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CAS No. : | 1012880-11-3 | MDL No. : | MFCD22494866 |
Formula : | C13H19BFNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | N/A |
M.W : | 251.10 g/mol | Pubchem ID : | - |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
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Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.9 g | Stage #1: With sodium hydrogencarbonate In tetrahydrofuran at 0 - 60℃; Inert atmosphere Stage #2: With triethylamine In toluene at 90℃; |
Method B: To 4 necked round bottom flask equipped with mechanical agitation, thermometer and N2 inlet is added 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (40g, 0.159 mol), THF (600 ml) and NaHC03 (16.0g, 0.19 mol, 1.20eq). The mixture is cooled to 0~5°C and phenyl chloroformate (26.14g, 0.167 mol, 1.05eq) is added dropwise. The reaction mixture is warmed to 60°C and stirred until the content of 2-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline < 2percent. The mixture is filtered and the solid (salt) is washed with THF (120 ml). The filtrate is concentrated to 65~80ml. To the residue, toluene (720 ml), 3,3-dimethylbutan-l-amine (HC1 salt, 26.14g, 0.19 mol, 1.2eq) and TEA (20.87g, 0.21 mol, 1.3eq) are added. The resulting mixture is heated to 90°C and stirred until the content of intermediate < 2percent. The mixture is cooled to 15~20°C, stirred for 2hrs and filtered. The solid is washed with toluene (120 ml), H20 (2 x 400 ml) and dried under high vacuum to afford title compound as a white solid. ( 54.9g, 91.3percent yield and 99percent purity detected by UV absorption at 210 nm);1H NMR (400 MHz, d6-DMSO): δ 8.34 (d, J = 9.1 Hz, 1H), 8.08 (s, 1H), 6.98 (d, J = 12.3 Hz, 1H), 6.41 (s, 1H), 3.08 (s, 2H), 2.38 (s, 3H), 1.36 (m, 14H), 0.90 (s, 9H);13C NMR (500MHz, d6-DMSO): δ 21.12,24.65,29.37,29.58, 35.65,43.50,83.25, 104.32116.09, 125.02, 128.19, 138.71, (152.40,154.34) ,154.81; 19F NMR (400 MHz, d6-DMSO): δ 136.34 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydrogencarbonate In water; ethyl acetate at 20℃; for 6h; | |
With sodium hydrogencarbonate In water; ethyl acetate at 20℃; for 6h; | 3 Preparation 3 Prop-l-en-2-yl 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenylcarbamate Add 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (5.0 g, 19.91 mmol) and isopropenyl chloroformate (2.40 mL, 21.90 mmol) in EtOAc (60 mL) and saturated aqueous NaHC03 (60 mL) and stir at RT for 6 h. Separate the layers, extract the aqueous layer with EtOAc (2x), wash the combined organics with brine, dry over Na2S04 and concentrate to obtain the title compound. Use for the next reaction without further purification (assuming 100% yield). MS (m/z): 336.2 (M+l). | |
With sodium hydrogencarbonate In ethyl acetate at 20℃; for 6h; | 31 Synthesis of prop-1-en-2-yl 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate Combine 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (5.0 g, 19.91 mmol) and isopropenyl chloro formate (2.40 mL, 21.90 mmol) in EtOAc (60 mL) and saturated NaHC03 (60 mL) and stir at RT for 6 h. Separate the layers, extract the aqueous layer with EtOAc (2x), wash the combined organics with brine, dry over Na2S04 and concentrate to obtain the title compound. Use for the next reaction without further purification (assuming 100% yield). MS (m/z): 336.2 (M+ H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.9 g | Method B: To 4 necked round bottom flask equipped with mechanical agitation, thermometer and N2 inlet is added 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (40g, 0.159 mol), THF (600 ml) and NaHC03 (16.0g, 0.19 mol, 1.20eq). The mixture is cooled to 0~5C and phenyl chloroformate (26.14g, 0.167 mol, 1.05eq) is added dropwise. The reaction mixture is warmed to 60C and stirred until the content of 2-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline < 2%. The mixture is filtered and the solid (salt) is washed with THF (120 ml). The filtrate is concentrated to 65~80ml. To the residue, toluene (720 ml), 3,3-dimethylbutan-l-amine (HC1 salt, 26.14g, 0.19 mol, 1.2eq) and TEA (20.87g, 0.21 mol, 1.3eq) are