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CAS No. : | 943994-02-3 | MDL No. : | MFCD12755796 |
Formula : | C14H18BNO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZXOSNHPLTJAXSA-UHFFFAOYSA-N |
M.W : | 275.11 | Pubchem ID : | 46856474 |
Synonyms : |
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 79.74 |
TPSA : | 56.79 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.66 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.86 |
Log Po/w (WLOGP) : | 0.75 |
Log Po/w (MLOGP) : | 0.57 |
Log Po/w (SILICOS-IT) : | 1.36 |
Consensus Log Po/w : | 0.91 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.87 |
Solubility : | 0.368 mg/ml ; 0.00134 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.67 |
Solubility : | 0.583 mg/ml ; 0.00212 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.23 |
Solubility : | 0.0163 mg/ml ; 0.0000593 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.01 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 90℃; Inert atmosphere | To the solution of XXXV-2 (2.3 g, 10 mmol) in dioxane (20 mL), bis (pinacolato)diboron (3.05 g, 12 mmol), potassium acetate (2 g , 20 mmol) and Pd(dppf)C12 (730 mg, 1 mmol) was added. The mixture was purged with nitrogen and sitiffed at 90°C overnight. Then the mixture was diluted with EA (200 mL) and filtrated. The organic phase was washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product. The residue was purification by column chromatography on silica gel (PE:EA=3: ito 1:1) to give XXXV-4 (1.9 g, 69percent yield) |
56% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 24 h; Inert atmosphere | A solution of the compound 4a (3.33g, 14.67mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (4.48g, 17.61mmol), potassium acetate (2.88g, 29.34mmol), Pd (dppf) Cl2 (0.15g, 0.20mmol) in dioxane (40mL) was heated to 100 °Cunder N2 for 24 hours. The reaction mixture was filtered and concentrated under reduced pressure, the residue was purified by column chromatography to afford the compound 5a (2.25g, 56percent). MS: 276 (M+H) +. |
55% | at 100℃; for 16 h; Inert atmosphere | Preparation 13: 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylboronic acid; Step 1 : 6-(4,4,5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-2H-benzorbiπ.41oxazin-3(4H)- one; A mixture of 6-Bromo-4H-benzo[1 ,4]oxazin-3-one (100 mg, 0.439 mmol), 4,4,5,5,4I,4I,5l,5I-Octamethyl-[2,2']bi[[1 ,3,2]dioxaborolanyl] (123 mg, 0.483 mmol), potassium acetate (159 mg, 1.54 mmol), 1 ,1-bis(diphenylphosphino)ferrocene (12.2 mg, 0.022 mmol) in dioxane (4 ml_). The mixture was degassed with nitrogen for approximately 20 minutes. [1 ,1-bis(diphenylphosphino) ferrocene]dichloropalladium (II) (18.0 mg, 0.220 mmol) was added followed by additional 5 minutes of degassing. The mixture was heated to 100°C for 16 h. The reaction mixture was cooled to room temperature, filtered through celite and concentrated. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 25percent-50percent ethyl acetate/ heptane. The title compound was obtained as a white solid (66 mg, 55percent). 1 H NMR (400 MHz, METHANOL-^) δ ppm 1.33 (12 H, s), 4.60 (2 H, s), 6.93 (1 H, d, J=8.3 Hz), 7.26 (1 H, s), 7.36 (1 H, d, J=I.9 Hz). |
320 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 100℃; for 4 h; Inert atmosphere | 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (275 mg, 1.21 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (466 mg, 1.84 mmol), potassium acetate (184 mg, 1.87 mmol), and Dichloro 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (47 mg, 0.06 mmol) were added to a flask and container was evacuated and backfilled with argon. Reagents were taken up in dioxane (9 mL) and system was again purged with argon. Mixture was then heated at 100° C. for 4 hours. After cooling to rt, reaction mixture was filtered over celite, washing with ethyl acetate. Filtrate was concentrated under reduced pressure and resulting reside was purified by silica gel column chromatography (0-40percent ethyl acetate/hexanes) to yield 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one 7.17 (320 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With hydrogenchloride; water In acetonitrile at 20℃; for 16 h; | Step 2: 3-oxo-3,4-dihvdro-2H-benzorbiri .41oxazin-6-vlboronic acid; A mixture of 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2H-benzo[b][1 ,4]oxazin-3(4H)-one (500 mg, 1.82 mmol), polymer supported phenyl boronic acid (2200 mg, 6.4 mmol), 1 M aqueous hydrochloric acid (132 mg, 3.63 mmol) in acetonitrile (12 ml_) was stirred at room temperature 16 h. The reaction mixture was filtered and concentrated to yield the title compound as a solid (232 mg, 66percent). 1 H NMR (400 MHz, METHANOL-dΛ) δ ppm 4.79 (2 H, s), 6.94 (1 H, d, J=8.0 Hz), 7.18 (1 H, d, J=1.2 Hz), 7.27 (1 H, dd, J=8.0, 1.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere; | To the solution of XXXV-2 (2.3 g, 10 mmol) in dioxane (20 mL), bis (pinacolato)diboron (3.05 g, 12 mmol), potassium acetate (2 g , 20 mmol) and Pd(dppf)C12 (730 mg, 1 mmol) was added. The mixture was purged with nitrogen and sitiffed at 90C overnight. Then the mixture was diluted with EA (200 mL) and filtrated. The organic phase was washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product. The residue was purification by column chromatography on silica gel (PE:EA=3: ito 1:1) to give XXXV-4 (1.9 g, 69% yield) |
56% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 24.0h;Inert atmosphere; | A solution of the compound 4a (3.33g, 14.67mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (4.48g, 17.61mmol), potassium acetate (2.88g, 29.34mmol), Pd (dppf) Cl2 (0.15g, 0.20mmol) in dioxane (40mL) was heated to 100 Cunder N2 for 24 hours. The reaction mixture was filtered and concentrated under reduced pressure, the residue was purified by column chromatography to afford the compound 5a (2.25g, 56%). MS: 276 (M+H) +. |
56% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 24.0h;Inert atmosphere; | Compound 4a (3.33 g, 14.67 mmol), boronic acid pinacol ester (4.48 g, 17.61 mmol), potassium acetate (2.88 g, 29.34 mmol), Pd(dppf)Cl2 (0.15 g, 0.20 mmol) was added in a nitrogen atmosphere in 1,4-dioxane (40 mL), stirred 100 C at 24 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography to give compound 5a (2.25 g, 56%) |
55% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 100℃; for 16.0h;Inert atmosphere; | Preparation 13: 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylboronic acid; Step 1 : 6-(4,4,5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-2H-benzorbi?.41oxazin-3(4H)- one; A mixture of 6-Bromo-4H-benzo[1 ,4]oxazin-3-one (100 mg, 0.439 mmol), 4,4,5,5,4I,4I,5l,5I-Octamethyl-[2,2']bi[[1 ,3,2]dioxaborolanyl] (123 mg, 0.483 mmol), potassium acetate (159 mg, 1.54 mmol), 1 ,1-bis(diphenylphosphino)ferrocene (12.2 mg, 0.022 mmol) in dioxane (4 ml_). The mixture was degassed with nitrogen for approximately 20 minutes. [1 ,1-bis(diphenylphosphino) ferrocene]dichloropalladium (II) (18.0 mg, 0.220 mmol) was added followed by additional 5 minutes of degassing. The mixture was heated to 100C for 16 h. The reaction mixture was cooled to room temperature, filtered through celite and concentrated. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 25%-50% ethyl acetate/ heptane. The title compound was obtained as a white solid (66 mg, 55%). 1 H NMR (400 MHz, METHANOL-^) delta ppm 1.33 (12 H, s), 4.60 (2 H, s), 6.93 (1 H, d, J=8.3 Hz), 7.26 (1 H, s), 7.36 (1 H, d, J=I.9 Hz). |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 60℃; for 78.0h; | A mixture of 6-bromo-2H-l, 4-benzoxazin-3 (4H) -one (5.00 g) , bis (pinacolato) diboron (5.84 g) , [1,1- bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane adduct (0.54 g) and potassium acetate (8.34 g) in DMF (100 mL) was heated at 600C for 16 hr under a nitrogen atmosphere. Then [1,1- bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane adduct (1.08 g) was added, and the mixture was stirred at 60C for an additional 62 hr and treated with ethyl acetate and water. The insoluble material was filtered off, and the organic layer was separated, washed with water, dried over MgSO4 and concentrated. The residue was chrornatographed on silica gel using hexane/ethyl acetate as an eluent to give the title compound as colorless crystals (0.58 g) .1H-NMR (300 MHz, CDCl3) delta: 1.33 (12H, s) , 4.64 (2H, s) , 6.96 (IH, d, J = 7.8 Hz), 7.21 (IH, d, J = 1.2 Hz), 7.44 (IH, dd, J = 7.8, 1.2 Hz), 7.90 (IH, br) . | |
