under vacuum, and purified by silica gel chromatography (50% ether in hexanes) to afford [4-BROMO-2-METHYLPYRIDINE] [(5.] 48 g, 89% yield).
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 3h;
Preparation 77 <strong>[22282-99-1]4-bromo-2-methylpyridine</strong>-1-oxide To a solution of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (20 g, 1 16.3 mmol) in dichloromethane (250 mL) was added mefa-chloroperoxybenzoic acid (26 g, 151.2 mmol) at 0C (ice-bath). The ice-bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated sodium bicarbonate (100 mL), the aqueous layer was further extracted with dichloromethane (50 mL) and the combined organic layers were dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (60 mL), filtered through a pad of silica gel eluting with ethyl acetate (60 mL) and the solvent was evaporated in vacuo to give the title compound as dark oil (15.92 g, 73%). (1008) 1 H NMR (400MHz, CDCI3): delta ppm 2.48 (s, 3H), 7.25 (dd, 1 H), 7.40 (d, 1 H), 8.08 (d, 1 H). LCMS Rt = 1.49 minutes MS m/z 189 [M+H]+
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0℃; for 16h;
To a solution of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> 1-oxide (10 g, 0.058 mol) in dichloromethane (150 niL) was added 3-chlorobenzoperoxoic acid (12.08 g, 0.07 mol) in portions at 0 C. The reaction mixture was stirred for 16 hr. TLC showed the starting material was consumed completely and saturated NaHC03 solution (100 mL*2) was added. The organic layer was separated, dried over anhydrous Na2S04i filtered and concentrated to afford crude product (9.8 g, crude), which was used in the next step without further purification.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 3.5h;
A solution of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (5 g, 29 mmol) in DCM (20 mL) is cooled toO0C and m-CPBA (7.55 g, 43.87 mmol, 1.5 equiv.) is added portionwise over 30 min. The ice bath is then removed and the mixture is allowed to stir at room temperature for 3 hours. The resulting solution is diluted with sodium bicarbonate (sat. aq.) and extracted with DCM. The organic layers are combined, washed with sodium bicarbonate (sat. aq.), dried over Na2SOzI, and concentrated under vacuum to afford the title compound as a pale orange oil which is without further purification.
With 2,2,2-Trifluoroacetophenone; dihydrogen peroxide; In acetonitrile; tert-butyl alcohol; at 22℃; for 21h;
4-Bromo-2- methylpyridine 1 -oxide was synthesized following the literature protocol found at Chem. Eur. J., 2014, 20, 559-563: A 500-mL round-bottomed flask was charged with 4-bromo- 2-methypyridine (15.96 g, 92.75 mmol) and 2,2,2-trifluoro-1-phenylethanone (1.30 mL, 9.28 mmol, 10 mol %). Then, f-BuOH (46 mL), aqueous buffer solution (46 mL, 0.6 M K2CO3 x 10 s M EDTA tetrasodium salt), MeCN (7.27 mL, 139 mmol, 1 .5 equiv), and 30 % aqueous H2O2 (31.6 mL, 232 mmol, 2.5 equiv) were added consecutively. The reaction mixture was left stirring for 21 h open to air at 22 C. After this period, the reaction was diluted with H2O (100 mL) and extracted with CH2CI2 (3 c 100 mL) using a separatory funnel. The combined organic layers were dried over anhydrous NaaSCk, filtered, and concentrated in vacuo to give 4~bromo-2-methylpyridine 1 -oxide as a pale-yellow oil. The conversion of the crude material was determined to be 76% by 1H NMR, and the material was used directly in the next step without further purification.
b 4-Bromo-2-picoline A mixture of <strong>[13508-96-8]4-nitro-2-picoline</strong> (1.0 g, 7.2 mmol) and acetyl bromide (3 mL) was heated at reflux under argon for 11 hours. The reaction mixture was poured onto ice and neutralized with sodium bicarbonate. The product was extracted with ethyl acetate and purification by flash chromatography (elution with ethyl acetate-hexanes) afforded the title compound (0.62 g, 50%) as an oil.
50%
b) 4-Bromo-2-picoline A mixture of <strong>[13508-96-8]4-nitro-2-picoline</strong> (1.0 g, 7.2 mmol) and acetyl bromide (3 mL) was heated at reflux under argon for 11 hours. The reaction mixture was poured onto ice and neutralized with sodium bicarbonate. The product was extracted with ethyl acetate and purification by flash chromatography (elution with ethyl acetate-hexanes) afforded the title compound (0.62 g, 50%) as an oil.
4.1.12 5-Bromopyridine-2-carboxylic acid (16) In a 250 mL three-necked flask equipped with a stirrer, a thermometer, and a condenser, 100 mL water and <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (15) (4.0 g, 23 mmol) was added to it and stirring until the temperature was raised to 80 C, then KMnO4 (16.6 g, 105 mmol) was added in three batches at intervals of 1 h. The mixture was stirred at the same temperature for 3-4 h. Suction filtration to give a clear solution, the solution was adjusted to pH 4-5 with concentrated HCl, some white solid precipitated, the filter cake is a small amount of the product (16). After filtration and concentration in vacuo, an appropriate amount of ethanol was added to the residues to dissolve the residue compound (16), a lot of white solid precipitated, discarded it after subjected to suction filtration again, finally the filtrate was concentrated in vacuo, total yielding (16) (1.70 g, 33%) as light yellow solid.
22%
4-Bromopyridine-2-carboxylic acid (154) EPO <DP n="294"/>A stirred solution of pyridyl bromide 153 (5.03 g, 29.0 mmol) in water (130 mL) is treated at RT with KMnO4 (4.72 g, 29.5 mmol) in one portion then heated to reflux 1.5 h. At this juncture more KMnO4 is added (4.72 g, 29.5 mmol) and the solution heated at reflux a further 2 h. Another portion of KMnO4 is then added (9.43 g, 59 mmol), the reaction heated at reflux a further 3 h then filtered whilst still hot, washing the isolated solids with boiling water (200 mL). The aqueous filtrate is then concentrated in vacuo to approximately 40 mL, acidified to pH 4 by careful addition of 1 M HCl and the resultant white precipitate isolated by filtration. The filtrate is then reduced in vacuo to approximately 10 mL and the forthcoming precipitate also isolated by filtration. Combining these two isolated precipitates gives the title compound. Yield: 1.28 g (22%). LC/MS U 0.67 min. MS(ES+) m/z 204, 202 (M+H).
22%
4-Bromopyridine-2-carboxylic acid (154)A stirred solution of pyridyl bromide 153 (5.03 g, 29.0 mmol) in water (130 mL) was treated at RT with KMnO4 (4.72 g, 29.5 mmol) in one portion then heated to reflux 1.5 h. At this juncture more KMnO4 was added (4.72 g, 29.5 mmol) and the solution heated at reflux a further 2 h. Another portion OfKMnO4 was then added (9.43 g, 59 mmol), the reaction heated at reflux a further 3 h then filtered whilst still hot, washing the isolated solids with boiling water (200 mL). The aqueous filtrate was then concentrated in vacuo to approximately 40 mL, acidified to pH 4 by careful addition of 1 M HCl and the resultant white precipitate isolated by filtration. The filtrate was then reduced in vacuo to approximately 10 mL and the forthcoming precipitate also isolated by filtration. Combining these two isolated precipitates gave the title compound. Yield: 1.28 g (22%). LC/MS tr 0.67 min. MS(ES+) m/z 204, 202 (M+H).
22%
4-Bromopyridine-2-carboxylic acid (154); EPO <DP n="294"/>A stirred solution of pyridyl bromide 153 (5.03 g, 29.0 mmol) in water (130 mL) is treated at RT with KMnO4 (4.72 g, 29.5 mmol) in one portion then heated to reflux 1.5 h. At this juncture more KMnO4 is added (4.72 g, 29.5 mmol) and the solution heated at reflux a further 2 h. Another portion OfKMnO4 is then added (9.43 g, 59 mmol), the reaction heated at reflux a further 3 h then filtered whilst still hot, washing the isolated solids with boiling water (200 mL). The aqueous filtrate is then concentrated in vacuo to approximately 40 mL, acidified to pH 4 by careful addition of 1 M HCl and the resultant white precipitate isolated by filtration. The filtrate is then reduced in vacuo to approximately 10 mL and the forthcoming precipitate also isolated by filtration. Combining these two isolated precipitates gives the title compound. Yield: 1.28 g (22%). LC/MS ty 0.67 min. MS(ES+) m/z 204, 202 (M+H).
22%
4-Bromopyridine-2-carboxylic acid (154); A stirred solution of pyridyl bromide 153 (5.03 g, 29.0 mmol) in water (130 mL) is treated at RT with KMnO4 (4.72 g, 29.5 mmol) in one portion then heated to reflux 1.5 h. At this juncture more KMnO4 is added (4.72 g, 29.5 mmol) and the solution heated at reflux a further 2 h. Another portion Of KMnO4 is then added (9.43 g, 59 mmol), the reaction heated at reflux a further 3 h then filtered whilst still hot, washing the isolated solids with boiling water (200 mL). The aqueous filtrate is then concentrated in vacuo to approximately 40 mL, acidified to pH 4 by careful addition of 1 M HCl and the resultant white precipitate isolated by filtration. The filtrate is then reduced in vacuo to approximately 10 mL and the forthcoming precipitate also isolated by filtration. Combining these two isolated precipitates gives the title compound. Yield: 1.28 g (22%). LC/MS ttau 0.67 min. MS(ES+) m/z 204, 202 (M+H).
With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene; at 100℃; for 16h;
Step 1: 4-(2-Methyl-pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester To a degassed solution of <strong>[22282-99-1]4-bromo-2-methyl-pyridine</strong> (1.99 g, 11.55 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.78 g, 13.86 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (3.24 g, 28.87 mmol, 2.5 equiv), dicyclohexyl-(2',4',6'-triisopropyl-biphenyl-2-yl)-phosphane (0.11 g, 0.23 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone) dipalladium(0) (0.96 g, 0.92 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100 C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluding with a gradient of ethyl acetate/triethylamine (10:0?9:1) to provide 1.75 g (52%) of the title compound in 90% purity according to 1H NMR. 1H NMR (400 MHz, DMSO): delta 1.14-1.29 (m, 2H), 1.40 (s, 9H), 1.84 (d, J=12.8 Hz, 2H), 2.24 (s, 3H), 2.90 (br s, 2H), 3.40-3.53 (m, 1H), 3.86 (d, J1=13.0 Hz, 2H), 6.23-6.33 (m, 2H), 6.35 (s, 1H), 7.87 (d, J=5.8 Hz, 1H). MS (ESI): 292.2 [M+H]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 4h;Inert atmosphere; Sealed tube;
To a previously degassed solution of 4-bromo-2-methylpidine (0.500 g, 2.906 mmol),4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi( 1 ,3,2-dioxaborolane) (0.812 g, 3.997 mmol),potassium acetate (0.854 g, 8.720 mmol) in 1,4-dioxane (5mL) in 50 mL sealed tube was added [1,1 ?-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.021 g, 0.029 mmol) and stirred at 80C 4 h. Evaporated off the solvent and purified column chromatography on silica gel (ethyl acetate pet ether = 3070) to give the titledcompound (0.250 g, 39%) as a off white solid .LCMS: mlz 220.1 [M+H] .
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); at 80℃; for 12h;
To a solution of 4-bromo-2-methylpyridine [(1] g, 5. 81 mmol) in DMF (25 mL) was added bis-boron pinacol ester (810 mg, 3.2 mmol), potassium acetate (1.71 g, 17.4 [MMOL),] Pd [(DPPF) 2 (140] mg, 0.174 mmol) and heated to [80] C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with DCM and filtered through celite, washed with DCM and concentrated under vacuum to afford [2-METHYL-4- (4,] 4,5, [5-TETRAMETHYL-1,] 3,2-dioxaborolan-2-yl) pyridine [(1.] 25 g). (Note: This material can be used w/o further purification in Example 12.)
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere;
a) 2-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine; To a solution of 4-bromo-2-methyl-pyridine (2.0 g, 12 mmol) in dioxane (20 mL) was added Pd(dppf)Cl2 (0.3 g, 1.0 mmol), potassium acetate (3.4 g, 35 mmol) and bis(pinacolato)diboron (3.8 g, 15 mmol) under an argon atmosphere and the reaction was heated at 80 C. for 12 hours. The resulting black suspension is diluted with dichloromethane, filtered and concentrated under vacuum to afford a black oil (1.53 g, 60%) which is used crude for the next step. 1H NMR (CDCl3, 300 MHz): delta (ppm)=8.53-8.51 (m, 1H), 7.51 (m, 1H), 7.43-7.41 (m, 1H), 2.56 (s, 3H), 1.35 (s, 12H).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere;
To a solution of 4-bromo-2-methyl-pyridine (2.0 g, 12 mmol) in dioxane ( 20 mL) was added Pd(dppf)Cl2 (0.3 g, 1.0 mmol), potassium acetate (3.4 g, 35 mmol) and bis(pinacolato)diboron (3.8 g, 15 mmol) under an argon atmosphere and the reaction was heated at 80C for 12 hours. The resulting black suspension is diluted with dichloromethane, filtered and concentrated under vacuum to afford a black oil (1.53 g, 60%) which is used crude for the next step.1H NMR (CDCls, 300 MHz): delta (ppm) = 8.53-8.51 (m, 1H), 7.51 (m, 1H), 7.43-7.41 (m, 1H), 2.56 (s, 3H), 1.35 (s, 12H).
With potassium acetate;palladium(0)bis(tricyclohexylphosphine); In 1,4-dioxane; at 120℃;Sealed tube;
EXAMPLE 4; 5-(2-METHYLPYRIDIN-4-YL)-2-[7-(2,3,6-TRIFLUOROBEN2YL)IMIDAZO[l,5- &]P YRID AZIN-5 - YL] PYRIMIDIN-4- AMINE; Step A; A solution of 4-bromo-2-methyl pyridine (2g, 9.59 mmol) in 1,4-dioxane in a pressure tube was added potassium acetate (3.39g, 34.5 mmol), bis(pinacolato)diboron and the resulting mixture de-gassed. Bis(tricyclohexylphosphino)palladium (0) (0.64g, 0.959 mmol) was added and the reaction stirred at 120C for several hours. The reaction mixture was cooled to room temperature and quenched with IN HCI until the pH was 6. The resulting mixture was concentrated. The residue was purified by reverse phase HPLC (Gilson) using a gradient of 10-10%acetonitrile/water with 0.1%TFA to afford the desired product as a white solid. LC-MS:m/z=138.17 (M+1); rtO.56 min (Method C).