added. The resulting mixture is heated to 90C and stirred until the content of intermediate < 2%. The mixture is cooled to 15~20C, stirred for 2hrs and filtered. The solid is washed with toluene (120 ml), H20 (2 x 400 ml) and dried under high vacuum to afford title compound as a white solid. ( 54.9g, 91.3% yield and 99% purity detected by UV absorption at 210 nm);1H NMR (400 MHz, d6-DMSO): delta 8.34 (d, J = 9.1 Hz, 1H), 8.08 (s, 1H), 6.98 (d, J = 12.3 Hz, 1H), 6.41 (s, 1H), 3.08 (s, 2H), 2.38 (s, 3H), 1.36 (m, 14H), 0.90 (s, 9H);13C NMR (500MHz, d6-DMSO): delta 21.12,24.65,29.37,29.58, 35.65,43.50,83.25, 104.32116.09, 125.02, 128.19, 138.71, (152.40,154.34) ,154.81; 19F NMR (400 MHz, d6-DMSO): delta 136.34 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃;Inert atmosphere; | Combine <strong>[945244-29-1]5-bromo-2-fluoro-4-methylaniline</strong> (3.1 g, 15.2 mmol), bis(pinacolato)diboron (4.24 g, 16.7 mmol), and potassium acetate (4.47 g, 45.6 mmol) in dioxane (40 mL) and sparge with argon. Add [l,l'-bis(diphenylphosphino)ferrocene]- dichloropalladium(II)-dichloromethane complex (0.620 g, 0.760 mmol), sparge again with argon and heat at 100C overnight. Filter the reaction mixture and concentrate in vacuo. Purify by silica gel chromatography (EtOAc/hexanes) to give the title compound (3.24 g, 85%). MS (m/z): 252.1 (M+ H+). |
74% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In Isopropyl acetate; at 50℃;Inert atmosphere; Reflux; | Method B: To 4 necked round bottom flask, equipped with mechanical agitation, thermometer, and N2 inlet is added 5-bromo-2-fiuoro-4-methylaniline (200g, 0.98 mol), CH3COOK (192g, 1.95 mol, 2.0eq), bis(pinacolato)diboron (248g, 0.98 mol,1.0eq) and IPAC (3L). After degassing with N2 for 30 min, the mixture is warmed to 50C and Pd(dppf)Cl2 (8g, 4wt%) is added. The reaction mixture is heated under reflux for at least lOh until the content of starting material <2% (GC). The mixture is cooled to 20~30C, filtered through a pad of Celite and rinsed with IPAC (1L). The filtrate is concentrated to 400~500ml remaining. The residue is mixed with n-Heptane (700ml), filtered through a Si02 pad and eluted with IPAC/n-Heptane(l/5 first, ~2L, and then 2/5, ~3L ). The filtrate is concentrated to 350~400ml. n-Heptane (300ml) is added and the mixture is again concentrated to 350~400ml. The residue (suspension) is cooled to -10- -20C and filtered after stirring for 2- 5 h. The crude product is dissolved in MeOH (200 ml) at 30-40 C, then slowly add H20 (600 ml) dropwise in 0.5~lh. The suspension is cooled to 20-30 C and filtered after stirring for 1-2 h .The solid is dried under high vacuum to afford the title compound as off- white solid (183g, 74% yield and 99% purity detected by UV absorption at 210 nm; 1H NMR (400 MHz, CDC13): delta 7.42 (d, J = 10.2 Hz, 1H), 7.01 (d, J = 12.4 Hz, 1H), 3.76 (s, 2H), 2.64 (s, 3H), 1.55 (s, 12H); 13C NMR(500MHz,CDC13): delta 20.66, 20.67, 24.40, 82.93, 116.20, 124.37, 130.64, 135.02, (151.93, 153.37);19F NMR (400 MHz,CDC13): delta 145.72 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sulfuric acid; potassium nitrate / -10 - 20 °C / Cooling with ice; Inert atmosphere 2: iron; hydrogenchloride / ethyl acetate; water / 20 - 30 °C / Inert atmosphere 3: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / Isopropyl acetate / 50 °C / Inert atmosphere; Reflux | ||
Multi-step reaction with 3 steps 1: nitric acid; sulfuric acid / -5 - 20 °C 2: hydrogen / ethanol / 2062.71 Torr 3: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 100 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: nitric acid; sulfuric acid / 0.83 h / -5 - 20 °C 2: hydrogen / ethanol / 2062.71 Torr 3: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 60℃; for 1h; Inert atmosphere; | 38 Synthesis of 5 -(7-chloro-2 -methyl[1,6]naphthyridin-3-yl)-2-fluoro-4-methylaniline. Sparge a mixture of 7-chloro-2-methyl-l,6-naphthyridin-3-yl trifluoromethanesulfonate (2.250 g, 6.89 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.729 g, 6.89 mmol) in dioxane (32 mL) with argon, add a solution of K2CO3 (2.86 g, 20.66 mmol) in H20 (16 mL) followed by Pd(PPh3)4 (252 mg, 0.689 mmol) and heat at 60°C for 1 h. Cool to RT, add EtOAc, wash successively with H20, satd. NaHC03, then brine, dry over Na2S04, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (1.277 g, 61%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (d, J = 0.8 Hz, 1 H), 8.28 (s, 1 H), 8.00 (s, 1 H), 7.00 (d, J = 12.4 Hz, 1 H), 6.59 (d, J = 9.3 Hz, 1 H), 5.08 (s, 2 H), 2.42 (s, 3 H), 1.85 (s, 3 H); MS (ESI) m/z: 302.1(M+H+). |