320 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 4.0h;Inert atmosphere; | 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (275 mg, 1.21 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (466 mg, 1.84 mmol), potassium acetate (184 mg, 1.87 mmol), and Dichloro 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (47 mg, 0.06 mmol) were added to a flask and container was evacuated and backfilled with argon. Reagents were taken up in dioxane (9 mL) and system was again purged with argon. Mixture was then heated at 100 C. for 4 hours. After cooling to rt, reaction mixture was filtered over celite, washing with ethyl acetate. Filtrate was concentrated under reduced pressure and resulting reside was purified by silica gel column chromatography (0-40% ethyl acetate/hexanes) to yield 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one 7.17 (320 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; for 14.0h;Heating / reflux; | A mixture of alpha-bromocinnamaldehyde (0.53 g), 6- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -2H-1, 4- benzoxazin-3 (4H) -one (0.58 g) , [1,1- bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane adduct (0.33 g) , 2M Cs2CO3 (4.0 mL) and THF (20 mL) was refluxed for 14 hr, and then treated with ethyl acetate and water. The organic layer was separated, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel using hexane/ethyl acetate as an eluent to give the title compound as colorless crystals (0.34 g) . mp. 2000C (decomp.).1H-NMR (300 MHz, CDCl3) delta: 4.65 (2H, s) , 6.77 (IH, d, J = 1.5 Hz), 6.80 (IH, dd, J = 8.4, 1.5 Hz), 6.99 (IH, d, J = 8.4 Hz), 7.23 - 7.33 (5H, m) , 7.38 (IH, s) , 8.00 (IH, br) , 9.73 (IH, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; for 12.0h;Heating / reflux; | A mixture of 3- (4-fluorophenyl) -2-iodoacrylaldehyde (2.2 g) , 6- (4, 4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) - 2H-l,4-benzoxazin-3 (4H) -one (2.19 g) , [1,1- bis (diphenylphosphino) ferrocene] dichloropalladium (II ) dichloromethane adduct (1.46 g) , 2M Cs2CO3 (13 ml) and THF (80 ml) was stirred under reflux for 12 hr, and then treated with ethyl acetate and water. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel with hexane/ethyl acetate as an eluent to give the title compound (1.25 g) .1H-NMR (300 MHz, DMSO-d6) delta: 4.63 (2H, s) , 6.65 - 6.69 (2H, m) , 6.98 - 7.01 (IH, m) , 7.16 - 7.22 (2H, m) , 7.32 - 7.36 <n="305"/>( 2H , m) , 7 . 66 ( IH , s ) , 9 . 70 ( IH , s ) , 10 . 71 ( IH , s ) ; MS ( ES I ) m/z : 2 68 ( M+ l ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 48.0h; | A mixture of 3-bromo-2-phenylpyridine (0.17 g) , 6- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -2H-1, 4- benzoxazin-3 (4H) -one (0.2 g) , tris (dibenzylideneacetone) dipalladium (0) (33.3 mg) , 2- dicyclohexylphosphino-2' , 4 ' , 6' -triisopropylbiphenyl (34.7 mg) and tripotassium phosphate (0.46 g) in water (1 ml) and DMF (5 ml) was heated at 100C for 48 hr. The solvent was removed under reduced pressure. The residue was dissolved <n="221"/>in EtOAc, and the solution was washed with aqueous NaHCO3 and water, dried and concentrated. Column chromatography on silica gel gave crystals. Recrystallization from EtOAc- hexane afforded the title compound as colorless crystals (26 mg) . mp. 176-178C.1H-NMR (300 MHz, CDCl3) delta: 4.62 (2H, s), 6.55 (IH, d, J = 2.4 Hz), 6.81 (IH, dd, J = 2.1, 8.4 Hz), 6.90 (IH, d, J = 8.1 Hz), 7.23 - 7.41 (6H, m) , 7.68 (IH, dd, J = 1.8, 7.8 Hz), 7.80 (IH, br) , 8.69 (IH, dd, J = 2,1, 5.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.37. 6-[5-(4-Fluorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (6a); Yield (22%). 1H NMR (DMSO-d6) delta 2.17 (3H, s), 3.64 (3H, s), 4.53(2H, s), 6.57 (1H, dd, J = 8.1, 2.1 Hz), 6.65 (1H, d, J = 1.9 Hz), 6.83(1H, d, J = 8.3 Hz), 7.18-7.42 (4H, m), 10.58 (1H, s). Anal. Calcd forC19H15N3O2F2: C, 64.22; H, 4.25; N, 11.83. Found: C, 64.09; H,4.21; N, 11.75. |
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150 - 160℃; for 0.25h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (245 mg), 4-bromo-5-(4-fluorophenyl)-1,3-dimethyl-1H-pyrazole (200 mg), Cesium carbonate (726 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (61 mg) in tetrahydrofuran/H2O (5/1) (4 ml) was exposed to microwave irradiation at 150 to 160 C. for 15 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel using ethyl acetate/hexane as an eluent and followed by recrystallization from ethyl acetate/hexane to give the title compound (55 mg).1H-NMR (DMSO-d6) delta: 2.17 (3H, s), 3.64 (3H, s), 4.53 (2H, s), 6.57 (1H, dd, J=8.1, 2.1 Hz), 6.65 (1H, d, J=1.9 Hz), 6.83 (1H, d, J=8.3 Hz), 7.18-7.42 (4H, m), 10.58 (1H, s).LCMS (ESI+) M+H+: 338.03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; for 12.0h;Reflux; Inert atmosphere; | A mixture of 4-[4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]butan-2-one (780 mg), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (700 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (210 mg), cesium carbonate (1.70 g), water (6 ml) and tetrahydrofuran (30 ml) was refluxed for 12 h under argon atmosphere. Water and ethyl acetate was added to the mixture and the mixture was filtered. The organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=4:1 to ethyl acetate). Resulting crystals were washed with diethyl ether/diisopropyl ether to give the title compound as crystals (260 mg).Mp 148-151 C.1H-NMR (300 MHz, DMSO-d6) delta: 2.08 (3H, s), 2.17 (3H, s), 2.99 (2H, t, J=6.9 Hz), 4.04 (2H, t, J=6.9 Hz), 4.53 (2H, s), 6.56 (1H, dd, J=8.3, 2.1 Hz), 6.63 (1H, d, J=2.1 Hz), 6.81 (1H, d, J=8.3 Hz), 7.22-7.38 (4H, m), 10.59 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). 1H NMR(300 MHz,DMSO-d6) delta 3.68 (3H, s), 4.51 (2H, s), 6.59-6.73 (2H, m), 6.82 (1H, d, J = 8.9 Hz),7.24-7.49 (4H, m), 7.66 (1H, s), 10.62 (1H, s). Anal. Calcd for C18H14N3O2F: C, 66.87; H, 4.36; N, 13.00. Found: C, 66.77; H, 4.34;N, 12.93. The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. |