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In Isopropyl acetate; at 75℃; for 18h;
Example 34N-((2',3-dimethyl-r2,4'-bipyridinl-5-yl)methyl)-5-(pyrazin-2-yl)picolinamide fumarate MF: C16H24BN04 MW: 305.18Preparation of Intermediates[0239] 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl pyridine (34b). To a 5-L four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged 4-bromo-2-methylpyridine (34a, 192.7 g, 1120 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (312.9 g, 1232 mmol), Pd(dppf)Cl2'CH2Cl2 (4.57 g, 5.6 mmol), KOAc (219.7 g, 2240 mmol), and isopropyl acetate (1920 mL). The mixture was stirred at 75 C for 18h, cooled to 50 C and filtered through Celite. Concentration of the filtrate to almost dryness afforded the crude 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (34b) as a black oil.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; at 80℃; for 15h;Inert atmosphere;
6.1.2 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4) To a solution of 4-bromo-2-methylpyridine (3) (1.5 g, 8.72 mmol), bis(pinacolato)diboron (2.4 g, 9.42 mmol) and Pd(dppf)Cl2 (142 mg, 0.17 mmol) in THF (20 mL) was added KOAc (1.7 g, 17.4 mmol). The reaction mixture was stirred at 80 C under N2 for 15 h. After cooling to room temperature, the mixture was diluted with dichloromethane (200 mL) and then filtered. The filtrate was concentrated to give 4 (3.3 g, crude) as a black oil, which was used directly in the next step without further purification.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; at 80℃;Inert atmosphere;
To a suspension of 4-bromo-2-methylpyridine (500 mg, 2.90 mmol), bis(pinacolato)diboron (795 mg, 3.13 mmol) and Pd(dppf)Cl2 (42 mg, 0.058 mmol) in THF (10 mL) was added KOAc (568 mg, 5.80 mmol). The reaction mixture was stirred at 80 C under N2 overnight. After cooling to room temperature, the mixture was diluted with dichloromethane (200 mL) and then filtered. The filtration was concentrated to give the desired product (1.27 g, crude) as a black oil, which was used directly in the next step without further purification. To a suspension of the above crude oil (1.27 g), ethyl 2-(4-bromophenyl)acetate (640 mg, 2.63 mmol) and Pd(PPh3)4 (243 mg, 0.21 mmol) in THF (10 mL) was added Cs2CO3 (1.7 g, 5.26 mmol). The mixture was stirred at 75 C under N2 for 12 h. After cooling to room temperature, the mixture was evaporated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give the desired product (500 mg, 75%) as a colorless oil.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran;Inert atmosphere; Reflux;
To the 250 ml round-bottom flask compound A1-1 (6.9g, 40mmol), bis(pinacolato)diboron (11.2g, 44mmol), KOAc (7.8g, 80mmol), Pd (dppf)2Cl2 (1.63g, 2 . 0mmol) and tetrahydrofuran (100 ml) were added, purged with nitrogen, stirred aand reflux overnight, cooled to the room temperature, celite filtration, the filtrate was spin-dried to give crude black oil (15.6 g of, content: 27%), was used directly in the next step.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; at 80℃;Inert atmosphere;
To a suspension of 4-bromo-2-methylpyridine (2.0 g,11.6 mmol), Pd(dppf)Cl2 (169 mg, 0.23 mmol) and KOAc (2.27 g,23.2 mmol) in THF (40 mL) was added bis(pinacolato)diboron (3.18 g, 12.5 mmol). The mixture was stirred at 80 C under N2 overnight. After cooling to room temperature, the mixture was diluted with DCM (250 mL) and then filtered. The filtrate was concentrated to give a black oil (5.1 g, crude), which was used directly in the next step without further purification.
With tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; for 4h;Reflux; Inert atmosphere;
[0569] To a stirred solution of 4-bromo-2-methylpyridine (150 mg, 0.8 mmol) in 1,4- dioxane (5 mL) under argon atmosphere were added bis (pinacolato) diboron (243 mg, 0.9 mmol), potassium phosphate (171 mg, 2 mmol), Pd2(dba)3 (39 mg, 0.04 mmol), tricyclohexyl phosphine (366 mg, 1 mmol) and degassed under argon atmosphere for 30 mm at room temperature. The reaction mixture was stirred at reflux for 4 h.
31.4 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; for 5h;Inert atmosphere; Reflux;
Under a nitrogen atmosphere, 4-bromo-2-methylpyridine (24.8 g), bispinacolatodiboron (36.8 g),Potassium acetate (42.8 g), PdCl 2 (dppf) (2.5 g) and cyclopentyl methyl ether (400 ml)The flask containing was stirred at reflux temperature for 5 hours.After cooling the reaction solution to room temperature, the insoluble matter was filtered off with suction filtration,The solvent was removed under reduced pressure.The obtained solid was purified by activated carbon column chromatography (toluene), and the solvent of the eluate was distilled off under reduced pressure to give 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2). -Dioxaborolan-2-yl) pyridine(31.4 g) was obtained.
EXAMPLE 5 Preparation of 4-Bromo-2-methylpyridine To a cooled (-78° C.) suspension of 4-bromopyridine hydrochloride (5.0 g, 25.7 mmol) in anhydrous THF (90 mL) was added dropwise a solution of MeMgCl (3.0 M in THF, 21 mL, 63.0 mmol). After addition, the reaction mixture was stirred at -78° C. for 15 min. Phenyl chloroformate (3.8 mL, 30 mmol) in THF (10 mL) was added slowly and the mixture was allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl at 0° C. and extracted with Et2O. The combined organic extracts were washed successively with H2O, aqueous 1 N HCl and H2O, dried (MgSO4) and concentrated. The residue was dissolved in andydrous toluene (100 mL) and a solution of o-chloranil (7.8 g, 32 mmol) in glacial AcOH (60 mL) was added dropwise and the mixture was stirred for 22 h. a red suspension was formed and was made basic using 10percent NaOH until a black emulsion was obtained. The mixture was filtered through Celite and washed with H2O. The organic layer was extracted three times with aqueous 1 N HCl. The aqueous layers were basified with aqueous 50percent NaOH and extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and the solvent was removed under vacuum to give the title compound (2.35 g, 53percent) as an oil. MS (+) EI: 171 M+.
With copper(l) iodide; potassium carbonate; In ISOPROPYLAMIDE; at 115℃; for 6h;
B-C Moiety 10: [Show Image] <strong>[114872-98-9](R)-2-Amino-3-(2,4-dichloro-phenyl)-propionic acid</strong> (700 mg), K2CO3 (621 mg), and Cul (57 mg) were dissolved in DMA (10 ml). 4-Bromo-2-methylpyridine (312 mul) was added and the mixture was stirred at 115C for 6 h. The solvent was evaporated in vacuo and to the obtained residue were added MeCN (40 ml) and water (6 ml). The mixture was filtrated and the solution was evaporated in vacuo. The crude product was purified by preparative HPLC-MS.
To a solution of 4-bromo-2-methyl-pyridine (5.70 g, 32.14 mmol) in methanol (100 ml_), H2SO4 (0.3 ml_) is added. The mixture is heated to reflux before a solution of ammonium peroxydi sulfate (7.33 g, 32.14 mmol) in water (53 ml_) is carefully added. The mixture is stirred at reflux fr 2 h before two more portions of ammonium peroxydisulfate (2x7.33 g) is added as a sat. aq. solution. Stirring is continued at reflux for 3 h. Methanol is removed under reduced pressure and the remaining solution is diluted with sat. aq. NaHCO3 solution and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 3:7 to give (4-bromo-6- methyl-pyhdin-2-yl)-methanol (1.31 g) as pale yellow solid; LC-MS: tR = 0.31 min; [M+1]+ = 201.96; 1H NMR (CDCI3): £2.55 (s, 3 H), 3.59 (s br, 1 H), 4.72 (s br, 2 H), 7.28 (s, 2 H); A solution of 4-bromo-2-methyl-pyridine (735 mg, 4.14 mmol) in methanol (80 ml_) and H2SO4 (20 mul_) is heated to reflux. A solution of (NH4J2S2O8 (3.78 g, 16.6 mmol) in water (6.5 mL) is added dropwise to the stirred mixture. Upon completion of the addition, refluxing is continued for 2 h. The mixture is cooled and the reaction is quenched by adding 1 M aq. NaS2O3 solution. The mixture is furhter diluted with sat. aq. NaHCO3 solution and extracted twice with EA (2x300 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 3:2 to give (4-bromo-6-methyl- <n="82"/>pyridin-2-yl)-methanol (156 mg) as a white solid; LC-MS: tR = 0.32 min, [IVM]+ = 201.93.
a) To a solution of 4-bromo-2-methyl-pyridine (5.70 g, 32.14 mmol) in methanol (100 mL), H2SO4 (0.3 mL) is added. The mixture is heated to reflux before a solution of ammonium peroxydisulfate (7.33 g, 32.14 mmol) in water (53 mL) is carefully added. The mixture is stirred at reflux fuer 2 h before two more portions of ammonium peroxydisulfate (2*7.33 g) is added as a sat. aq. solution. Stirring is continued at reflux for 3 h. Methanol is removed under reduced pressure and the remaining solution is diluted with sat. aq. NaHCO3 solution and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 3:7 to give (4-bromo-6-methyl-pyridin-2-yl)-methanol (1.31 g) as pale yellow solid; LC-MS: tR=0.31 min; [M+1]+=201.96; 1H NMR (CDCl3): delta 2.55 (s, 3H), 3.59 (s br, 1H), 4.72 (s br, 2H), 7.28 (s, 2H).
To a solution of 4-bromo-2-methyl-pyridine (5.70 g, 32.14 mmol) in methanol (100 mL), H2SO4 (0.3 mL) is added. The mixture is heated to reflux before a solution of ammonium peroxydisulfate (7.33 g, 32.14 mmol) in water (53 mL) is carefully added. The mixture is stirred at reflux for 2 h before two more portions of ammonium peroxydisulfate (2x7.33 g) are added as a sat. aq. solution. Stirring is continued at reflux for 3 h. Methanol is removed under reduced pressure and the remaining solution is diluted with sat. aq. NaHCO3 solution and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 3:7 to give (4-bromo- 6-methyl-pyridin-2-yl)-methanol (1.31 g) as pale yellow solid; LC-MS: tR = 0.31 min; [M+1]+ = 201.96; 1H NMR (CDCI3): delta 2.55 (s, 3 H), 3.59 (s br, 1 H), 4.72 (s br, 2 H), 7.28 (s, 2 H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 8.0h;Inert atmosphere;
Synthesis of 4-(2-methylpyridin-4-yl) aniline [0288] To stirred solution of 4-bromo-2-methylpyridine (2 g, 12.00 mmol) in 1, 4- dioxane (50 mL) and water (12 mL), under argon atmosphere were added sodium carbonate (3.08 g, 29.00 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.05 g, 14.00 mmol) and Pd(dppf)Cl2 (0.25 g, 0. 3 mmol) at RT and purged under argon atmosphere for 10 minutes. The reaction mixture was stirred at 100 C for 8 h. After the completion of the reaction (monitored by TLC), the reaction was filtered through celite and the filtrate was concentrated in vacuo. The crude material was purified through column chromatography using EtOAc to afford 4-(2-methylpyridin-4-yl)aniline (2 g, 92%) as an off white solid. 1H- NMR (DMSO-<, 400 MHz): delta 8.34 (d, 1H), 7.52 (d, 2H), 7.46 (s, 1H), 7.43 (d, 1H), 6.62 (d, 2H), 5.48 (s, 2H), 2.47 (s, 3H); LCMS: 184.9 [M++l] at 2.31 RT (98.49%);TLC: 100% EtOAc (Rf. 0.3).
92%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 8.0h;Inert atmosphere;
To stirred solution of 4-bromo-2-methylpyridine (2 g, 12.00 mmol) in 1, 4- dioxane (50 mL) and water (12 mL), under an argon atmosphere were added sodium carbonate (3.08 g, 29.00 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.05 g, 14.00 mmol) and Pd(dppf)Cl2 (0.25 g, 0. 3 mmol) at room temperature and purged under an argon atmosphere for 10 minutes. The reaction mixture was stirred at 100 OC for 8 h. After consumption of the starting material (monitored by TLC), the reaction was filtered through celite and the filtrate was concentrated in vacuo. The crude material was purified through silica gel column chromatography using EtOAc to afford 4-(2-methylpyridin-4-yl)aniline (2 g, 92%) as an off-white solid. 1H-NMR (DMSO-d6, 400 MHz): delta 8.34 (d, 1H), 7.52 (d, 2H), 7.46 (s, 1H), 7.43 (d, 1H), 6.62 (d, 2H), 5.48 (s, 2H), 2.47 (s, 3H); LCMS: 184.9 [M++1] at 2.31 RT (98.49%);TLC: 100% EtOAc (Rf: 0.3).
92%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 8.0h;Inert atmosphere;
Example 1 Synthesis of 4-(2-methylpyridin-4-yl)aniline To stirred solution of 4-bromo-2-methylpyridine (2 g, 12.00 mmol) in 1,4-dioxane (50 mL) and water (12 mL), under an argon atmosphere were added sodium carbonate (3.08 g, 29.00 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.05 g, 14.00 mmol) and Pd(dppf)Cl2 (0.25 g, 0.3 mmol) at room temperature and purged under an argon atmosphere for 10 minutes. The reaction mixture was stirred at 100 C. for 8 h. After consumption of the starting material (monitored by TLC), the reaction was filtered through celite and the filtrate was concentrated in vacuo. The crude material was purified through silica gel column chromatography using EtOAc to afford 4-(2-methylpyridin-4-yl)aniline (2 g, 92%) as an off-white solid. 1H-NMR (DMSO-d6, 400 MHz): delta 8.34 (d, 1H), 7.52 (d, 2H), 7.46 (s, 1H), 7.43 (d, 1H), 6.62 (d, 2H), 5.48 (s, 2H), 2.47 (s, 3H); LCMS: 184.9 [M++1] at 2.31 RT (98.49%); TLC: 100% EtOAc (Rf: 0.3).
