With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 85℃; for 24 h; Inert atmosphere
A mixture of potassium acetate (1.56 g, 15.91 mmol) , Pd (dppf) Cl2 (190 mg, 0.27 mmol) , 1- (cyclopropylmethyl) -4-iodo-1H-pyrazole (1.31 g, 5.30 mmol) and bis (pinacolato) diboron (1.62 g, 6.36 mmol) in DMF (25.00 mL) was stirred at 85 under N2 for 24 h and cooled to rt, and then filtered through a Celite pad. The filtrate was diluted with water (50 mL) , and then extracted with EtOAc (50 mL × 3) . The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 3/1 to give a yellow oily product (1.11 g, 84.9) .[1449]MS (ESI, pos. ion) m/z: 249.1 [M+1] +
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 12 h; Inert atmosphere; Sealed tube
b) 1 -(Cyclopropylmethyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 H- pyrazoleTo a degassed (N2 bubbling) solution of the compound of Intermediate Example 9(a) (0.15 g, 0.75 mmol) in 1,4-dioxane (10 ml) were added 4,4,4*,4',5,5,5',5'-octa- methyl-2,2'-bi(l,3,2-dioxaborolane) (0.23 g, 0.9 mmol, 1.2 eq.), Pd(dppf Cl2 (0.12 g, 0.15 mmol, 0.2 eq.) and potassium acetate (0.25 g, 2.55 mmol, 3.4 eq.). using the procedure of Intermediate Example 1(b). The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 30 percent ethyl acetate in hexane) to give the product in 81 percent yield (0.15 g). LC-MS (ESI):Calculated mass: 248.13; Observed mass: 249.2 [(M+H]+ (rt: 1.58 min).
0.15 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 12 h; Sealed tube; Inert atmosphere
To a degassed (N2 bubbling) solution of the compound of Intermediate Example 9(a) (0.15 g, 0.75 mmol) in 1,4-dioxane (10 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.23 g, 0.9 mmol, 1.2 eq.), Pd(dppf)Cl2 (0.12 g, 0.15 mmol, 0.2 eq.) and potassium acetate (0.25 g, 2.55 mmol, 3.4 eq.). using the procedure of Intermediate Example 1(b). The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 30percent ethyl acetate in hexane) to give the product in 81percent yield (0.15 g). LC-MS (ESI): Calculated mass: 248.13; Observed mass: 249.2 [(M+H]+ (rt: 1.58 min).
With potassium acetate In N,N-dimethyl-formamide at 100℃; for 2 h; Inert atmosphere
A vial was charged with 5-bromo-2-fluoroaniline (1 g, 5.26 mmol), bis(pinacolato)diboron (1.6 g , 6.31 mmol), potassium acetate (1.03 g, 10.52 mmol), Pd(dppf)Cl2 * CH2C12 (129 mg, 0.158 mmol), and DMF (10 mL) under nitrogenatmosphere. After stirring for 2 h at 100 °C the reaction mixture was concentrated in vacuo, the residue was triturated with EtOAc and filtered through a pad of celite. The filtrate was adsorbed on silica gel. Purification by flash silica gel chromatography using a gradient of 0- 30percent EtOAc/hexane afforded 1.25 g of pinacol 3-amino-4-fluoroboronate as a light yellow oil (quant.): 1H NMR (CDC13, ppm) δ 1.36 (s, 12H), 3.71 (broad s, 2H), 7.00 (dd, 1H), 7.19 (m, 1H), 7.26 (dd, 1H); [M+H]+ m/z 238.
