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CAS No. : | 832114-00-8 | MDL No. : | MFCD05863910 |
Formula : | C11H18BNO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CVLHETBAROWASE-UHFFFAOYSA-N |
M.W : | 223.08 | Pubchem ID : | 2758656 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.73 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 62.91 |
TPSA : | 44.49 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) : | -6.13 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.16 |
Log Po/w (WLOGP) : | 1.59 |
Log Po/w (MLOGP) : | 0.59 |
Log Po/w (SILICOS-IT) : | 1.68 |
Consensus Log Po/w : | 1.2 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.75 |
Solubility : | 0.397 mg/ml ; 0.00178 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.73 |
Solubility : | 0.418 mg/ml ; 0.00188 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.62 |
Solubility : | 0.0535 mg/ml ; 0.00024 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.43 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
63% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 150℃; for 0.75h;Microwave irradiation; | Example 56; A Smith Process vial was charged with 48 (54 mg, 0.10 mmol), <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (28 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol), 0.1 mL of 2M K2CO3, and 2.5 mL of DMF. The reaction mixture was degassed by bubbling nitrogen through for 15 min, then sealed and exposed to microwave irradiation for 30 min at 150 C. The reaction was cooled, filtered and purified by HPLC to give 35 mg (63%) of 56. MS found: (M+H)+557. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With sodium carbonate;chloro(di-2-norbornylphosphino)(20-dimethylamino-1,10-biphenyl-2-yl)palladium; In ethanol; water; toluene; at 80℃; for 16h; | To 72C (1.74 g, 5 mmol) and DIEA (1.62 g 12.5 mmol) in DCE (10 mL) was added dropwise freshly prepared (S)-2-phenyl-propionyl chloride (2.1 g 16.5 mmol) in DCE (10 mL). The resulting mixture was stirred at rt for 16 h, then the solvent was evaporated and the crude product was purified by flash chromatography to give (S)-1-[7-bromo-3-(3-methoxy-phenoxy)-2,3,4,5-tetrahydro-1-benzazepin-1-yl]-2-phenyl-propan-1-one as a foamy solid (1.8 g, 72%). LC/MS m/z 498 (M+H)+. To this intermediate (96 mg, 0.2 mmol) were added <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolane-2-yl)isoxazole</strong> (90 mg, 0.4 mmol) and chloro(di-2-norbornylphosphino)(20-dimethylamino-1,10-biphenyl-2-yl)palladium (10 mg) in 5:4:3 toluene/EtOH/2N Na2CO3 (2.4 mL). The resulting mixture was heated at 80 C. under an argon atmosphere for 16 h. Aqueous work-up and removal of solvent, followed by purification by prep-HPLC, gave Example 77 as an oil (22.7 mg, 23%). LC/MS m/z 497.26 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 95℃; for 16h;Inert atmosphere; | To a solution of 3,5-dibromopyridine (0.20 g, 0.85 mmol) in 1,4-dioxane (8 mL) and H20 (0.55 mL) under nitrogen was added 3,5-dimethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (0.13 g, 0.93 mmol), and potassium carbonate (0.35 g, 2.5 mmol). The reaction mixture was degassed with nitrogen for 15 min. (l, l'-Bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (62 mg, 0.08 mmol) was added and the reaction mixture was again degassed for 10 min with nitrogen. The reaction mixture was stirred at 95 C for 16 h, then allowed to cool to room temperature and quenched by the addition of water. The reaction mixture was transferred to a separation funnel and the aqueous layer extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide 4-(5- bromopyridin-3-yl)-3,5-dimethylisoxazole (0.15 g, 71 %) as a white solid. LCMS Method T: retention time 1.52min, [M+l] = 253. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 2h;Inert atmosphere; | Example No. 103; Preparation of Compound No. 137[0400] To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5- tetrahydro-lH-pyrido[4,3-b]indole (100 mg, 0.280 mmol), <strong>[832114-00-8]3,5-dimethylisoxazole-4-boronic acid pinacol ester</strong> (124 mg, 0.556 mmol) and K2C03 (116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90 C for 2h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 4-(6-(2,8-dimethyl-3,4-dihydro- lH-pyrido[4,3-b]indol-5(2H)-yl)pyridin-3-yl)-3,5-dimethylisoxazole as the TFA salt. 1H NMR (CD3OD, TFA salt) d (ppm): 8.6 (s, 1H), 8.06 (d, 1H), 7.78 (d, 1H), 7.57 (d, 1H), 7.38 (s, 1H), 7.17 (d, 1H), 4.7 (m, 1H), 4.4 (d, 1H), 3.82 (bs, 1H), 3.46-3.62 (m, 2H), 3.2 (s, 3H), 3.17 (m, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H). | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 2h; | Example No. 103: Preparation of Compound No. 137[0391] To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indole (100 mg, 0.280 mmol), <strong>[832114-00-8]3,5-dimethylisoxazole-4-boronic acid pinacol ester</strong> (124 mg, 0.556 mmol) and K2C03 (116 mg, 0.839 mmol) in DME (4 mL) and water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90 C for 2h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 4-(6-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol- 5(2H)-yl)pyridin-3-yl)-3,5-dimethylisoxazole as the TFA salt. 1H NMR (CD3OD, TFA salt) delta (ppm): 8.6 (s, IH), 8.06 (d, IH), 7.78 (d, IH), 7.57 (d, IH), 7.38 (s, IH), 7.17 (d, IH), 4.7 (m, IH), 4.4 (d, IH), 3.82 (bs, IH), 3.46-3.62 (m, 2H), 3.2 (s, 3H), 3.17 (m, IH), 2.51 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 80℃;Inert atmosphere; | Step 2. 1-[4-chloro-6-(3,5-dimethylisoxazol-4-O-3'-fluoro-5-methylbiphenyl-2-yl]ethanone To a solution of sodium hydrogenecarbonate (49 mg, 0.58 mmol) in water (1 mL) was added a solution of 1-(6-bromo-4-chloro-3'-fluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g, 0.29 mmol) in toluene (1 mL) followed by <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (78 mg, 0.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol). The reaction mixture was bubbled with N2 for 5 min and then heated at 80 C. overnight. The organic layer was concentrated and flashed on silica gel (eluting with 0-35% of ethyl acetate in hexanes) to afford the desired product (40 mg, 38%). LCMS calculated for C20H18ClFNO2 (M+H)+: m/z=358.1. found: 358.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 5h;Inert atmosphere; Sealed tube; | A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (318 mg, 1.424 mmol), Methyl 2-(3-bromo-5,7-difluoroquinolin-6-yl)acetate (E1.i) (300 mg, 0.949 mmol), and sodium carbonate (201 mg, 1.898 mmol) in dioxane (15 mL) was added water (1.5 mL), and the mixture was bubbled with argon for 3 min.PdCI2(dppf) CH2CI2 (78 mg, 0.095 mmol) was added. The reaction vial was sealed and heated at 100 C for 5 h. LCMS showed the reaction was complete. The reaction mixture was diluted with EtOAc, washed successively with satd. NaHC03 aqueous solution, water, brine, dried, concentrated, and purified by column chromatography to afford 244 mg of the title compound as gray solid. H-NMR (400MHz, CDCI3) delta ppm 8.87 (s, 1 H), 8.25 (s, 1 H), 7.68 (s, 1 H), 3.95 (s, 2H), 3.78 (s, 3H), 2.50 (s, 3H), 2.35 (s, 3H). LCMS (method A): [MH]+ = 333, tR = 2.44 min. | |
244 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 5h;Inert atmosphere; Sealed tube; | A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (318 mg, 1.424 mmol), Methyl 2-(3-bromo-5,7-difluoroquinolin-6-yl)acetate (E1.i) (300 mg, 0.949 mmol), and sodium carbonate (201 mg, 1.898 mmol) in dioxane (15 mL) was added water (1.5 mL), and the mixture was bubbled with argon for 3 min. PdCl2(dppf)CH2Cl2 (78 mg, 0.095 mmol) was added. The reaction vial was sealed and heated at 100 C. for 5 h. LCMS showed the reaction was complete. The reaction mixture was diluted with EtOAc, washed successively with satd. NaHCO3 aqueous solution, water, brine, dried, concentrated, and purified by column chromatography to afford 244 mg of the title compound as gray solid. 1H-NMR (400 MHz, CDCl3) delta ppm 8.87 (s, 1H), 8.25 (s, 1H), 7.68 (s, 1H), 3.95 (s, 2H), 3.78 (s, 3H), 2.50 (s, 3H), 2.35 (s, 3H). LCMS (method A): [MH]+=333, tR=2.44 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In tetrahydrofuran; water; at 110℃; for 12h; | General procedure: To a mixture of Cs2CO3 (2 equiv), arylboronic acid (1.2 equiv), and aryl bromide (1equiv) in wet 1,4-dioxane was added Pd(PPh3)4 (10 mol%), and the mixture was heatedat 110 C with stirring. The progress of the reaction was monitored by TLC. Aftercomplete consumption of 2, the reaction mixture was poured into cold water andextracted three times with CH2Cl2. The organic layer was dried over MgSO4. Afterremoval of solvents under reduced pressure, the residue was purified by columnchromatography on silica (hexane:ethylacetate = 19: 1). The solvent was evaporated andthe product was dried in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 1h;Microwave irradiation; | A solution of {S)-tert-butyl (1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (100 mg, 0.282 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoxazole (126 mg, 0.565 mmol) and PdCl2(dppf)-CH2Cl2 adduct (11 mg, 0.014 mmol) in dioxane (1.0 mL) and 3 M aqueous potassium carbonate (1.01 mL, 3.02 mmol) were heated at 120C for 1 hour in a microwave reactor. The mixture was diluted with EtOAc (50 mL), washed with saturated aqueous ammonium chloride (50 mL) and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified on a silica gel column (24 g) eluting with a 0-50% EtOAc gradient in hexanes to give the title compound as a clear, colorless oil (107 mg, 100%). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.27 - 1.35 (m, 9 H), 2.05 (d, J=12.6 Hz, 3 H), 2.20 - 2.28 (m, 3 H), 3.77 - 3.85 (m, 3 H), 4.52 - 4.68 (m, 1 H), 6.59 (d, J=3.0 Hz, 1 H), 6.81 - 6.90 (m, 1 H), 7.68 (d, J=3.3 Hz, 1 H), 7.71 (d, J=8.8 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H26N403, 371; found 371. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 20h;Inert atmosphere; | [0170] A mixture of 26 (10.0 g 53.2 mmol), 22 (13.1 g, 58.5 mmol), K2CO3 (22.2 g, 160 mmol) and water (15 mL) in dioxane (150 mL) was purged with N2 for 20 min at rt. Pd(PPh3)4 (3.1 g, 2.66 mmol) was added and the mixture was purged H2 for additional 15 min. The reaction was stirred at 80 C for 20 h under N2. The reaction was cooled to rt and concentrated. The residue was dissolved in dichloromethane, washed with water, then brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane to 98:2 dichloromethane /methanol) to give 27 (10.2 g, 94%) as a white solid: NMR (400 MHz, CDCI3) delta 8.07 (d, J - 1.95 Hz, 1H), 7.47 (dd, J = 8.6, 2.34 Hz, 1H), 6.84 (d, J = 8,6 Hz, 1H), 3.98 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H), |
89% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | General procedure: Step 1: [0759] To a solution of 12 (5.6 g, 29.9 mmol) in 1,4-dioxane (120 mL) and water (24 mL) was added <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (8.0 g, 35.9 mmol), sodium carbonate (6.34 g, 59.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (863 mg, 0.75 mmol). The reaction mixture was purged with nitrogen and was heated at 100 C. for 16 h. The mixture was diluted with methylene chloride (200 mL) and washed with brine (2×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-15% ethyl acetate/hexanes) afforded 13 (5.4 g, 89%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) delta 7.20 (dd, J=2.5 Hz, 0.6 Hz, 1H), 7.76 (dd, J=8.6 Hz, 2.5 Hz, 1H), 6.93 (dd, J=8.5 Hz, 0.7 Hz, 1H), 3.89 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; | General procedure: Step 3: [0792] To a solution of 28 (10.0 g, 49.3 mmol) in 1,4-dioxane (400 mL) and water (40 mL) was added <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (13.2 g, 59.1 mmol), potassium carbonate (13.6 g, 98.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.71 g, 1.48 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to give 29 (9.26 g, 86%) as a yellow solid: 1H NMR (500 MHz, CDCl3) delta 7.45 (d, J=2.0 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 4.02 (s, 3H), 3.87 (s, 2H), 2.37 (s, 3H), 2.23 (s, 3H) |
65% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | To a solution of 1 (5.0 g, 24.6 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)isoxazole (6.6 g, 29.6 mmol) in 1,4-dioxane (260 mL) and H20 (20 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.42 g, 1.23 mmol) and potassium carbonate (6.8 g, 49.3 mmol). The reaction mixture was purged with nitrogen and heated at 90 C for 16 h. The mixture was diluted with methylene chloride (100 mL) and washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-75% ethyl acetate/hexanes) afforded 2 (3.53 g, 65%) as a yellow solid: *H NMR (300 MHz, DMSO-cf6) delta 7.35 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 5.07 (s, 2H), 3.89 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H); ESI m/z 220 [M + H]+. |
65% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | [0150] To a solution of 1 (5.0 g, 24.6 mmol} and 3,5-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (6.6 g, 29.6 mmol) in 1,4-dioxane (260 mL) and H20 (20 mL) was added tetrakis(triphenylphosphine)palladium(O) (1.42 g, 1.23 mmol) and potassium carbonate (6.8 g, 49.3 mmol). The reaction mixture was purged with nitrogen and heated at 90 C for 16 h. The mixture was diluted with methylene chloride (100 mL) and washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-75% ethyl acetate/hexanes) afforded 2 (3.53 g, 65%) as a yeliow soiid: JH NMR (300 MHz, DMSO-d6) delta 7.35 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 5.07 (s, 2H), 3.89 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H); ESI m/z 220 [M + EtaGamma. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 90℃; for 17h;Inert atmosphere; | Step 2: [0824] To a solution of 39 (3.70 g, 12.4 mmol) in 1,4-dioxane (180 mL) and water (20 mL) was added <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (3.47 g, 14.9 mmol), potassium carbonate (3.42 g, 24.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (286 mg, 0.248 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 17 h. The reaction mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 40 (2.52 g, 65%) as a yellow solid: 1H NMR (500 MHz, CDCl3) delta 7.42 (d, J=2.3 Hz, 1H), 7.32-7.41 (m, 5H), 7.08 (d, J=2.3 Hz, 1H), 5.22 (s, 2H), 2.29 (s, 3H), 2.14 (s, 3H); ESI m/z 315 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere; | A mixture of 2-[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253 g, 500 mg, 0.96 mmol), 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (320 mg, 1.44 mmol), cesium fluoride (437 mg, 2.88 mmol) and tetrakis(triphenylphosphine)palladium(0) (70.0 mg, 0.06 mmol) in dioxane (20 mL) was degassed with nitrogen, then stirred at 100 C. for 18 hours. After cooling, the mixture was partitioned between water (15 mL) and ethyl acetate (3*20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 10:1 petroleum ether/ethyl acetate), affording 2-[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (253h, 400 mg, 78% yield) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | Step 5. 7-(3, 5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[l,5,4- dejf 1 ,4] benzoxazin-2( lH)-one 7-Bromo-4-phenyl-4, 5-dihydroimidazo[l,5,4-de][l,4]benzoxazin-2(7H)-one (200 mg, 0.6 mmol) and 3, 5-dimethyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)isoxazole (160 mg, 0.72 mmol) [Aldrich, cat. 643882] were dissolved in 1, 4-dioxane (20 mL) and potassium carbonate (200 mg, 1 mmol) in water (8 mL). The reaction was deoxygenated with nitrogen and the catalyst [1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (1 : 1) (20 mg, 0.03 mmol) was added. The reaction mixture was deoxygenated with nitrogen and was heated at 100 C. After heating for 2 h the reaction was complete by LCMS. The reaction mixture was allowed to cool to room temperature, EtOAc was added and the mixture was washed with water, brine, then dried over magnesium sulfate and concentrated to give the crude product. The product was purified on preparative HPLC on a C- 18 column eluting with a water : MeCN gradient buffered pH 2 with TFA to give 7-(3,5-dimethylisoxazol-4-yl)-4- phenyl-4,5-dihydroimidazo[l, 5, 4-de][l, 4]benzoxazin-2(7H)-one as white solid (0.10 g, 50%). LCMS calc. for C2oH18 303 (M+H)+: m/z = 348.1 ; found: 348.1. XH NMR (500 MHz, DMSO-i/6) delta 10.96 (s, 1H), 7.38 - 7.24 (m, 3H), 7.16 (d, J= 7.2 Hz, 2H), 6.84 (d, J= 8.0 Hz, 1H), 6.76 (d, J= 8.0 Hz, 1H), 5.47 (s, 1H), 4.57 (dd, J= 11.6, 2.2 Hz, 1H), 4.40 (dd, J= 11.6, 3.1 Hz, 1H), 2.25 (s, 3H), 2.08 (s, 3H). |
50% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | Step 5. 7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one7-Bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (200 mg, 0.6 mmol) and <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (160 mg, 0.72 mmol) [Aldrich, cat. 643882] were dissolved in 1,4-dioxane (20 mL) and potassium carbonate (200 mg, 1 mmol) in water (8 mL). The reaction was deoxygenated with nitrogen and the catalyst [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (1:1) (20 mg, 0.03 mmol) was added. The reaction mixture was deoxygenated with nitrogen and was heated at 100 C. After heating for 2 h the reaction was complete by LCMS. The reaction mixture was allowed to cool to room temperature, EtOAc was added and the mixture was washed with water, brine, then dried over magnesium sulfate and concentrated to give the crude product. The product was purified on preparative HPLC on a C-18 column eluting with a water: MeCN gradient buffered pH 2 with TFA to give 7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as white solid (0.10 g, 50%). LCMS calc. for C20H18N3O3(M+H)+: m/z=348.1. found: 348.1. 1H NMR (500 MHz, DMSO-d6) delta 10.96 (s, 1H), 7.38-7.24 (m, 3H), 7.16 (d, J=7.2 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.47 (s, 1H), 4.57 (dd, J=11.6, 2.2 Hz, 1H), 4.40 (dd, J=11.6, 3.1 Hz, 1H), 2.25 (s, 3H), 2.08 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With palladium diacetate; caesium carbonate; triphenylphosphine; In 1,2-dimethoxyethane; at 90℃; for 16h;Inert atmosphere; | Intermediate step 5 toward Example 1: 3-(3,5-dimethylisoxazol-4-yl)-4-methoxy-aniline [00231] Pd(OAc)2 (1.42 g, 6.34 mmol) and PPh3 (3.33 g, 12.7 mmol) were weighed into a 2-necked flask equipped with a reflux condenser, and the flask was flushed with N2 gas. Degassed DME (60.0 mL) was added, and the mixture was stirred for 30 m at rt. 3,5-Dimethyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (34.0 g, 152 mmol), 3-iodo-4- methoxy-aniline (15.8 g, 63.4 mmol), and Cs2C03 (51.7 g, 159 mmol) were weighed into a second flask, and the flask was flushed with N2 gas. Degassed DME (300 mL) and degassed water (30.0 mL) were added. The mixture was stirred for 20 m and then added to the first flask. The second flask was rinsed with degassed DME (15.0 mL), and the liquid was transferred to the first flask. The resulting mixture was heated to 90C for 16 h and then cooled to rt. The mixture was diluted with saturated aq NaHC03 (100 mL) and EtOAc (100 mL), and the aq phase was extracted with EtOAc (3X150 mL). The combined organic phases were dried over MgS04, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography on silica gel, eluting with mixtures of EtOAc and hexanes to provide the title compound as a solid (12.9 g, 93%). 1H NMR (500 MHz, CDC13) delta 6.80 (d, J = 8.7 Hz, 1H), 6.69 (dd, J = 8.6, 2.9 Hz, 1H), 6.48 (d, J = 2.9 Hz, 1H), 3.70 (s, 3H), 3.49 (s, 2H), 2.29 (s, 3H), 2.16 (s, 3H); [M+H]+ 219.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 110℃; for 1h; | [00450] Methyl 5- romo~2-(me&ylaiaino)-3-mtroben3ate (20.1 g, 96.5 mmol), 3,5- dimemyl~4"(4,4,5,5~tetfamethy^ (24.82 g, 11 1.25 rnmol), PEPPSF-IPr catalyst (2.63 g, 3.86 mmol), Cesium carbonate (67.96 g, 208.59 mmol), 1,2- Dimethoxyethane (100 ml) and. Water (30 nil) were mixed together and fee solution degassed for 5 minutes before heating to HO for 1 hour. Reaction mixture was then cooled, diluted with EtAc and water and extracted EtAc (3x). Organics were washed with water then brine, dried over sodium sulfate and evaporated to dryness under reduced pressure. Crude material purified by silica gel chromatography using EtAc/Hex as the eluent to methyl. 5-(3,5~ dunefeylisGxazol~4~yl)-2~(meft^ (20.5 g, 96%). |