83%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; acetonitrile; at 130℃;
To a solution of <strong>[214360-73-3]4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine</strong> (25 g, 114.1 mmol, Aldrich), 4-bromo-2-picoline (19.63 g, 114.1 mmol) and sodium carbonate (6.04 g, 57.05 mmol) in 225 mL acetonitrile:water (2:1), tetrakistriphenylphosphine palladium(0) (3.96 g, 3.423 mmol) was added and the mixture was refluxed at 130oC overnight. The reaction was cooled to room temperature diluted with ethyl acetate (100 mL) and filtered through a plug of celite; the filtrate was concentrated to remove ethyl acetate and acetonitrile and then azeotroped with toluene to remove water. The desired product was purified by washing with methanol and collected via filtration. The residue was washed with 20% ethyl acetate in hexane to obtain 17.5 g of 4-(2-Methyl-pyridin-4-yl)-phenylamine with 83% yield. TLC: 5% Methanol, DCM; Rf=0.31H NMR (DMSO, 400 MHz) delta 8.34 (d, 1H, J=5.2Hz), 7.5 (dd, 2H, J=2.8Hz, J=8.8Hz), 7.43 (s, 1H), 7.34 (dd, 1H, J=1.6Hz, J=1.8Hz), 6.65 (dd, 2H, J=2.8Hz, J=11Hz), 5.47 (s, 2H), 2.46 (s, 3H).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 130℃; for 15.0h;
Reference A; Synthesis of 4-(2-methylpyridin-4-yl)benzenamine <n="99"/>To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzenamine (11.7 g, 53.5 mmol), 4-bromo-2-methylpyridine (9.20 g, 53.5 mmol), Na2CO3 (2.83 g, 26.7 mmol) in 50 mL MeCN/ 50 mL H2O, was added Pd(PPh3)4 (1.85 g, 1.60 mmol), and the reaction mixture was refluxed at 130 0C for 15 h. The solution was cooled, and the solids were collected by filtration, and the residue was concentrated and extracted with ethyl acetate. Ethyl acetate solution was evaporated and the residue was combined with the solids obtained from filtration. The crude materials were subjected to silica gel chromatography with 25% EtOAc in CH2Cl2 gave 4-(2-methylpyridin-4-yl)benzenamine.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 130℃; for 15.0h;
To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzenamine (11.7 g, 53.5 mmol), 4-bromo-2-methylpyridine (9.20 g, 53.5 mmol), Na2CO3 (2.83 g, 26.7 mmol) in 50 mL MeCN/ 50 mL H2O, was added Pd(PPh3)4 (1.85 g, 1.60 mmol), and the reaction mixture was refluxed at 130 0C for 15 h. The solution was cooled, and the solids were collected by filtration, and the residue was concentrated and extracted with ethyl acetate. Ethyl acetate solution was evaporated and the residue was combined with the solids obtained from filtration. The crude materials were subjected to silica gel chromatography with 25% EtOAc in CH2Cl2 gave 4-(2-methylpyridin-4-yl)benzenamine.
With potassium acetate;palladium diacetate; In ISOPROPYLAMIDE; at 150℃;Inert atmosphere;
Process Step [V7]: 4-[4-(4-Fluorophenyl)-2-isopropyl-1,3-thiazol-5-yl]-2-methylpyridine (Ex. 100)Under argon, 200 mg (0.90 mmol) of 2-isopropyl-4-(4-fluorophenyl)-1,3-thiazole, 77 mg (0.45 mmol) of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong>, 133 mg (1.35 mmol) of potassium acetate and 0.4 mg (2 mumol) of palladium(II) acetate in 5 ml of DMA are heated to 150 C. After 3 h, 50 ml of ethyl acetate are added and the reaction mixture is filtered through a silica gel cartridge. 10 ml of water are added to the filtrate. The organic phase is separated off, washed once more with 10 ml of water, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 115 mg (41%) of the desired product; 1H-NMR(DMSO-(D6) delta: 8.39 (d, 1H), 7.48 (m, 2H), 7.22 (m, 2H), 7.17 (s, 1H), 7.03 (d, 1H), 3.35 (m, 1H), 2.43 (s, 3H), 1.39 (d, 6H).
With potassium phosphate;bis-triphenylphosphine-palladium(II) chloride; In butan-1-ol; at 100℃; for 1.5h;Inert atmosphere;
3-(2-Methylpyridin-4-yl)-5-nitrobenzenamine (51.1B). To a rt solution of51. IA (available from Frontier Scientific, Inc.) (3.00 g, 17.0 mmol) in n-BuOH (40 rnL) was added 3-amino-5-nitrophenylboronic acid hydrochloride (available from Combi-Blocks Inc.) (3.50 g, 19.0 mmol), potassium phosphate (available from Strem Chemicals, Inc.) (11.0 g, 52.0 mmol) and bis(triphenylphosphine)palladium(ii) chloride (available from Aldrich) (0.64g, 0.85 mmol). After being purge with N2 for 15 mins, the mixture was stirred at 100 0C under N2 atmosphere for 1.5 hrs. The reaction solution was concentrated. The residue was re- dissolved in 30% 1PrOHZCHCl3 (45 mL), washed with H2O and brine, and dried over MgSO4. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-70% EtOAc/Hexanes for elution gave the title product 51.1B as yellow solid (3.21 g, 80%).
(1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one[ No CAS ]
(1R*,2S*)-2-(3-((E)-2-(2-methylpyridin-4-yl)vinyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With N-ethyl-N,N-diisopropylamine;palladium diacetate; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; at 125℃; for 2h;Microwave irradiation; Inert atmosphere;
Example A 161. (1 R*.2S*)-2-(3-((E)-2-(2-methylpyridin-4-yl)vinyl)- 1 H-indazol-6-yl) spiro[cvclopropane- 1 ,3'-indolin]-2'-one To a mixture of (l R*,2S*)-2-(3-vinyl-l H-indazol-6-yl)spiro[cyclopropane-l ,3'- indolin]-2'-one (60.2 mg, 0.2 mmol) and <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (34.4 mg, 0.2 mmol) in DMF (2 mL) was added 'Pr2NEt (0.07 niL), followed by Pd(OAc)2 (2.2 mg, 0.01 mmol) and P(o-tol)3 (6.7 mg, 0.022 mmol). The resulting mixture was purged with argon, and then microwaved 2 h at 125 0C. Purification by prep-HPLC gave the title compound as a yellow solid (23 mg, 23%). NMR indicated 7% of the branched isomer. 1 H NMR (400 MHz, CD3OD) delta 8.53 (d, J = 6.4 Hz, I H), 8.13-8.03 (m, 4H), 7.59 (d, J = 16.4 Hz, I H), 7.53 (s, I H), 7.10 (d, J = 8.4 Hz, I H), 7.05 (t, J = 7.6 Hz, I H), 6.94 (d, J = 8.4 Hz, I H), 6.56 (t, J = 7.6 Hz, I H), 5.97 (d, J = 7.6 Hz, I H), 3.56 (t, J = 8.0 Hz, I H), 2.77 (s, 3H), 2.25 (dd, J = 7.6 Hz, J = 4.8 Hz, 1 H), 2.18 (dd, J = 9.2 Hz, 4.8 Hz, IH); MS ESI 393.2 [M + H]+, calcd for [C25H20N4O + H]+ 393.2.
8-(3-methoxyphenyl)-N-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With sodium t-butanolate;2,2'-bis[di(3,5-dimethylphenyl)phosphino]-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 110℃; for 0.166667h;Inert atmosphere; Microwave irradiation;
A suspension of 8-(3-methoxyphenyl)-[l,2,4]triazolo[l,5-a]pyridin-2- amine (0.150 g, 0.625 mmol, 1 equiv), <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (0.160 g, 0.935 mmol, 1.5 equiv ), tris(dibenzylideneacetone)dipalladium (0) (27.5 mg, 0.03 mmol, 0.05 equiv), sodium terr-butoxide (0.90 g, 0.94 mmol, 1.5 equiv), and 2,2'-bis[di(3,5-xylyl)phosphino]-l,l'-binaphthyl (38.9 mg, 0.625 mmol, 0.1 equiv) in toluene (2 mL) was purged with nitrogen for 15 min. The reaction mixture was heated at 110 C by microwave for 10 min. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered through celite. The filtrate was then washed with brine (3 X 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded 8-(3-methoxyphenyl)-7V-(2-methylpyridin-4-yl)- [1 ,2,4]triazolo[l ,5-Omega]pyridin- 2-amine (80 mg, 39%). LCMS (ESI) m/z: 332.1; 1H NMR (400 MHz, DMSO-J6) delta: 10.45 (br s, 1 H), 8.81 (dd, J= 6.4, 0.8 Hz, 1 H), 8.23 (d, J= 6.0 Hz, 1 H), 7.88 (dd, J = 6.8, 0.8 Hz, 1 H), 7.74 (s, 1 H), 7.64 (d, J = 8.0 Hz, 1H), 7.57 (s, 1 H), 7.54 (dd, J= 6.0, 2.0 Hz, 1 H), 7.41 (t, J= 8.0 Hz, 1 H), 7.15 (t, J= 6.8 Hz, 1 H), 7.00 (dd, J= 8.0, 2.4 Hz, 1 H), 3.83 (s, 3 H), 2.42 (s, 3 H).
With triethylamine;bis[1,2-bis(diphenylphosphino)ferrocene]-palladium(0); In methanol; N,N-dimethyl-formamide; at 75℃;Inert atmosphere;
4-Bromo-2-methylpyridine (70 g, 407 mmol) and triethylamine (141 mL, 1.02 mol) were combined in DMF (400 mL) and MeOH (400 mL). The solution was purged with N2 for 10 minutes, and then Pd(dppf)2 (15 g, 20.35 mmol) was added. Carbon monoxide was bubbled through the mixture for 10 minutes, and then the reaction was stirred at 75 C overnight. The mixture was concentrated and the residue was diluted with 1 : 1 EtOAc:hexanes (2L) and washed 10 times with H20/brine. The aqueous layer was back-extracted 6 times, and the combined organic layers were dried, filtered, and concentrated. The residue was purified by silica gel chromatography to give the title compound.
With dodecane; N,N,N,N,-tetramethylethylenediamine; di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium; zinc; In water; at 20℃; for 48h;Inert atmosphere;
General procedure: In a 5 mL round-bottom flask under argon containing zinc powder (197 mg, 3 mmol) and PdCl2(Amphos)2 (7 mg, 0.01 mmol) was added 2% PTS solution in water (1.5 mL). N,N,N',N'-Tetramethylethylenediamine (TMEDA, 232 mg, 2 mmol) was added at rt followed by the addition of the alkyl halide (2 mmol) and the heteroaromatic halide (0.5 mmol). The flask was stirred vigorously at rt for the indicated time. The product was extracted with EtOAc.11 Silica gel (1 g) was added to the combined organic phase and solvents were removed under vacuum. The resulting dry, crude silica was introduced on top of a silica gel chromatography column to purify the product.
To a mixture of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> [22282-99-1] (350 mg, 2.05 mmol), 1H-pyrazole (140 mg, 2.05 mmol), 1 ,10-phenanthroline (74 mg, 0.41 mmol) and K2C03 (567 mg, 4.1 mmol) in toluene (2 ml_), Cul (19 mg, 0.1 mmol) was added and the reaction mixture was heated at 120C for 70 h in a sealed tube. The reaction mixture was cooled to rt, quenched with water (50 ml_) and extracted with dichloromethane (150 ml_). The organic layer was washed with brine and dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified flash column chromatography (eluent: 30% ethyl acetate in hexane) to yield the title compound (300 mg, 92%). [ H NMR (300 MHz, CDCI3) USD ppm 8.53 (d, 1 H), 8.02 (d, 1 H), 7.77 (d, 1 H), 7.55 (d, 1 H), 7.44-7.40 (m, 1 H), 6.52 (t, 1 H), 2.62 (s, 3 H); TLC Rf = 0.28 (ethyl acetate/hexane 30:70)].
With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; 1,3-bis-(diphenylphosphino)propane; In water; toluene; for 20h;Reflux;
Scheme 1: Preparation of (2S)-l-[4-(3,4-dimethoxyphenyl)-2-methylpiperidin-l- -2-(4-isobutylphenyl)propan-l-one (la) la Preparation of 4-(3,4-Dimethoxyphenyl)-2-methylpyridine (103). To a solution of <strong>[22282-99-1]2-methyl-4-bromopyridine</strong> 101 (650 mg, 378 mmol) in toluene/water (40/4 mL) was added 3,4-dimethoxyphenyl boronic acid 102 (500 mg, 3.65 mmol), potassium phosphate (1.20 g, 5.65 mmol), PdCl2(dppf) (240 mg, 0.29 mmol) and dppp (120 mg, 0.29 mmol). The reaction mixture was refluxed for 20 h. Subsequently it was diluted with ethyl acetate (15 mL), brine (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 1 :3 Hexanes/EtOAc) to yield 103 (633 mg, 76%) as a clear oil: 1H NMR (400 MHz, CDC13) delta 8.51 (d, J= 3.9 Hz, 1H), 7.33 (s, 1H), 7.28 (s, 1H), 7.22 (d, J= 4.8 Hz, 1H), 7.13 (s, 1H), 6.98 (d, J= 6.0 Hz, 1H), 3.96 (d, J = 9.0 Hz, 6H), 2.62 (s, 3H).
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 80℃; for 4h;
A mixture of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (25.0 g, 145 mmol), 2-fluoropyridin-3- ylboronic acid (22.5 g, 160 mmol), Pd(PPh3)2Cl2 (5.10 g, 7.27 mmol), and sodium carbonate (46.2 g, 436 mmol) in l ,2-dimethoxyethane:ethanol: water (7:2:0.75, 292.5 ml total volume) was heated to 80 C for 4 h. After cooling to room temperature, the mixture was diluted with saturated aqueous sodium bicarbonate solution and water, then extracted with dichloromethane (3 x). The combined organic extracts were then extracted with 2 N aqueous HC1 solution (4 x). The combined aqueous layers were washed with dichloromethane, then the pH was raised to 10 with 10 N NaOH. The resulting suspension was extracted with dichloromethane (3 x). The combined extracts were concentrated in vacuo to give 2-fluoro-3-(2-methylpyridin-4-yl)pyridine (22.14 g, 118 mmol, 81% yield).
With lithium diisopropyl amide; In tetrahydrofuran; n-heptane; ethylbenzene; at -70℃; for 2h;
Intermediate 331 -(4-Bromo-pyridin-2-yl)-cvclopropanecarboxylic acid ethyl esterStep 1 : (4-bromo-pyridin-2-yl)-acetic acid ethyl ester; Lithium diisopropylamide (2 mol/L in tetrahydrofuran/heptane/ethylbenzene, 3.00 mL) was added to a solution of 4-bromo-2-methylpyridine (2.00 g) and diethyl carbonate (1 .8 mL) in tetrahydrofuran (30 mL) cooled to -70 'C. The solution was stirred for 1 h prior to the addition of another portion of lithium diisopropylamide (2 mol/L in tetrahydrofuran/heptane/ ethylbenzene, 3.00 mL). Stirring was continued at -70 C for one more hour and then the reaction was quenched by the addition of water. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (Na2S04). The solvent was evaporated and the residue was chromatographed on silica gel(cyclohexane/ethyl acetate 95:5?1 :1 ) to give the title compound. Yield: 2.35 g (83% of theory); LC (method 3): tR = 2.86 min; Mass spectrum (ESI+): m/z = 244/246 (Br) [M+H]+.