With (2,2,2-trifluoroethoxy)trimethylsilane; cesium fluoride; dichlorobis(trimethylphosphine)nickel In tetrahydrofuran at 100℃; for 12 h; Inert atmosphere; Sealed tube
Under an argon atmosphere,4.2 mg (0.015 mmol) of dichlorobis (trimethylphosphine) nickel,72.8 mg (0.5 mmol) of 5-chloro-2-fluoroaniline,152 mg (1.0 mmol) of cesium fluoride,140 mg (0.55 mmol) of 4,4,5,5,4 ', 4', 5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolanyl)180 mg (1.05 mmol) of trimethyl (2,2,2-trifluoroethoxy) silane and 0.5 mL of tetrahydrofuran were added and sealed,And the mixture was stirred at 100 ° C. for 12 hours.After the reaction vessel was cooled to room temperature, 1 mL of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with 8 mL of ethyl acetate, and the obtained organic phases were combined.The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: chloroform: ethyl acetate = 4: 1: 0 to 4: 1: 1)96 mg (pale yellow liquid, yield 81percent) of 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline was obtained
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 2 h; Microwave irradiation
A solution of 5-bromo-1-methylpyridin-2-one (200.0 mg, 1.06 mmol), bis(pinacolato)diboron (410.0 mg, 1.61 mmol), potassium acetate (270 mg, 2.67 mmol), Pd (dppf)Cl2 (80 mg, 0.11 mmol) in dioxane (5 mL) was heated at 100° C. for 2 h under microwave. The mixture was filtered, washed with water and extracted with ethyl acetate (20 mL*3). The combined organics were dried over Na2SO4, filtered and concentrated to give the crude title compound (59.0 mg, 23.6percent). LCMS (M+H)+ 236.
160 mg
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In ethylene glycol at 80℃; for 3 h;
To a stirred suspension of 5-bromo-l-methylpyridin-2(lH)-one (470 mg, 2.49 mmol), potassium acetate (736 mg, 7.49 mmol) and bis(pinacolato)diboron (952 mg, 3.74 mmol) in degassed polyethylene glycol-400 (15 mL) was added [1, 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (204 mg, 0.24 mmol) at RT. The resultant suspension was stirred for 3 h at 80 °C. The reaction mixture was cooled to RT, diluted with ethyl acetate (100 mL) and washed with water (100 mL) followed by brine (100 mL). The organic layer was concentrated and the residue obtained purified by flash column chromatography to afford 160 mg of the titled product; 1H NMR (300 MHz, CDC13) δ 1.30 (s, 12H), 3.54 (s, 3H), 6.53 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.75 (s, 1H); APCI- MS (m/z) 236 (M+H)+.
With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; tricyclohexylphosphine In 1,4-dioxane at 80℃; for 5 h; Inert atmosphere
To a mixture of 5-bromo-1-methylpyridin-2(1H)-one (1.0 g, 5.32 mmol), KOH (0.78 g, 7.98 mmol) and bis(pinacolato)diboron (0.162 g, 6.38 mmol) in 1 ,4-dioxane (20 mL), tricyclohexyiphosphine (149 mg, 0.532 mmol), Pd2dba3 (487 mg, 0.532 mmol) were added under N2 atmosphere. The mixture was stirred at about 80 °C for about 5 h. Then water was added, the aqueous layer was extracted with EtOAc (50 mL x 2), and the organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and the residue was purified by column chromatograph on silica gel to provide ]-methyl-5-(4, 4,5, 5-tetramethyl-], 3, 2-dioxaborolan-2-yl)pyridin-2(]H)-one (0.80 g, 64percent): ‘H NMR (CDC13) 7.70 (s, 1 H), 7.54 (d, J= 8.8 Hz, 1 H), 6.47 (d, J= 8.8 Hz, 1 H), 3.49 (s, 3 H), 1.24(s, 12 H).
With potassium acetate In dimethyl sulfoxide at 20 - 80℃;
To a solution of compound 4-bromo-l -phenyl- lH-pyrazo Ie (0.5 g, 2.3 mmol) in DMSO (50 mL) was added KOAc (0.66 g, 6.8 mmol), bis(pinacolato)diboron (0.63 g, 2.5 mmol) and .yen.dCb(dpp{) (0.076g, 0.11 mmol) at room temperature. The reaction mixture was stirred overnight at 8O0C. The result mixture was diluted with EA, washed with brine, dried over Na2SO4, concentrated, purified by chromatography (EA:PE=1: 12) to give l-phenyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH- pyrazole (0.3 g, 50percent) as light yellow solid
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 8 h; Inert atmosphere
A mixture of 4-iodo-1-phenyl-1H-pyrazole (706 mg, 2.59 mmol) , potassium acetate (762 mg, 7.76 mmol) , bis (pinacolato) diboron (860 mg, 3.37 mmol) and Pd (dppf) Cl2(212 mg, 0.26 mmol) was suspended in DMSO (15 mL) . The system was exchanged with N2. The mixture was stirred at 80 for 8 h. The reaction mixture was diluted with water (60 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were washed with saturated aqueous NaCl (15 mL) , dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 20/1 to give a yellow solid product (340 mg, 48.15) .[1650]MS (ESI, pos. ion) m/z: 271.05 [M+1]+.