61% | With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In lithium hydroxide monohydrate at 60℃; for 1h; Inert atmosphere; | |
41% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 80℃; for 1h; Inert atmosphere; | D7 Example D1: 2,4-difluoro-5-(isoquinolin-7-yl)aniline General procedure: A solution of 7-chloro-2-methyl-1,6-naphthyridin-3-yl trifluoromethanesulfonate (B27, 3.0 g, 9.2 mmol), 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A6, 2.2 g, 9.2 mmol) and K2CO3 (3.81 g, 28 mmol) in 1,4-dioxane (15 mL) and water (2.5 mL) was degassed with Ar for 5 min. PdCl2(dppf) (0.34 g, 0.46 mmol) was added and the reaction mixture was heated at 80 C for 1 h. The reaction mixture was cooled to rt and then the solution was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the crude was purified by silica gel column chromatography (0 to 100% EtOAc/hexanes) to afford 3-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)- 2-fluoroaniline (2.0 g, 76% yield) as a brown solid.1H NMR (500 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.45 (s, 1H), 8.02 (s, 1H), 7.03 (t, J = 7.7 Hz, 1H), 6.90 (t, J = 8.3 Hz, 1H), 6.56 (t, J = 6.9 Hz, 1H), 5.35 (s, 2H); MS (ESI) m/z: 288.0 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 75℃; for 8h; Inert atmosphere; | 42 Synthesis of 5-(7-chloro[1,6]naphthyridin-3-yl)-2-fluoro-4-methylaniline Sparge a solution of 3-bromo-7-chloro-l,6-naphthyridine (0.5 g, 2.053 mmol) and 2-fiuoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.516 g, 2.053 mmol) in dioxane (15 mL) with Ar, add a solution of K2CO3 (0.568 g, 4.11 mmol) in H20 (3 mL), followed by Pd(PPh3)4 (0.237 g, 0.205 mmol), heat at 75°C for 8 h, then cool to RT. Add H20, extract with EtO Ac (2x), wash the combined organics with brine, dry over Na2S04, concentrate to dryness and purify via silica gel chromatography (EtO Ac/Hex) to afford the title compound (470 mg, 80%) as an off-white solid. MS(ESI) m/z: 288.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / water; ethyl acetate / 6 h / 20 °C 2.1: phenyl chloroformate; sodium hydrogencarbonate / tetrahydrofuran / 0 - 60 °C / Inert atmosphere 2.2: 2 h / 20 - 90 °C 3.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 100 °C / Inert atmosphere 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 4.2: 20 °C | ||
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / water; ethyl acetate / 6 h / 20 °C 2.1: 1-Methylpyrrolidine / 1,4-dioxane / 75 °C 3.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 100 °C / Inert atmosphere 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 4.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / water; ethyl acetate / 6 h / 20 °C 2.1: phenyl chloroformate; sodium hydrogencarbonate / tetrahydrofuran / 0 - 60 °C / Inert atmosphere 2.2: 2 h / 20 - 90 °C 3.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 100 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 6 h / 20 °C 2: 1-Methylpyrrolidine / 1,4-dioxane / 75 °C 3: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 60℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.8% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In tetrahydrofuran; water at 70℃; for 2h; Inert atmosphere; | 86.I Step I, 2-Fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6- yl)aniline To a stirred solution of 7-m ethyl -2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl tnfluoromethane sulfonate (1.0 g, 2.95 mmol, 1.0 equiv.) (Henry et. al. J. Med. Chem. 2015, 58 (10), 4165-4179) in THF (25 mL, 25 vol. equiv.) was added 2-fluoro-4-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (888 mg, 3.54 mmol, 1.0 equiv.) (Henry et. al. J. Med. Chem. 2015, 58 (10), 4165-4179), potassium carbonate (1.22 g, 8.84 mmol, 