59.63%
With lithium diisopropyl amide; In tetrahydrofuran; at -70℃; for 2h;Inert atmosphere;
To a solution of compound 5-5 (26 g, 151.14 mmol, 1 eq) and compound 5-6 (23.40 g, 198.09 mmol, 24 mL, 1.31 eq) in tetrahydrofuran (300 mL) was added LDA (2 M, 39 mL) at -70C under nitrogen atmosphere. The mixture was stirred at -70C for 1 hour prior to the addition of LDA (2 M, 39.00 mL). The reaction was stirred at -70C for another 1 hour. LCMS showed 25% of starting material remained and 54% of desired compound mass was detected. The reaction mixture was quenched with water (50 mL), and extracted with ethyl acetate (100 mLx3). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse phase flash (trifluoroacetic acid condition). Then basified with saturated sodium bicarbonate (10 mL), extracted with ethyl acetate (100 mLx3). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give compound 5-7 (22 g, 59.63% yield) as yellow oil. 1H NMR (CDCl3, 400 MHz): d 8.45 (d, J = 5.6 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.50 (dd, J1 =5.6 Hz, J2 = 2.0 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.89 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H).
46%
With lithium diisopropyl amide; In tetrahydrofuran; at -60℃; for 2h;
To a solution of 4-bromo-2-methyl-pyridine (2.00 g, 11.6 mmol, CAS 22282-99- 1) and diethyl carbonate (1.65 g, 13.9 mmol, 1.68 mL) in THF (15.0 mL) was added LDA (2 M, 11.63 mL) at -60 C dropwise. Then the mixture was stirred at -60 C for 2 hours. On completion, the reaction mixture was quenched by addition of saturated ammonium chloride solution 30 mL at 0 C, and extracted with ethyl acetate 60 mL (3 X 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 8:1) to give the title compound (1.30 g, 46% yield) as a yellow oil.1H NMR (400MHz, CDCl3) delta = 8.40 (d, J = 5.2 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 1.6, 5.2 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.83 (s, 2H), 1.29 (t, J = 7.2 Hz, 3H).
30%
With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 2h;
[0566] Step 1: ethyl 2-(4-bromopyridin-2-yl)acetate - To a stirred solution of 4-bromo-2-methylpyridine (1.2 g, 4.93 mmol, 1.0 eq) in THF (15 mL), was added diethyl carbonate (0.698 mL, 5.92 mmol, 1.2 eq) and the mixture stirred at -78C under nitrogen atmosphere. LDA(2'-78C for 2h. The reaction was then quenched with saturated sodium chloride solution and the product extracted with EtOAc (2'-(4-bromopyridin-2-yl)acetate (0.500 g, 30%) as a pale yellow liquid.
With lithium diisopropyl amide; In tetrahydrofuran; n-heptane; ethylbenzene; at -78 - -70℃; for 2h;
To a stirred solution of 4-bromo-2- methylpyridine (3 g, 17.44 mmol) and diethyl carbonate (2.75 ml, 22.67 mmol) in THF (30 ml)was added LDA (4mL) (2M in THF/hept/ethylbenzene) at -78C. The solution was stirred for 1 h prior to the addition of another portion of LDA (4.00 mL). Stirring was continued at -70C for one more hour and then the reaction was quenched by the addition of water. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (Na2504). The solvent was evaporated and the residue was purified byflash columnchromatography on silica gel (0-100% EtOAc in Hex) to give the title compound. LC/MS =245.75 [M+lj
With sodium carbonate In water; N,N-dimethyl-formamide at 80℃; for 0.5h; Inert atmosphere;
174.B
3-fluoro-4-(2-methylpyridin-4-yl)benzonitrileA mixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (14.0 g), 4-bromo-2-methylpyridine (5.84 mL), tetrakis(triphenylphosphine)palladium(0) (5.24 g) and 2N aqueous sodium carbonate solution (91 mL) in 1,2-dimethoxyethane (20 mL) was stirred at 80° C. for 30 min under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.41 g).1H NMR (400 MHz, CDCl3) δ 2.65 (3H, s), 7.27 (1H, s), 7.32 (1H, s), 7.50 (1H, d, J=10.4 Hz), 7.57-7.58 (2H, m), 8.62 (1H, d, J=5.2 Hz).
With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃; for 18h;
In a 250 mL round-bottomed flask at 0C under nitrogen was added methyl 4- methoxybenzoate (Aldrich, 3.32 g, 20.00 mmol) and <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (Frontier, 1.72 g, 10.00 mmol) in anhydrous tetrahydrofuran (40.0 mL) to give a yellow solution. Lithiumhexamethyldisilazide (1 in tetrahydrofuran, 20 mL, 20 mmol) was added dropwise over 15 minutes via a dropping addition funnel to produce an orange transparent solution that was stirred for 18 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2S04), filtered and concentrated to a reddish oil. Purification by flash chromatography on a silica 80 g cartridge eluting with 10-60%o ethyl acetate in hexane gave the title compound (2.68 g, 88%). MS (APCI+) m/z 306/308 (M+H)+.
75%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 72h;
Intermediate 1A2-(4-Bromopyridin-2-yl)-1-(4-methoxyphenyl)ethanone To a stirred solution of <strong>[22282-99-1]4-bromo-2-methyl pyridine</strong> (2.9 g, 16.8 mmol) and methyl 4- methoxybenzoate (2.8 g, 16.8 mmol) in tetrahydrofuran (42 mL) at 0 C was added dropwise a 1 M solution of lithium £>/s(trimethylsilyl)amide (33.6 mL, 33.6 mmol). The mixture was allowed to warm to room temperature and stirred for 3 days. A saturated solution of ammonium chloride (40 mL) was added and the mixture was diluted with ethyl acetate (50 mL). The separated aqueous layer was then extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous MgS04, filtered and concentrated under reduced pressure to afford a residue which was purified by automated flash-chromatography (ethyl acetate / hexanes ; 15 / 85). The title compound was obtained as a bright yellow solid (3.8 g, 75%). LCMS m/z 306.0; 308.0 (M + H) ret. time= 2.48 min.
5.1 2-(4-bromopyridin-2-yl)-1-(4-fluorophenyl)ethanone Under a stream of nitrogen, 5.0 g (29.07 mmol) of <strong>[22282-99-1]4-bromo-2-picoline</strong> and 10.2 g (60.95 mmol) of ethyl 4-fluorobenzoate are placed in a round-bottomed flask and dissolved in 50 mL of anhydrous tetrahydrofuran. The mixture is cooled to 0 C. and 70 mL (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 hours, cooled to 5 C., and 100 mL of water are then gradually added. The medium is then diluted with 250 mL of ethyl acetate and 100 mL of water. The organic phase is separated out and the aqueous phase is extracted twice with 100 mL of ethyl acetate. The organic phases are then combined, dried over sodium sulfate and filtered. 15 g of silica are then added to the filtrate, and the resulting mixture is stirred and then concentrated under reduced pressure. The powder obtained is used as a solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 7.5 g (88%) of compound are obtained in the form of a yellow powder. LC-MS: M+H=294 (ketone/enol ratio: 43/57) 1H NMR (DMSO) delta (ppm): 4.56 (s, 2H); 6.34 (s, 1H); from 7.23 to 7.40 (m, 5H); 7.53 (d, 1H); 7.56 (m, 1H); 7.70 (d, 1H); from 7.81 to 7.92 (m, 2H); from 8.04 to 8.16 (m, 2H); 8.29 (d, 1H); 8.37 (d, 1H); 15.0 (s, 1H).
88%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃;
2.1 2-(4-Bromopyridin-2-yl)-1-(4-fluorophenyl)ethanone 5.0 g (29.07 mmol) of <strong>[22282-99-1]4-bromo-2-picoline</strong> and 10.2 g (60.95 mmol) of ethyl 4-fluoro-benzoate are placed under a stream of nitrogen in a round-bottomed flask and dissolved in 50 ml of anhydrous tetrahydrofuran. The solution is cooled to 0 C. and 70 ml (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h before being cooled to 5 C. and gradually adding 100 ml of water to the medium. The medium is subsequently diluted with 250 ml of ethyl acetate and 100 ml of water. The organic phase is separated and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and filtered. 15 g of silica are subsequently added to the filtrate before concentrating it under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel with a mixture of cyclohexane and ethyl acetate (9/1) as eluent. 7.5 g (88%) of compound are obtained in the form of a yellow powder. LC-MS: M+H=294 (keto/enol ratio: 43/57) 1H NMR (d6-DMSO) delta (ppm): 4.56 (s, 2H); 6.34 (s, 1H); from 7.23 to 7.40 (m, 5H); 7.53 (d, 1H); 7.56 (m, 1H); 7.70 (d, 1H); from 7.81 to 7.92 (m, 2H); from 8.04 to 8.16 (m, 2H); 8.29 (d, 1H); 8.37 (d, 1H); 15.0 (s, 1H).
88%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
5.1 2-(4-bromopyridin-2-yl)-1-(4-fluorophenypethanone 5.0 g (29.07 mmol) of <strong>[22282-99-1]4-bromo-2-picoline</strong> and 10.2 g (60.95 mmol) of ethyl 4-fluorobenzoate are placed under a stream of nitrogen in a round-bottomed flask and dissolved in 50 ml of anhydrous tetrahydrofuran. The solution is cooled to 0 C. and 70 ml (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h and cooled to 5 C., and then 100 ml of water are gradually added. The medium is subsequently diluted with 250 ml of ethyl acetate and 100 ml of water. The organic phase is separated and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and filtered. 15 g of silica are subsequently added to the filtrate and the mixture is stirred and then concentrated under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel with a mixture of cyclohexane and ethyl acetate (9/1) as eluent. 7.5 g (88%) of compound are obtained in the form of a yellow powder. LC-MS: M+H=294 (keto/enol ratio: 43/57) 1H NMR (d6-DMSO) delta (ppm): 4.56 (s, 2H); 6.34 (s, 1H); from 7.23 to 7.40 (m, 5H); 7.53 (d, 1H); 7.56 (m, 1H); 7.70 (d, 1H); from 7.81 to 7.92 (m, 2H); from 8.04 to 8.16 (m, 2H); 8.29 (d, 1H); 8.37 (d, 1H); 15.0 (s, 1H).
1.1 2-(4-Bromopyridin-2-yl)-1-(4-chlorophenyl)ethanone Under a stream of nitrogen, 5 g (29.07 mmol) of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> and 11.27 g (61.04 mmol) of ethyl 4-chlorobenzoate are placed in a round-bottomed flask and dissolved in 50 mL of anhydrous tetrahydrofuran. The solution is cooled to 5 C. and 70 mL (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 hours, cooled to 5 C., and 100 mL of water are then gradually added. The medium is then diluted with 250 mL of ethyl acetate and 100 mL of water. The organic phase is separated out and the aqueous phase is extracted twice with 100 mL of ethyl acetate. The organic phases are then combined, dried over sodium sulfate and filtered. 15 g of silica are then added to the filtrate, which is then concentrated under reduced pressure. The powder obtained is used as solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 8.4 g (93%) of compound are obtained in the faun of a yellow powder. LC-MS: M+H=310 1H NMR (DMSO) delta (ppm): 4.6 (s, 2H); 6.4 (s, 1H); 7.4 (s, 1H); from 7.5 to 7.6 (m, 6H); 7.7 (s, 1H); 7.9 (d, 2H); 8.1 (d, 2H); 8.3 (d, 1H); 8.4 (d, 1H); 15.0 (s, 1H) (ketone/enol mixture: 40/60).
93%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 5 - 20℃;Inert atmosphere;
1.1 2-(4-Bromopyridin-2-yl)-1-(4-chlorophenyl)ethanone 5 g (29.07 mmol) of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> and 11.27 g (61.04 mmol) of ethyl 4-chlorobenzoate are placed under a stream of nitrogen in a round-bottomed flask and dissolved in 50 ml of anhydrous tetrahydrofuran. The solution is cooled to 5 C. and 70 ml (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h and cooled to 5 C., and then 100 ml of water are gradually added. The medium is subsequently diluted with 250 ml of ethyl acetate and 100 ml of water. The organic phase is separated and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and filtered. 15 g of silica are subsequently added to the filtrate and the mixture is concentrated under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel, with a mixture of cyclohexane and ethyl acetate (9/1) as eluent. 8.4 g (93%) of compound are obtained in the form of a yellow powder. LC-MS: M+H=310 1H NMR (d6-DMSO) delta (ppm): 4.6 (s, 2H); 6.4 (s, 1H); 7.4 (s, 1H); from 7.5 to 7.6 (m, 6H); 7.7 (s, 1H); 7.9 (d, 2H); 8.1 (d, 2H); 8.3 (d, 1H); 8.4 (d, 1H); 15.0 (s, 1H). (Keto/enol mixture: 40/60).
93%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 5 - 20℃; for 2h;Inert atmosphere;
2.1 2-(4-bromopyridin-2-yl)-1-(4-chlorophenypethanone 5 g (29.07 mmol) of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> and 11.27 g (61.04 mmol) of ethyl 4-chlorobenzoate are placed under a stream of nitrogen in a round-bottomed flask and dissolved in 50 ml of anhydrous tetrahydrofuran. The solution is cooled to 5 C. and 70 ml (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h and cooled to 5 C., and then 100 ml of water are gradually added. The medium is subsequently diluted with 250 ml of ethyl acetate and 100 ml of water. The organic phase is separated and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and filtered. 15 g of silica are subsequently added to the filtrate and the mixture is concentrated under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel, with a mixture of cyclohexane and ethyl acetate (9/1) as eluent. 8.4 g (93%) of compound are obtained in the form of a yellow powder. LC-MS: M+H=310 1H NMR (d6-DMSO) delta (ppm): 4.6 (s, 2H); 6.4 (s, 1H); 7.4 (s, 1H); from 7.5 to 7.6 (m, 6H); 7.7 (s, 1H); 7.9 (d, 2H); 8.1 (d, 2H); 8.3 (d, 1H); 8.4 (d, 1H); 15.0 (s, 1H). (Keto/enol mixture: 40/60).