With potassium acetate In N,N-dimethyl-formamide at 95℃; for 5.16667 h;
Step 3:A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for an additional 5 min before being heated to 950C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield).
84%
With potassium acetate In N,N-dimethyl-formamide at 95℃; for 5.16 h;
A solution of the 6-iodochroman 11c (1.O g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for about an additional 5 min before being heated to 950C for about 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield).
84%
Stage #1: With potassium acetate In N,N-dimethyl-formamide for 0.0833333 h; Stage #2: at 95℃; for 5.08 h;
A solution of the 6-ιodochroman 11c (1 0 g, 3 85 mmol), bιs[pιnocolato]dιborane (1 22 g, 4 81 mmol) and potassium acetate (1 10 g, 11 5 mmol) in DMF (36 mL) is degassed with Ar for 5 mm followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0 38 mmol) The reaction mixture is then degassed for an additional 5 mm before being heated to 950C for 5 h The reaction is then cooled to RT The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 100 mL) The combined organics are washed with water (100 mL) and brine (100 mL) The organic phase is then dried over MgSO4 and filtered and concentrated The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield)
With potassium acetate In N,N-dimethyl-formamide at 95℃; for 5 h;
A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for an additional 5 min before being heated to 950C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield).
With potassium acetate In N,N-dimethyl-formamide at 95℃; for 3 h; Inert atmosphere
Step 1. 2-(Chroman-6-yl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolaneTo a solution of 6-bromochroman (400 mg, 1.88 mmol) in N,N-dimethylformamide (50 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (620 mg, 2.44 mmol), KOAc (552.1 mg, 5.63 mmol) and Pd(dppf)Cl2 (155 mg, 0.19 mmol) with stirring for 3 h at 95°C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was diluted with water, extracted with ethyl acetate (80 mL x 3) and the organic layers combined, dried over anhydrous magnesium sulfate, concentrated under vacuum to give the residue, which was applied onto a silica gel column with 1 percent ethyl acetate in petroleum ether to afford 2-(chroman-6-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane as colorless oil (320 mg, 59percent).*H-NMR (300 MHz, CDC13): δ 7.54 (d, J = 7.5 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 4.19 - 4.23 (t, J = 5.4 Hz, 2H), 2.78 - 2.83 (t, J = 6.3 Hz, 2H), 1.98 - 2.05 (m, 2H), 1.28 (s,12H)
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 100℃; for 13 h; Inert atmosphere
To a solution of 4-bromo-1- (3-methoxypropyl) -1H-pyrazole (2.1 g, 9.6 mmol) in DMSO (20 mL) were added bis (pinacolato) diboron (3.7 g, 15 mmol) , potassium acetate (2.4 g, 24 mmol) and Pd (dppf) Cl2(900 mg, 1.22 mmol) . The mixture was stirred at 100 under N2for 13 h, cooled to rt and quenched with saturated aqueous NaCl (30 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combinded orgainc layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 2/1 to give a light yellow oily product (1.3 g, 51) .[1271]MS (ESI, pos. ion) m/z: 267.0 [M+1]+
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 8 h; Inert atmosphere
Synthesis of 2-methoxy-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 28.12 To potassium acetate (8.9 g, 90.83 mmol), bis-(pinacolato)-diboron (8.1 g, 31.86 mmol) and bis(diphenylphosphine) ferrocene dichloropalladium (II) (0.34 g, 0.48 mmol) was added an anhydrous solution of 5-bromo-2-methoxyaniline (3.22 g, 15.93 mmol) in DMSO (40 mL) under anhydrous conditions in an atmosphere of nitrogen. The mixture was stirred at 80° C. for 8 h after which time the reaction was quenched with saturated NaCl aqueous solution (30 mL) and extracted with diethyl ether (3*20 mL). The combined ether extracts were dried over magnesium sulphate, filtered and concentrated. The crude product was purified by flash column chromatography (stationary phase; silica gel 230-400 mesh, mobile phase; 9:1 hexane/ethyl acetate). All homogenous fractions were collected and reduced in volume to afford the product 28.12 as a brown syrup (3.18 g, 80percent). νmax (DCM)/cm-1: 2926.38, 1599.02, 1431.11, 1356.01, 1221.39, 1142.48 1H NMR (CDCl3, 400 MHz) δH ppm: 1.35 (12H, s, 2*C(CH3)2), 3.89 (3H, s, OCH3), 6.15 (2H, br, NH2), 7.18 (1H, d, J 8.0 Hz, ArH), 7.25 (1H, d, J 2.5 Hz, ArH), 7.29 (1H, s, ArH). 13C NMR δc ppm: 24.5 (4*CH3), 55.1 (OCH3), 83.2 (2*C(CH3)2) 105.5 (ArCH), 113.7 (ArC), 120.6 (ArCH), 125.8 (ArCH), 135.0 (ArC), 149.7 (ArC).