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; for 18.0h;Reflux; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg), 4-bromo-5-(4-fluorophenyl)-1-methyl-1H-pyrazole (500 mg), Cesium carbonate (1.92 g), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg) in tetrahydrofuran/H2O (5/1) (10 ml) was well evacuated, and refluxed for 18 h. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on basic silica gel using ethyl acetate/hexane as an eluent and followed by recrystallization from ethyl acetate/hexane to give the title compound (196 mg).1H-NMR (300 MHz, DMSO-d6) delta: 3.68 (3H, s), 4.51 (2H, s), 6.59-6.73 (2H, m), 6.82 (1H, d, J=8.9 Hz), 7.24-7.49 (4H, m), 7.66 (1H, s), 10.62 (1H, s).LCMS (ESI+) M+H+: 324.08. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 0.25h;Microwave irradiation; | A mixture of 4-bromo-1-ethyl-5-(4-fluorophenyl)-1H-pyrazole (588 mg), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (500 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (297 mg) and Cs2CO3 (1.80 g) in tetrahydrofuran (15 ml) and H2O (3 ml) was stirred for 15 min. at 150 C. under microwave irradiation. After cooling, the reaction mixture was treated with ethyl acetate and H2O. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using n-hexane/ethyl acetate as an eluent to give the title compound (39 mg, 5%).1H-NMR (300 MHz, DMSO-d6) delta: 1.24 (3 H, t, J=7.0 Hz), 3.94 (2H, q, J=7.0 Hz), 4.51 (2H, s), 6.61-6.72 (2H, m), 6.74-6.87 (2H, m), 7.24-7.46 (4H, m), 7.69 (1H, s), 10.63 (1H, br. s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 130℃; for 0.25h;Microwave irradiation; | A mixture of 4-bromo-1-(2,2-difluoropropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazole (535 mg), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (528 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (261 mg) and Cs2CO3 (1.56 g) in tetrahydrofuran (15 ml) and H2O (3 ml) was stirred for 15 min. at 130 C. under microwave irradiation. After cooling, the reaction mixture was treated with ethyl acetate and H2O. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using n-hexane/ethyl acetate as an eluent to give the title compound (400 mg, 62%). The obtained compound was recrystallized from ethyl acetate and hexane.1H-NMR (300 MHz, DMSO-d6) delta: 1.57 (3H, t, J=19.0 Hz), 2.21 (3H, s), 4.38 (2H, t, J=13.0 Hz), 4.54 (2H, s), 6.58 (1H, dd, J=8.5, 2.0 Hz), 6.65 (1H, d, J=2.0 Hz), 6.82 (1H, d, J=8.5 Hz), 7.22-7.35 (4H, m), 10.61 (1H, br. s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; for 12.0h;Inert atmosphere; Reflux; | A mixture of 1-[3-(benzyloxy)-2-fluoropropyl]-4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazole (730 mg), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (500 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (150 mg), cesium carbonate (1.20 g), water (4 ml) and tetrahydrofuran (20 ml) was refluxed for 12 h under argon atmosphere. Water and ethyl acetate was added to the mixture and the mixture was filtered. The organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=4:1 to 1:2) followed by crystallization from ethyl acetate/hexane to give the title compound as crystals (375 mg).Mp 138-140 C.1H-NMR (300 MHz, DMSO-d6) delta: 2.20 (3H, s), 3.48-3.82 (2H, m), 4.09-4.32 (2H, m), 4.47 (2H, s), 4.53 (2H, s), 4.91-5.23 (1H, m), 6.58 (1H, dd, J=8.3, 2.1 Hz), 6.65 (1H, d, J=2.1 Hz), 6.82 (1H, d, J=8.3 Hz), 7.16-7.42 (9H, m), 10.60 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; for 12.0h;Reflux; Inert atmosphere; | A mixture of 1-(benzyloxy)-3-[4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]propan-2-one (500 mg), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (350 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (110 mg), cesium carbonate (850 mg), water (3 ml) and tetrahydrofuran (15 ml) was refluxed for 12 h under argon atmosphere. Water and ethyl acetate was added to the mixture and the mixture was filtered. The organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=4:1 to 1:3) followed by crystallization from ethyl acetate/hexane to give the title compound as crystals (240 mg).Mp 154-155 C.1H-NMR (300 MHz, DMSO-d6) delta: 2.19 (3H, s), 4.19 (2H, s), 4.43 (2H, s), 4.54 (2H, s), 4.99 (2H, s), 6.59 (1H, dd, J=8.1, 1.9 Hz), 6.68 (1H, d, J=1.9 Hz), 6.83 (1H, d, J=8.1 Hz), 7.16-7.42 (9H, m), 10.61 (1H s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 24.0h;Inert atmosphere; Reflux; | A mixture of 35b (600 mg, 1.37 mmol), 15a (490 mg, 1.78 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (220 mg, 0.27 mmol), cesium carbonate (1.20 g, 3.69 mmol) in THF/water (25 mL/5 mL) was stirredat reflux for 24 h under argon atmosphere, diluted with water and EtOAc, and then filtered. The organic layer was separated,washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/EtOAc as an elutant, and crystallized from IPE/hexane to give 36b (420 mg, 61%). 1H NMR (300 MHz, DMSO-d6) delta 2.20 (3H, s), 3.74 (2H, t, J = 13.3 Hz),4.41-4.57 (6H, m), 6.58 (1H, dd, J = 8.2, 2.0 Hz), 6.66 (1H, d,J = 2.0 Hz), 6.82 (1H, d, J = 8.2 Hz), 7.18-7.40 (9H, m), 10.61 (1H, s). The compound 36a,c were prepared in a manner similar to that described for 36b. |
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; for 24.0h;Reflux; Inert atmosphere; | A mixture of 1-[3-(benzyloxy)-2,2-difluoropropyl]-4-bromo-5-(4-Fluorophenyl)-3-methyl-1H-pyrazole (600 mg), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (490 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (220 mg), cesium carbonate (1.20 g), water (5 ml) and tetrahydrofuran (25 ml) was refluxed for 24 h under argon atmosphere. Water and ethyl acetate was to added to the mixture and the mixture was filtered. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=10:1 to 2:3) followed by crystallization from diisopropyl ether/hexane to give the title compound as crystals (420 mg).Mp 154-155 C.1H-NMR (300 MHz, DMSO-d6) delta: 2.20 (3H, s), 3.74 (2H, t, J=13.3 Hz), 4.41-4.57 (6H, m), 6.58 (1H, dd, J=8.2, 2.0 Hz), 6.66 (1H, d, J=2.0 Hz), 6.82 (1H, d, J=8.2 Hz), 7.18-7.40 (9H, m), 10.61 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 24.0h;Inert atmosphere; Reflux; | General procedure: 5.85. 6-{1-[3-(Benzyloxy)-2,2-difluoropropyl]-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl}-2H-1,4-benzoxazin-3(4H)-one (36b); A mixture of 35b (600 mg, 1.37 mmol), 15a (490 mg, 1.78 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (220 mg, 0.27 mmol), cesium carbonate (1.20 g, 3.69 mmol) in THF/water (25 mL/5 mL) was stirredat reflux for 24 h under argon atmosphere, diluted with water and EtOAc, and then filtered. The organic layer was separated,washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/EtOAc as an elutant, and crystallized from IPE/hexane to give 36b (420 mg, 61%). The compound 36a,c were prepared in a manner similar to that described for 36b. 5.87. 6-{1-[4-(Benzyloxy)-2,2-difluorobutyl]-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl}-2H-1,4-benzoxazin-3(4H)-one (36c); Yield (55%). 1H NMR (300 MHz, DMSO-d6) delta 2.11-2.31 (5H, m),3.51 (2H, t, J = 6.4 Hz), 4.36-4.56 (6H, m), 6.58 (1H, dd, J = 8.3,1.9 Hz), 6.65 (1H, d, J = 1.9 Hz), 6.82 (1H, d, J = 8.3 Hz), 7.18-7.39(9H, m), 10.61 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 1.0h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (92 mg), 1-[4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]pentan-3-ol (88 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (42 mg), cesium carbonate (252 mg) in tetrahydrofuran/water (2/1 mL) was exposed to microwave irradiation at 150 C. for 1 h, treated with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane. Crystallization from ethyl acetate/hexane gave the title compound (51 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.77 (3H, t, J=7.4 Hz), 1.17-1.37 (2H, m), 1.51-1.74 (1H, m), 1.72-1.94 (1H, m), 2.18 (3H, s), 3.16-3.31 (1H, m), 3.77-4.11 (2H, m), 4.43 (1H, d, J=5.3 Hz), 4.53 (2H, s), 6.56 (1H, dd, J=8.3, 1.9 Hz), 6.64 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.3 Hz), 7.14-7.39 (4H, m), 10.59 (1H, s).LCMS (ESI+) M+H+: 410. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 1.0h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (314 mg), 1-[5-(benzyloxy)pentyl]-4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazole (410 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (155 ml), cesium carbonate (929 mg) in tetrahydrofuran/water (12/5 mL) was exposed to microwave irradiation at 150 C. for 1 h, treated with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give the title compound as an oil (210 mg).1H-NMR (300 MHz, DMSO-d6) delta: 1.11-1.29 (2H, m), 1.32-1.47 (2H, m), 1.55-1.72 (2H, m), 2.18 (3H, s), 3.27-3.36 (2H, m), 3.88 (2H, t, J=7.2 Hz), 4.39 (2H, s), 4.53 (2H, s), 6.56 (1H, dd, J=8.1, 2.1 Hz), 6.65 (1H, d, J=2.1 Hz), 6.81 (1H, d, J=8.1 Hz), 7.20-7.37 (9H, m), 10.60 (1H, s).LCMS (ESI+) M+H+: 500. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.63. 6-[5-(4-Fluorophenyl)-1-isobutyl-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (24b); The compound 24b were prepared in a manner similar to thatdescribed for 5. Yield (43%).1H NMR (DMSO-d6) delta 2.17 (3H, s), 3.64 (3H, s), 4.53(2H, s), 6.57 (1H, dd, J = 8.1, 2.1 Hz), 6.65 (1H, d, J = 1.9 Hz), 6.83(1H, d, J = 8.3 Hz), 7.18-7.42 (4H, m), 10.58 (1H, s). Anal. Calcd forC19H15N3O2F2: C, 64.22; H, 4.25; N, 11.83. Found: C, 64.09; H,4.21; N, 11.75. |