10.1 2-(4-Bromopyridin-2-yl)-1-p-tolylethanone Under a stream of nitrogen, 1 g (5.81 mmol) of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> and 1.75 g (11.60 mmol) of methyl 4-methylbenzoate are placed in a round-bottomed flask and dissolved in 30 mL of anhydrous tetrahydrofuran. The solution is cooled to 5 C. and 14 mL (14 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 hours 30 minutes and then cooled to 5 C., followed by gradual addition of 20 mL of water. The medium is then diluted with 200 mL of ethyl acetate and 200 mL of water. The organic phase is separated out, dried over sodium sulfate and filtered. 5 g of silica are then added to the filtrate, which is then concentrated under reduced pressure. The powder obtained is used as a solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (95/5) to give 1.03 g (61%) of compound in the form of a yellow powder. LC-MS: M+H=290
61%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 5 - 20℃;Inert atmosphere;
8.1 2-(4-Bromopyridin-2-yl)-1-(p-tolyl)ethanone1 g (5.81 mmol) of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> and 1.75 g (11.60 mmol) of methyl 4-methylbenzoate are placed in a round-bottomed flask and dissolved in 30 ml of anhydrous tetrahydrofuran under a stream of nitrogen. The solution is cooled to 5 C. and 14 ml (14 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h 30 and then cooled to 5 C., before gradually adding 20 ml of water. The medium is subsequently diluted with 200 ml of ethyl acetate and 200 ml of water. The organic phase is separated, dried over sodium sulphate and filtered. 5 g of silica are subsequently added to the filtrate before concentrating it under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel with a mixture of cyclohexane and ethyl acetate (95/5) as eluent. 1.03 g (61%) of compound are obtained in the form of a yellow powder.LC-MS: M+H=290
A 0.5 M sol. of 9-BBN (120 mL) in THF was added to a degassed intermediate 10 (11.3 g, 57.36 mmol) and the r.m. was heated at reflux for 1 h. After cooling to r.t., the r.m. was added to a mixture of <strong>[22282-99-1]4-bromo-2-methyl-pyridine</strong> (10.8 g, 63.09 mmol),Pd(dppf)Cl2 (1.259 g, 1.721 mmol) and K2C03 (23.7 g, 172.1 mmol) in DMF/water 10/1 (250 mL) and the r.m. was heated at 60 C for 4 h. Then the r.m. was cooled to r.t. and poured into water. The pH was adjusted to 11 by the addition of a 10% aq. NaOH sol. and extracted with EtOAc. The separated organic layer was dried (MgSC^), filtered and the solvent was evaporated. The residue was purified by flash columnchromatography (eluent: petroleum ether/EtOAc 20/1). The product fractions were collected and concentrated in vacuo. Yield: 7.6 g of intermediate 11 (46 %).
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 18h;
Step 6. Synthesis of methyl 2-methoxy-2'-methyl-3,4'-bipyridine-6-carboxylate (C32) Degassed 1,2-dimethoxyethane (60 mL) and water (0.5 mL) were added to a flask charged with <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (1.20 g, 6.98 mmol), methyl 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (C31) (3.07 g, 10.5 mmol), potassium phosphate (4.44 g, 20.9 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.81 g, 0.70 mmol). The mixture was heated to 80 C. for 18 hours, then cooled to room temperature and concentrated in vacuo. Silica gel chromatography (Eluant: ethyl acetate) provided a solid, which was triturated twice with a 1:5 mixture of ethyl acetate and heptane to provide the title compound as a white solid. Yield: 1.68 g, 6.50 mmol, 93%. LCMS m/z 259.1 (M+1). 1H NMR (400 MHz, CDCl3) delta 2.63 (s, 3H), 4.00 (s, 3H), 4.09 (s, 3H), 7.32 (br d, J=5.5 Hz, 1H), 7.36 (br s, 1H), 7.79 (AB quartet, JAB=7.3 Hz, DeltanuAB=24.1 Hz, 2H), 8.57 (d, J=5.0 Hz, 1H).
With N-Bromosuccinimide; In tetrachloromethane; at 100℃;
4-bromo-2-(bromomethyl)pyridineA mixture of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (2.0 g, 1 1.63 mmol), NBS (2.69 g, 15.1 1 mmol), and diphenylperoxyanhydride (0.282 g, 1.163 mmol) in carbon tetrachloride (50 mL) was heated to 100 C overnight. Cooled to RT, diluted with saturated NaHC03, and extracted with ethyl acetate (3x). The combined organic extracts were washed with saturated NaCl (2x), dried over Na2S04, filtered, and concentrated. The residue was purified via silica gel chromatography (ISCO, 120 g silica, 60 mL/min, 0-80% EtOAc/Hexanes over 45 min) to afford 4-bromo-2- (bromomethyl)pyridine (1.05 g, 36%). MS (m/z) 251.9.
33%
With N-Bromosuccinimide; In tetrachloromethane; for 12h;Reflux;
General procedure: A mixture of corresponding aromatic heterocyclic compound (2.9mmol, 1.0 eq.), NBS (566mg, 3.2mmol) and AIBN (50mg, 0.3mmol) in 10mL of CCl4 was stirred at reflux overnight. After concentration, the residue was diluted with water (50mL) and extracted with dichloromethane (50mL×3). The combined organic layers was dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1) to give the desired product. 6.1.15.1 4-Bromo-2-(bromomethyl)pyridine (34a) Compound 34a was obtained as a colorless oil (240?mg, 33%). 1H NMR (400?MHz, CDCl3) delta 8.39 (s, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 4.64 (d, J?=?3.8?Hz, 1H), 4.50 (s, 2H).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In fluorobenzene; at 90℃; for 1h;
Preparation 23. Synthesis of 4-bromo-2-(bromomethyl)pyridine[00250] Step 1 : <strong>[22282-99-1]4-bromo-2-methyl-pyridine</strong> (5 g, 29.07 mmol), 2-[(E)-(l-cyano-l- methyl-ethyl)azo]-2-methyl-propanenitrile (954.7 mg, 5.814 mmol) and N-bromosuccinimide (7.244 g, 40.70 mmol) were added to fluorobenzene (8 mL) and the mixture heated to 90 C for 1 hour. Reaction mixture was purified by filtering through a silica gel pad and eluting with 50% diethylether/petroleum ether. Product fractions were combined and concentrated in vacuo to give the crude sub-title product (7.294 g, assumed 100% yield). 1H NMR (400.0 MHz, DMSO-de) delta 4.52 (s, 2H), 7.42 (d, 1H), 7.65 (s, 1H) and 8.42 (d, 1H) ppm.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 85℃; for 1h;
To a solution of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (1.0 g) in carbon tetrachioride (10.0 mL) wasadded NBS (1.25 g) and AIBN (50 mg) and the mixture was stirred at 85 C for ihour. Aftercooling, the reaction mixture was filtered to remove the insoluble materials and the filtrite wasconcentrated. The crude material (120 mg) was used for the next step immediately. ?H NMR(400 MHz, CDCI3) oe 8.32 (d, J 4.0 Hz, 1H), 7.57 (s, 1H), 7.33 (d, J 4.0 Hz, 1H), 4.43 (s,211).
With O-mesitylenesulfonylhydroxylamine; lithium hexamethyldisilazane In tetrahydrofuran at 5 - 20℃; for 2.5h; Inert atmosphere;
7.1
7.1 5-Bromo-2-(2-fluorophenyl)pyrazolo[1,5-a]pyridine 1 g (5.81 mmol) of 4-bromo-2-methylpyridine and 1.88 g (12.20 mmol) of methyl 2-fluorobenzoate are placed in a round-bottomed flask and dissolved in 25 ml of anhydrous tetrahydrofuran under a stream of nitrogen. The solution is cooled to 5° C. and 14 ml (14 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h 30 and cooled to 5° C., and then 15 ml of water are gradually added. The medium is subsequently diluted with 100 ml of ethyl acetate and 100 ml of water. The organic phase is separated and the aqueous phase is extracted with 100 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and filtered. 6 g of silica are subsequently added to the filtrate and the mixture is concentrated under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel with a mixture of cyclohexane and ethyl acetate (95/5) as eluent. 1.71 g of a yellow powder are recovered, which powder is placed in a round-bottomed flask in the presence of 1.60 g (23.02 mmol) of hydroxylamine hydrochloride, 5 ml (61.95 mmol) of pyridine and 30 ml of ethanol. The medium is left stirring overnight at ambient temperature and then the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 50 ml of ethyl acetate and 50 ml of water. The organic phase is recovered and then the aqueous phase is extracted with 50 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and then concentrated under reduced pressure. 1.05 g of an orange wax are obtained, which wax is placed in a round-bottomed flask containing 50 ml of 1,2-dichloroethane. The mixture is then cooled to approximately 5° C. and then 61 ml of a solution of O-(mesitylenesulphonyl)hydroxylamine in 1,2-dichloroethane (c=0.11 mol/l) are added dropwise. The medium is stirred overnight at a.t. and then 50 ml of water, 50 ml of an aqueous NaOH solution (1N) and 100 ml of dichloromethane are added. The organic phase is recovered and then the aqueous phase is extracted with 100 ml of dichloromethane. The organic phases are subsequently combined, dried over sodium sulphate and filtered. 5 g of silica are subsequently added to the filtrate and then the mixture is concentrated under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel with a mixture of cyclohexane and ethyl acetate (8/2) as eluent. 0.675 g (39.9%) of the expected product is recovered in the form of a yellow powder. LC-MS: M+H=291 1H NMR (d6-DMSO) δ (ppm): 7.03 (d, 1H); 7.1 (dd, 1H); from 7.33 to 7.43 (m, 2H); from 7.48 to 7.55 (m, 1H); from 8.05 to 8.18 (m, 2H); 8.73 (d, 1H).
4-fluoro-3-(trifluoromethyl)phenylboronic acid[ No CAS ]
[ 1434817-74-9 ]
Yield
Reaction Conditions
Operation in experiment
99.4%
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In water; toluene; at 88℃; for 23h;Reflux;
To a stirred suspension of 4-fluoro-3-(trifluoromethyl)phenylboronic acid (42.6 g, 205 mmol) in toluene (200 mL) were added <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (34.4 g, 200 mmol) and 2 M aqueous potassium carbonate (200 mL). After the addition of 1,1?-bis(diphenylphosphino)- ferrocene-palladium(II)dichloride ichioromethane complex (81.7 mg, 0.1 mmol), the two-phase, yellowish reaction mixture was stirred under reflux at 88C for 23 h. The resultant brownish reaction mixture was cooled to room temperature and extracted with toluene (200 mL). After washing with 10% brine (200 mL), the toluene layer was dried with Na2SO4 (50 g) and then treated under stirring with charcoal (2 g) for 30 mm. Filtration and evaporation (50C/ 10 mbar) afforded the crude title product (50.7 g, 99.4%) as an off-white, crystalline residue which was used without purification in the next step. 1H NMR (CDC13, 400 MHz) delta 2.64 (s, 3H), 7.25-7.36 (m, 3H), 7.76-7.82 (m, 1H), 7.84 (dd, J1 = 6.7 Hz, J2 = 2.4 Hz, 1H), 8.58 (d, J 5.0 Hz, 1H). ESI-MS (m/z) [M+H] 256.3 (100).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; toluene; at 88℃; for 23h;
a) 4-(4-Fluoro-3-trifluoromethyl-phenyl)-2-methyl-pyridine To a stirred suspension of 4-fluoro-3-(trifluoromethyl)phenylboronic acid (42.6 g, 205 mmol) in toluene (200 mL) were added <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (34.4 g, 200 mmol) and 2 M aqueous potassium carbonate (200 mL). After the addition of 1,1'-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (81.7 mg, 0.1 mmol), the two-phase, yellowish reaction mixture was stirred under reflux at 88 C. for 23 h. The resultant brownish reaction mixture was cooled to room temperature and extracted with toluene (200 mL). After washing with 10% brine (200 mL), the toluene layer was dried with Na2SO4 (50 g) and then treated under stirring with charcoal (2 g) for 30 min. Filtration and evaporation (50 C./?10 mbar) afforded the crude title product (50.7 g, 99.4%) as an off-white, crystalline residue which was used without purification in the next step. 1H NMR (CDCl3, 400 MHz) delta 2.64 (s, 3H), 7.25-7.36 (m, 3H), 7.76-7.82 (m, 1H), 7.84 (dd, J1=6.7 Hz, J2=2.4 Hz, 1H), 8.58 (d, J=5.0 Hz, 1H). ESI-MS (m/z) [M+H]+256.3 (100).
To a solution of compound la (10.0 g, 58.1 mmol, 1 eq) in THF (70.0 mL) was added dropwise LDA (2 M, 69.7 mL, 2.4 eq) at -78C. Then the mioxture was stirred at -78C for 15 min. After that dimethyl carbonate (6.28 g, 69.7 mmol, 5.87 mL, 1.2 eq) was added dropwise to the mixture. The reaction was stirred at 0C for 4 hrs. TLC (Petroleum ether : Ethyl acetate = 3 : 1, Rf= 0.57) showed the reaction was completed. The reaction mixture was quenched by addition HC1 (1M, 100.0 mL), and then diluted with FLO (50.0 mL) and extracted with EtOAc (100.0 mL x 3). The combined organic layers were washed with brine (30.0 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC , Petroleum ether/Ethyl acetate=30/l to 0/1). Give compound 2a (9.00 g, 39.1 mmol, 67.3% yield) as a brown oil.
Step A: methyl 2-(4-bromopyridin-2-yl)acetate To a mixture of 4-bromo-2-methylpyridine (1 g, 5.8 mmol) in 15 mL of anhydrous THF was added LDA (9.2 mL, 2M) dropwise at -70, stirred for 30 min dimethyl carbonate (630 mg, 7.0 mmol) was added dropwise to the above solution. After stirring for another 1 h, LC-MS found the reaction finished. It was quenched by Sat. NH4Cl solution and extracted with EtOAc. The organic layer was separated and evaporated under reduced pressure. The crude product was purified by a standard method to give desired product. LC-MS: m/z (M+H) 231.1.
Step A: methyl 2-(4-bromopyridin-2-yl)acetate To a mixture of 4-bromo-2-methylpyridine(lg,5.8mmol) in 15mL of anhydrous THF was added LDA (9.2mL,2M) dropwise at -70, stirred for 30min. dimethyl carbonate(630mg, 7.0mmol) was added dropwise to the above solution. After stirring for another lh, LC-MS found the reaction finished. It was quenched by Sat. NH4C1 solution and extracted with EtOAc. The organic layer was separated and evaporated under reduced pressure. The crude product was purified by a standard method to give desired product. LC-MS: m/z (M+H) 231.1.