30%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 48 h; Inert atmosphere
2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (60a) (0303) 5-Bromo-2-methoxyaniline (500 mg, 2.48 mmol, 1.0 equiv), bis(pinacolato)diboron (691 mg, 2.72 mmol, 1.1 equiv), potassium acetate (730 mg, 7.44 mmol, 3.0 equiv) and Pd(dppf)Cl2 (54.4 mg, 74.4 μmol, 0.03 equiv) were dissolved under Argon atmosphere in 7 ml DMSO and the mixture was stirred at 80° C. for 48 h. Water was added and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to dryness. The raw product was purified by flash chromatography; yield: 30percent (184 mg). 1H NMR (300 MHz, acetone-d6): δ 7.11-7.02 (m, 2H), 6.81 (d, J=7.9 Hz, 1H), 3.84 (s, 3H), 1.29 (s, 12H).
With isopropylmagnesium chloride; In tetrahydrofuran; at -10 - 30℃; for 9h;Inert atmosphere; Large scale;
1.3 kg of compound (CZT-8) was dissolved in 6.5 liters of dry tetrahydrofuran,Nitrogen protection,Down to -10 degrees,A solution of 3.2 liters of 2N isopropylmagnesium chloride in tetrahydrofuran was slowly added,After the completion of heating to 20 degrees,Add 1.0 publicjinEven boronic acid6.5 liters of tetrahydrofuran solution,Control the temperature between 20 degrees to 30 degrees,After the completion of the reaction at room temperature for 9 hours.Add 9 liters of ethyl acetate and 10 liters of water,Stir for 2 hours,Dispensing,Dried and concentrated.Recrystallization gave 1.2 kg of a white solid(CZT-9). Yield 81%
44%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 0.166667h;Inert atmosphere;
C. A mixture of tert-butyl 4-(4-bromo- lH-pyrazol- 1 -yl)piperidine- 1-carboxylate (20.0 g, 0.61 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (30.8 g, 0.12 mmol) and potassium acetate (17.8 g, 0.18 mol) in 50 mL of dimethyl sulfoxide was purged with nitrogen gas for 10 min. After the addition of [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.55 g, 4.85 mmol), the mixture was purged with nitrogen gas for another 10 minutes, heated at 80 C overnight under nitrogen atmosphere and filtered through celite and washed with ethyl acetate. The filtrate was extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and removal of the solvent, the residue was purified by column chromatograph eluted with hexane to afford an oil which was recrystallized from hexane to afford tert-butyl 4-(4-(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazol- 1 -yl)piperidine- 1 -carboxylate as a white solid in 44% yield (10 g). 1H NMR (400 MHz, CDC13) delta 7.79 (s, 1H), 7.72 (s, 1H), 4.32-4.13 (m, 3H), 2.95-2.80 (m, 2H), 2.15-2.05 (m, 2H), 1.93-1.82 (m, 2H), 1.47 (s, 9H), 1.31 (s, 12H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere;
As shown in step 3-iii of Scheme 3, tert-butyl 4-(4-bromo-lH-pyrazol-l- yl)piperidine-l-carboxylate (Compound 1014, 10.52 g, 31.86 mmol), 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (9.71 g, 38.23 mmol), and potassium acetate (9.38 g, 95.58 mmol) were taken up in 105 mL of 1,4-dioxane. The mixture was flushed with nitrogen for 20 minutes and PdCl2(dppf) (1.3 g, 1.59 mmol) was added. The reaction was heated at 900C for 11 hours. The reaction was cooled to room temperature and filtered through a plug of Florisil, which was subsequently rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford a dark brown oil that was dissolved in hexanes and eluted through a second plug of Florisil with 1 :2 EtOAc/hexanes. The filtrate was concentrated under reduced pressure to give a tan oil, which was triturated with hexanes and stirred at 00C until a white precipitate formed. The precipitate was collected by vacuum filtration, washed with hexanes, and dried to afford 6.79 g of tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine- 1-carboxylate (Compound 1015).