3.0 equiv.), water (2 mL, 2 vol. equiv.) and PdCl2(dppf).DCM adduct (241 mg, 0.295 mmol, 0.1 equiv.). The reaction mixture was degassed three times with alternating vacuum and nitrogen. The resulting reaction mixture was heated at 70°C for 2.0 h. The progress of the reaction was monitored by TLC (70% EtOAc in -hexane) to ensure completion of the reaction. The reaction mixture was filtered through a Celite pad, rinsed with EtOAc. Water (50 mL) was added to the filtrate and the product was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water and brine (60 mL), dried (Na2S04), and concentrated. The residue was purified on Si02 cartridge (80 g) using a gradient of EtOAc in hexanes (10-70%) to afford the title compound (563 mg, 60.8%) as a yellow solid. The product was triturated with ether (10 mL) and hexanes (25 mL) to afford the title compound. Rf = 0.48 (70% EtOAc in hexanes). MR (400 MHz, CDCb) 5 9.11 (s, 1H), 7.86 (s, 1H), 6.96 (d, J = 11.7 Hz, 1H), 6.58 (d, J = 8.9 Hz, 1H), 3.71 (s, 2H), 2.77 (s, 3H), 2.55 (s, 3H), 1.94 (s, 3H). 19F NMR (376 MHz, CDCb) δ - 135.85 (dd, J = 11.7, 9.0 Hz). LRMS (m/z) calculated for Ci6Hi5FN4S, 314.10; found 336.90 (M+Na)+, 314.96 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane; water at 80℃; for 16h; | 3 Step 3: 2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-[2-(oxan-2-yloxy)ethoxylpyridin-3-yllaniline To a solution of 4-[5-bromo-2-[2-(oxan-2-yloxy)ethoxy]pyridin-3-yl]morpholine (550.00 mg, 1.42 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (534.93 mg, 2.13 mmol) in 1,4-dioxane (0.5 mL) and ThO (0.1 mL) were added NaiCCb (301.05 mg, 2.84 mmol) and l, l-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (463.91 mg, 0.57 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (1-10%). The fractions contained desired product were combined and concentrated to afford 2-fluoro-4- methyl-5-[5-(morpholin-4-yl)-6-[2-(oxan-2-yloxy)ethoxy]pyridin-3-yl]aniline (580 mg, 95%) as a yellow solid. MS ESI calculated for C23H30FN3O4[M + H]+, 432.22; found 432.30.1H-NMR (400 MHz, -DMSO) d 7.63 (d, J= 2.0 Hz, 1H), 7.05 (d, J= 2.0 Hz, 1H), 6.93 (d, J= 12.4 Hz, 1H), 6.65 (d, J= 9.6 Hz, 1H), 4.96 (s, 2H), 4.48 - 4.44 (m, 2H), 3.92 (s, 1H), 3.82 - 3.68 (m, 6H), 3.50 - 3.46 (m, 1H), 3.10 - 3.06 (m, 4H), 2.08 (s, 3H), 1.73 - 1.58 (m, 2H), 1.57 - 1.45 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane; water at 80℃; for 3h; | 2 Step 2: 2-fluoro-4-methyl-5-(5-morpholino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)aniline To a solution of 4-[5-bromo-2-(oxan-4-yloxy)pyridin-3-yl]morpholine (940.00 mg, 2.74 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (894.05 mg, 3.56 mmol) in dioxane (15.00 mL) and H2O (3.00 mL) were added NaiCCL (580.55 mg, 5.48 mmol) and 1, 1- bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (223.66 mg, 0.27 mmol). The reaction mixture was degassed with nitrogen for three times and stirred at 80 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 10% MeOH in CH2CI2. The fractionscontained desired product were combined and concentrated to afford 2-fluoro-4-methyl-5-[5- (morpholin-4-yl)-6-(oxan-4-yloxy)pyridin-3-yl]aniline (0.86 g, 81%) as an off-white solid. MS ESI calculated for C21H26FN3O3[M + H]+, 388.20; found 388.20.1H-NMR (400 MHz, /6-DMSO) d 7.62 (d, J= 2.0 Hz, 1H), 7.04 (d, J= 2.0 Hz, 1H), 6.91 (d, J= 12.4 Hz, 1H), 6.63 (d, J= 9.2 Hz, 1H), 5.31- 5.30 (m, 1H), 4.96 (brs, 2H), 3.89 - 3.79 (m, 2H), 3.75 - 3.73 (m, 4H), 3.58 - 3.53 (m, 2H), 3.07 - 3.05 (m, 4H), 2.11 - 1.95 (m, 5H), 1.72 - 1.65 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane; water at 80℃; for 1h; | 3 Step 3 : 2-fluoro-4-methyl-5-(2-morpholino-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)aniline To a solution of 4-[4-iodo-6-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]morpholine (5.75 g, 13.24mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.66 g, 14.56 mmol) in dioxane (170 mL) and water (40 mL) were added NaiCCb (4.21 g, 39.72 mmol) and 1,1- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.08 g, 1.32 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 80 °C. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 150 mL). The combined organic layers was washed with brine (3 x 100 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 40% EA in PE. The fractions contained desired product were combined and concentrated to afford 2-fluoro-4-methyl-5-[2-(morpholin-4-yl)-6-[2- (oxan-2-yloxy)ethoxy]pyridin-4-yl]aniline (4.4 g, 77%) as a yellow oil. MS ESI calculated for C23H30FN3O4[M + H]+, 432.22; found 432.25. H-NMR (300 MHz, CDCb) d 6.87 (d, 7= 11.7 Hz, 1H), 6.65 (d, J= 9.0 Hz, 1H), 6.11 - 6.07 (m, 2H), 4.70 (t, J= 3.6 Hz, 1H), 4.54 - 4.41 (m, 2H),4.11 - 4.02 (m, 1H), 3.94 - 3.77 (m, 6H), 3.54 - 3.47 (m, 5H), 2.14 (s, 3H), 1.89 - 1.43 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.928 g | Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 3-(trifluoromethyl)pyrrolidine hydrochloride In tetrahydrofuran at 20℃; | 1 Intermediate 2: A-[2-fluoro-4-methyl-5-t4,4,5,5-tetramethyl-l,3.,2-dioxaborolan-2- yl)nhenyll-3-itrifluoromethyl)nyrrolidine-l-carboxamide To a stirred solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (800 mg, 3.19 mmol) and ditri chi orom ethyl carbonate (378.16 mg, 1.27 mmol) in THF (40 mL) was added DIEA (2.63 mL, 20.37 mmol) dropwise at 0 °C. After stirring for 0.5 h, 3-(trifluoromethyl)pyrrolidine hydrochloride (559.37 mg, 3.19 mmol) in THF (1 mL) was added to the reaction mixture. The reaction mixture was stirred for 0.5 h at ambient temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 33% EA in PE. The fractions contained desired product were concentrated to afford /V-[2-fluoro-4-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrrolidine-l-carboxamide (0.928 g, 64%) as an off-white solid. MS ESI calculated for C19H25BF4N2O3 [M + H]+, 417.19, found 417.15. NMR (400 MHz, CDCb) d 8.34 (d, J= 9.2 Hz, 1H), 6.86 (d, J = 12.0 Hz, 1H), 6.17 (s, 1H), 3.81 - 3.53 (m, 4H), 3.06 - 2.96 (m, 1H), 2.47 (s, 3H), 2.32 - 2.16 (m, 2H), 1.31 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-(tert-butyl)morpholine hydrochloride In tetrahydrofuran at 0℃; for 1h; | 22.1; 23.1 Step 1: To a solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (400 mg, 1.59 mmol) and DIEA (1.0 g, 7.75 mmol) in THF (20 mL) was added a solution of BTC (191 mg, 0.64 mmol) in THF (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then 2-(tert-butyl)morpholine hydrochloride (344 mg, 1.91 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for lh. The reaction mixture was concentrated. The residue was purified by FCC (PE:EA = 2: 1) to afford 2-(tert-butyl)-N-(2-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxamide (460 mg, 62%). MS Calcd.: 420, MS Found: 421 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-(2,2,2-trifluoroethyl)morpholine hydrochloride In tetrahydrofuran at 0℃; for 1h; | 25.1; 26.1 Step 1: To a solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (251 mg, 1.00 mmol) and DIEA (646 mg, 5.00 mmol) in THF (20 mL) was added a solution of BTC (119 mg, 0.40 mmol) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then 2-(2,2,2-trifluoroethyl)morpholine hydrochloride (308 mg, 1.50 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for lh. The reaction mixture was concentrated. The residue was purified by FCC (PE:EA = 2: 1) to afford N-(4-methyl-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-(2,2,2-trifluoroethyl)morpholine-4- carboxamide (286 mg, 64%).MS Calcd. : 428, MS Found: 429 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 70℃; for 16h; Inert atmosphere; | 3.1 Step 1: To a solution of 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6- yltrifluoromethanesulfonate (1.5 g, 4.9 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxab orolan-2-yl)aniline (1.6 g, 6.3 mmol) and CS2CO3 (3.2 g, 9.7 mmol) in dioxane (30 mL) and water (5 mL) was added Pd(dppf)Cl2 (356 mg, 0.5 mmol) under N2, and the mixture was stirred at 70 °C for 16 h. The mixture was cooled down to RT diluted with water (100 mL) and extracted with DCM (100 mL*3). The combined organic layers were washed with LbO (100 mL*2) and brine (200 mL), dried over NaiSCL, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=10: 1 to PE:EA=2: 1) to afford 