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 1.0h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (136 mg), 4-bromo-5-(4-fluorophenyl)-3-methyl-1-(2-methylpropyl)-1H-pyrazole (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (52.5 mg), cesium carbonate (314 mg) in tetrahydrofuran/water (3/1 mL) was exposed to microwave irradiation at 150 C. for 1 h, treated with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane. Crystallization from ethyl acetate/hexane gave the title compound (52 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.70 (6H, d, J=6.8 Hz), 1.88-2.16 (1H, m), 2.19 (3H, s), 3.71 (2H, d, J=7.2 Hz), 4.53 (2H, s), 6.56 (1H, dd, J=8.3, 1.9 Hz), 6.65 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.3 Hz), 7.24-7.32 (4H, m), 10.60 (1H, s).LCMS (ESI+) M+H+: 380.Anal. Calcd for C22H22N3O2F: C, 69.64; H, 5.84; N, 11.07. Found: C, 69.45; H, 5.84; N, 11.05 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 1.0h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (209 mg), 4-bromo-5-(4-fluorophenyl)-3-methyl-1-(2-methylbutyl)-1H-pyrazole (206 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (103 mg), cesium carbonate (619 mg) in tetrahydrofuran/water (3/1 mL) was exposed to microwave irradiation at 150 C. for 1 h, and then passed through a celite pad, treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate. Crystallization from ethyl acetate/hexane gave the title compound (113 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.60-0.77 (6H, m), 0.84-1.04 (1H, m), 1.07-1.28 (1H, m), 1.65-1.88 (1H, m), 2.19 (3H, s), 3.58-3.74 (1H, m), 3.75-3.91 (1H, m), 4.53 (2H, s), 6.56 (1H, dd, J=8.3, 1.9 Hz), 6.65 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.3 Hz), 7.22-7.40 (4H, m), 10.59 (1H, s).LCMS (ESI+) M+H+: 394.Anal. Calcd for C23H24N3O2F: C, 70.21; H, 6.15; N, 10.68. Found: C, 70.11; H, 6.13; N, 10.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 1.0h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (314 mg), 4-bromo-1-(2-ethylbutyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazole (323 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (156 mg), cesium carbonate (931 mg) in tetrahydrofuran/water (3/1 mL) was exposed to microwave irradiation at 150 C. for 1 h, and then passed through a celite pad, treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate. Crystallization from ethyl acetate/hexane gave the title compound (97 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.63 (6H, t, J=7.4 Hz), 0.97-1.22 (4H, m), 1.51-1.68 (1H, m), 2.19 (3H, s), 3.82 (2H, d, J=7.2 Hz), 4.53 (2H, s), 6.56 (1H, dd, J=8.1, 1.9 Hz), 6.65 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.1 Hz), 7.16-7.39 (4H, m), 10.59 (1H, s).LCMS (ESI+) M+H+: 408.Anal. Calcd for C24H26N3O2F: C, 70.74; H, 6.43; N, 10.31. Found: C, 70.67; H, 6.3; N, 10.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 1.0h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (45.7 mg), 4-bromo-5-(4-fluorophenyl)-3-methyl-1-(3-methylbutyl)-1H-pyrazole (45.0 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (23 mg), cesium carbonate (135 mg) in tetrahydrofuran/water (1.2/0.5 mL) was exposed to microwave irradiation at 150 C. for 1 h, and then passed through a celite pad, treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate. Crystallization from ethyl acetate/hexane gave the title compound (17 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.73 (6H, d, J=6.4 Hz), 1.29-1.47 (1H, m), 1.47-1.57 (2H, m), 2.18 (3H, s), 3.80-3.99 (2H, m) 4.53 (2H, s), 6.56 (1H, dd, J=8.1, 1.9 Hz), 6.65 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.1 Hz), 7.20-7.40 (4H, m), 10.59 (1H, s).LCMS (ESI+) M+H+: 394. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.62. 6-[1-Butyl-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (24a); The compound 24a were prepared in a manner similar to thatdescribed for 5. Yield (43%). 1H NMR (DMSO-d6) delta 0.75(3H, t, J = 7.3 Hz), 1.04-1.25 (2H, m), 1.52-1.69 (2H, m), 2.19 (3H,s), 3.88 (2H, t, J = 7.2 Hz), 4.53 (2H, s), 6.56 (1H, dd, J = 8.3,2.1 Hz), 6.65 (1H, d, J = 2.1 Hz), 6.81 (1H, d, J = 8.3 Hz), 7.21-7.34(4H, m), 10.60 (1H, s). Anal. Calcd for C22H22FN3O2: C, 69.64; H,5.84; N, 11.07. Found: C, 69.63; H, 5.72; N, 11.1. |
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 0.5h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (224 mg), 4-bromo-1-butyl-5-(4-fluorophenyl)-3-methyl-1H-pyrazole (211 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (110 mg), cesium carbonate (663 mg) in tetrahydrofuran/water (3/1 mL) was exposed to microwave irradiation at 150 C. for 30 min, and then passed through a celite pad, treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate. Crystallization from ethyl acetate/hexane gave the title compound (110 mg).1H-NMR (300 MHz, DMSO-d6) 0.75 (3H, t, J=7.3 Hz), 1.04-1.25 (2H, m), 1.52-1.69 (2H, m), 2.19 (3H, s), 3.88 (2H, t, J=7.2 Hz), 4.53 (2H, s), 6.56 (1H, dd, J=8.3, 2.1 Hz), 6.65 (1H, d, J=2.1 Hz), 6.81 (1H, d, J=8.3 Hz), 7.21-7.34 (4H, m), 10.60 (1H, s).LCMS (ESI+) M+H+: 380.Anal. Calcd for C22H22N3O2F: C, 69.64; H, 5.84; N, 11.07. Found: C, 69.63; H, 5.72; N, 11.1. |
Yield | Reaction Conditions | Operation in experiment |
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With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 0.5h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (163 mg), 4-bromo-5-(4-fluorophenyl)-3-methyl-1-pentyl-1H-pyrazole (161 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (81 mg), cesium carbonate (483 mg) in tetrahydrofuran/water (3/1 mL) was exposed to microwave irradiation at 150 C. for 30 min, and then passed through a celite pad, treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate. Crystallization from ethyl acetate/hexane gave the title compound (68 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.77 (3H, t, J=7.2 Hz), 1.01-1.21 (4H, m), 1.56-1.70 (2H, m), 2.19 (3H, s), 3.87 (2H, t, J=7.4 Hz), 4.53 (2H, s), 6.56 (1H, dd, J=8.3, 1.9 Hz), 6.65 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.3 Hz), 7.24-7.32 (4H, m), 10.59 (1H, s).LCMS (ESI+) M+H+: 394.Anal. Calcd for C23H24N3O2F: C, 70.21; H, 6.15; N, 10.68. Found: C, 70.08; H, 6.07; N, 10.59. |
Yield | Reaction Conditions | Operation in experiment |