5.4 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; Sealed tube;
d) tert-Butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine- 1 -carboxylateTo a (N2 bubbling) solution of the compound of Intermediate Example 5(c) (8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- (1,3,2-dioxaborolane) (7.36 g, 29 mmol, 1.2 eq.), Pd(dppf)Cl2 (2 g, 2.42 mmol, 0.1 eq.) and potassium acetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 10 % ethyl acetate in hexane) to give the product in 59 % yield (5.4 g). LC-MS (ESI): Calculated mass: 377.29; Observed mass: 378.3[(M+H]+ (RT: 1.83 min).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 10h;Inert atmosphere;
General procedure: To a solution of 4-bromo-1-(oxan-4-yl)-1H-pyrazole 26a (1.00 g, 4.33 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.32 g, 5.19 mmol) in 10 mL of DMF was added potassium acetate (1.27 g, 12.98 mmol), followed by 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (177 mg, 0.22 mmol) under argon. The resulting mixture was stirred at 80 C for 10 h and then diluted with 40 mL of water. The mixture was extracted with EA (3 × 30 mL). The combined organic phase was washed with water (3 × 30 mL), brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EA/PE, 1:4) to afford 25c as white solid in 68% yield.
5.4 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 12h;Inert atmosphere;
To a (N2 bubbling) solution of the compound of Intermediate Example 5(c) (8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-(1,3,2-dioxaborolane) (7.36 g, 29 mmol, 1.2 eq.), Pd(dppf)Cl2 (2 g, 2.42 mmol, 0.1 eq.) and potassium acetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 10% ethyl acetate in hexane) to give the product in 59% yield (5.4 g). LC-MS (ESI): Calculated mass: 377.29; Observed mass: 378.3 [(M+H]' (RT: 1.83 min).
With potassium phosphate tribasic heptahydrate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; XPhos; In ethanol; at 20℃; for 0.5h;
General procedure: Method (1): Synthesis from 4-tert-butylchlorobenzene as a raw material: K3P04 · 7H20 (3.0 g, 8.85 mmol) and bis-pinacol borate (749 mg, 2.95 mmol) were sequentially added to the reaction flask.The catalyst-chloro (2-dicyclohexyl phosphino-2 ', 4', 6'-tri - triisopropyl-1,1'-biphenyl) (1,1'-biphenyl -2-amino-2'_ -yl)palladium(II) (12 mg, 0.015 mmol) and ligand 2-dicyclohexylphosphine-2',4',6/-triisopropylbiphenyl (4 mg, 0.008 mmol), followed by EtOH (6 mL) The mixture was stirred, and p-tert-butylchlorobenzene (0.5 mL, 2.95 mmol) was added and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (2 mL) After washing with ethyl acetate (6 mL) in three portions, the filtrate was combined, and the solvent was evaporated to dryness, and the solvent was separated by silica gel (200 to 300 mesh). The eluent was petroleum ether and ethyl acetate. 10~80:1), obtained as a white solid, identified by NMR spectrum as 4-tert-butylphenylboronic acid pinacol ester, yield 98%
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 85℃; for 18h;Inert atmosphere;
(IV) Synthesis of Compound (12); (4-[{4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl}(4H-1,2,4-triazol-4-yl)amino]benzonitrile); <Method A>; Compound (12) was synthesized according to the scheme below.; Here, Compound (16) was synthesized according to the scheme below.; (i) Synthesis of Compound (14) (4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl alcohol) (see Non-patent Literature 14 (Filippis, A.; Morin, C.; Thimon, C., Synth. Commun. 2002, 32, 2669-2676)); Under argon atmosphere, PdCl2(dppf)·CH2Cl2 (245 mg, 300 mumol), potassium acetate (2.94 g, 30.0 mmol) and bis(pinacolato)diboron (2.79 g, 11.0 mmol) were sequentially added to a DMSO (30 mL) solution of Compound (13) (2.34 g, 10.0 mmol) at room temperature, and the mixture was stirred at 85 C for 18 hours. The mixture was cooled to room temperature, and then water (250 mL) was added to the mixture and the mixture was extracted with ethyl acetate (100 mL × 3). All the organic phases were mixed, sequentially rinsed with water (100 mL × 3) and a saline solution (100 mL × 1), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (60 g of silica gel, n-hexane/EtOAc = 5/1) to obtain Compound (14) as a colorless solid. TLC Rf = 0.41 (n-hexane/EtOAc = 2/1) 1H NMR (300 MHz, CDCl3) delta 1.35 (s,12H,4CH3), 4.72 (s, 2H, benzylic CH2), 7.34-7.41 (AA'BB', 2H, aromatic), 7.78-7.84 (AA'BB', 2H, aromatic).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In water; dimethyl sulfoxide; at 85℃; for 18h;Inert atmosphere;