38% | With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 20 - 110℃; for 1.5h;Inert atmosphere; | To a stirred solution of methyl 5-bromo-2-(methylamino)-3-nitrobenzoate (1.5 g, 5.2 mmol) in 1,2-deimethoxyethane (15 mL) and water (3 mL), <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (2.1 g, 9.3 mmol) was added, followed by cesium carbonate (2.8 g, 8.6 mmol). After addition was completed, resulting reaction mixture was stirred at rt for 30 min. followed by degas with argon for 15 min. Then PEPPSI-IPr catalyst (0.2 g, 0.2 mmol) was added and again reaction mixture was degas with argon for another 15 min. Then resulting reaction mixture was heated to stir at 110 C. for 1 h under argon atmosphere. Reaction monitored by LCMS till completion. Reaction was cooled to rt then diluted with EtOAc (25 mL) and water (15 mL). EtOAc (25 mL) was used twice to extract product. Organic layers were combined and dried with magnesium sulfate and condensed. The resulting mixture was purified via normal phase 0-25% (EtOAc/Hexanes) to give methyl 5-(3,5-dimethylisoxazol-4-yl)-2-(methylamino)-3-nitrobenzoate (1.5 g, 38%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; for 0.5h; | 4-Bromo-2-nitroaniline (1g, 4.6mmol) and <strong>[832114-00-8]3,5-dimethylisoxazole-4-boronic acid pinacol ester</strong> (2g, 9.2mmol) were added to a solvent mixture of 1,2-dimethoxyethane (12mL) and water (6mL). PEPPSI-IPr (312mg, 0.46mmol) and Cs2CO3 (4.5g, 13.8mmol) were added to the above mixture. The reaction mixture was heated at 120C for 30min. The reaction mixture was then diluted with 100mL EtOAc and washed with brine (50mL×2). The organic solvent was evaporated and the residue dissolved in dichloromethane and purified with silica gel column chromatography (product eluted at 50% [v/v] EtOAc/hexane) to afford the title compound as a yellow solid. LCMS m/z [M+H]+C11H11N3O3 requires: 234. 08. Found 234.3. |
88% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | To a solution of 9 (1.00 g, 4.61 mmol) in 1 ,4-dioxane (40 mE) and water (4 mE) was added 3,5-dim- ethyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)isox- azole (1.23 g, 5.53 mmol) potassium carbonate (1.27 g, 9.22 mmol), and tetrakis(triphenylphosphine)palladium(0) (266 mg, 0.231 mmol). The reaction mixture was purged with nitrogen and heated at 90 C. for 16 h. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to give 10(950mg, 88%) as a yellow solid: ?H NMR (500 MHz, CDC13) oe 8.02 (d, J=2.1 Hz, 1H), 7.26 (dd, 2.1 Hz, 8.5 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 6.14 (s, 2H), 2.40 (s, 3H), 2.26 (s, 3H); ESI mlz 234 [M+H]. |
88% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | General procedure: To a 9 (1.00g, 4.61mmol) in 1,4-dioxane (40 mL) and water (4mL)was added <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong>(1.23g, 5.53mmol), Potassium carbonate (1.27g, 9.22mmol) and tetrakis(triphenylphosphine)palladium(266mg, 0.231mmol). The reaction mixture was purged with nitrogenAnd heated at 90 16h. The reaction mixture wascooled to room temperature, concentrated and purified by chromatography (silicagel, 0-30% ethyl acetate / hexylDioxane) to give the 10 (950mg, 88% yellow solid) |
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h; | Starting material 4-bromo-2-nitroaniline (1 g, 4.6 mmol) and <strong>[832114-00-8]3,5-dimethylisoxazole-4-boronic acid pinacol ester</strong> (2 g, 9.2 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (12 ml) and water (6 ml). To the above mixture were added PEPPSI-IPr (312 mg, 0.46 mmol) and Cs2CO3 (4.5 g, 13.8 mmol). The reaction mixture was heated at 120 C. for 30 mins. The reaction mixture was then diluted with EtOAc (100 ml), washed with bring (50 mL*2). The organic solvent was evaporated and the residue was dissolved in DCM and purified with silica gel chromatography (product came out at 50% EtOAc/Hexane) to afford 4-(3,5-dimethylpyrazol-4-yl)-2-nitroaniline as a yellow solid. C11H11N3O3. 234.3 (M+1) | |
150 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 95℃; | 100527] To a mixture of 4~bromo-2-iiii3X)-phen.ylamine (150 g, 0.691 mol, 1.0 eq) and 3,5~dimeihylisoxazole~4--boronic acid pkiacol ester (169 g, 0,725 mol, 1.05 eq) in 1,2·· dime&oxyethane (1.5 L) and water (700 mL) were added PdC(dppi) (56 g, 69 mmol, 0.1 eq) and K2CO3 (1 0 g, L38 rno, 2.0 eq). The reaction mixture was heated at 95 C overnight, The reaction mixture was diluted with EtOAc (3 L), washed with brine (2 x 500 mL). Tbe organic solvent was evaporated and fee residue was purified with flash, chromatography on silica (PE/EA = 10:1 - 1 : 1) to give 150 g 4-(3,S-dimetbylisoxa^ol"4"yl)--2"mtroaniline as a red solid. [ThetaTheta528] C H] ; 303. 234.2 (M+l) |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; | To a solution of 29 (1.00 g, 4.61 mmol) in 1,4-dioxane (40 m L) and water (4 mL) was added 3;5-dimeihyl-4-(4,4 5,5 etratTiethv'i-l,3,2-dioxaboroian-2-y)isOxazoie (1.23 g, 5.53 mmol), potassium carbonate (1.27 g, 9.22 mmol), and tetrakis(triphenyphosphine)paliadium(0) (266 mg, 0.231 mmol). The reaction mixture was purged with nitrogen and heated at 90 C overnight. The reaction mixture was cooled to room temperature, concentrated and purified bychromatography (silica gel, 0-30% ethyl acetate/hexanes) to give a yellow solid which was dissolved in acetic acid (15 mL), W-bromosuccinimide (753 mg, 4.23 mmol) was added at 0 C. The reaction was warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo. The residue was suspended in hot MeOH, cooled to room temperature and basified with 10% aq.NaHCOj. The mixture was diluted with water and filtered. The filter cake was washed with water and dried in vacuo to afford 30 (1.10 g, 87%) as a yellow solid:XH IM R (500 M Hz, CDCI3) delta 8.04 (d, J = 2.1 Hz, 1H), 7.61 (d, J - 2.1 Hz, 1H), 6.69 (bs, 2H), 2.40 (s, 3H), 2.26 (s, 3H); ESI m/z 312 [M + H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 2h;Microwave irradiation; | <strong>[180624-08-2]4-bromo-2-iodo-6-nitroaniline</strong> (150 mg, 0.44 mmol) and 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (390 g, 1.75 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (2 ml) and water (1 ml). To the above mixture were added PEPPSI-Ipr (30 mg, 0.04 mmol) and Cs2CO3 (0.86 g, 2.64 mmol). The reaction mixture was heated at 120 C. in microwave reactor for 2 hs. The reaction mixture was then diluted with EtOAc (100 ml), washed with bring (50 ml, 2 times). The organic solvent was evaporated and the residue was dissolved in DCM and purified with combi-flash column chromatography (product came out at 25% MeOH/DCM) to afford 2,4-bis(3,5-dimethylisoxazol-4-yl)-6-nitroaniline. C16H16N4O4. 329.2 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 18h;Inert atmosphere; | To a solution of 20 (3.00 g, 10,8 mmoi) in 1,4-dioxane (60 m L) and water (6 mL) was added 3.5-dmethyi-4-{4J4,5,.5- tetramethyS-l,3,2-dioxaboroian-2--yiJisoxazoe (2.90 g, .13.0 mmoi), tetrakis(triphenyiphosphine)paliadium(0) (624 mg, 0.54 mmoi) and potassium carbonate (2,98 g, 21.6 mmoi). The reaction mixture was purged with nitrogen and heated at 90 "C for 18 h. The mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-20% ethyl acetate in hexanes) to afford 110 (3.18 g, 99%) as a yellow solid: Eta NMR (500 MHz, CDC 6 7,38 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 7,3 Hz, 2H), 7,28 (t, J = 7.1 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 6.55 (del, J = 1.8, 7.7 Hz, IH), 6.43 (d, J = 1.8 Hz, IH), 4.35 (s, 2H), 3.88 (s, 1H), 3.42 (s, 2.H), 2.23 (s, 3H), 2.11 (s, 3H); ESi m/z 294 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h; | To a mixture of 26 (1.00 g, 5.32 mmol) and 3 (1.78 g, 7,98 mmol) in 1,4- dioxarse (35 rnL) and water (7.5 mL) was added potassium carbonate (1.47 g, 10.6 mmol) and tetrakis{triphenyphosphine)paiadium{0) (307 mg, 0.27 mmoi). The reaction was stirred and heated at 90 C for 16 h. The reaction mixture was diluted with metha nol (20 mL) and silica gel (15 g) was added. The slurry was concentrated to dryness and the resulting powder was loaded onto silica gel and eluted with 0-90% ethyl acetate in hexanes. The clean product was concentrated to give 27 (939 mg, 70%) as a yelow-green solid:JH EsSMR (500 MHz, CDC3) 6 7.45 (t, J = 2.0 Hz, 1H), 6.78 (t, J = 2.0 Hz, 1H), 2.37 (s, 3 H), 2.22 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 17.0h; | To a mixture of 32 (1.50 g, 6.46 mmol) and 3 (2.16 g, 9.70 mmol) in 1,4- dioxane (40 mi.) and water (4 mL) was added potassium carbonate (1.79 g, 12.9 mmol) and tetrakis(triphenyiphosphine)pailadiurn(Q) (373 mg, 0.32 mmol). The reaction was stirred and heated at 90 C for 17 h. The reaction mixture was diluted with methanol (20 mL) and silica gel (20 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded onto silica gel and eluted with 0-50% ethyl acetate in hexanes. The clean product was concentrated to give 87 (585 mg, 36%) as a brown solid; H N R (500 MHz, CDCI3) delta 7.62 (d, J = 2.0 Hz, 1H), 6,81 (d, J = 2.0 Hz, 1H), 6.01 ibr s, 2H), 3.52 (br s, 2H), 2.39 (s, 3H), 2.25 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 17h; | To a mixture of 33 (200 mg, 0.78 rnmo) and 3 (262 mg, 1.17 mmol) in 1,4- dioxane (6 mL) and water (1.5 mL) was added potassium carbonate (216 mg, 1.56 mmol) and tetrakis(triphenyphosphine)pailadium(0) (45 mg, 0.04 mmol). The reaction was stirred and heated at 90 C for 17 h. The reaction mixture was diluted with methanol (20 mL) and silica gel (15 g) was added. The suspension was concerstrated to dryness and the resulting powder was purified by chromatography (silica ge, 0-90% hexanes/ethyl acetate) to give 34 (187 mg, 88%) as a yeiiow solid;":H NMR (500 Hz, CDC3) delta 8,00 (d, J = 1.5 Hz, 1H), 7.89 (s, 1H), 2.76 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 90℃; for 16h;Inert atmosphere; | To a solution of 46 (1.0 g, 5.08 mmoi) in 1,4-dioxane (50 mL) was added 3,5-dirnethyl-4-(4,4,5,5-tetr3methyi-l,3/2-dioxaboroian-2-y)isoxazoie (1.47 g, 6.6 mrnol), sodium carbonate (1.10 g in 8 mL Eta20, 10.2 mmoi) and tetrakis(triphenylphosphine)paliadum(Q) {587 mg, 0.51 mmoi), The reaction mixture was purged with nitrogen and heated at 90 C for 16 h, The mixture was filtered through a layer of Celtte and the filtrate was concentrated. Purification by chromatography (silica ge, 0-50% ethyi acetate/dichloromethane) afforded 63 (850 mg, 79%) as a yellow solid : H N MR (300 Hz, DMSO-d6) delta 11.4 (s, 1H), 8.30 (t, i = 2.1 Hz, 1H), 7.75 (dd, J = 1.8, 0.9 Hz, 1H), 7.70 (t, J = 3.0 Hz, 1H), 6.61-6.59 (m, 1H), 2.42 (s, 3H), 2.24 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 17h; | To a mixture of 55 (261 mg, 