With lithium diisopropyl amide; In tetrahydrofuran; at -70℃; for 1.5h;
Step A To a mixture of 4-bromo-2-methylpyridine(lg,5.8mmol) in 15mL of anhydrous THF was added LDA (9.2mL,2M) dropwise at -70, stirred for 30min. dimethyl carbonate(630mg, 7.0mmol) was added dropwise to the above solution. After stirring for another lh, LC-MS found the reaction finished. It was quenched by Sat. NH4C1 solution and extracted with EtOAc. The organic layer was separated and evaporated under reduced pressure. The crude product was purified by a standard method to give desired product. LC- MS: m/z (M+H) 231.1.
With 2,6-dimethylpyridine; bis(1,5-cyclooctadiene)nickel (0); Ir(dF(CF3)ppy)2(bpy)PF6; 4,4'-di-tert-butyl-2,2'-bipyridine In methanol; acetone at 20℃; for 24h; Irradiation;
4-(2,3-dihydro-1H-inden-2-yl)-2-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With pyridine; tetrabutylammomium bromide; 4,4'-di-tert-butyl-2,2'-bipyridine; magnesium chloride; nickel dibromide; zinc; In N,N-dimethyl acetamide; at 30℃;Schlenk technique; Inert atmosphere; Glovebox;
General procedure: To a flame-dried Schlenk tube equipped with a magnetic stir bar was loaded alkyl bromide (0.15 mmol, 100 mol%, solid), halogenated pyridine (0.30 mmol, 300 mol%, solid), ligand (0.015 mmol, 10 mol%), zinc powder (0.45 mmol, 300 mol%). The tube was capped with a rubber septum and moved to a dry glove box, at which NiBr2 (0.015 mmol, 10 mol%), MgCl2 (0.15 mmol, 100 mol%) and Bu4NBr (0.075 mmol, 50 mol%) were added. Then the tube was moved out of the glove box. Alkyl bromide (0.15 mmol, 100 mol%, liquid), halogenated pyridine (0.30 mmol, 300 mol%, liquid), pyridine (0.15 mmol, 100 mol%) and DMA(1.0 mL) were added via syringe. After the reaction mixture was allowed to stir overnight under N2 atmosphere at 30 C, it was directly loaded onto a silica column without work-up. The residue in the reaction vessel was rinsed with small amount of DCM or eluent. Flash column chromatography provided the product as solid or oil.
rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone[ No CAS ]
rac-1-((2S,3R,4R)-2,3-dimethyl-4-((2-methylpyridin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;
To a greenhouse test tube was added rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin- 1(2H)-yl)ethanone (for a preparation see Intermediate 6, 51 .0 mg, 0.234 mmol), Pd2(dba)3 (21 .5 mg,0.023 mmol), DavePhos (5.2 mg, 0.013 mmol), sodium tert-butoxide (67.2 mg, 0.699 mmol), 1,4-dioxane (2 mL) and <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (0.033 mL, 0.280 mmol). The reaction mixture was stirred at 100 C under nitrogen for 16 hours. The reaction mixture was allowed to cool to rt then filtered through a celite cartridge, washing with ethyl acetate. The filtrate was evaporated under a stream of nitrogen and the residue dissolved in methanol (1 mL). The dissolved material was purified by MDAP (Formic). The required fractions were combined and evaporated in vacuo to give therequired product, as a white solid (61.0 mg, 0.197 mmol, 84%). LCMS (2 mm Formic): Rt = 0.59 mi MH = 310.
4-(2-methylpyridin-4-yl)-1H-pyrrole-2-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
200 mg
A mixture of 4-bromo-lH-pyrrole-2-carboxylic acid methyl ester (3 g, 15 mmol), bis(pinacolato)diboron (3.9 g, 15 mmol), tris(dibenzylideneacetone)dipalladium (206 mg, 0.22 mmol), butyldi-l-adamantylphosphine (236 mg, 0.66 mmol) and potassium acetate (4.4 g, 45 mmol) in DME (50 mL) was heated at 90 C for 6 hours, then cooled to room temperature. The above reaction mixture (10 mL), 4-bromo-2-methyl-pyridine (430 mg, 2.5 mmol), K2C03 (828 mg, 6 mmol), dioxane (5 mL) and water (2 mL) were added into a 20 mL microwave vial. The mixture was heated at 105 C for 1.5 hours under microwave radiation, and then diluted by EtOAc (50 mL). The organic layer was washed with water (50 mLx3), and then dried over anhydrous Na2S04. The residue was purified by flash chromatography to give 4-(2-methyl- pyridin-4-yl)-lH-pyrrole-2-carboxylic acid methyl ester (200 mg).
4-(2-fluoro-4-nitrophenyl)-2-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
Synthesis of 3-fluoro-4-(2-methylpyridin-4-yl) aniline Ra-Ni/H2 MeOH / RT, 4 h e ux, 4-(2-fluoro-4-nitrophenyl)-2-methylpyridine [0291] To a stirred solution of 4-bromo-2-methylpyridine (3 g, 17.44 mmol) in 1, 4- dioxane (150 mL) under argon atmosphere were added Bis (pinacolato) diboron (4.87 g, 19.18 mmol), tricyclohexyl phosphine (732 mg, 2.61 mmol), potassium acetate (3.4 g, 34.88 mmol), Pd2(dba)3 (798 mg, 0.87 mmol) and purged under argon for 10 min at RT. The mixture was heated to 100 C and stirred for 3 h. After disappearance of 4-bromo-2- methylpyridine (monitored by TLC), the reaction mixture was cooled to RT, l-bromo-2- fluoro-4-nitrobenzene (3.8 g, 17.43 mmol), cesium carbonate (25.49 g, 78.43 mmol), Pd(PPh3)4 (2.01 g, 1.74 mmol) were added and refluxed for 16 h. After consumption of 1- bromo-2-fluoro-4-nitrobenzene (monitored by TLC), the volatile components were evaporated in vacuo. The crude material was purified through silica gel column chromatography (20% EtOAc:hexanes) to afford 4-(2-fluoro-4-nitrophenyl)-2- methylpyridine (2.4 g, 59%) as a pale yellow solid. 1H-NMR (DMSO-< 5, 500 MHz): delta 8.60 (d, 1H), 8.29-8.26 (m, 1H), 8.20-8.18 (m, 1H), 7.91 (t, 1H), 7.51 (s, 1H), 7.44 (d, 1H), 2.56 (s, 3H); LC-MS: 232.9 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 mu); RT 2.28 min. 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 40% EtOAc:hexanes (R 0.2).
59%
To a stirred solution of 4-bromo-2-methylpyridine (3 g, 17.44 mmol) in 1, 4- dioxane (150 mL) under an argon atmosphere were added Bis (pinacolato) diboron (4.87 g, 19.18 mmol), tricyclohexyl phosphine (732 mg, 2.61 mmol), potassium acetate (3.4 g, 34.88 mmol), Pd2(dba)3 (798 mg, 0.87 mmol). The reaction was purged under an argon atmosphere for 10 min at room temperature, heated to 100 oC and stirred for 3 h. After the disappearance of 4-bromo-2-methylpyridine (monitored by TLC) the reaction mixture was cooled to room temperature, <strong>[185331-69-5]1-bromo-2-fluoro-4-nitrobenzene</strong> (3.8 g, 17.43 mmol), cesium carbonate (25.49 g, 78.43 mmol) and Pd(PPh3)4 (2.01 g, 1.74 mmol) were added and refluxed for 16 h. After consumption of <strong>[185331-69-5]1-bromo-2-fluoro-4-nitrobenzene</strong> (monitored by TLC), the volatile components were evaporated in vacuo to afford the crude material which was purified through silica gel column chromatography (20% EtOAc:hexanes) to afford 4-(2-fluoro-4- nitrophenyl)-2-methylpyridine (2.4 g, 59%) as a pale yellow solid. 1H-NMR (DMSO-d6, 500 MHz): delta 8.60 (d, 1H), 8.29-8.26 (m, 1H), 8.20-8.18 (m, 1H), 7.91 (t, 1H), 7.51 (s, 1H), 7.44 (d, 1H), 2.56 (s, 3H); LC-MS: 232.9 (M+1); (column; X-Bridge C-18 (50 × 3.0 mm, 3.5 mum); RT 2.28 min. 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 40% EtOAc:hexanes (Rf: 0.2).
N-(2-methoxy-2'-methyl-[3,4'-bipyridin]-6-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
Synthesis of N-(2-methoxy-2'-methyl- [3 , 4'-bipyridin] -6-yl) acetamide [0298] To a stirred solution of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (1.8 g, 10.46 mmol) in 1, 4- dioxane (50 mL) under argon atmosphere were added Bis (pinacolato) diboron (2.92 g, 11.51 mmol), potassium acetate (2.05 g, 20.92 mmol) tricyclohexyl phosphine (0.44 g, 15.69 mmol) and purged under argon for 10 min. To this mixture was added Pd2(dba)3 (383 mg, 0.41 mmol) and refluxed for 4 h. The reaction mixture was cooled to RT, then N-(5-bromo-6- methoxypyridin-2-yl) acetamide (0.96 g, 3.92 mmol), cesium carbonate (5.75 g, 17.63 mmol), Pd(PPh3)4 (452 mg, 0.39 mmol), 1, 4-Dioxane (50 mL) and water (10 mL) was added at RT. The mixture was stirred for 30 min then refluxed for 16 h and cooled to RT, filtered through celite. The filtrate was concentrated in vacuo. The crude material was purified through silica gel column chromatography to afford N-(2-methoxy-2'-methyl-[3, 4'- bipyridin]-6-yl) acetamide (0.9 g, 89%) as a colorless semisolid. 1H-NMR (CDC13, 400 MHz): delta 8.52 (d, 1H), 7.86-7.84 (m, 1H), 7.54-7.52 (m, 1H), 7.32 (s, 1H), 7.29-7.28 (m, 1H), 3.91 (s, 3H), 2.62 (s, 3H), 2.24 (s, 3H); Mass (ESI): 258 [M+1]; TLC: 100% EtOAc (R 0.4).
Synthesis of 2'-methyl-5-nitro-2, 4'-bipyridine [0300] To a stirred solution of 4-bromo-2-methylpyridine (5 g, 28.57 mmol) in 1, 4- dioxane (275 mL) under argon atmosphere were added potassium acetate (5.6 g, 57.14 mmol), bis (pinacolato) diboron (7.9 g, 31.42 mmol), tricyclohexyl phosphine (1.2 g, 4.28 mmol), Pd2(dba)3 (1.3 g, 1.42 mmol). The mixture was purged under argon for 30 min, then was stirred at 110 C for 6 h. After disappearance of 4-bromo-2-methylpyridine (monitored by TLC), the reaction mixture was brought to RT, <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> (5.7 g, 28.57 mmol), cesium carbonate (37 g, 114.28 mmol), Pd(PPh3)4 (3.3 g, 2.85 mmol), and water (25 mL) were added to the reaction. The reaction mixture was then heated to 110 C and stirred for 3 h. After completion of the reaction (monitored by TLC), the reaction was filtered through celite and the filtrate dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel column chromatography using 70% EtOAc:hexanes to afford 2'-methyl-5-nitro-2, 4'-bipyridine (6 g, 96%) as a yellow solid. 1H- NMR (DMSO-< 5, 500 MHz): delta 8.75-8.73 (m, 1H), 8.65-8.64 (m, 1H), 8.39 (d, 1H), 8.03 (s, 1H), 7.94-7.93 (m, 1H), 7.64-7.61 (m, 1H), 2.59 (s, 3H); LC-MS: 215.9 (M+l); (column; X- Bridge C-18 (50 3.0 mm, 3.5 mu); RT 1.98 min. 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (R 0.1).
Synthesis of 4-(2-methoxy-4-nitrophenyl)-2-methylpyridine [0289] To a stirred solution of 4-bromo-2-methylpyridine (2.5 g, 14.53 mmol) in 1, 4- dioxane (50 mL) under argon atmosphere were added bis (pinacolato) diborane ester (4.04 g, 15.98 mmol), potassium acetate (2.84 g, 29.06 mmol), tricyclohexylphosphine (0.61 g, 21.81 mmol) and purged for 30 min. To this was added Pd2(dba)3 (0.66 g, 0.726 mmol) and stirred at reflux for 4 h. After consumption of 4-bromo-2-methylpyridine (monitored by TLC), the reaction mixture was cooled to RT, then added 4-bromo-2-methylpyridine (2.71 g, 14.49 mmol), cesium carbonate (21.2 g, 65.21 mmol), Pd(PPh3)4 (1.68 g, 14.49 mmol), 1,4-dioxane (50 mL), and water (10 mL) were added and stirred for 30 min. The reaction mixture was then heated to reflux and stirred for 16 h. After consumption of l-chloro-2-methoxy-4- nitrobenzene (monitored by TLC), the reaction was cooled to RT, and filtered through celite. The filtrate was concentrated in vacuo. The crude material was purified through silica gel column chromatography to afford 4-(2-methoxy-4-nitrophenyl)-2-methylpyridine (3.0 g, 85%) as a solid. 1H-NMR (CDC13, 400 MHz): delta 8.56 (d, 1H), 7.94 (d, 1H), 7.87 (s, 1H), 7.71- 7.68 (m, 1H), 7.28 (s, 1H), 7.24-7.21 (m, 1H), 3.94 (s, 3H), 2.62 (s, 3H); Mass (ESI): 245 [M+l], 279 [M+Na]; TLC: 30% EtOAc:hexane (R 0.9).
85%
To a stirred solution of 4-bromo-2-methylpyridine (2.5 g, 14.53 mmol) in 1, 4- dioxane (50 mL) under an argon atmosphere were added bis (pinacolato) diborane ester (4.04 g, 15.98 mmol), potassium acetate (2.84 g, 29.06 mmol), tricyclohexylphosphine (0.61 g, 21.81 mmol) and purged for 30 min. To this was added Pd2(dba)3 (0.66 g, 0.726 mmol) and stirred at reflux for 4 h. After consumption of 4-bromo-2-methylpyridine (monitored by TLC), the reaction mixture was cooled to RT, then added 4-bromo-2-methylpyridine (2.71 g, 14.49 mmol), cesium carbonate (21.2 g, 65.21 mmol), Pd(PPh3)4 (1.68 g, 14.49 mmol), 1,4- dioxane (50 mL), water (10 mL) and stirred for 30 min. The reaction mixture was heated to reflux and stirred for 16 h. After consumption of <strong>[1009-36-5]1-chloro-2-methoxy-4-nitrobenzene</strong> (monitored by TLC), the reaction was cooled to RT and filtered through celite. The filtrate was concentrated in vacuo to afford the crude product. The crude was purified through silica gel column chromatography to afford 4-(2-methoxy-4-nitrophenyl)-2-methylpyridine (3.0 g, 85%) as a colorless semisolid. 1H-NMR (CDCl3, 400 MHz): delta 8.56 (d, 1H), 7.94 (d, 1H), 7.87 (s, 1H), 7.71-7.68 (m, 1H), 7.28 (s, 1H), 7.24-7.21 (m, 1H), 3.94 (s, 3H), 2.62 (s, 3H); Mass (ESI): 245 [M+1], 279 [M+Na]; TLC: 30% EtOAc:hexane (Rf: 0.9).