The compound 1(1 eq, 0.53 mmol) was dissolved in DMSO (2 mL) followed by the addition of potassium acetate (3 eq, 1.59 mmol), bis(pinacolato)diboron (1.1 eq, 0.59 mmol) and Pd(dppf)Cl2 (0.2 eq, 0.11 mmol). The mixture was deoxygenated by three successive argon bubbling/vaccum cycles. The reaction was then heated at 85C under argon for 18h. Water (5 mL) was added and the resulting black solution was extracted 3 times with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried, filtered and evaporated under vaccum. The resulting paste was purified using column chromatography (silica gel, 70/30 Hex/EtOAc) to afford the desired compound (Rf = 0.3) as a colourless oil (113 mg, 91%). 1H-NMR (CDCI3, 600 MHz) delta 7.79 (d, J = 7.7 Hz, 2H), 7.36 (d, J = 7.7 Hz, 2H), 4.71 (s, 2H), 1.35 (s, 12H); 13C-NMR (CDC13, 150 MHz) delta 144.1, 135.2, 126.2, 83.9, 65.4, 25.0.
90%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;
p-Bromobenzyl alcohol (Compound 1, 1.0 g, 5.35 mmol) was dissolved in 10 mL of dry 1,4-dioxane solution, and boranoic acid pinacol ester (247 mg, 5.88 mmol), potassium acetate and pdCl 2 ( Dppf), under N2 protection, heat to 85 C to stir the reaction. After the reaction was completed by thin layer chromatography, the solvent was evaporated under reduced pressure, and ethyl acetate (200 ml) was added and thenThe organic phase was dried over anhydrous sodium sulfate and concentrated under reduced vacuo.The crude product was purified by column chromatography (mobile phase ethyl acetate: petroleum ether = 1:8-1:4)Obtained 181 mg of a pale yellow oily liquid with a yield of 90%.
With potassium acetate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
Under an argon atmosphere, (4-bromophenyl)methanol (3.0 g) and bis(pinacolato)diboron (4.5 g) was dissolved in dioxane (35 ml), and dichlorobis(triphenylphosphine)palladium(II) (567 mg) and potassium acetate (4.7 g) were added thereto, followed by stirring at 80 C. for 1 day. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in DME (35 ml) and water (18 ml), and tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (3.5 g) was added thereto under an argon atmosphere. In addition, sodium carbonate (3.1 g) and tetrakis(triphenylphosphine)palladium (339 mg) were added thereto, followed by stirring at 70 C. for 1 day. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl {2-[{[4'-(hydroxymethyl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (2.8 g).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 6h;Inert atmosphere;
(3) 1 g of 1- (4-bromobenzene) ethanol was dissolved30 ml 1,4-dioxane solution,Two equivalents of bis (pinacolato) diboron,3 equivalents of potassium acetate,5% equivalent of [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride Under argon atmosphere at 80 C,After 6 hours of reaction, the product was obtained by column chromatography.
1500 mg
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 16h;
A mixture of (4-bromophenyl)methanol (1 g, 5.35 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.07 g, 16.04 mmol), KOAc (1.05 g, 10.69 mmol) and Pd(dppf)Cl2.CH2Cl2 (873.27 mg, 1.07 mmol) in 1,4-Dioxane (20 mL) was stirred at 90 C for 16 hours. After cooling to r.t., the mixture was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0 to 50%) to give the product (1500 mg) as oil. H NMR (400MHz DMSO-d6) _ = 7.63 (d, 2H), 7.32 (d, 2H), 5.23 (t, 1H), 4.51 (d, 2H), 1.29 (s, 12H).