0.81 mmol) and 3 (217 mg, 0.97 mmol) in 1,4- dioxane (7 mL) and water (1.5 mL) was added potassium carbonate (224 mg, 1.62 mmol) and tetrakis(tripnenyphosphine)palladium(0) (47 mg, 0.04 mmol). The reaction was stirred and heated at 90 C for 17 h. The reaction mixture was diluted with methanol (20 ml.) and silica gel (15 g) was added, The suspension was concentrated to dryness and the resulting powder was loaded onto silica gei and eiuted with 0-50% ethyl acetate in hexanes. The clean product was concentrated to give 56 (226 mg, 82%) as a yellow solid ::H N M (500 MHz, CDCI3) delta 8.19 id, J = 4.5 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.40-7.28 (m, 5H), 6.89 (d, J = 2.0 Hz, 1H), 4.66 (quint, J = 5.0 Hz, 1H), 2.10 (s, 3H), 1.94 (s, 3H), 1.71 (d, y = 7.0 H2, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 99% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; | To a solution of 58 (1.00 g, 5.76 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added 3,5-dirnethyl-4-(4,4,5,5-tetrarrethy -l,3/2--dioxaboroian-2-yi)isoxazoe (1.93 g, 8.64 mmol), potassium carbonate (1.59 g, 11.5 mmol), and tetrakis(triphenylphosphine)pailadium(0) (333 mg, 0.288 mmol). The reaction mixture was purged with nitrogen and heated at 90 °C overnight. The reaction mixture was cooled to room temperature, concentrated and purified bychromatography (silica gel, 0-100percent ethyl acetate in hexanes) to afford 59 (1.42 g, >99percent) as a yellow solid: H N (300 MHz, CDCI3) delta 9.26 (s, 1H), 6.67 (s, 1H), 6.90-6.00 (bs, 2H), 2.61 (s, 3H), 2.44 (s, 3H); ESI m/z 235 IM + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | To a solution of 65 ( 190 mg, 0.84 mmol) in 1,4-dioxane (5 mL) was added 3,5-dimethy-4-(4,4,5,5-tetramethyi~l,3,2-dioxaboroian-2-yi)isoxazoie (245 mg, 1.09 mmol), sodium carbonate (178 mg in 1 mL H20, 1.68 mmo) and Eetrakis(triphenylphosphine)paadium(Q) (97 mg, 0.08 mmol). The reaction mixture was purged with nitrogen and heated at 90 C for 16 h. The mixture was filtered through a layer of Celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichoromethane) afforded 66 (135 mg, 67%) as an off-white solid: Eta NMR (300 MHz, D SO-cy delta 12.5 (s, 1H), 10.2 (s, 1H , 8.51 {d, J = 1.8 Hz, 1H), 8.49 (d, J = 3.0 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 2.44 (s, 3H), 2.26 (s, 3H); ESI MS m/z 242 [M + Hf. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere; | To a solution of 77 (4.4 g, 16,5 rnmoi) in 1,4-dioxane (100 rnL) was added 3,5-dimethy-4-(4,4,5,5-tetramethyi-l,3,2-dioxaborolan-2-yl)isoxazoe (4.4 g, 19.8 mmol), Na2C03(2.0 M in H?0, 25 mL, 50.0 mmol} and tetrakis(triphenyphosphine)paiadium(0) (959 mg, 0.83 mmol). The reaction mixture was purged with nitrogen and heated at 80 "C for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL). The organic ayer was dried over NazS04, and filtered. The fitrate was concentrated and then purified by chromatography (silica gel, 0-60% ethyi acetate/hexanes) to afford 78 (2.64 g, 57%) as an off-white solid: H N R (300 MHz, DMSO-d6) delta 7.71 (s, 1H), 6.32 (s, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); potassium hydrogencarbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere; | To a solution of 94 (75 mg, 0.17 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 3,5-dimethy-4-(4,4,5,5-tetramethyi-l,3,2-dioxaboroan-2-yl)isoxazoe (58 mg, 0.26 mmol), potassium bicarbonate (70 mg, 0.70 mmol), and tetrakis(triphenyiphosphine}paiadium(0) (10 mg, 0.0087 mmoi). The reaction mixture was purged with nitrogen and heated at 90 C for 2h. The reaction mixture was cooled to room temperature, concentrated and purified bychromatography (silica gei, 0-100% ethyl acetate in hexanes) to give 95 (53 mg, 70%) as an off-white solid: H NMR (500 M Hz, CD3OD) delta 7.33 (t, J = 6.3 Hz, 2H), 7.27 (t, J - 5.1 Hz, 1H), 7.14 (d, J = 7.1 Hz, 2H), 6.89 (d, J = 1.3 Hz, 1 H), 6.58 {d, J = 1.3 Hz, 1H), 5.45 (s, 2 H), 2.59 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3 H), 1.05 (s, 9H), 0.30 (s, 6H); HPLC >99%, ts= 16.4 min; ESi m/z 448 [M + H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 17h; | To a mixture of 103 (300 mg, 1.24 mmoi) and 3 (415 mg, 1.86 mmoi) in 1,4- dioxane (10 mL) and water (2,5 mL) was added potassium carbonate (343 mg, 2.48 mmol) and tetrakis(triphenyiphosphine)pailadium(0) (76 rng, 0.062 mmol). The reaction was stirred and heated at 90 C for 17 h. The mixture was diluted with methanol (20 mL) and silica gel (10 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded onto silica gel (80 g) and euted with 0-80% ethyi acetate in hexanes. The clean product was concentrated to give 104 (312 mg, 97%) as a yellow solid:5H NMR (500 MHz, CDC13) delta 7,48 {d, J - 1.5 Hz, 1 H), 6.61 (d, J = 1.5 Hz, 1H), 4.27 (br s, 2 H), 3.39 (br s, 1H), 2.92 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 1.18-1.09 (m, 1H), 0.63-0.56 (m, 2H), 0.28-0.22 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 17h; | To a mixture of 105a (500 mg, 1.76 mmo), 3,5-dimethyl-4-(4,4,5,5- tetramethy-l,3,2-ciioxaboroian-2-yi)isoxazole (589 mg, 2.64 rrtmo), potassium carbonate (487 mg, 3.52 mmoi), water (4 mL) and 1,4-dioxane (16 mL} was added tetrakis{tnphenyiphosphine)palIadium (0) and the mixture was heated to 90 C for 17 h. The two phase mixture was diluted with methanol (20 mL) and siiica gel was added. After concentrating to dryness the material was purified by chromatography (silica gel, 0-80% EtGAc/bexane) to afford 106a (551 mg, 99%) as a brown solid: NMR (500 MHz, CDCI3) delta 7.47 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 4.25 (br s, 2H), 3.34 (br s, 1H), 2.92 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 1.88-1.67 (m, 4H), 1.67-1.56 (m, 1H), 1.33-1.19 (m, 4H), 1.10-0.96 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetone; toluene; at 130℃; for 1h;Microwave irradiation; | A mixture of intermediate 12 (37 mg, 0.1 mmol), 3,5-dimefhylisoxazole-4-boronic acid pinacol ester (33.6 mg, 0.15 mmol), catalyst Pd(pddf)Cl2 (8.2 mg, 0.01 mmol), and base K2CO3 (27.6 mg, 0.2 mmol) in 2 mL of a solvent of 4:4: 1 acetone:toluene:H20 was heated under microwave at 130 C for 60 min. See, e.g., Lu et ah, QSAR Comb. Sci. 2004, 23, 827- 835. The reaction mixture was filtered, and the residue was washed with ethyl acetate. The concentrated filtrate was purified by flash chromatography (5:5 hexanes:EtOAc) to afford compound UMB28 (25 mg, 65% yield). XH NMR (300 MHz, CDC13) delta 8.18 (m, 4 H), 7.58 (d, .7 =6.0 Hz, 1 H), 7.38 (m, 2 H), 7.16 (m, 1 H), 2.24 (s, 3 H), 2.36 (s, 3 H), 1.6 (m, 6 H), 1.2 (m, 5 H) ppm. 13C NMR (75 MHz, CDCI3) delta 195.2, 165.1, 152.8, 129.2, 128.4, 124.0, 122.8, 116.6, 112.0, 57.6, 34.0, 25.2, 7.4 ppm. MS (APCI) m/z: 387.2 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetone; toluene; at 130℃; for 1h;Microwave irradiation; | A mixture of intermediate 14 (30 mg, 0.09 mmol), 3,5-dimefhylisoxazole-4- boronic acid pinacol ester (30 mg, 0.135 mmol), catalyst Pd(pddf)Ci2 (5.7 mg, 0.007 mmol), and base K2CO3 (25 mg, 0.18 mmol) in 2 mL of 4:4: 1 acetone:toluene:H20 was heated under microwave at 130 C for 60 min. The reaction mixture was filtered, and the residue was washed with ethyl acetate. The concentrated filtrate was purified by flash chromatography (7:3 hexanes:EtOAc) to afford compound UMB32 (16.3 mg, 50% yield). XH NMR (300 MHz, CDCI3) delta 8.93 (s, 1 H), 8.10 (d, / = 6.0 Hz, 1 H), 7.95-8.08 (m, 2 H), 7.80 (d, J = 6.6 Hz, 1 H), 7.28 (d, J = 6.6 Hz, 2 H), 2.38 (s, 3 H), 2.24 (s, 3 H), 1.00 (s, 9 H) ppm. 13C NMR (75 MHz, CDCI3) delta 216.1, 201.2, 164.1, 129.2, 128.7, 118.2, 116.5, 30.6, 11.10, 7.81 ppm. MS (APCI) m/z: 362.2 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetone; toluene; at 130℃; for 0.583333h;Microwave irradiation; | General procedure: These compounds were prepared by direct Suzuki coupling of fluorous arylsulfonates with the boronic ester. The Suzuki coupling reactions were carried out following the general procedure as shown. [00325] 3,5-Dimethyl-4-phenylisoxazole (la). Yellow oily compound, 58% yield, lH NMR (300 MHz, CDC13) 57.15-7.62 (m, 5H), 2.41 (s, 3H), 2.25 (s, 3H) ; MS(APCI) m/z 174.1 (M+ + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; | The compound of example 208 (300 mg, 0.671 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoxazole (180 mg, 0.805 mmol) and sodiumcarbonate (142 mg, 1.341 mmol) were mixed with DMF (10 mL) and water (1 mL). The reaction mixture was degassed with nitrogen for 10 minutes. PdCI2(dppf)-CH2CI2 adduct (27.4 mg, 0.034 mmol) catalyst was added and the reaction mixture was heated to 120 C for 2 h. The reaction mixture was cooled and diluted with ethylacetate and the resulting suspension was filtered through celite bed, and the filtrate was washed with water. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed to yield the crude product, which was purified by column chromatography (silica gel, 9:1 CHCI3: MeOH) to obtain the title compound.Yield: 240 mg (77 %); 1H NMR (300 MHz, DMSO-d6): O 2.02 (d, 3H, J= 7.2 Hz, CH3),2.07 (5, 3H, CH3), 2.27 (5, 3H, CH3), 4.15 (5, 1H, CH), 4.83 (5, 1H, CH), 6.43 (q, 1H, J= 7.2 Hz, Ar), 6.70 (5, 1H, Ar), 7.41 (m, 5H, Ar), 8.00 (5, 1H, Ar), 8.88 (5, 1H, Ar),13.78 (5, 1H, NH, exchangeable with D20); MS (El, 70 eV): m/z 464.2 (M+Hj: HPLCpurity: 97.75 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 80℃; for 1h;Inert atmosphere; | Step 1: 5-(3,5-Dimethylisoxazol-4-yl)pyridin-3-amineTo a 40 mL vial containing 5-bromopyridin-3-amine (Aldrich, 200 mg, 1.16 mmol) and 3,5 -dimethyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoxazole(Aldrich, 516 mg, 2.31 mmol) in THF (10 mL) was added aq. tripotassium phosphate (2M, 1.7 mL, 3.47 mmol) to give a yellow suspension. Pd(dppf)C12-CH2C12 (94 mg, 0.12 mmol) was then added and N2 was bubbled into the mixture for 2 mm. The resulting reaction mixture was heated at 80 C for 1 h, concentrated and purified using ISCO silica gel chromatography (40 g column, gradient from 0% to 10% MeOH/CH2C12) to give the title compound (213 mg, 97%) as a pale orange solid. LCMS (M+H) = 190; HPLC RT = 0.51 mm (Column: Chromolith ODS S5 4.6 x 50mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA;Temperature: 40 C; Gradient: 0-100% B over 4 mm; Flow: 4 mL/min). |
97% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 80℃; for 1h;Inert atmosphere; | To a 40 mL vial containing 5-bromopyridin-3-amine (Aldrich, 200 mg, 1.16 mmol) and <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (Aldrich, 516 mg, 2.31 mmol) in THF (10 mL) was added aq. tripotassium phosphate (2M, 1.7 mL, 3.47 mmol) to give a yellow suspension. Pd(dppf)Cl2-CH2Cl2 (94 mg, 0.12 mmol) was then added and N2 was bubbled into the mixture for 2 min. The resulting reaction mixture was heated at 80 C. for 1 h, concentrated and purified using ISCO silica gel chromatography (40 g column, gradient from 0% to 10% MeOH/CH2Cl2) to give the title compound (213 mg, 97%) as a pale orange solid. LCMS (M+H)=190; HPLC RT=0.51 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40 C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere; | Step 2: Methyl 5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3- (3,5-dimethylisoxazol-4-yl)-5H-pyrido [3 ,2-bj indole-7-carboxylate A mixture of methyl 3 -bromo-5 -((2,5 -difluorophenyl)(tetrahydro-2H-pyran-4- yl)methyl)-5H-pyrido [3 ,2-b]indole-7-carboxylate (200 mg, 0.388 mmol), 3,5 -dimethyl-4- (4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoxazole (130 mg, 0.582 mmol), K2C03 (161 mg, 1.16 mmol), PdC12(dppf)-CH2C12 adduct (31.7 mg, 0.0390 mmol), 1,4-dioxane(6.5 mL), and water (1.3 mL) in a vial was purged with a stream of argon for 5 mm. Thevial was capped with a septum, evacuated and filled with argon, and then was heated to100 C for 1 h. The mixture was diluted with 30 mL of water and extracted with EtOAc(45 mL x 2), dried over Na2SO4, filtered, concentrated, and crude product was purifiedusing silica gel column chromatography using an ISCO (Silica gel, 12 g flash column, 0to 2% MeOH/CHC13 over 30 mm) to give methyl 5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3 -(3,5 -dimethylisoxazol-4-yl)-5H-pyrido [3 ,2-b]indole-7-carboxylate(200 mg, 0.376 mmol, 97 %) as a yellow liquid. LCMS: RT=0.96 mm; MS (ES): mlz532 [M+ 1 ] (ACN/H20 with NH4OAc, Acquity BEH Cl 8 1.7 1.Im (50 x 2.1) mm,gradient = 3 mm, wavelength = 220 nm). |
97% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; di-isopropyl azodicarboxylate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere; Sealed tube; | A mixture of methyl 3-bromo-5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (200 mg, 0.388 mmol), <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (130 mg, 0.582 mmol), K2CO3 (161 mg, 1.16 mmol), PdCl2(dppf)-CH2Cl2 adduct (31.7 mg, 0.0390 mmol), 1,4-dioxane (6.5 mL), and water (1.3 mL) in a vial was purged with a stream of argon for 5 min. The vial was capped with a septum, evacuated and filled with argon, and then was heated to 100 C. for 1 h. The mixture was diluted with 30 mL of water and extracted with EtOAc (45 mL×2), dried over Na2SO4, filtered, concentrated, and crude product was purified using silica gel column chromatography using an ISCO (Silica gel, 12 g flash column, 0 to 2% MeOH/CHCl3 over 30 min) to give methyl 5-((2,5-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-3-(3,5-dimethylisoxazol-4-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (200 mg, 0.376 mmol, 97%) as a yellow liquid. LCMS: RT=0.96 min; MS (ES): m/z=532 [M+1]+ (ACN/H2O with NH4OAc, Acquity BEH C18 1.7 mum (50×2.1) mm, gradient=3 min, wavelength=220 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium fluoride; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; toluene; at 100℃; for 12h;Inert atmosphere; | Step 3: Synthesis of 4-(3,4-difluoro-2-methoxy-5-nitrophenyl)-3,5-dimethylisoxazole To a round-bottom flask was charged with YH10 (1.4 g, 5 mmol), <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (1.4 g, 6 mmol), Pd(dppf)CH2Cl2 (408 mg, 0.5 mmol), KF (696 mg, 12 mmol), toluene (10 mL) and water (10 mL). The reaction mixture was heated up under N2 at 100 C. for 12 h. The solution was cooled prior to being extracted with EtOAc (2×100 mL). The organic layers were combined and washed with brine (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated under vacuum. The residue was purified through column chromatography (eluent: hexanes/EtOAc=4/1 to 2:1) to afford YH11 as a red solid, which was triturated with diethyl ether, followed by filtration to give YH11 as a yellow solid (1.0 g, 70%). 1H NMR (300 MHz, CDCl3): 7.80-7.64 (m, 1H), 4.05 (s, 3H), 2.35 (s, 3H), 2.18 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In water; acetonitrile; at 160℃; for 0.333333h;Inert atmosphere; | Step 1-Preparation of 4-(1H-indazol-5-yl)-3,5-dimethyl-isoxazole (35): To 5-bromo-1H-indazole (34, 2.20g, 11 2mmol)inacetonitrile(51 ml) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)isoxazole(4.98 g, 22 3 mmol), 1 M potassium carbonate in water (17 ml), and [1,1 ?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.85 g, 0.11 mmol) under nitrogen. The reaction was heated in a microwave at 160 C. for 20 minutes. The reaction was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried oversodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 0% to 60% ethyl acetate in hexane to give product 35 (1.74 g,73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In water; acetonitrile; at 110℃; for 0.25h;Microwave irradiation; | Step 1-Preparation of 3,5-dimethyl-4-(1H-pyrazolo[3,4-b]pyridin-5-yl)isoxazole (42): To <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (41, 1.5 g, 7.58 mmol) in acetonitrile (18 ml) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (3.38 g, 15.15 mmol), 1 M potassium carbonate in water (9 ml), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.58 g, 0.76 mmol). The reaction was allowed to stir at 110 C. in a microwave for 15 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 0% to 100% ethyl acetate in hexane to give product 42 (900 mg, 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In water; acetonitrile; at 160℃; for 0.333333h;Microwave irradiation; | Step 1-Preparation of 3,5-dimethyl-4-(5H-pyrrolo[2,3-b]pyrazin-2-yl)isoxazole (22): To 2-bromo-5H-pyrrolo[2,3-b]pyrazine (21, 1.36 g, 6.87 mmol) in acetonitrile (51 ml) was added <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (1.87 g, 8.39 mmol), 1M potassium carbonate in water (17 ml), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.2 g, 0.26 mmol) under nitrogen. The reaction was heated at 160 C. in a microwave for 20 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 0% to 60% ethyl acetate in hexane to give product 22 (1.11 8g, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 24h;Inert atmosphere; | To a mixture of <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (0.50 g, 2.2 mmol), 3-bromobenzaldehyde (0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g,0.12 mmol) and sodium carbonate (0.71 g, 6.7 mmol) in toluene/ethanol/H2O (10 mL, 3/1/3) was refluxed under nitrogen atmosphere for 24 h. Then the mixture was diluted with saturatedammonium chloride solution and EtOAc, and the insoluble materialwas filtered through Celite. The organic layer of the filtrate waswashed with water (30 mL) and brine (30 mL), dried over Na2SO4,and evaporated in vacuo. The residue was purified by columnchromatography (EtOAc/petroleum ether, 1/15 to 1/5) to give 7a(0.37 g, 77%) as a white solid. 1H NMR (300 MHz, DMSO-d6) d: 10.08(s, 1H), 7.99e7.85 (m, 2H), 7.81e7.63 (m, 2H), 2.43 (s, 3H), 2.25 (s,3H). |
77% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃;Inert atmosphere; | To a mixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50g, 2.2mmol), 3-bromobenzaldehyde (0.50g, 2.7mmol), Pd(PPh3)4 (0.13g, 0.12mmol) and sodium carbonate (0.71g, 6.7mmol) in toluene/ethanol/ H2O (35mL, 3/1/3) was refluxed under nitrogen atmosphere for 24h. Then the mixture was diluted with saturated ammonium chloride solution and ethyl acetate, and the insoluble material was filtered through Celite. The organic layer of the filtrate was washed with water (25mL) and brine (25mL), dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography using a mixture of petroleum ether/ ethyl acetate (10: 1, v/v) as eluent to afford the desired product 37a (0.37g, 77%) as a white solid. 1H NMR (300MHz, DMSO-d6) delta: 10.08 (s, 1H), 7.99-7.85 (m, 2H), 7.81-7.63 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H). |
77% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃;Inert atmosphere; | General procedure: Step 1: 3-(3,5-dimethylisoxazol-4-yl)benzaldehyde (11a). To amixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde(0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g, 0.12 mmol) and sodium carbonate(0.71 g, 6.7 mmol) in toluene/ethanol/H2O (35 mL, 3/1/3)was refluxed under nitrogen atmosphere for 24 h. Then the mixturewas diluted with saturated ammonium chloride solutionand ethyl acetate, and the insoluble material was filtered throughCelite. The organic layer of the filtrate was washed with water(25 mL) and brine (25 mL), dried over anhydrous sodium sulfate,and evaporated in vacuo. The residue was purified by column chromatographyusing a mixture of petroleum ether/ethyl acetate (10:1, v/v) as eluent to afford the desired product 11a (0.37 g, 77%) as awhite solid. 1H NMR (300 MHz, DMSO-d6) d: 10.08 (s, 1H), 7.99-7.85 (m, 2H), 7.81-7.63 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H). |
77% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 24h;Reflux; Inert atmosphere; | To a mixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(0.50 g, 2.2 mmol), 3-bromobenzaldehyde (0.50 g, 2.7mmol), Pd(PPh3)4 (0.13 g, 0.12 mmol) and sodium carbonate(0.71 g, 6.7 mmol) in toluene/ethanol/H2O (35 mL, 3/1/3) wasrefluxed under nitrogen atmosphere for 24 h. Then the mixture was diluted withsaturated ammonium chloride solution and ethyl acetate, and the insoluble materialwas filtered through Celite. The organic layer of the filtrate was washed withwater (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, andevaporated in vacuo. The residue was purified by column chromatography usinga mixture of petroleum ether/ethyl acetate (10 : 1, v/v) as eluent to affordthe desired product 15a(0.37 g, 77%) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta: 10.08 (s, 1H), 7.99-7.85 (m, 2H), 7.81-7.63 (m,2H), 2.43 (s, 3H), 2.25 (s, 3H). |
77% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃;Inert atmosphere; | To a mixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50g, 2.2mmol), 3-bromobenzaldehyde (0.50g, 2.7mmol), Pd(PPh3)4 (0.13g, 0.12mmol) and sodium carbonate (0.71g, 6.7mmol) in toluene/ethanol/H2O (35mL, 3/1/3) was refluxed under nitrogen atmosphere for 24h. Then the mixture was diluted with saturated ammonium chloride solution and ethyl acetate, and the insoluble material was filtered through Celite. The organic layer of the filtrate was washed with water (25mL) and brine (25mL), dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography using a mixture of petroleum ether/ethyl acetate (10 : 1, v/v) as eluent to afford the desired product 8a (0.37g, 77%) as a white solid. 1H NMR (300MHz, DMSO-d6) delta: 10.08 (s, 1H), 7.99-7.85 (m, 2H), 7.81-7.63 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H). |
71% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 24h;Inert atmosphere; | The 3, 5 - dimethyl isoxazole -4 - boric acid pinacone ester (0.4g, 2 . 67mmol), 3 - bromophenylacetic formaldehyde (0.54g, 2 . 67mmol) dissolved in 21 ml in the mixed solvent (water/ethanol/toluene, 3:1: 3, v/v), adding sodium carbonate (0.71g, 6 . 67mmol), Pd (PPh3) 4 (0.09g, 0 . 08mmol), resulting the mixed liquid under the protection of nitrogen heating 80 C reaction 24h, cooling to room temperature, water 20 ml dilution, diatomite groundwork for filtering, ethyl acetate (15 ml × 3) washing the filter cake, the filtrate with ethyl acetate (30 ml × 4) extraction, the combined organic phase to saturated NaCl solution (20 ml × 2) washing, to obtained organic phase dried with anhydrous sodium sulfate, filtered, filtrate is decompressed and evaporate the solvent, the residue by column chromatography (petroleum ether/ethyl acetate, 70:30, v/v) to obtain the gray solid 0.38g, yield 71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde (0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g,0.12 mmol) and sodium carbonate (0.71 g, 6.7 mmol) in toluene/ethanol/H2O (10 mL, 3/1/3) was refluxed under nitrogen atmosphere for 24 h. Then the mixture was diluted with saturatedammonium chloride solution and EtOAc, and the insoluble materialwas filtered through Celite. The organic layer of the filtrate waswashed with water (30 mL) and brine (30 mL), dried over Na2SO4,and evaporated in vacuo. The residue was purified by columnchromatography (EtOAc/petroleum ether, 1/15 to 1/5) to give 7a(0.37 g, 77%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde (0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g,0.12 mmol) and sodium carbonate (0.71 g, 6.7 mmol) in toluene/ethanol/H2O (10 mL, 3/1/3) was refluxed under nitrogen atmosphere for 24 h. Then the mixture was diluted with saturatedammonium chloride solution and EtOAc, and the insoluble materialwas filtered through Celite. The organic layer of the filtrate waswashed with water (30 mL) and brine (30 mL), dried over Na2SO4,and evaporated in vacuo. The residue was purified by columnchromatography (EtOAc/petroleum ether, 1/15 to 1/5) to give 7a(0.37 g, 77%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde (0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g,0.12 mmol) and sodium carbonate (0.71 g, 6.7 mmol) in toluene/ethanol/H2O (10 mL, 3/1/3) was refluxed under nitrogen atmosphere for 24 h. Then the mixture was diluted with saturatedammonium chloride solution and EtOAc, and the insoluble materialwas filtered through Celite. The organic layer of the filtrate waswashed with water (30 mL) and brine (30 mL), dried over Na2SO4,and evaporated in vacuo. The residue was purified by columnchromatography (EtOAc/petroleum ether, 1/15 to 1/5) to give 7a(0.37 g, 77%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde (0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g,0.12 mmol) and sodium carbonate (0.71 g, 6.7 mmol) in toluene/ethanol/H2O (10 mL, 3/1/3) was refluxed under nitrogen atmosphere for 24 h. Then the mixture was diluted with saturatedammonium chloride solution and EtOAc, and the insoluble materialwas filtered through Celite. The organic layer of the filtrate waswashed with water (30 mL) and brine (30 mL), dried over Na2SO4,and evaporated in vacuo. The residue was purified by columnchromatography (EtOAc/petroleum ether, 1/15 to 1/5) to give 7a(0.37 g, 77%) as a white solid. | |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃;Inert atmosphere; | General procedure: To a mixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50g, 2.2mmol), 3-bromobenzaldehyde (0.50g, 2.7mmol), Pd(PPh3)4 (0.13g, 0.12mmol) and sodium carbonate (0.71g, 6.7mmol) in toluene/ethanol/ H2O (35mL, 3/1/3) was refluxed under nitrogen atmosphere for 24h. Then the mixture was diluted with saturated ammonium chloride solution and ethyl acetate, and the insoluble material was filtered through Celite. The organic layer of the filtrate was washed with water (25mL) and brine (25mL), dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography using a mixture of petroleum ether/ ethyl acetate (10: 1, v/v) as eluent to afford the desired product 37a (0.37g, 77%) as a white solid. | |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 12h;Inert atmosphere; | General procedure: To amixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde(0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g, 0.12 mmol) and sodium carbonate(0.71 g, 6.7 mmol) in toluene/ethanol/H2O (35 mL, 3/1/3)was refluxed under nitrogen atmosphere for 24 h. Then the mixturewas diluted with saturated ammonium chloride solutionand ethyl acetate, and the insoluble material was filtered throughCelite. The organic layer of the filtrate was washed with water(25 mL) and brine (25 mL), dried over anhydrous sodium sulfate,and evaporated in vacuo. The residue was purified by column chromatographyusing a mixture of petroleum ether/ethyl acetate (10:1, v/v) as eluent to afford the desired product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde (0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g,0.12 mmol) and sodium carbonate (0.71 g, 6.7 mmol) in toluene/ethanol/H2O (10 mL, 3/1/3) was refluxed under nitrogen atmosphere for 24 h. Then the mixture was diluted with saturatedammonium chloride solution and EtOAc, and the insoluble materialwas filtered through Celite. The organic layer of the filtrate waswashed with water (30 mL) and brine (30 mL), dried over Na2SO4,and evaporated in vacuo. The residue was purified by columnchromatography (EtOAc/petroleum ether, 1/15 to 1/5) to give 7a(0.37 g, 77%) as a white solid. | |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃;Inert atmosphere; | General procedure: To a mixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50g, 2.2mmol), 3-bromobenzaldehyde (0.50g, 2.7mmol), Pd(PPh3)4 (0.13g, 0.12mmol) and sodium carbonate (0.71g, 6.7mmol) in toluene/ethanol/ H2O (35mL, 3/1/3) was refluxed under nitrogen atmosphere for 24h. Then the mixture was diluted with saturated ammonium chloride solution and ethyl acetate, and the insoluble material was filtered through Celite. The organic layer of the filtrate was washed with water (25mL) and brine (25mL), dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography using a mixture of petroleum ether/ ethyl acetate (10: 1, v/v) as eluent to afford the desired product 37a (0.37g, 77%) as a white solid. | |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 12h;Inert atmosphere; | General procedure: To amixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde(0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g, 0.12 mmol) and sodium carbonate(0.71 g, 6.7 mmol) in toluene/ethanol/H2O (35 mL, 3/1/3)was refluxed under nitrogen atmosphere for 24 h. Then the mixturewas diluted with saturated ammonium chloride solutionand ethyl acetate, and the insoluble material was filtered throughCelite. The organic layer of the filtrate was washed with water(25 mL) and brine (25 mL), dried over anhydrous sodium sulfate,and evaporated in vacuo. The residue was purified by column chromatographyusing a mixture of petroleum ether/ethyl acetate (10:1, v/v) as eluent to afford the desired product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde (0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g,0.12 mmol) and sodium carbonate (0.71 g, 6.7 mmol) in toluene/ethanol/H2O (10 mL, 3/1/3) was refluxed under nitrogen atmosphere for 24 h. Then the mixture was diluted with saturatedammonium chloride solution and EtOAc, and the insoluble materialwas filtered through Celite. The organic layer of the filtrate waswashed with water (30 mL) and brine (30 mL), dried over Na2SO4,and evaporated in vacuo. The residue was purified by columnchromatography (EtOAc/petroleum ether, 1/15 to 1/5) to give 7a(0.37 g, 77percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 24h;Inert atmosphere; | General procedure: To a mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde (0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g,0.12 mmol) and sodium carbonate (0.71 g, 6.7 mmol) in toluene/ethanol/H2O (10 mL, 3/1/3) was refluxed under nitrogen atmosphere for 24 h. Then the mixture was diluted with saturatedammonium chloride solution and EtOAc, and the insoluble materialwas filtered through Celite. The organic layer of the filtrate waswashed with water (30 mL) and brine (30 mL), dried over Na2SO4,and evaporated in vacuo. The residue was purified by columnchromatography (EtOAc/petroleum ether, 1/15 to 1/5) to give 7a(0.37 g, 77percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 24h;Inert atmosphere; | To a mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.0 mmol), 16 (0.41 g,2.0 mmol), Pd(PPh3)4 (0.12 g, 0.10 mmol) and sodium carbonate(0.43 g, 4.0 mmol) in toluene/ethanol/H2O (15 mL, 3/1/3) wasrefluxed under nitrogen atmosphere for 24 h. Then the mixture wasdiluted with saturated ammonium chloride solution and EtOAc,and the insoluble material was filtered through Celite. The organiclayer of the filtrate was washed with water (30 mL) and brine(30 mL), dried over Na2SO4, and evaporated in vacuo. The residuewas purified by column chromatography (EtOAc/petroleum ether,1/5 to 1/3) to give 17 (0.30 g, 69%) as a pale yellow solid. 