With n-butyllithium; In tetrahydrofuran; hexane; N,N-dimethyl-formamide; at -78℃; for 1.58333h;
Example 117 Preparation of 2-(2-methylpyridin-4-yl)-6-(morpholinomethyl)quinazolin-4(3H)-one A solution of n-butyllithium (1.6 M solution in hexanes, 6.32 mL, 12.6 mmol) in THF (50 mL) was cooled to -78° C. A solution of 4-bromo-2-methyl-pyridine (2.00 g, 11.6 mmol.) in anhydrous THF (5 mL) was added. The resulting mixture was stirred for 5 minutes, then anhydrous N,N dimethylformamide (3.39 g, 46.4 mmol,) was added. The solution was stirred for 90 min at -78° C. and quenched with saturated aqueous NH4Cl solution (30 mL). The reaction mixture was warmed to room temperature. The mixture was extracted with ethyl acetate (3*100 mL), and the combined organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give 2-methyl-pyridine-4-carbaldehyde. Yield: 1.20 g, (85percent).
30%
To a stirred solution of 4-bromo-2-methylpyridine (1.00 g, 5.81 mmol) in anhydrous diethyl ether (70 mL) was added n-BuLi (2.5 M, 2.56 mL, 6.39 mmol) at -78 °C under N2. After stirring at -78 °C for 15 mi DMF (0.54 mL, 6.92 mmol) was added slowly. The mixture was stirred for another 30 mm and warmed to 0 °C. The mixture was quenched with 20 mL of aq. NaHCO3, extracted with EA (50 mL x 2). The combined organics was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The resulted residue was purified by column chromatography eluted with PE/EA (5:1) to give the title product (210 mg, 30percent) as a light yellow solid. ?HNMR (400 MHz, CDCl) 10.05 (s, 1H),8.76 (d, J=4.8 Hz, 1H),7.56 (s, 1H),7.51 (d, J=4.8 Hz, 1H), 2.68 (s, 3H)
1 g
Intermediate H: Preparation of 2-methylisonicotinaldehyde Under a nitrogen atmosphere, to a solution of 4-bromo-2-methylpyridine (2.00 g, 11.63 mmol) in anhydrous Et20 (150 mL) was added t-butyllithium (0.82 g, 12.79 mmol) at -78 °C. The reaction was kept at that temperature for 30 min. Anhydrous DMF (0.85 g, 11.63 mmol) was added and the mixture was stirred at -78 °C for an additional 30 min. Saturated aqueous NH4C1 (50 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were washed with Et20 (6 x 50 mL). The combined organics were washed with saturated NaCl (2 x 50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo to provide 2-methylisonicotinaldehyde (lg, 8.3 mmol). GCMS [M] = 121
[00243] Under a nitrogen atmosphere, to a solution of 4-bromo-2-methylpyridine (2.00 g, 11.63 mmol) in anhydrous Et20 (150 mL) was added t-butyllithium (0.82 g, 12.79 mmol) at -78 °C. The reaction was kept at that temperature for 30 min. Anhydrous DMF (0.85 g, 11.63 mmol) was added and the mixture was stirred at -78 °C for an additional 30 min. Saturated aqueous NH4C1 (50 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were washed with Et20 (6 x 50 mL). The combined organics were washed with saturated NaCl (2 x 50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo to provide 2-methylisonicotinaldehyde (lg, 8.3 mmol). GC/MS [M] = 121.
4-methyl-2-(2-methylpyridin-4-yl)oxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
To a solution of <strong>[693-93-6]<strong>[693-93-6]4-methyloxazol</strong>e</strong> (254 mg) in THF (2 ml) was added at -78 C n-BuLi (1.6 M in THF, 2.3 ml) and zinc chloride (2 M in 2-methyl-tetrahydrofuran, 2.3 ml) and stirring was continued at 22 C for 30min. 4-Bromo-2-methylpyridine (526 mg) and tetrakis(triphenylphosphine)palladium(0) (353 mg) were added and stirring was continued at 60 C for 2 h. The mixture was partitioned between water and EtOAc, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, gradient, 30% to 70% EtOAc in n-heptane) to give the title compound (375 mg, 70%) as a light yellow viscous oil. MS (ESI, m/z): 175.5 [(M+H)+].
4-(5-chloro-2-methoxyphenyl)-2-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 18h;Inert atmosphere;
Preparation 59 4-(5-chloro-2-methoxyphenyl)-2-methylpyridine To a mixture of <strong>[89694-48-4](5-chloro-2-methoxyphenyl)boronic acid</strong> (56.89 g, 0.31 mol), 4-bromo-2- methylpyridine (50 g, 0.29 mol) and sodium carbonate (98.57 g, 0.91 mol) was added 1 ,4, dioxane (0.9 L) and water (0.18 L). The reaction was sparged with nitrogen and degassed in vacuo. Pd(dppf)Cl2 (12.66 g, 16 mmol) was added and the reaction heated to 100C for 18 hours. The reaction was cooled to room temperature, filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc. The residue was dissolved in EtOAc and extracted into 1 M HCI (2 x 2 L). The aqueous layers were combined, basified with concentrated aqueous NaOH solution and extracted into EtOAc (2 x 750 mL). The organic layers were combined, washed with brine (300 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (64.5 g, 95%). (0911) 1 H NMR (400MHz, CDCI3): delta ppm 2.60 (s, 3H), 3.81 (s, 3H), 6.91 (d, 1 H), 7.28 (m, 4H), 8.51 (d, 1 H).
2-(4-bromopyridin-2-yl)-1-cyclopropylethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
Stage #1: 4-bromo-2-methylpyridine With sodium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 1h;
Stage #2: methyl cyclopropylcarboxylate In tetrahydrofuran at -78 - 20℃; for 16h;
28 2-(4-Bromopyridin-2-yl)-1-cyclopropylethanone
To a solution of 18 (5.5 g, 32.0 mmol) in THF (40 mL) was addedNaHMDS (1.9 M THF solution, 20.2 mL, 38.4 mmol) at 78 C, andthe mixture was stirred at rt for 1 h. Methyl cyclopropanecarboxylate(3.27 mL, 32.0 mmol) was added at 78 C, and the mixturewas allowed to warm to rt for 16 h. The mixture was quenchedwith satd NaHCO3 solution and extracted with EtOAc. The organiclayer was separated, washed with satd NaHCO3 solution and brine,dried over MgSO4, and concentrated. The residue was purified bycolumn chromatography (silica gel, hexane/EtOAc = 90/10 to50/50) to give the title compound (4.3 g, 56%) as a yellow oil. 1HNMR (400 MHz, CDCl3) d 0.92 (2H, dd, J = 7.5, 3.3 Hz), 1.04-1.14(2H, m), 2.00-2.10 (1H, m), 4.03 (2H, s), 7.37 (1H, d, J = 5.1 Hz),7.44 (1H, s), 8.38 (1H, d, J = 5.3 Hz).
ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)propanoate[ No CAS ]
ethyl 2-(4-(2-methylpyridin-4-yl)cyclohex-3-en-1-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere;
To a solution of ethyl 2-(4-(4,4,S ,S -tetramethyl- i ,3 ,2-dioxaborolan-2-yl)cyclohex-3-en-i-yl)propanoate (i20 mg, 0.389 mmol) in dioxane (3 mL) was added <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (67.0 mg, 0.389 mmol), water (i mL) and Na2CO3 (i65 mg,i.557 mmol). The mixture was degassed with N2 for iO minutes. Pd(Ph3P)4 (22.49 mg,0.0i9 mmol) was then added. The mixture was heated to iOO C for i6h. The cooledmixture was diluted with EtOAc, washed with water and brine The solution was driedover Na2SO4, filtered and evaporated. The crude material was purified by ISCO silica gelchromatography (0-50% EtOAc/Hexane). Fractions containing product were concentratedto yield ethyl 2-(4-(2-methylpyridin-4-yl)cyclohex-3 -en-i -yl)propanoate (i 00 mg, 0.366 mmol, 94 % yield) as a yellow oil. ?H NMR (400MHz, chloroform-d) oe 8.61 - 8.11 (m, 1H), 7.09 - 6.68 (m, 2H), 4.15 (qdd, J=7.1, 3.3, 1.8 Hz, 2H), 2.71 - 2.57 (m, 1H), 2.53 (d, J5.3 Hz, 3H), 2.47 - 2.35 (m, 0.5H), 2.29 (t, J7.1 Hz, 0.5H), 1.98 - 1.75 (m, 3H), 1.67 - 1.38 (m, 4H), 1.32 - 1.22 (m, 4H), 1.21 - 1.09 (m, 4H).
With [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine]nickel(II) dichloride; tris-(trimethylsilyl)silane; [Ir[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine]2(4,4′-di-t-Bu-2,2′-bipyridine)]PF6; lithium hydroxide In 1,2-dimethoxyethane at 20℃; for 6h; Inert atmosphere; Irradiation;
3-bromo-5-[(2-methylpyridin-4-yl)oxy]benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 48h;
106 3-bromo-5-[(2-methylpyridin-4-yl)oxy]benzoic acid
Intermediate 1(2.3 g, 9.95 mmol), 4-bromo-2-methylpyridine (2.05 g, 11.95 mmol) and Cs2CO3 (19.5 g, 59.7 mmol) in DMF (150 mL) were stirred at 120 °C for 48 hours. The reaction mixture was cooled to RT, filtrated and evaporated to dryness. The crude material was purified by column chromatography (silica gel, hexane/ EEgradient) to afford the title compound 1.1 g (36% yield).
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 80℃;Inert atmosphere;
To a solution of 4-bromo-2-methylpyridine (10.0 g, 58 mmol) in toluene (100 mL) was added tributyl(l-ethoxyvinyl)stannane (39.7 g, 110 mmol) and Pd(PPh3)4 (5.8 g, 5 mmol). The mixture was stirred at 80 C under a nitrogen atmosphere overnight. IM HCl was added at 0 C until the pH of the mixture was adjusted to 1-2. The mixture was stirred for 0.5 h. The pH was adjusted to 6-7 by adding IM NaOH. The mixture was extracted with ethyl acetate (150 mL*3). The organics layer was washed with brine and dried over sodium sulfate. Concentration and purification by column chromatography on silica gel (petroleum ether/ethyl acetate = 30/1-4/1) afforded l-(2-methylpyridin-4-yl)ethanone as light yellow solid (3.0 g, 44%).
Synthesis of 4-(2-methoxy-4-nitrophenyl)-2-methylpyridine To a stirred solution of 4-bromo-2-methylpyridine (2.5 g, 14.53 mmol) in 1,4-dioxane (50 mL) under an argon atmosphere were added bis(pinacolato)diborane ester (4.04 g, 15.98 mmol), potassium acetate (2.84 g, 29.06 mmol), tricyclohexylphosphine (0.61 g, 21.81 mmol) and purged for 30 min. To this was added Pd2(dba)3 (0.66 g, 0.726 mmol) and stirred at reflux for 4 h. After consumption of 4-bromo-2-methylpyridine (monitored by TLC), the reaction mixture was cooled to RT, then added 4-bromo-2-methylpyridine (2.71 g, 14.49 mmol), cesium carbonate (21.2 g, 65.21 mmol), Pd(PPh3)4 (1.68 g, 14.49 mmol), 1,4-dioxane (50 mL), water (10 mL) and stirred for 30 min. The reaction mixture was heated to reflux and stirred for 16 h. After consumption of <strong>[1009-36-5]1-chloro-2-methoxy-4-nitrobenzene</strong> (monitored by TLC), the reaction was cooled to RT and filtered through celite. The filtrate was concentrated in vacuo to afford the crude product. The crude was purified through silica gel column chromatography to afford 4-(2-methoxy-4-nitrophenyl)-2-methylpyridine (3.0 g, 85%) as a colorless semisolid. 1H-NMR (CDCl3, 400 MHz): delta 8.56 (d, 1H), 7.94 (d, 1H), 7.87 (s, 1H), 7.71-7.68 (m, 1H), 7.28 (s, 1H), 7.24-7.21 (m, 1H), 3.94 (s, 3H), 2.62 (s, 3H); Mass (ESI): 245 [M+1], 279 [M+Na]; TLC: 30% EtOAc:hexane (Rf: 0.9).
4-(2-fluoro-4-nitrophenyl)-2-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
Synthesis of 4-(2-fluoro-4-nitrophenyl)-2-methylpyridine To a stirred solution of 4-bromo-2-methylpyridine (3 g, 17.44 mmol) in 1,4-dioxane (150 mL) under an argon atmosphere were added Bis(pinacolato)diboron (4.87 g, 19.18 mmol), tricyclohexyl phosphine (732 mg, 2.61 mmol), potassium acetate (3.4 g, 34.88 mmol), Pd2(dba)3 (798 mg, 0.87 mmol). The reaction was purged under an argon atmosphere for 10 min at room temperature, heated to 100 C. and stirred for 3 h. After the disappearance of 4-bromo-2-methylpyridine (monitored by TLC) the reaction mixture was cooled to room temperature, <strong>[185331-69-5]1-bromo-2-fluoro-4-nitrobenzene</strong> (3.8 g, 17.43 mmol), cesium carbonate (25.49 g, 78.43 mmol) and Pd(PPh3)4 (2.01 g, 1.74 mmol) were added and refluxed for 16 h. After consumption of <strong>[185331-69-5]1-bromo-2-fluoro-4-nitrobenzene</strong> (monitored by TLC), the volatile components were evaporated in vacuo to afford the crude material which was purified through silica gel column chromatography (20% EtOAc:hexanes) to afford 4-(2-fluoro-4-nitrophenyl)-2-methylpyridine (2.4 g, 59%) as a pale yellow solid. 1H-NMR (DMSO-d6, 500 MHz): delta 8.60 (d, 1H), 8.29-8.26 (m, 1H), 8.20-8.18 (m, 1H), 7.91 (t, 1H), 7.51 (s, 1H), 7.44 (d, 1H), 2.56 (s, 3H); LC-MS: 232.9 (M+1); (column; X-Bridge C-18 (50*3.0 mm, 3.5 mum); RT 2.28 min. 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 40% EtOAc:hexanes (Rf: 0.2).