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With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 1.0h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (122 mg), 4-bromo-5-(4-fluorophenyl)-3-methyl-1-[(1-methylcyclopropyl)methyl]-1H-pyrazole (119 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (60 mg), cesium carbonate (360 mg) in tetrahydrofuran/water (3/1 mL) was exposed to microwave irradiation at 150 C. for 1 h, and then passed through a celite pad, treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate. Crystallization from ethyl acetate/hexane gave the title compound (67.5 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.10-0.29 (4H, m), 0.78 (3H, s), 2.20 (3H, s), 3.84 (2H, s), 4.53 (2H, s), 6.56 (1H, dd, J=8.3, 1.9 Hz), 6.65 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.3 Hz), 7.21-7.36 (4H, m), 10.60 (1 H, s).LCMS (ESI+) M+H+: 392.Anal. Calcd for C23H22N3O2F (0.1 ethyl acetate): C, 70.22; H, 5.74; N, 10.50. Found: C, 70.2; H, 5.55; N, 10.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 0.5h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (107 mg), 3-[4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]-2-methylpropan-1-ol (106 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (53 mg), cesium carbonate (317 mg) in tetrahydrofuran/water (3/1 mL) was exposed to microwave irradiation at 150 C. for 30 min, and then filtered, treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate. Crystallization from ethyl acetate/hexane gave the title compound (52 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.65 (3H, d, J=6.4 Hz), 1.94-2.11 (1H, m), 2.19 (3H, s), 3.07-3.24 (2H, m), 3.56-3.74 (1H, m), 3.90-4.06 (1H, m), 4.49 (1H, t, J=5.1 Hz), 4.53 (2H, s), 6.56 (1H, dd, J=8.1, 1.9 Hz), 6.64 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.1 Hz), 7.22-7.32 (4H, m), 10.60 (1H, s).LCMS (ESI+) M+H+: 396.Anal. Calcd for C22H22N3O3F: C, 66.82; H, 5.61; N, 10.63. Found: C, 66.57; H, 5.53; N, 10.42. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 0.5h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (651 mg), 1-({1-[(benzyloxy)methyl]cyclopropyl}methyl)-4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazole (846 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (322 mg), cesium carbonate (1.90 g) in tetrahydrofuran/water (12/5 mL) was exposed to microwave irradiation at 150 C. for 30 min, and then filtered, treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate. Crystallization from ethyl acetate/hexane gave the title compound (370 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.33-0.51 (4H, m), 2.19 (3H, s), 3.10 (2H, s), 4.01 (2H, s), 4.24 (2H, s), 4.53 (2H, s), 6.54 (1H, dd, J=8.3, 2.1 Hz), 6.64 (1H, d, J=2.1 Hz), 6.81 (1H, d, J=8.3 Hz), 7.10-7.22 (4H, m), 7.24-7.36 (5H, m), 10.59 (1H, s).LCMS (ESI+) M+H+: 498.Anal. Calcd for C30H28N3O3F: C, 72.42; H, 5.67; N, 8.45. Found: C, 72.63; H, 5.71; N, 8.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 0.5h;Microwave irradiation; | To a suspension of lithiumalminum hydride (20 mg) in tetrahydrofuran (1 mL) was added dropwise a solution of methyl 3-[4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]-2,2-dimethylpropanoate (199 mg) in tetrahydrofuran (1 mL) at room temperature. The mixture was stirred for 1 h, treated with aqueous Rochelle salt solution and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo to give crude 3-[4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]-2,2-dimethylpropan-1-ol as oil (161 mg). A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (156 mg), crude material of 3-[4-Bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]-2,2-dimethylpropan-1-ol (161 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (77 mg), cesium carbonate (461 mg) in tetrahydrofuran/water (3 mL/1 mL) was exposed to microwave irradiation at 150 C. for 30 min, and then filtered. The filtrate was treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate. Crystallization from ethyl acetate/hexane gave the title compound (69 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.63 (6H, s), 2.19 (3H, s), 3.07 (2H, d, J=5.5 Hz), 3.86 (2H, s), 4.49-4.57 (3H, m), 6.54 (1H, dd, J=8.3, 1.9 Hz), 6.63 (1H, d, J=1.9 Hz), 6.80 (1H, d, J=8.3 Hz), 7.23-7.31 (4H, m), 10.59 (1H, s).LCMS (ESI+) M+H+: 410.Anal. Calcd for C23H24N3O3F 0.3 ethyl acetate): C, 66.7; H, 6.10; N, 9.64. Found: C, 66.47; H, 5.98; N, 9.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; for 8.0h;Inert atmosphere; Reflux; | A mixture of 4-bromo-1-(4-fluorobutyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazole (640 mg), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (802 mg), 2M aqueous cesium carbonate (1.94 ml), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (318 mg) in 1,2-dimethoxyethane (6.5 ml) was well evacuated, and refluxed for 8 h under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on basic silica gel using hexane/ethyl acetate as an eluent, and crystallized from hexane/ethyl acetate to give the title compound (247 mg).1H-NMR (300 MHz, DMSO-d6) delta: 1.40-1.63 (2H, m), 1.73 (2H, qd, J=7.3, 7.0 Hz), 2.19 (3H, s), 3.92 (2H, t, J=7.0 Hz), 4.33 (2H, dt, J=47.3, 5.9 Hz), 4.53 (2H, s), 6.57 (1H, d, J=8.7 Hz), 6.65 (1H, s), 6.81 (1H, d, J=8.3 Hz), 7.21-7.36 (4H, m), 10.59 (1H, s).LCMS (ESI+) M+H+: 397.82. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 1.0h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (311 mg), 4-bromo-5-(4-fluorophenyl)-3-methyl-1-[(2-methylcyclopropyl)methyl]-1H-pyrazole (304 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (154 mg), cesium carbonate (919 mg) in tetrahydrofuran/water (3/1 mL) was exposed to microwave irradiation at 150 C. for 30 min, and then filtered, treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate. Crystallization from ethyl acetate/hexane gave the title compound (155 mg).1H-NMR (300 MHz, DMSO-d6) delta: 0.07-0.28 (2H, m) 0.35-0.64 (1H, m) 0.68-0.82 (1H, m) 0.84-0.95 (3H, m) 2.19 (3H, s) 3.63-4.01 (2H, m) 4.53 (2H, s) 6.49-6.62 (1H, m) 6.61-6.70 (1H, m) 6.76-6.86 (1H, m) 7.19-7.43 (4H, m) 10.60 (1H, s).LCMS (ESI+) M+H+: 392.Anal. Calcd for C23H22N3O2F: C, 70.57; H, 5.66; N, 10.73. Found: C, 70.64; H, 5.65; N, 10.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 150℃; for 1.0h;Microwave irradiation; | A mixture of <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (254 mg), 1-({1-[(benzyloxy)methyl]cyclobutyl}methyl)-4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazole (341 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (126 mg), cesium carbonate (752 mg) in tetrahydrofuran/water (3/1 mL) was exposed to microwave irradiation at 150 C. for 1 h, and then filtered, treated with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (150 mg).1H-NMR (300 MHz, DMSO-d6) delta: 1.52-1.93 (6H, m), 2.18 (3H, s), 3.25 (2H, s), 4.05 (2H, s), 4.34 (2H, s), 4.53 (2H, s), 6.53 (1H, dd, J=8.3, 1.9 Hz), 6.64 (1H, d, J=1.9 Hz, 1H), 6.81 (1H, d, J=8.3 Hz), 7.10-7.34 (9H, m), 10.59 (1H, s).LCMS (ESI+) M+H+: 512. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 4-bromo-5-(4-fluorophenyl)-3-methyl-1-(1-methylethyl)-1H-pyrazole (0.40 g), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.41 g), 2 N cesium carbonate aqueous solution (2.0 mL), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (0.22 g) and 1,4-dioxane (10 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.18 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 1.34 (6H, d, J=6.8 Hz), 2.20 (3H, s), 4.14-4.25 (1H, m), 4.53 (2H, s), 6.56 (1H, dd, J=8.3, 2.3 Hz), 6.65 (1H, d, J=1.9 Hz), 6.80 (1H, d, J=8.3 Hz), 7.25-7.33(4H, m), 10.61 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 1-benzyl-4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazole (0.51 g), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.44 g), 2 N cesium carbonate aqueous (2.2 mL), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (0.24 g) and 1,4-dioxane (10 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.23 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 2.21 (3H, s), 4.53 (2H, s), 5.15 (2H, s), 6.59 (1H, dd, J=8.3, 2.1 Hz), 6.68 (2H, d, J=2.1 Hz), 6.82 (1H, d, J=8.3 Hz), 6.97 (2H, dd, J=7.9, 1.5 Hz), 7.19-7.32 (7H, m), 10.60 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 4-bromo-5-(4-fluorophenyl)-3-methyl-1-(2-phenylethyl)-1H-pyrazole (0.50 g), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.42 g), 2 N cesium carbonate aqueous solution (2.1 mL), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (0.23 g) and 1,4-dioxane (10 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.18 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 2.23 (3H, s), 3.00 (2H, t, J=7.3 Hz), 4.05 (2H, t, J=7.3 Hz), 4.52 (2H, s), 6.53 (1H, dd, J=8.3, 2.1 Hz), 6.63 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.3 Hz), 6.90-7.03 (4H, m), 7.11-7.28 (5H, m), 10.59 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 4-bromo-5-(4-fluorophenyl)-3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole (0.82 g), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.70 g), 2 N cesium carbonate aqueous solution (3.5 mL), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (0.19 g) and 1,4-dioxane (10 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.34 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 2.05-2.16 (4H, m), 2.59-2.68 (4H, m), 3.32 (3H, s), 3.75-3.92 (1H, m), 4.52 (2H, s), 6.56 (1H, dd, J=8.1, 2.1 Hz), 6.64 (1H, d, J -1.9 Hz), 6.80 (1H, d, J=8.3 Hz), 10.60 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.46. 