1H NMR(300 MHz, DMSO-d6) d: 10.15 (s,1H), 9.96 (s,1H), 7.37 (s,1H), 7.25 (s,1H), 7.08 (s, 1H), 2.42 (s, 3H), 2.24 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium fluoride; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere; | [00327] Step 3: Synthesis of tert-butyl 2-(tert-butyldimethylsilyloxy)-3-(3-(4-(3,5- dimethyl-isoxazol-4-yl)-5-formyl-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2- yl)phenoxy)propyl (methyl)carbamate. To a solution of tert-butyl 2-(tert- butyldimethylsilyloxy)-3-(3-(4-chloro-5-formyl-6- (tetrahydro-2H-pyran-4- ylamino)pyrimidin-2-yl)phenoxy)propyl(methyl)carbamate (600 mg, 0.95 mmol) in degassed dioxane and H2O (10/1, 50 mL) was added Pd2(dba)3(92 mg, 0.10 mmol),tricyclohexylphosphine (80 mg, 0.30 mmol), KF (18 mg, 0.30 mmol) and 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoxazole (255 mg, 1.1 mmol). The system was purged with N2stream, placed in a microwave reactor and irradiated for 1h at 110oC. After being cooled down to room temperature, the mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL x 2). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatographic column on silicagel (petroleum ether/EtOAc = 5/1 to 1/1) to give tert-butyl 2-(tert-butyldimethylsilyloxy)-3-(3- (4-(3,5-dimethylisoxazol- 4-yl)-5-formyl-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2- yl)phenoxy) propyl(methyl)carbamate (530 mg, 80% yield). ESI- LCMS (m/z): 696.0[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In water; acetonitrile; at 125℃; for 0.583333h;Microwave irradiation; | Step 2--Preparation of 4-[5-[dideuterio-(4,4-dif- luorocyclohexyl)methyl]pyrrolo[2,3-b]pyrazin-3-yl] -3,5-dimethyl-isoxazole (P-2038): To 3-bromo-5-[dideuterio-(4, 4-difluorocyclohexyl)methyl]pyrrolo[2,3-b]pyrazine (6, 0.3 g, 0.9 mmol) in acetonitrile (12 ml) was added 3,5-dimethyl- 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)isoxazole(0.3 g, 1.34 mmol), [1,1?-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.05 g, 0.07 mmol), and 1 M potassium carbonate in water (5 ml). The reaction was heated under microwave at 125 C. for 35 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in methylene chloride to give product P-2038 (0.28 g, 89%) MS (ESI) MH(+)=349.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.3% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 12h;Inert atmosphere; | 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrobenzofuro[5,6-b][1,4]dioxin-8-yl)acetic acid methyl ester 6c (100 mg, 0.25 mmol), <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (66 mg, 0.30 mmol) , Tetrakistriphenyl-palladium(14 mg, 0.01 mmol) and Sodium carbonate (79 mg, 0.74 mmol) was dissolved in a mixed solvent of 5.5 mL of dioxane and water (V / V = 10: 1), heated to 90 C and stirred for 12 hours. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using eluent system B to give the title product 2-((8S)-3-(3-(3,5-dimethylisoxazol-4-yl)phenyl)-2,3,7,8-tetrahydrobenzofuro[5,6-b][1,4]dioxin8-yl)acetic acid methyl ester 43a (70 mg, yellow liquid), yield: 67.3% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.32% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In methanol; dichloromethane; N,N-dimethyl-formamide; toluene; at 70℃; for 24h;Inert atmosphere; | A mixture of 6-bromo-4-phenyl-3 - ((1-phenyl -1H-1,2,3- triazolo) methyl) -3,4-dihydroquinazolin--2 (1H ) - one (0.24g, 0.52mmol), 3,5- dimethyl-4-boronic acid pinacol ester (0.23g, 1.04mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (0.038g, 0.052mmol) and potassium carbonate(0.144g, 1.04mmol) was dissolved 1mlN, N- dimethylformamide, a mixture of methanol and 3ml 1ml of toluene, a nitrogen atmosphere, the reaction was heated to 70 stirred for 24 hours, 10ml of water and 10ml of ethyl acetate was added, the solution was suction filtered through celite, and the filtrate was collected, extracted with ethyl acetate, the organic layer was collected, dried over anhydrous sodium sulfate, the organic solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, using petroleum ether / ethyl acetate ester (V / V = 2 / 1-1 / 1) to afford 6- (3,5-dimethyl-isoxazole) -4-phenyl-3 - ((1-phenyl -1H-1, 2,3-triazole) methyl) -3,4-dihydroquinazolin--2 (1H) - -one 0.13g, as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In 1,4-dioxane; water; at 105℃; for 16h;Inert atmosphere; | [0164] To a solution of 17 (70 mg, 0.30 mmol) in dioxane (2 mL) was added 3,5- dimethyl-4-(4,4(5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (133 mg, 0.60 mmol), K3P04 (3.0 M in H20, 0.20 mL, 0.60 mmol), S-Phos (25 mg, 0.06 mmol) and Pd(OAc)2 (20 mg, 0.03 mmol). The reaction mixture was purged with nitrogen for 5 minutes. The mixture was heated at 105 C for 16 h. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 50-100% ethyl acetate/hexanes) afforded Example 4 (154 mg, 71%) as an off-white solid: JH NMR (300 MHz, CDCI3) delta 7.83 (d, J = 2.1 Hz, 1H), 7.35- 7.34 (m, 2H), 7.20-7.13 (m, 1H), 7.03-7.00 (m, 3H), 4.05 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H); ESI m/z 297 [C17H16N203 + Hj+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 24h;Inert atmosphere; | [0166] A solution of 23 (10 g, 43.1 mmol), 22 (12.5 g, 56.0 mmol), aqueous K2CO3 (2 M, 43 mL, 86 mmol) and Pd(PPh3),, (2.5 g, 2.2 mmol) in 1,4-dioxane (200 mL) was degassed with N2. The reaction was stirred at 90 C for 24 h under N2, The reaction was cooled to rt and concentrated. The residue was dissolved in dichloromethane (300 mL), washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 80:20 hexanes/ethyl acetate to 60:40 hexanes/ethyl acetate) to give 24 (7.3 g, 67%) as a yellow solid: 1H NMR (400 MHz, CDCI3) delta 8.38 (d, J - 2.0 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.28 (br s, 1H), 3.24 (d, J = 4.8 Hz, 3H), 2.41 (s, 3H,), 2.28 (s, 3H); ESI MS m/z 249 [M + H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16.0h;Inert atmosphere; | [0153] To a solution of <strong>[848366-28-9]5-bromo-3-chloro-2-methoxypyridine</strong> (5.0 g, 22.5 mmol), and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (6.0 g, 27.0 mmol) in 1,4-dioxane (188 mL) and water (19 mL) was added potassium carbonate (6.2 g, 44.9 mmol). The mixture was purged with nitrogen for 10 min, and tetrakis(triphenylphosphine)palladium(0) was added (1.3 g, 1.12 mmoi). The mixture was heated to 90 C for 16 h, then diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0- 30% ethyl acetate/hexanes) to afford 4 as a white solid (4.2 g, 78%): JH NMR (300 MHz, DMSO-d6) delta 8.18 (d, J = 2.1 Hz, 1H), 8.01 (d, J - 2.1 Hz, 1H), 3.99 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H); ESI m/z 239 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | [0161] To a solution of 11 (202 mg, 1.0 mmol) in dioxane (10 mL) was added 3,5- dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (335 mg, 1.5 mmoi), sodium carbonate (2.0 M in H20, 1.0 mL, 2.0 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol). The reaction mixture was purged with nitrogen and was heated at 90 C for 16 h. The mixture was diluted with CH2CI2 (100 mL) and washed with brine (2 * 30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 50-100% ethyl acetate/hexanes) afforded 12 (154 mg, 71%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) delta 7.37 (d, J = 1.8 Hz, 1H), 6.66 (d, J = 2.1 Hz, 1H), 5.70 (q, J = 4.5 Hz, 1H), 4.78 (s, 2H), 2.86 (d, J = 4.8 Hz, 3H), 2.34 (s, 3H), 2.17 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 1.5h;Inert atmosphere; | In a 2-neck flask was placed ethyl 6-brorno-4-((3-chlorobenzyl)arn ino)quinazol ine-2-carboxylate (1.69 g, 4 rnrnol), 3,5-dirnethyl-4-(4,4,5,5-tetrarnethyl-1 ,3,2-dioxaborolan-2-yl)isoxazole (1.34 g, 6.0 mmol), PdCI2(dppf)-CH2CI2 adduct (0.33 g, 0.40 mmol), and K2003(2.49 g, 18.0 mmol). The air was removed and re-filled with N2 (2-3 times). Then a mixture of1,4-dioxane (16 mL) and water (8 mL) was added and stirred at85 00 (pre-heated) for 1.5 h.After cooling to rt, the organic layer was separated and extracted with EtOAc (10 mL x 3). Thecombined organic layer was dried over Na2SO4 and filtered. After removal of the solvent, theproduct was purified by silica gel chromatography using 50-75-90% EtOAc/hexane as the eluent to give ethyl 4-((3-chlorobenzyl)ami no)-6-(3, 5-dimethylisoxazol-4-yl)quinazol ine-2-carboxylate (1.7 g, 3.89 mmol, 97 % yield). MS (M+H)= 437. |
97% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 1.5h;Inert atmosphere; | In a 2-neck flask was placed ethyl 6-bromo-4-((3-chlorobenzyl)amino)quinazoline-2-carboxylate (1.69 g, 4 mmol), <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (1.34 g, 6.0 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.33 g, 0.40 mmol), and K2CO3 (2.49 g, 18.0 mmol). The air was removed and re-filled with N2 (2-3 times). Then a mixture of 1,4-doxane (16 ml) and water (8 ml) was added and stirred at 85 C (pre-heated) for 1.5 h. After cooling to rt, the organic layer was separated and extracted with EtOAc (10 mL x 3). The combined organic layer was dried (Na2SO4) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 50-75-90% EtOAc/hexane as the eluent to give ethyl 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxylate (1.7 g, 3.89 mmol, 97 % yield). LC-MS (Method 1): tR = 3.29 min, m/z (M+H)+ = 437. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 1.5h;Inert atmosphere; | In a microwave tube was placed ethyl (S)-6-bromo-4-(3-phenylmorpholino)quinazoline-2-carboxylate (1190 mg, 2.69 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoxazole (900 mg, 4.04 mmol), PdCI2(dppf)-CH2CI2 adduct (220 mg, 0.269 mmol), and K2003 (1673 mg, 12.11 mmol). The air was removed and re-filled with N2 (3 times). Then, 1,4- dioxane (10 mL)/water (5 mL) was added and heated at 9000 for 1.5 h. After cooling to rt, the layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combinedorganic layer was dried over Na2504 and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 50-100% EtOAc/hexane as the eluentto give ethyl (S)-6-(3, 5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxylate (1225 mg, 2.67 mmol, 99 % yield). MS (M+H)= 459. |
99% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 70℃; for 1.5h;Inert atmosphere; | In a microwave tube was placed ethyl (S)-6-bromo-4-(3-phenylmorpholino)quinazoline-2-carboxylate (1190 mg, 2.69 mmol), <strong>[832114-00-8]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (900 mg, 4.04 mmol), PdCl2(dppf)-CH2Cl2 adduct (220 mg, 0.269 mmol), and K2CO3 (1673 mg, 12.11 mmol). The air was removed and re-filled with N2 (3 times). Then, 1,4-dioxane (10 ml)/water (5 ml) was added and heated at 70 C for 1.5 hr. After cooling to rt, the layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic layer was dried (Na2SO4) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 50-100% EtOAc/hexane as the eluent to give ethyl (S)-6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxylate (1225 mg, 2.67 mmol, 99 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 75 - 80℃; for 1.5h;Inert atmosphere; | In a 2-neck flask was placed 6-bromo-2-chloro-N-(3-chlorobenzyl)-N- cyclopropylquinazolin-4-amine (1058 mg, 2.5 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1 3,2-dioxaborolan-2-yl)isoxazole (613 mg, 2.75 mmol), PdCI2(dppf)-CH2CI2 adduct (204 mg, 0.25mmol), and potassium carbonate (1140 mg, 8.25 mmol). The air was removed and re-filled withN2 (3 times). Then, 1,4-dioxane (10 mL)/water (4 mL) was added and heated at 7580 00 for 1.5h. After cooling to rt, the layer was separated and the aqueous layer was extracted with EtOAc(5 mL x 2). The combined organic layer was dried over Na2504 and filtered. After removal ofsolvent, the product was purified by silica gel chromatography using 20-70% EtOAc/hexane asthe eluent to give 2-chloro-N-(3-chlorobenzyl)-N-cyclopropyl-6-(3, 5-dimethyl isoxazol-4- yl)quinazolin-4-amine (1013 mg, 2.306 mmol, 92 % yield). MS (M+H)= 440. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 95℃; for 2h;Inert atmosphere; | In a 2-neck flask was placed 7-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine (383 mg, 1 mmcl), 3, 5-dimethyl-4-(4,4, 5, 5-tetramethyl- 1, 3,2-dioxaborolan-2-yl)isoxazole (223mg, 1.000 mmol), PdCI2(dppf)-CH2CI2 adduct (82 mg, 0.1 mmol), and K2003 (415 mg, 3.0 mmol). The air was removed and re-filled with N2 (2-3 times). Then a mixture of 1 ,4-dioxane (3 ml) and water (1.5 ml) was added and stirred at 95 00 (pre-heated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic was dried (Na2SO4) and filtered. After removal of solvent, the product was purified bysilica gel chromatography using 25-60% EtOAc/hexane as the eluent to give 2-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (370 mg, 0.927 mmol, 93 %yield). 25 mg of material was submitted for HPLC purification to give TFA salt for screening. MS(M+H)= 399. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃;Inert atmosphere; | General procedure: To a mixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50g, 2.2mmol), 3-bromobenzaldehyde (0.50g, 2.7mmol), Pd(PPh3)4 (0.13g, 0.12mmol) and sodium carbonate (0.71g, 6.7mmol) in toluene/ethanol/ H2O (35mL, 3/1/3) was refluxed under nitrogen atmosphere for 24h. Then the mixture was diluted with saturated ammonium chloride solution and ethyl acetate, and the insoluble material was filtered through Celite. The organic layer of the filtrate was washed with water (25mL) and brine (25mL), dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography using a mixture of petroleum ether/ ethyl acetate (10: 1, v/v) as eluent to afford the desired product 37a (0.37g, 77%) as a white solid. | |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 12h;Inert atmosphere; | General procedure: To amixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.50 g, 2.2 mmol), 3-bromobenzaldehyde(0.50 g, 2.7 mmol), Pd(PPh3)4 (0.13 g, 0.12 mmol) and sodium carbonate(0.71 g, 6.7 mmol) in toluene/ethanol/H2O (35 mL, 3/1/3)was refluxed under nitrogen atmosphere for 24 h. Then the mixturewas diluted with saturated ammonium chloride solutionand ethyl acetate, and the insoluble material was filtered throughCelite. The organic layer of the filtrate was washed with water(25 mL) and brine (25 mL), dried over anhydrous sodium sulfate,and evaporated in vacuo. The residue was purified by column chromatographyusing a mixture of petroleum ether/ethyl acetate (10:1, v/v) as eluent to afford the desired product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With [(1,2-bis(diphenylphosphino)ethane)CuCl]; sodium t-butanolate; In toluene; at 50℃; for 2h;Glovebox; Sealed tube; | In the glove box, the DPPECuCl (25 mg, 10 muM %) and NaOt Bu (15 mg, 30 muM %) is added to the in tube sealing, and then adding 4-(boronic acid pinacol ester)-3,5-dimethylisoxazole (0.5 mmol, 1.0 equiv, 112 mg) and compound I-1 (0.6 mmol, 1.2 equiv, 178 mg), 2 ml toluene, 50 C stirring 2 h. After the reaction, steaming and under reduced pressure, the residue passes through the rapid silica gel column chromatography, to obtain yellowish liquid 96 mg, yield 75%. After hydrogen spectrum identifying the purity of greater than 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In toluene; at 70℃; for 24h;Inert atmosphere; | Bromo-1-methyl-4-phenyl-3,4-dihydroquinazolin-2 (1H) -one (0.5 g, 1.58 mmol), <strong>[832114-00-8]3,5-dimethylisoxazole-4-boronic acid pinacol ester</strong>(0.38 g, 0.16 mmol) was dissolved in 3 ml of toluene, protected under nitrogen and heated to 70 C for 24 hours. The reaction was carried out at 0 C, 10 ml of water and 10 ml of ethyl acetate were added and the solution was filtered through celite. The filtrate was collected and extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (3.5% -4-phenyl-3,4-dihydroquinazolin-2 (1-piperone, 0.42 g, white solid in 79% yield). |
70% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 18h;Inert atmosphere; | In a round-bottom flask, the intermediate 30 (0.50 g, 1.58 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)isoxazole(0.51 g, 1.73 mmol), sodium carbonate (0.50 g, 4.73 mmol) and tetraphenylphosphinepalladium (0.18 g, 0.16 mmol) were dissolved in amixture of toluene (3 mL), ethanol (1 mL) and water (3 mL). Then thereaction solution was heated to 80 C and stirred for 18 h under nitrogen.After that, the reaction mixture was filtered through Celite andthe filtrate was extracted with ethyl acetate. The organic layer waswashed with saturated sodium bicarbonate and saturated brine, thendried over anhydrous sodium sulfate. After evaporation, the crudeTable 2Structures of compounds 17-24, and their inhibitory activity for BRD4 BD1.Compound Linker X BRD4 (BD1)Inh% (at 500 nM)aBRD4 (BD1)IC50 (nM)b17 CH2 99 14.2 ± 1.618 CH2 100 15.4 ± 2.319 CH2 100 22.1 ± 2.920 CH2 100 22.6 ± 3.721 CO 99 41.8 ± 7.822 CO 93 67.7 ± 9.023 CO 86 68.5 ± 8.524 CO 60 173.4 ± 23.26 100 46.4 ± 6.7JQ1 100 27.9 ± 4.5a Inhibition rate mean values at a screening concentration of 500 nM were obtained from three independent experiments.b IC50 values are the mean of at least three independent assays, presented as mean ± SD.Fig. 4. Preliminary screening of in vitro antiproliferative activity of selectedcompounds against HL-60, Raji, and THP-1 cancer cell lines at the concentrationof 2.5 muM. Inhibition values were obtained from three independent experiments.Compound 6, JQ1 and pomalidomide (P indicates pomalidomide)were used as the positive controls.F. Zhang, et al. Bioorganic & Medicinal Chemistry 28 (2020) 1152286 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; | Pd (pph3) 4 (900mg, 0.8mmol), 3,5-dimethylisoxazole-4-boronic acid pinacolate (5g, 22.5mmol), Na2CO3 (4.74g, 45mmol) and 5-bromo-2- Methylaniline (2.79g, 15mmol) was added to the flask at the same time, and then H2O (20ml) and 1,4-dioxane (37ml) were added to pump nitrogen 3 times, heated to 90 C and stirred overnight.Cooled to room temperature, diluted with water, extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, purified by silica gel column (PE: EA = 2: 1) to obtain 2g of light yellow solid, namely intermediate 5- ( 3,5-Dimethylisoxazole-4-)-2-methylaniline, yield: 66.0%. |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 6h; | General procedure: Under N2 atmosphere, a mixture of 6 (100.0 mg, 0.26 mmol),Pd(pph3)4 (30.0 mg, 0.026 mmol), 2.0M aq Na2CO3 (0.29 ml,0.78 mmol) and 1-Methyl-1H-pyrazole-5-boronic acid pinacolester (108.2 mg, 0.52 mmol) in 1,4-Dioxane (0.65 ml) was heated to90 C and stirred for 6 h. The reaction mixture was cooled, dilutedwith ethyl acetate, washed with water, dried over anhydrousNa2SO4, filtered and concentrated under vacuum. Purification onsilica using a solvent gradient of 10-30% ethyl acetate in hexanesyielded the desired compound 1j (77.0 mg, 77.5%). Compounds 1akwere prepared according to general procedure as described forcompound 1j using corresponding aryl bromide 2-4 and theappropriate boronic acid or boronic acid pinacol ester. The characterizationdata for compounds 1a-k were provided below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.2% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; at 100℃;Inert atmosphere; | Compound 110a. To a solution of ethyl 3-bromoisonicotinate (0.1 g, 0.463 mmol, 1.0 equiv) in Toluene (5 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.126 g, 0.926 mmol, 2 equiv), K2CO3 (0.192 g, 1.39 mmol, 3.0 equiv) and resulting reaction mixture purged with N2 gas for 10 minute, followed by the addition of Pd(PPh3)4 (0.027 g, 0.023 mmol. 0.05 equiv). The resulting reaction mixture was heated at 100 C. for overnight. Product formation was confirmed by LCMS. After the completion of reaction, the mixture was filtered through celite bed, washed with ethyl acetate (100 mL). Filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography (0-30% ethyl acetate in hexane as an eluent) to obtain methyl 3-(3,5-dimethylisoxazol-4-yl)isonicotinate (0.105 g, 97.2% Yield) as an yellow liquid. (0891) LCMS 233.2 [M+H]+ (0892) 1H NMR (400 MHz, DMSO-d6) delta 8.81 (d, J=4.8 Hz, 1H), 8.65 (s, 1H), 7.85 (d, J=5.3 Hz, 1H), 3.32 (s, 3H), 2.23 (s, 3H), 2.09-1.90 (m, 3H). |
[ 1346808-41-0 ]
5-Methylisoxazole-4-boronic Acid Pinacol Ester
Similarity: 0.91
[ 16114-47-9 ]
3,5-Dimethylisoxazole-4-boronic acid
Similarity: 0.78
[ 928664-98-6 ]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole
Similarity: 0.78
[ 1012084-56-8 ]
2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Similarity: 0.65
[ 758699-74-0 ]
4-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Similarity: 0.64
[ 1346808-41-0 ]
5-Methylisoxazole-4-boronic Acid Pinacol Ester
Similarity: 0.91
[ 16114-47-9 ]
3,5-Dimethylisoxazole-4-boronic acid
Similarity: 0.78
[ 928664-98-6 ]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole
Similarity: 0.78
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H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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