6-(5-amino-4-fluoro-2-methylphenyl)-N, 7-dim ethylpyrido[2,3-d]pyrimidin-2-amine (1.0 g, 72%). MS Calcd.: 297, MS Found: 298 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; | 76.76B Preparation 76B: (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide A mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.00 g, 7.965 mmol, 1.00 equiv), DIEA (5.15 g, 0.040 mmol, 5 equiv) and Triphosgene (0.95 g, 0.003 mmol, 0.4 equiv) in THF (19 mL) was stirred for 30 min at room temperature under nitrogen atmosphere. To the above mixture was added (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride (1.51 g, 0.008 mmol, 1.00 equiv). The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc/EtOH (4/3/1) to afford (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3.2 g, 75%) as an off-white solid. MS ESI calculated for C20H27BF4N2O3[M + H]+, 431.21, found 431.25.1H NMR (400 MHz, Chloroform-d) δ 8.38 (d, J = 9.3 Hz, 1H), 6.88 (dd, J = 12.3, 0.8 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 3.83 (dd, J = 9.9, 7.5 Hz, 1H), 3.67-3.63 (m, 1H), 3.46 (td, J = 9.7, 6.8 Hz, 1H), 3.13 (t, J = 9.5 Hz, 1H), 2.66-2.51 (m, 1H), 2.46 (s, 3H), 2.35-2.17 (m, 3H), 1.78-1.74 (m, 1H), 1.33 (s, 12H). [00545] |
75% | Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; | 70.1 Preparation 70A: (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide A mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.00 g, 7.965 mmol, 1.00 equiv), DIEA (5.15 g, 0.040 mmol, 5 equiv) and triphosgene (0.95 g, 0.003 mmol, 0.4 equiv) in tetrahydrofuran (19 mL) was stirred for 30 min at room temperature under nitrogen atmosphere. To the above mixture was added (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride (1.51 g, 0.008 mmol, 1.00 equiv). The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc/EtOH (4/3/1) to afford (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3.2 g, 75%) as an off-white solid. MS ESI calculated for C20H27BF4N2O3 [M + H]+, 431.21, found 431.25.1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 9.3 Hz, 1H), 6.88 (dd, J = 12.3, 0.8 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 3.83 (dd, J = 9.9, 7.5 Hz, 1H), 3.67-3.63 (m, 1H), 3.46 (td, J = 9.7, 6.8 Hz, 1H), 3.13 (t, J = 9.5 Hz, 1H), 2.66-2.51 (m, 1H), 2.46 (s, 3H), 2.35-2.17 (m, 3H), 1.78-1.74 (m, 1H), 1.33 (s, 12H). |
75% | Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; | 70.1 Preparation 70A: (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide A mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.00 g, 7.965 mmol, 1.00 equiv), DIEA (5.15 g, 0.040 mmol, 5 equiv) and triphosgene (0.95 g, 0.003 mmol, 0.4 equiv) in tetrahydrofuran (19 mL) was stirred for 30 min at room temperature under nitrogen atmosphere. To the above mixture was added (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride (1.51 g, 0.008 mmol, 1.00 equiv). The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc/EtOH (4/3/1) to afford (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3.2 g, 75%) as an off-white solid. MS ESI calculated for C20H27BF4N2O3 [M + H]+, 431.21, found 431.25.1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 9.3 Hz, 1H), 6.88 (dd, J = 12.3, 0.8 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 3.83 (dd, J = 9.9, 7.5 Hz, 1H), 3.67-3.63 (m, 1H), 3.46 (td, J = 9.7, 6.8 Hz, 1H), 3.13 (t, J = 9.5 Hz, 1H), 2.66-2.51 (m, 1H), 2.46 (s, 3H), 2.35-2.17 (m, 3H), 1.78-1.74 (m, 1H), 1.33 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane; water at 80℃; for 1h; Inert atmosphere; | 77.77A Preparation 77A: (2R)-2-[[4-(5-amino-4-fluoro-2-methylphenyl)-6-(morpholin-4-yl)pyridin-2- yl]amino]propan-1-ol To a stirred solution of (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (200 mg, 0.551 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (138 mg, 0.551 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added Na2CO3(175 mg, 1.652 mmol) and Pd(dppf)Cl2CH2Cl2(45 mg, 0.055 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc/EtOH(6/3/1) to afford (2R)-2-[[4-(5-amino-4-fluoro- 2-methylphenyl)-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (140 mg, 38%) as an off- white solid. MS ESI calculated for C19H25FN4O2[M + H]+, 361.20, found 361.15.1H NMR (300 MHz, chloroform-d) δ 6.88 (d, J = 11.9 Hz, 1H), 6.64 (d, J = 9.2 Hz, 1H), 5.81 (d, J = 14.5 Hz, 2H), 4.08 (s, 1H), 3.88-3.73 (m, 5H), 3.68-3.53 (m, 3H), 3.49 (s, 4H), 2.17 (s, 3H), 1.25 (d, J = 6.7 Hz, 3H).19F NMR (282 MHz, chloroform-d) δ -136.65. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.8% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; Cs2CO3 In 1,4-dioxane; water monomer at 90℃; for 16h; Inert atmosphere; | 175.2 Step 2: Synthesis of isopropyl (6-(5-amino-4-fluoro-2-methylphenyl)-8,9- dihydroimidazo[1',2' : l,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate A mixture of isopropyl (6-bromo-8,9-dihydroimidazo[1',2' : l,6]pyrido[2,3- d]pyrimidin-2-yl)carbamate (25 mg, 0.071 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline (22 mg, 0.085 mmol), CS2CO3 (69 mg, 0.213 mmol), and Pd(dppf)C12 (5 mg, 0.007 mmol) in dioxane (5 mL) and H2O (0.5 mL) was degassed, charged with N2 three times and stirred at 90 °C for 16h under N2.The reaction mixture was concentrated in vacuum and purified by column chromatography on silica gel (DCM/MeOH=15/l) to give isopropyl (6-(5-amino-4-fluoro-2-methylphenyl)-8,9-dihydroimidazo[1',2' : l,6]pyrido[2,3- d]pyrimidin-2-yl)carbamate (23 mg, 81.8% yield) as brown solid. LCMS (M+H+) m/z: 397.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With tripotassium phosphate tribasic; chloro‐(2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)‐2‐(2′‐amino‐1,1′‐biphenyl)palladium(II) In tetrahydrofuran; water monomer at 80℃; for 2h; Inert atmosphere; | 67.2; 74.2 Preparation 67B: 2-fluoro-4-methyl-5-[2-(1-methylpyrazol-4-yl)-6-(morpholin-4-yl)pyridin-4- yl]aniline A mixture of 4-[4-chloro-6-(1-methylpyrazol-4-yl)pyridin-2-yl]morpholine (1 g, 3.588 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.99 g, 3.947 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (2nd Generation XPhos precatalyst) (280 mg, 0.359 mmol) and potassium phosphate (1.52 g, 7.176 mmol) in tetrahydrofuran (10 mL) and H2O (1 mL) was stirred for 2 h at 80 oC under nitrogen atmosphere. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (1/1) to afford 2-fluoro-4-methyl-5-[2-(1- methylpyrazol-4-yl)-6-(morpholin-4-yl)pyridin-4-yl]aniline (707 mg, 51%) as a light brown solid. MS ESI calculated for C20H22FN5O [M + H]+, 368.18, found 368.30. 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.89 (s, 1H), 6.92 (d, J = 12.0 Hz, 1H), 6.81-6.80 (m, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 3.97 (s, 3H), 3.89-3.86 (m, 4H), 3.61-3.59 (m, 4H), 2.18 (s, 3H).19F NMR (376 MHz, CDCl3) δ -136.37 (1F). |
51% | With tripotassium phosphate tribasic; chloro‐(2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)‐2‐(2′‐amino‐1,1′‐biphenyl)palladium(II) In tetrahydrofuran; water monomer at 80℃; for 2h; Inert atmosphere; | 67.2; 74.2 Preparation 67B: 2-fluoro-4-methyl-5-[2-(1-methylpyrazol-4-yl)-6-(morpholin-4-yl)pyridin-4- yl]aniline A mixture of 4-[4-chloro-6-(1-methylpyrazol-4-yl)pyridin-2-yl]morpholine (1 g, 3.588 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.99 g, 3.947 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (2nd Generation XPhos precatalyst) (280 mg, 0.359 mmol) and potassium phosphate (1.52 g, 7.176 mmol) in tetrahydrofuran (10 mL) and H2O (1 mL) was stirred for 2 h at 80 oC under nitrogen atmosphere. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (1/1) to afford 2-fluoro-4-methyl-5-[2-(1- methylpyrazol-4-yl)-6-(morpholin-4-yl)pyridin-4-yl]aniline (707 mg, 51%) as a light brown solid. MS ESI calculated for C20H22FN5O [M + H]+, 368.18, found 368.30. 