With (1,2-dimethoxyethane)dichloronickel(II); pyridine-2,6-bis(carboximidamide) dihydrochloride; trifluoroacetic acid; sodium iodide; zinc at 60℃; for 7h; Inert atmosphere;
2-dicyclohexylphosphino-2',6'-bis(2-methylpyrid-4-yl)biphenyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53.4 mg
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 140℃; for 36h;Schlenk technique; Inert atmosphere;
In a 25 mL Schlenk tube,A solution of 70.1 mg (0.2 mmol) of 2-dicyclohexylphosphine biphenyl (<strong>[247940-06-3]CyJohnPhos</strong>), (1, 5-cyclooctadiene) chlorideRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), replacing argon The mixture was heated under argon and a solution of 1,4-dioxane 1 mL, 4-bromo-2-methylpyridine (82.6 mg, 0.48 mmol) was added under argon.140 C for 36 hours, cooled to room temperature and evaporated under reduced pressure. The solvent was separated on a 200-300 mesh silica gel column. The petroleum ether: ethyl acetate =60: 1 and dried in vacuo to give 53.4 mg of product as a white solid with a gas chromatographic purity of 78%.
diethyl 2-(2-methyl-4-pyridinyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With benz<b>oxazole; copper(l) iodide; triethylamine; In dimethyl sulfoxide; at 60℃; for 0.25h;
(1) <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> was dissolved in DMSO at a concentration of 1 mol / L to give solution a; (2) diethyl malonate, ligand benzoxazole, The molar ratio of diethyl malonate to <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> in DMSO was 1.5: 1, the molar ratio of benzoxazole to <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> was 0.4: 1, The molar ratio of triethylamine to <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> was 4: 1 to obtain solution b; (3) adding solid catalyst cuprous iodide to a fixed bed microchannel reaction apparatus, 2-methylpyridine is 0.2: 1; (4) The solution a and the solution b are simultaneously pumped into the fixed bed microchannel reaction apparatus after the treatment in step (3), and then the microcirculation reaction in the reaction apparatus (Diameter of 0.5mm, length of 20m) reaction.The flow rate ratio of solution a and solution b is controlled at 1: 1, flow rate 1ml / min, holding residence time 15min, reaction at 60 ; (5) collecting outflow liquid, EA / water extraction, combining organic phase, adding anhydrous sulfuric acid Sodium drying in addition to water, filtration, through silica gel column chromatography to petroleum ether / ethyl acetate configuration of a certain proportion of mobile phase, separation of impurities, the product is pure.Yield: 75%
75%
With benz<b>oxazole; potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 50℃; for 6h;Inert atmosphere; Sealed tube;
General procedure: Under Ar atmosphere, DMSO (2 mL), ArBr 1 (1.0 mmol), diethyl malonate 2 (1.5 mmol), CuI (0.1mmol), benzoxazole (0.2 mmol) and K3PO4 (3 mmol) were successively added into a sealed tube.The mixture was stirred at 50C for about 3-9 h. When the reaction completed indicated by TLC,the reaction mixture was poured into saturated ammonium chloride aqueous solution (20 mL)and extracted with ethyl acetate (3×20 mL).The combined organic phase was washed with saturated ammonium chloride aqueous solution(2×20 mL) and water (2×20 mL). Then the separated organic layer was dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. The residue waschromatographed on silica gel using hexane/ethyl acetate to afford the desired product.
4-(4-(benzyloxy)-1-methyl-1H-pyrazol-5-yl)-2-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; tetrabutylammonium acetate; palladium diacetate; In 1,4-dioxane; at 90℃; for 48h;Inert atmosphere;
General procedure: 4-Alkoxy/thioalkyl pyrazole (1.0 mmol, 1.0 eq.) (if solid), aryl halide (1.05 mmol, 1.05 eq.), palladium(II) acetate (11 mg, 0.05 mmol, 0.05 eq.), SPhos (31 mg, 0.075 mmol, 0.075 eq.) and tetrabutylammonium acetate (904 mg, 3.0 mmol, 3.0 eq.) were added to a reaction vial (ambient atmosphere). The vial was equipped with a stirring bar and placed under a nitrogen atmosphere. Dioxane (2.50 ml, 0.4M) was added or if liquid, 4-alkoxy/thioalkyl pyrazole (1.0 mmol, 1.0 eq.) was added as a solution in dioxane (2.50 ml, 0.4M). The mixture was stirred at 70-90 C under nitrogen for 24-72 h (complete consumption of starting materials or no further progress as monitored by UPLC/MS). The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography.
Stage #1: 4-bromo-2-methylpyridine With lithium diisopropyl amide In tetrahydrofuran; N,N-dimethyl-formamide at -78℃; for 1.25h;
Stage #2: With sodium tetrahydroborate; acetic acid In methanol at -78 - 20℃; for 1h;
Intermediate I-94A: 2-(4-bromopyridin-2-yl)ethanol
4-bromo-2-methylpyridine (2.5 g, 14.53 mmol) was dissolved in anhydrous THF (50 mL) at -78 °C. LDA (25.4 mL, 50.9 mmol) was added to the reaction mixture which was allowed to stir at -78 °C for 30 minutes. Anhydrous DMF (3.38 mL, 43.6 mmol) wasthen added to the reaction mixture which continued to stir at -78 °C for an additional 45 minutes. A mixture of acetic acid (3.33 mL, 58.1 mmol)/MeOH (10 mL) was then added to the mixture at -78 °C followed by sodium borohydride (0.55 0 g, 14.53 mmol). The reaction mixture was then allowed to warm to room temperature and was stirred for 1 h then quenched with 10% aqueous citric acid solution at room temperature and stirred foran additional 10 minutes. The reaction mixture was extracted with EtOAc (3x). The organic layer was washed with brine (lx), dried with sodium sulfate, filtered and concentrated to yield Intermediate I-94A which was brought forward without further purification. LC-MS: Method H, MS (ESI) m/z: 201.9 (M+H). ‘H NMR (400MHz,DMSO-d6) 8.37 (d, J=5.3 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.49 (dd, J5.4, 1.9 Hz, 1H), 3.78-3.70 (m, 1H), 2.89-2.86 (m, 2H), 2.28 (d, J=5.5 Hz, 1H).
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 130℃; for 0.333333h;Inert atmosphere; Sealed tube; Microwave irradiation;
To a mixture of 1-Boc-5,6-dihydro-2H-pyridine-3-boronic acid pinacol ester (CAS:885693-20-9; 600 mg, 1.94 mmol) and NaHCO3 (1.94 mL, 3.88 mmol, 2M solution in water) in 1 ,4-dioxane (20 mL), 4-bromo-2-methylpyridine (0.23 mL, 1.94 mmol) andtetrakis(triphenylphosphine)palladium(0) (112 mg, 0.097 mmol) were added at rt while N2 was bubbled through the solution. The mixture was heated at 130 °C for 20 mm in a sealed tube under microwave irradiation. Water and EtOAc were added and the organic layer was separated, dried over MgSO4, filtered and evaporated under vacuum. The residue thus obtained was purified by flash column chromatography (silica; EtOAc in heptane, 1/3 to 4/1) and the desired fractions were concentrated in vacuo affording intermediate 9 (170 mg, 32percent yield).
2-methyl-4-(4-nitro-1H-imidazol-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 130℃; for 3h;
A solution of 4-bromo-2-methylpyridine (437a) (3.05 g, 17.73 mmol; CAS 22282-99-1), 4- nitro-lH-imidazole (1.97 g, 17.42 mmol; CAS: 3034-38-6), potassium iodide (2.7 g, 16.26 mmol) and potassium carbonate (5.7 g, 41.2 mmol) in DMF (10 mL) was heated at 130C in a microwave reactor for 3 h. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography [silica gel (80g), eluting with ethyl acetate/methanol (9: 1) in hexanes from 50-100%] to furnish 2- methyl-4-(4-nitro-lH-imidazol-l-yl)pyridine (437b) (1.36 g, 38 % yield) as a yellow solid; NMR (300 MHz, DMSO-d) delta 9.19 (d, J= 1.6 Hz, 1H), 8.71 (d, J= 1.6 Hz, 1H), 8.62 (d, J= 5.5 Hz, 1H), 7.92 - 7.83 (m, 1H), 7.74 (ddd, J= 5.6, 2.3, 0.6 Hz, 1H), 2.56 (s, 3H); MS (ES+): 205.1 (M+l).
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 16h;Inert atmosphere;
To a mixture of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (2.5g, 14.5mmol) and tributyl 1-ethoxy vinyl tin (10.5g, 29.1 mmol) in toluene (15ml_) was purged N2 gas at rt for 10 min and Pd(PPh3)4 (1.7g, 1.45mmol) was added to it under N2 atmosphere. The reaction mixture was purged with N2 gas for 5 min at rt and stirred further at 1 10 C for 16h. The TLC showed the reaction to be complete. The reaction mixture was allowed to cool to rt before the solvent was removed under reduced pressure. The residue was stirred with hexane (25ml_) and filtered through celite bed. The celite bed was washed with hexane (50ml_). The combined filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel, eluting with 0-5% EtOAc in hexane to afford 4-(1-ethoxyvinyl)-2- methylpyridine as a colourless oil. Yield: 2.35 g (98%); (MS (ESI+) for CHNOS m/z 164.10 [M+H]+. 1 H NMR (400 MHz, DMSO-d6): delta 8.41 (d, J = 5.2 Hz, 1 H), 7.35 (s, 1 H), 8.41 (d, J = 4.7 Hz, 1 H), 5.01 (s, 1 H), 4.46 (s, 1 H), 3.91 (q, J = 6.9 Hz, 2H), 2.47 (s, 3H), 1.35 (t, J = 6.9 Hz, 3H).
tert-butyl 5-((tert-butyldimethylsilyl)oxy)-3-isopropyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate[ No CAS ]
tert-butyl 5-((tert-butyldimethylsilyl)oxy)-3-isopropyl-2-(2-methylpyridin-4-yl)-1H-indole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium phosphate; (chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II)); In tetrahydrofuran; water; at 75℃; for 18h;Sealed tube; Inert atmosphere;
To a mixture containing tert-huly] 5-((tert-butyldimethylsilyl)oxy)-3-isopropyl-2- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-indole-l-carboxylate (2.2 g, 4.3 mmol), <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (0.633 mL, 5.3 mmol), and Xphos Pd G2 (0.101 g, 0.13 mmol) in a screw cap vial was added THF (25 mL) followed by the addition of an aqueous solution of potassium phosphate, tribasic (4.5 mL, 13.5 mmol). The vial was fitted with a Teflon lined septum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repealed three times. The needle was removed and the vial was heated at 75 C for 18h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous NaCl solution (25 mL). The organic was dried (NazSOr), filtered and concentrated. The crude product was dissolved m a small amount of DCM and charged to an ISCO silica gel 40 g ISCO column which was eluted over a 15 min gradient with 0%-50% hexanes/ethyl acetate to afford tert-butyl 5-((tert~ butyldimethylsiJyl)oxy)-3-isopropyl-2-(2-methylpyridin-4-yJ)-lH-indoJe-l-carboxylate (1.8 g, 3 74 mmol, 88% yield). MS (M+] ) m/z: 481. LC retention time 1.12 min [B 1 ] .
ethyl 2-(2-methylpyridin-4-yl)-2-(pyridin-2-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With palladium diacetate; caesium carbonate; XPhos; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; Schlenk technique;
General procedure: An oven-dried Schlenk tube was charged with Pd(OAc)2 (0.015 mmol, 3.4 mg), X-Phos (0.015 mmol, 7.2 mg), Cs2CO3 (0.9 mmol, 293 mg), substrate 1 (0.3 mmol) and 2 (0.4 mmol). The reaction vessel was evacuated and backfilled again with nitrogen gas, and 1,4-dioxane (1 mL) was added via syringe under nitrogen. The reaction mixture was stirred at 100 C for 12 hours. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The crude was nextfiltered through a plug of celite, which was washed with ethyl acetate. The solution was concentrated and further purifiedby flash column chromatography to afford the corresponding product.
Stage #1: 4-bromo-2-methylpyridine; formamide With ammonium peroxydisulfate; sulfuric acid; water In acetonitrile at 75℃; for 4h;
Stage #2: With sodium hydroxide In water at 100℃; for 0.666667h;
159.A A) 4-bromo-6-methylpicolinic acid
To a mixture of 4-bromo-2-methylpyridine (20 g) and acetonitrile (200 mL) were added sulfuric acid (4.56 g), formamide (52.4 g) and water (40 mL) at room temperature. To the mixture was gradually added ammonium peroxodisulfate (39.8 g) at 70°C, and the mixture was stirred at 75°C for 4 hr. The reaction mixture was cooled to room temperature, diluted with water (150 mL) and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate/hexane mixed solvent to give a solid (15.4 g). A mixture of the obtained solid (15.4 g) and 2N aqueous sodium hydroxide solution (286 mL) was stirred at 100°C for 40 min. To the reaction mixture was added 6N hydrochloric acid at 0°C to adjust pH to 4. The solvent was evaporated under reduced pressure. To the residue was added methanol (700 mL), insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate to give the title compound (15.5 g). This compound was used in the next step without further purification. MS: [M+H]+ 215.9.
ethyl 2-(2-methylpyridin-4-yl)oxazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With palladium diacetate; caesium carbonate; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; at 70℃; for 12h;Inert atmosphere;
To a solution of 4-bromo-2-methyl-pyridine (1.50 g, 8.72 mmol, from CAS22282-99-1) and <strong>[23012-14-8]ethyl oxazole-4-carboxylate</strong> (1.23 g, 8.72 mmol, from CAS170487-38-4) in DMF (40 mL) was added tris-o-tolylphosphane (531 mg, 1.74 mmol), Pd(OAc)2 (196 mg, 872 umol) and Cs2CO3 (5.68 g, 17.4 mmol). The reaction mixture was stirred at 70 C. for 12 hours under nitrogen. On completion, the reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.10 g, 44% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.65 (d, J=5.2 Hz, 1H), 8.31-8.36 (m, 1H), 7.86 (s, 1H), 7.75 (d, J=5.2 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 2.64 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); LC-MS (ESI+) m/z 233.1 (M+H)+.
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