16 g
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In 1,4-dioxane; at 85℃; for 3h;Inert atmosphere;
4-Bromobenzyl alcohol (15 g, 80.2 mmol), bis(pinacolato)diboron (30.6 g, 120.3 mmol), potassium acetate (23.6 g, 240 mmol) and Pd (PPh3)2Cl2 (5.6 g, 8 mmol) were added to 150 mL of dioxane, and the mixture was stirred at 85 C. for 3 hours under a nitrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure, and then extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by column chromatography (eluent: petroleum ether:ethyl acetate 60:1-10:1) to give 16 g of title product.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; at 105℃;Inert atmosphere;
Under argon atmosphere, a mixture of <strong>[62162-97-4]2-bromophenanthrene</strong> (10.0 g, 38.9 mmol), bispinacolatodiboron (9.8 g, 38.9 mmol), dichloro[1,1?-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.953 g, 1.17 mmol), potassium carbonate (7.63 g, 78 mmol), and dioxane (200 mL) was stirred overnight at 105 C. After adding bispinacolatodiboron (2.02 g, 7.95 mmol) and dichloro[1,1?-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.953 g, 1.17 mmol), the mixture was stirred at 105 C. for 3 h. The reaction liquid was cooled to room temperature and purified by silica gel column chromatography to obtain the compound A6 (10.4 g, 88% yield).
78%
With 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride-chloroform adduct; potassium acetate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
Potassium acetate (11.03 g, 112 mmol),Bis (pinacol) diboron (17.12 g, 67.4 mmol),2-Bromophenanthrene (14.45 g, 56.2 mmol) and Pd(dppf)Cl2.CHCl3 complex (1.37 g, 1.686 mmol) were placed in an oven dried round bottom flask.Anhydrous dioxane (200 mL) was added and the mixture was bubbled with nitrogen for 15 min.The reaction was stirred at 100 C for 18 hours.Gas chromatography-mass spectrometry (GC-MS) analysis of the reaction mixture indicated complete conversion to the product.The reaction was cooled to room temperature and filtered to remove a base. The filtrate was concentrated in vacuo.The crude residue was partitioned between DCM and saturated NaHCO3 solution.The aqueous layer was re-extracted with DCM. The combined organics were washed sequentially with saturated aqueous NaHCO3 and brine then dried over sodium sulfate. The organics were then filtered and dried and loaded onto silica, and the mixture was purified by flash column chromatography (0-50% DCM / isohexane).4,4,5,5-tetramethyl-2-(phenanthr-2-yl)-1,3,2-dioxaborolane (13.32 g, 43.8 mmol, 78% yield) which foamed and solidified upon drying under high vacuum to give an off-white solid.
tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 95℃; for 16h;Inert atmosphere;
Step 2. tert-Butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate A 2 L round-bottomed flask was charged with <strong>[889858-12-2]tert-butyl 4-bromo-2-fluorobenzoate</strong> (30 g, 114 mmol), bis(pinocolato)diboron (41.5 g, 164 mmol), potassium acetate (32.1 g, 327 mmol), PdCl2(dppf)-CH2Cl2 (2.67 g, 3.27 mmol) and 1,4-dioxane (500 mL). The reaction mixture was degassed with argon for 15 min, then heated to 95° C. and maintained at this temperature for 16 h. After cooling down, the reaction mixture was evaporated to dryness, dissolved in DCM (300 mL), and filtered over celite washing with DCM (3*100 mL). The filtrate was washed with water (200 mL) and brine (2*200 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified using flash chromatography on silica gel (0 to 10percent EtOAc in heptane over 30 min), giving tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (27 g, 90percent) as a solid. LCMS (m/z): 267 (MH+ (-tBu)), 1.23 min; 1H NMR (500 MHz, DMSO-d6) delta ppm 7.83 (t, 1H) 7.57 (d, 1H) 7.43 (d, 1H) 1.62-1.46 (m, 9H) 1.34-1.25 (m, 12H).
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