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.89 (s, 1H), 6.92 (d, J = 12.0 Hz, 1H), 6.81-6.80 (m, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 3.97 (s, 3H), 3.89-3.86 (m, 4H), 3.61-3.59 (m, 4H), 2.18 (s, 3H).19F NMR (376 MHz, CDCl3) δ -136.37 (1F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.76% | Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole hydrochloride In tetrahydrofuran at 20℃; for 2h; | 69.1 Preparation 69A: N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]- 3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide A mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (700 mg, 2.788 mmol), DIEA (1.8 g, 13.940 mmol)and triphosgene (331 mg, 1.115 mmol) in tetrahydrofuran (67 mL) was stirred for 30 min at room temperature. To this was added 3- (trifluoromethyl)-2,5-dihydro-1H-pyrrole hydrochloride (611.52 mg, 4.461 mmol,) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc/EtOH (4:3:1) to afford N-[2- fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)-2,5- dihydropyrrole-1-carboxamide (794 mg, 68.76%) as an off-white solid. MS ESI calculated for C19H23BF4N2O3 [M + H]+, 415.17, found 415.30.1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 12.4 Hz, 1H), 6.44 (s, 1H), 6.17 (s, 1H), 4.48 (s, 4H), 2.50 (s, 3H), 1.34 (s, 12H). |
68.76% | Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole hydrochloride In tetrahydrofuran at 20℃; for 2h; | 69.1 Preparation 69A: N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]- 3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide A mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (700 mg, 2.788 mmol), DIEA (1.8 g, 13.940 mmol)and triphosgene (331 mg, 1.115 mmol) in tetrahydrofuran (67 mL) was stirred for 30 min at room temperature. To this was added 3- (trifluoromethyl)-2,5-dihydro-1H-pyrrole hydrochloride (611.52 mg, 4.461 mmol,) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc/EtOH (4:3:1) to afford N-[2- fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)-2,5- dihydropyrrole-1-carboxamide (794 mg, 68.76%) as an off-white solid. MS ESI calculated for C19H23BF4N2O3 [M + H]+, 415.17, found 415.30.1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 12.4 Hz, 1H), 6.44 (s, 1H), 6.17 (s, 1H), 4.48 (s, 4H), 2.50 (s, 3H), 1.34 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In dichloromethane at 0 - 20℃; | G1 Example G1: N-(6-bromoquinazolin-2-yl)acetamide A solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A1, 0.2 g, 0.80 mmol) in DCM (3 mL) was cooled to 0 C. Pyridine-3-sulfonyl chloride (0.14 g, 0.80 mmol) was added portion-wise and the reaction mixture was slowly warmed to rt overnight. [0320] The solvent was removed under reduced pressure and the crude was purified by silica gel column chromatogrphy (0 to 10% DCM/MeOH) to obtain N-(2-fluoro-4-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-3-sulfonamide (0.30 g, 98% yield) as a white solid.1H NMR (500 MHz, DMSO-d6): δ 10.2 (s, 1H), 8.80 (m, 2H), 8.03 (d, J = 8.2 Hz,1H), 7.62 (m, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 11.6 Hz, 1H), 2.41 (s, 3H), 1.29 (s, 12H); MS (ESI) m/z: 393.2 (M+H+). |
Tags: 1012880-11-3 synthesis path| 1012880-11-3 SDS| 1012880-11-3 COA| 1012880-11-3 purity| 1012880-11-3 application| 1012880-11-3 NMR| 1012880-11-3 COA| 1012880-11-3 structure
[ 1227210-37-8 ]
6-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Similarity: 0.96
[ 815631-56-2 ]
2-(4-Fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.91
[ 1418128-33-2 ]
5-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Similarity: 0.89
[ 1030832-38-2 ]
2-(5-Fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.88
[ 1030832-38-2 ]
2-(5-Fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.88
[ 1227210-37-8 ]
6-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Similarity: 0.96
[ 815631-56-2 ]
2-(4-Fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.91
[ 1418128-33-2 ]
5-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Similarity: 0.89
[ 1030832-38-2 ]
2-(5-Fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.88
[ 1030832-38-2 ]
2-(5-Fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.88
[ 1227210-37-8 ]
6-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Similarity: 0.96
[ 2121512-41-0 ]
2-(4-Fluoro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.91
[ 815631-56-2 ]
2-(4-Fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.91
[ 1418128-33-2 ]
5-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Similarity: 0.89
[ 1246632-96-1 ]
2-(2-Fluoro-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.88
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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