6-[5-(4-Fluorophenyl)-3-methyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16h); Yield (52 %). 1H NMR (DMSO-d6) delta 2.20 (3H, s), 4.54(2H, s), 5.22 (2H, s), 6.61 (1H, d, J = 8.1 Hz), 6.69 (1H, s), 6.83 (1H,d, J = 8.1 Hz), 7.02 (1H, d, J = 7.7 Hz), 7.16-7.37 (5H, m), 7.68-7.82 (1H, m), 8.49 (1H, d, J = 4.5 Hz), 10.60 (1H, s). Anal. Calcd forC24H19N4O2F: C, 69.55; H, 4.62; N, 13.52. Found: C, 69.28; H,4.66; N, 13.13. |
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 2-[4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]methyl}pyridine (0.24 g), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.21 g), 2 N cesium carbonate aqueous solution (1.0 mL), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (0.08 g) and 1,4-dioxane (5 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.15 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 2.20 (3H, s), 4.54 (2H, s), 5.22 (2H, s), 6.61 (1H, d, J=8.1 Hz), 6.69 (1H, s), 6.83 (1H, d, J=8.1 Hz), 7.02 (1H, d, J=7.7 Hz), 7.16-7.37 (5H, m), 7.68-7.82 (1H, m), 8.49 (1H, d, J=4.5 Hz), 10.60 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.47. 6-[5-(4-Fluorophenyl)-3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16i); Yield (21 %). 1H NMR (DMSO-d6) delta 2.21 (3H, s), 4.53(2H, s), 5.20 (2H, s), 6.60 (1H, dd, J = 8.3, 1.9 Hz), 6.68 (1H, d,J = 1.9 Hz), 6.82 (1H, d, J = 8.3 Hz), 7.21-7.35 (5H, m), 7.37-7.44(1H, m), 8.19 (1H, s), 8.45 (1H, d, J = 3.8 Hz), 10.60 (1H, s). Anal.Calcd for C24H19N4O2F 0.1(EtOAc): C, 69.24; H, 4.72; N, 13.24.Found: C, 68.92; H, 4.69; N, 13.16. |
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 3-[4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]methyl}pyridine (0.12 g), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.11 g), 2 N cesium carbonate aqueous solution (0.5 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.04 g) and 1,4-dioxane (3 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.03 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 2.21 (3H, s), 4.53 (2H, s), 5.20 (2H, s), 6.60 (1H, dd, J=8.3, 1.9 Hz), 6.68 (1H, d, J=1.9 Hz), 6.82 (1H, d, J=8.3 Hz), 7.21-7.35 (5H, m), 7.37-7.44 (1H, m), 8.19 (1H, s), 8.45 (1H, d, J=3.8 Hz), 10.60 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.48. 6-[5-(4-Fluorophenyl)-3-methyl-1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16j); Yield (5 %). 1H NMR (DMSO-d6) delta 2.22 (3H, s), 4.54 (2H,s), 5.20 (2H, s), 6.62 (1H, dd, J = 8.3, 2.3 H), 6.69 (1H, d, J = 1.9 Hz), 6.83 (1H, d, J = 8.0 Hz), 6.96 (2H, d, J = 6.1 Hz), 7.20-7.25 (4H, m),8.47 (2H, d, J = 6.1 Hz), 10.60 (1H, s). Anal. Calcd for C24H19N4O2F:C, 69.55; H, 4.62; N, 13.52. Found: C, 69.38; H, 4.75; N, 13.25. |
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 4-[4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]methyl}pyridine (0.16 g), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.14 g), 2 N cesium carbonate aqueous solution (0.7 mL), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (0.04 g) and 1,4-dioxane (4 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.01 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 2.22 (3H, s), 4.54 (2H, s), 5.20 (2H, s), 6.62 (1H, dd, J=8.3, 2.3H), 6.69 (1H, d, J=1.9 Hz), 6.83 (1H, d, J=8.0 Hz), 6.96 (2H, d, J=6.1 Hz), 7.20-7.25 (4H, m), 8.47 (2H, d, J=6.1 Hz), 10.60 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 5-(4-fluorophenyl)-3-methyl-1-(4-methylbenzyl)-1H-pyrazole (0.90 g), N-Bromosuccinimide (0.63 g) and acetonitrile (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate. The solution was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give 4-bromo-5-(4-fluorophenyl)-3-methyl-1-(4-methylbenzyl)-1H-pyrazole as crude product. The product was diluted with 1,4-dioxane (10 mL) and added to <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.97 g), 2 N cesium carbonate aqueous solution (4.8 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.39 g) and 1,4-dioxane (10 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.27 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 2.20 (3H, s), 2.24 (3H, s), 4.53 (2H, s), 5.09 (2H, s), 6.58 (1H, dd, J=8.3, 1.9 Hz), 6.67 (1H, d, J=1.9 Hz), 6.78-6.89 (3H, m), 7.08 (2H, d, J=7.6 Hz), 7.20-7.26 (4H, m), 10.59 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 1-(4-fluorobenzyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazole (0.89 g), N-Bromosuccinimide (0.62 g) and acetonitrile (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate. The solution was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give 4-bromo-1-(4-fluorobenzyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazole as crude product. The product was diluted with 1,4-dioxane (10 mL) and added to <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.95 g, 2 N cesium carbonate aqueous solution (4.7 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.39 g) and 1,4-dioxane (10 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.26 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 2.21 (3H, s), 4.53 (2H, s), 5.14 (2H, s), 6.59 (1H, dd, J=8.3, 1.9 Hz), 6.68 (1H, d, J=2.3 Hz), 6.82 (1H, d, J=8.3 Hz), 6.98-7.05 (2H, m), 7.07-7.15 (2H, m), 7.20-7.28 (4H, m), 10.60 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 4-bromo-5-(4-fluorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole (0.76 g), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.71 g), 2 N cesium carbonate aqueous solution (3.2 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.17 g) and 1,4-dioxane (10 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.28 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 0.93-1.10 (2H, m), 1.28-1.39 (2H, m), 1.89-2.07 (1H, m), 2.19 (3H, s), 3.12-3.23 (2H, m), 3.68-3.81 (4H, m), 4.53 (2H, s), 6.56 (1H, dd, J=8.3, 1.9 Hz), 6.65 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.3 Hz), 7.22-7.37 (4H, m), 10.59 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 2-fluoro-3-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]methyl}pyridine (0.34 g), N-Bromosuccinimide (0.22 g) and acetonitrile (8 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate. The solution was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was diluted with 1,4-dioxane (10 mL) and added to <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.49 g), 2 N cesium carbonate aqueous solution (1.8 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.10 g). The mixture was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound as colorless (0.24 g) crystals.1H-NMR (300 MHz, DMSO-d6) delta: 2.19 (3H, s), 4.54 (2H, s), 5.20 (2H, s), 6.60 (1H, dd, J=8.3, 2.1 Hz), 6.68 (1H, d, J=2.1 Hz), 6.83 (1H, d, J=8.3 Hz), 7.19-7.36 (5H, m), 7.50-7.61 (1H, m), 8.14 (1H, d, J=4.9 Hz), 10.61 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 4-bromo-5-(4-fluorophenyl)-3-methyl-1-(tetrahydro-2H-thiopyran-4-ylmethyl)-1H-pyrazole (0.44 g), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.50 g), 2 N cesium carbonate aqueous solution (1.8 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.10 g) and 1,4-dioxane (8 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.10 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 0.97-1.18 (3H, m), 1.65-1.91 (3H, m), 2.19 (3H, s), 2.45-2.56 (2H, m), 3.75 (2H, d, J=7.0 Hz), 4.53 (2H, s), 6.56 (1H, dd, J=8.3, 1.9 Hz), 6.64 (1H, d, J=1.9 Hz), 6.81 (1H, d, J=8.3 Hz), 7.28 (4H, d, J=7.2 Hz), 10.59 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of 3-[4-bromo-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]methyl}benzonitrile (0.49 g), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (0.55 g), 2 N cesium carbonate aqueous solution (2.0 mL), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (0.11 g) and 1,4-dioxane (8 mL) was degassed, charged with argon, and stirred at 100 C. for 12 h. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. To the filtrate was added ethyl acetate and the organic layer was separated. The organic layer was washed with H2O (10 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica-gel to give the title compound (0.13 g) as colorless crystals.1H-NMR (300 MHz, DMSO-d6) delta: 2.22 (3H, s), 4.53 (2H, s), 5.21 (2H, s), 6.61 (1H, dd, J=8.3, 2.1 Hz), 6.69 (1H, d, J=2.1 Hz), 6.82 (1H, d, J=8.1 Hz), 7.21-7.32 (5H, m), 7.41-7.45 (1H, m), 7.48-7.55 (1H, m), 7.73 (1H, d, J=7.7 Hz), 10.60 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 3.0h; | General procedure: A mixture of 5-bromo-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide (0.235 g, 0.870 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (0.243 g, 0.957 mmol) (Aldrich Cat. No. 473294), potassium acetate (0.213 g, 2.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (36 mg, 0.043 mmol); and 1,1'-bis(diphenylphosphino)ferrocene (0.024 g, 0.043 mmol) in 1,4-dioxane (4.3 mL) was degassed and stirred at 100 C. for 3 h. After cooling the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.27 g, 98%). LCMS (M+H)+=318.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With hydrogenchloride; water; In acetonitrile; at 20.0℃; for 16.0h; | Step 2: 3-oxo-3,4-dihvdro-2H-benzorbiri .41oxazin-6-vlboronic acid; A mixture of 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2H-benzo[b][1 ,4]oxazin-3(4H)-one (500 mg, 1.82 mmol), polymer supported phenyl boronic acid (2200 mg, 6.4 mmol), 1 M aqueous hydrochloric acid (132 mg, 3.63 mmol) in acetonitrile (12 ml_) was stirred at room temperature 16 h. The reaction mixture was filtered and concentrated to yield the title compound as a solid (232 mg, 66%). 1 H NMR (400 MHz, METHANOL-dLambda) delta ppm 4.79 (2 H, s), 6.94 (1 H, d, J=8.0 Hz), 7.18 (1 H, d, J=1.2 Hz), 7.27 (1 H, dd, J=8.0, 1.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 55.64. 6-[5-(4-Fluorophenyl)-3-methyl-1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (24c); The compound 24c were prepared in a manner similar to thatdescribed for 5. Yield (5%).1H NMR (DMSO-d6) delta 1.89(2H, m), 2.10-2.33 (5H, m), 3.96 (2H, t, J = 7.0 Hz), 4.53 (2H, s),6.58 (1H, dd, J = 8.3, 1.9 Hz), 6.66 (1H, d, J = 1.9 Hz), 6.82 (1H, d,J = 8.3 Hz), 7.22-7.40 (4H, m), 10.60 (1H, s). Anal. Calcd forC22H19N3O2F4: C, 60.97; H, 4.42; N, 9.70. Found: C, 60.59; H,4.16; N, 9.65. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.68. N-{2-[5-(4-Fluorophenyl)-3-methyl-4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1H-pyrazol-1-yl]ethyl}acetamide (27a); The compound 27a were prepared in a manner similar to that described for 5. Yield (44%). 1H NMR (DMSO-d6) delta 1.69(3H, s), 2.20 (3H, s), 3.32 (2H, q, J = 6.0 Hz), 3.90 (2H, t,J = 6.0 Hz), 4.53 (2H, s), 6.56 (1H, dd, J = 8.5, 2.0 Hz), 6.66(1H, d, J = 2.0 Hz), 6.81 (1H, d, J = 8.5 Hz), 7.20-7.34 (4H, m), 7.94(1H, t, J = 6.0 Hz), 10.61 (1H, br s). Anal. Calcd for C22H21N4O3F:C, 64.70; H, 5.18; N, 13.72. Found: C, 65.05; H, 5.53; N, 13.38. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.69. N-{2-[5-(4-Fluorophenyl)-3-methyl-4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1H-pyrazol-1-yl]ethyl}methanesulfonamide (27b); The compound 27b were prepared in a manner similar to that described for 5. Yield (33%).1H NMR (DMSO-d6) delta 2.20(3H, s), 2.81 (3H, s), 3.25-3.33 (2H, m), 3.97 (2H, t, J = 6.5 Hz),4.53 (2H, s), 6.57 (1H, dd, J = 8.5, 2.0 Hz), 6.61-6.68 (1H, m), 6.82(1H, d, J = 8.5 Hz), 7.18 (1H, t, J = 6.0 Hz), 7.22-7.41 (4H, m),10.60 (1H, br. s). Anal. Calcd for C21H21N4O4SF: C, 56.75; H, 4.76;N, 12.61. Found: C, 56.46; H, 4.70; N, 12.29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.72. 3-[5-(4-Fluorophenyl)-3-methyl-4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1H-pyrazol-1-yl]propanenitrile (30); The compound 30 were prepared in a manner similar to that described for 5. Yield (43%). 1H NMR (300 MHz, DMSO-d6) delta 2.21(3H, s), 3.01 (2H, t, J = 6.5 Hz), 4.12 (2H, t, J = 6.5 Hz), 4.54 (2H, s),6.59 (1H, dd, J = 8.5, 2.0 Hz), 6.66 (1H, d, J = 2.0 Hz), 6.83 (1H, d,J = 8.5 Hz), 7.23-7.40 (4H, m), 10.60 (1H, br s). Anal. Calcd forC21H17N4O2F: C, 67.01; H, 4.55; N, 14.89. Found: C, 66.67; H,4.68; N, 14.49. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 24.0h;Inert atmosphere; Reflux; | General procedure: 5.85. 6-{1-[3-(Benzyloxy)-2,2-difluoropropyl]-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl}-2H-1,4-benzoxazin-3(4H)-one (36b); A mixture of 35b (600 mg, 1.37 mmol), 15a (490 mg, 1.78 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (220 mg, 0.27 mmol), cesium carbonate (1.20 g, 3.69 mmol) in THF/water (25 mL/5 mL) was stirredat reflux for 24 h under argon atmosphere, diluted with water and EtOAc, and then filtered. The organic layer was separated,washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/EtOAc as an elutant, and crystallized from IPE/hexane to give 36b (420 mg, 61%). The compound 36a,c were prepared in a manner similar to that described for 36b. 5.86. 6-[1-(2,2-Difluorobutyl)-5-(4-fluorophenyl)-3-methyl-1Hpyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (36a); Yield (40%). 1H NMR (300 MHz, DMSO-d6) delta 0.86 (3H, t,J = 7.4 Hz), 1.84 (2H, m), 2.20 (3H, s), 4.38 (2H, t, J = 13.3 Hz),4.53 (2H, s), 6.58 (1H, dd, J = 8.1, 2.1 Hz), 6.65 (1H, d, J = 1.9 Hz),6.82 (1H, d, J = 8.3 Hz), 7.21-7.35 (4H, m), 10.61 (1H, s). Anal. Calcd for C22H20N3O2F3: C, 63.61; H, 4.85; N, 10.12. Found: C, 63.44; H,4.83; N, 10.03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 24.0h;Inert atmosphere; Reflux; | General procedure: 5.85. 6-{1-[3-(Benzyloxy)-2,2-difluoropropyl]-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl}-2H-1,4-benzoxazin-3(4H)-one (36b); A mixture of 35b (600 mg, 1.37 mmol), 15a (490 mg, 1.78 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (220 mg, 0.27 mmol), cesium carbonate (1.20 g, 3.69 mmol) in THF/water (25 mL/5 mL) was stirredat reflux for 24 h under argon atmosphere, diluted with water and EtOAc, and then filtered. The organic layer was separated,washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/EtOAc as an elutant, and crystallized from IPE/hexane to give 36b (420 mg, 61%). 5.93. 6-[1-(3,3-Difluorobutyl)-5-(4-fluorophenyl)-3-methyl-1Hpyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (41); The compound 41 were prepared in a manner similar to thatdescribed for 36b. Yield (30%). 1H NMR (300 MHz, DMSO-d6) delta 1.53 (3H, t, J = 19.2 Hz), 2.19 (3H, s), 2.38 (2H, m), 4.00-4.11 (2H,m), 4.53 (2H, s), 6.57 (1H, dd, J = 8.3, 2.1 Hz), 6.65 (1H, d,J = 2.1 Hz), 6.82 (1H, d, J = 8.3 Hz), 7.24-7.39 (4H, m), 10.59 (1H,s). Anal. Calcd for C22H20N3O2F3: C, 63.61; H, 4.85; N, 10.12. Found: C, 63.49; H, 4.77; N, 9.96. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 24.0h;Inert atmosphere; Reflux; | General procedure: 5.85. 6-{1-[3-(Benzyloxy)-2,2-difluoropropyl]-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl}-2H-1,4-benzoxazin-3(4H)-one (36b); A mixture of 35b (600 mg, 1.37 mmol), 15a (490 mg, 1.78 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (220 mg, 0.27 mmol), cesium carbonate (1.20 g, 3.69 mmol) in THF/water (25 mL/5 mL) was stirredat reflux for 24 h under argon atmosphere, diluted with water and EtOAc, and then filtered. The organic layer was separated,washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/EtOAc as an elutant, and crystallized from IPE/hexane to give 36b (420 mg, 61%). 5.95. 6-[1-(3,3-Difluoro-4-hydroxybutyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (43); The compound 43 were prepared in a manner similar to thatdescribed for 36b. Yield (34%). 1H NMR (300 MHz, DMSO-d6) delta 2.19 (3H, s), 2.25-2.48 (2H, m), 3.51 (2H, td, J = 13.7, 6.3 Hz),4.00-4.14 (2H, m), 4.53 (2H, s), 5.51 (1H, t, J = 6.2 Hz), 6.57 (1H,dd, J = 8.3, 2.1 Hz), 6.65 (1H, d, J = 2.1 Hz), 6.82 (1H, d, J = 8.3 Hz),7.22-7.42 (4H, m), 10.60 (1H, s). Anal. Calcd for C22H20N3O3F3: C,61.25; H, 4.67; N, 9.74. Found: C, 61.40; H, 4.65; N, 9.55. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.38. 6-[5-(2,4-Difluorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (6b); Yield (48 %). 1H NMR (300 MHz, DMSO-d6) delta 2.20 (3H, s), 3.59(3H, s), 4.53 (2H, s), 6.58 (1H, dd, J = 8.1, 2.1 Hz), 6.64 (1H, d,J = 2.3 Hz), 6.83 (1H, d, J = 8.3 Hz), 7.18 (1H, td, J = 8.6, 2.1 Hz),7.31-7.47 (2H, m), 10.59 (1H, s). Anal. Calcd for C19H15N3O2F2: C,64.22; H, 4.25; N, 11.83. Found: C, 64.09; H, 4.21; N, 11.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.40. 6-(1-Ethyl-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)-2H-1,4-benzoxazin-3(4H)-one (16a); Yield (28 %). 1H NMR (300 MHz, DMSO-d6) delta 1.24 (3H, t,J = 7.0 Hz), 2.19 (3H, s), 3.91 (2H, q, J = 7.0 Hz), 4.53 (2H, s), 6.57(1H, dd, J = 8.0, 2.0 Hz), 6.65 (1H, d, J = 2.0 Hz), 6.81 (1H, d,J = 8.0 Hz), 7.19-7.36 (4H, m), 10.60 (1H, s). Anal. Calcd for C20H18N3O2F:C, 68.36; H, 5.16; N, 11.96. Found: C, 68.58; H, 5.39; N, 11.72. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.41. 6-[5-(4-Fluorophenyl)-3-methyl-1-propyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16b); Yield (36 %). 1H NMR (300 MHz, DMSO-d6) delta 0.73 (3H, t,J = 7.5 Hz), 1.57-1.73 (2H, m), 2.19 (3H, s), 3.84 (2H, t, J = 7.5 Hz), 4.53 (2H, s), 6.56 (1H, dd, J = 8.5, 2.0 Hz), 6.65 (1H, d, J = 2.0 Hz),6.81 (1H, d, J = 8.5 Hz), 7.22-7.35 (4H, m), 10.60 (1H, br. s). Anal.Calcd for C21H20N3O2F: C, 69.03; H, 5.52; N, 11.50. Found: C,69.04; H, 5.51; N, 11.50. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.42. 6-[1-Benzyl-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16c); Yield (38 %). 1H NMR (300 MHz, DMSO-d6) delta 2.21 (3H, s), 4.53(2H, s), 5.15 (2H, s), 6.59 (1H, dd, J = 8.3, 2.1 Hz), 6.68 (2H, d,J = 2.1 Hz), 6.82 (1H, d, J = 8.3 Hz), 6.97 (2H, dd, J = 7.9, 1.5 Hz),7.19-7.32 (7H, m), 10.60 (1H, s). Anal. Calcd for C25H20N3O2F: C,72.63; H, 4.88; N, 10.16. Found: C, 72.61; H, 4.94; N, 10.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.43. 6-[5-(4-Fluorophenyl)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16d); Yield (16 %). 1H NMR (300 MHz, DMSO-d6) delta 2.26 (3H, s), 4.56(2H, s), 6.59-6.75 (2H, m), 6.68 (1H, d, J = 8.3 Hz), 7.10-7.23 (6H,m), 7.27-7.39 (3H, m), 10.65 (1H, s). Anal. Calcd for C24H18N3O2F:C, 72.17; H, 4.54; N, 10.52. Found: C, 72.18; H, 4.58; N, 10.48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.44. 6-[5-(4-Fluorophenyl)-1-(3-hydroxypropyl)-3-methyl-1Hpyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16e); Yield (17 %). 1H NMR (DMSO-d6) delta 1.73-1.90 (2H, m), 2.18 (3H,s), 3.27-3.40 (2H, m), 3.94 (2H, t, J = 7.2 Hz), 4.47 (1H, t,J = 4.9 Hz), 4.53 (2H, s), 6.56 (1H, dd, J = 8.1, 2.1 Hz), 6.64 (1H, d,J = 1.9 Hz), 6.81 (1H, d, J = 8.0 Hz), 7.17-7.41 (4H, m), 10.60 (1H,s). Anal. Calcd for C21H20N3O3F: C, 66.13; H, 5.29; N, 11.02. Found:C, 65.89; H, 5.16; N, 10.80. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; for 18.0h;Inert atmosphere; Reflux; | General procedure: 5.36. 6-[5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (5); Under argon atmosphere, a mixture of 14a (500 mg, 1.96 mmol), <strong>[943994-02-3]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one</strong> (647 mg, 2.35 mmol), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg, 0.196 mmol) and cesium carbonate (1.92 g, 5.89 mmol) in THF/H2O (8 mL/2 mL) was stirred at reflux for 18 h. The reaction mixture was diluted with brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on NH-silica gel with hexane/EtOAc as an eluent and crystallized from EtOAc/hexane to give 5 (196 mg, 31%). The compound 6a-c, 16a-e, 16g-i were prepared in a manner similar to that described for 5. 5.45. 6-{1-[4-(Benzyloxy)butyl]-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl}-2H-1,4-benzoxazin-3(4H)-one (16f); Yield (44 %). 1H NMR (CDCl3) delta 1.47-1.59 (2H, m),1.81-1.92 (2H, m), 2.30 (3H, s), 3.38 (2H, t, J = 6.3 Hz), 3.99 (2H,t, J = 7.5 Hz), 4.22 (2H, s), 4.57 (2H, s), 6.43 (1H, d, J = 2.1 Hz),6.65 (1H, dd, J = 8.4, 2.1 Hz), 6.84 (1H, d, J = 8.4 Hz), 6.98-7.08(2H, m), 7.11-7.18 (2H, m), 7.22-7.36 (5H, m), 7.97 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With dichloro[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium; sodium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; | [0938] To the solution of XXXV-4 (1.4 g, 5.1 mmol) in dioxane/H20 (15 mL/3 mL), XXXV-5 (1.47 g, 4.2 mmol), Na2CO3 (890 mg, 8.4 mmol) and Pd-118 (137 mg , 6.21 mmol) were added. The mixture was purged with nitrogen and stuffed at 90C overnight. Then the mixture was diluted with EA (100 mL) and filtrated. The organic phase was washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product. The residue was purified by column chromatography on silica gel (PE:EA=2: 1 to 1:1) to afford Compound 209 (1.36 g, 64% yield). ?H NMR (CDC13, 400 MHz) 5 9.05 (s, 1H), 7.49-7.45 (m, 2H), 7.35-7.32 (m, 2H), 7.16 (s, 1H), 7.03-7.00 (m, 1H), 6.89-6.87 (m, 1H) ,6.74 (s, 1H), 6.58 (s, 1H), 4.65 (s, 2H), 2.13 (s, 3H). MS (ES) m/z (M+H) 416.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water;Reflux; | Compound 567 was prepared by Suzuki-Coupling of XXXV-4 with SEMprotected 5-bromo-4-methylpyridin-2(1H)-one, followed by HC1 hydrolysis. ?H NMR (DMSO-d6, 300 MHz) (5 11.54 (s, 1H), 10.74 (s, 1H), 7.14 (s, 1H), 6.97 (d, J= 8.0 Hz, 1H), 6.85 (d, J= 6.0 Hz, 1H), 6.78 (s, 1H), 6.27 (s, 1H), 4.64 (s,2H), 2.04 (s, 3H). MS (ES) m/z (M+H) 257.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; water; at 75℃; for 4h;Inert atmosphere; | A solution of the compound 5a (2.20g, 8.00mmol), 3-bromo-5-chloropyrazin-2-amine (1.54g, 7.27mmol), potassium acetate (2.00g, 14.54mmol), Pd (dppf) Cl2 (0.15g, 0.20mmol), H2O (2mL) in dioxane (40mL) was heated to 75 C under N2 for 4 hours. Hexane (50mL) was added, the precipitate was filtered to afford the compound 5b as a brown solid (0.79g, 36%). MS: 277 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; water; at 75℃; for 4.0h;Inert atmosphere; | Compound 5a (2.20 g, 8.00 mmol), 2-amino-3-bromo-6-chloropyrazine (1.54 g, 7.27 mmol), potassium acetate (2.00 g, 14.54 mmol), Pd(dppf)Cl2 (0.15 g, 0.20 mmol), water (2 mL) was added in a nitrogen atmosphere in 1,4-dioxane (40 mL), stirred for 75 4 hours.The reaction was cooled to room temperature, hexane (50 mL), filtered to give a brown solid compound 5b (0.79 g, 36%) |
Tags: 943994-02-3 synthesis path| 943994-02-3 SDS| 943994-02-3 COA| 943994-02-3 purity| 943994-02-3 application| 943994-02-3 NMR| 943994-02-3 COA| 943994-02-3 structure
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