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CAS No. : | 1425045-01-7 | MDL No. : | MFCD16996317 |
Formula : | C13H20BNO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WYLZKEAKTKRGKT-UHFFFAOYSA-N |
M.W : | 249.11 | Pubchem ID : | 71270309 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.62 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 73.41 |
TPSA : | 40.46 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) : | -6.9 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.3 |
Log Po/w (WLOGP) : | 0.99 |
Log Po/w (MLOGP) : | 1.01 |
Log Po/w (SILICOS-IT) : | 1.38 |
Consensus Log Po/w : | 0.94 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.38 |
Solubility : | 1.03 mg/ml ; 0.00413 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.75 |
Solubility : | 4.43 mg/ml ; 0.0178 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.49 |
Solubility : | 0.0814 mg/ml ; 0.000327 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.07 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane; water at 85℃; for 16 h; Inert atmosphere | Nitrogene was passed through dioxane and this solution ( 2.0 mL) was then added to a mixture of the 5-bromo-1,3-dimethylpyridin-2(1H)-one (75 mg, 0.37 mmol), bis(pinacolato)diboron ( 113 mg, 0.445 mmol) and KOAc (109 mg, 1.11 mmol) followed by the addition of the catalyst PdCl2(dppf).CH2Cl2 (30 mg, 0.037 mmol). The reaction mixture was heated at 85 oC for 16 hours then diluted with EtOAc and and filtered on a pad of Celite®. The filtrate was concentrated under vacuum, resulting in the crude title compound (169 mg, 0.678 mmol, quantitative yield) as brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With [2,2]bipyridinyl; (1,5-cyclooctadiene)(methoxy)iridium(I) dimer In 1,4-dioxane at 40℃; for 4 h; Inert atmosphere; Schlenk technique | General procedure: Ligand (0.010 mmol) and [Ir(OMe)(cod)]2 (3.3 mg, 0.0050 mmol) were placed in a 20-mL two-necked reaction flask, which was filled with N2 by using the standard Schlenk technique. Solvent (0.50 mL) was injected via a syringe, and the mixture was stirred for 5 min at r.t. A solution of 2-pyridone (0.25 mmol) and bis(pinacolato)diboron(0.38–0.75 mmol) in solvent (1.0 mL) was then added, and the suspension was stirred under the indicated conditions. The resulting mixture was allowed to cool to r.t., diluted with EtOAc, and filtered through a short pad of neutral alumina and anhyd Na2SO4. After concentration under reduced pressure, purification by GPC (EtOAc) afforded the corresponding borylated 2-pyridone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16.0h;Sealed tube; | (005851 Step B: Preparation of 5-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)- 1,3- dimethylpyridin-2(1H)-one: 5-Amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl trifluoromethane sulfonate [Preparation E] (516 mg, 1.6 mmol), 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2(1H)-one (600 mg, 2.41 mmol), K2C03 (888 mg, 6.42 mmol) and Pd(PPh3)4 (185 mg, 0.16 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 C in a sealed vessel for 16 hours. The cooled mixture was filtered through GF paper and the filtrate was partitioned between water (50 mE) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 30 mE) and the combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica column chromatography eluting with 2% MeOHJDCM to afford 5-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)- 1,3 -dimethylpyridin2(1H)-one (363 mg, 77% yield) as a dark pink foam. MS (apci) mlz = 295.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; water; at 85℃; for 16.0h;Inert atmosphere; | Nitrogene was passed through dioxane and this solution ( 2.0 mL) was then added to a mixture of the 5-bromo-1,3-dimethylpyridin-2(1H)-one (75 mg, 0.37 mmol), bis(pinacolato)diboron ( 113 mg, 0.445 mmol) and KOAc (109 mg, 1.11 mmol) followed by the addition of the catalyst PdCl2(dppf).CH2Cl2 (30 mg, 0.037 mmol). The reaction mixture was heated at 85 oC for 16 hours then diluted with EtOAc and and filtered on a pad of Celite. The filtrate was concentrated under vacuum, resulting in the crude title compound (169 mg, 0.678 mmol, quantitative yield) as brown oil. |
With potassium acetate; palladium diacetate; XPhos; In 1,4-dioxane; at 100℃; for 16.0h;Inert atmosphere; Sealed tube; | (005841 Step A: Preparation of I ,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one: 5-Bromo- 1 ,3-dimethylpyridin- 1(1 H)-one (1.0 g, 4.94 mmol), bis(pinnacolato)diboron (1.38 g, 5.44 mmol) and potassium acetate (1.46 g, 14.8 mmol) were combined in dioxane (10 mE) in a sealed vessel and the mixture was de-gassed with argon for 5 minutes. Palladium acetate (111 mg, 0.49 mmol) and XPHOS (354 mg, 0.74 mmol) were added, and the mixture was degassed for an additional minute. The vessel was sealed and heated at 100 C for 16 hours. The cooled mixture was filtered through GF paper and the filtrate was concentrated. The residue was triturated with ether and filtered, and the filtrate was concentrated to afford 1,3 -dimethyl-5 -(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2- yl)pyridin-2(1H)-one (assume quantitative yield) as a tan solid. MS (apci) mlz = 250.2 (M+H). | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 3.5h;Inert atmosphere; | 1,3-Dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one J-1 5-Bromo-1,3-dimethyl-1H-pyridin-2-one C-1 (10.0 g; 48.0 mmol), bis(pinacolato)diboron (16.0 g; 63.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichlormethane (2.00 g; 2.376 mmol) and potassium acetate (9.423 g; 96.016 mmol) are introduced into a flask. 1,4-Dioxane (100.0 mL) is added and the flask is flushed with argon. The reaction is heated to 90 C. for 3 h. A second portion of bis(pinacolato)diboron (1.200 g; 4.726 mmol) is added and the solution is stirred for an additional 30 min. The reaction mixture is then cooled to RT and filtered through a plug of celite, washed with dioxane (2*100.0 mL). The filtrate is concentrated under reduced pressure. The residue is then dissolved in DCM (200.0 mL) and washed with water (1*100.0 mL). The water layer is extracted DCM (1*100.0 mL). The combined organic layer is dried with Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified by silica gel chromatography Combiflash (Column Redisep Rf, 330 g; gradient: cyclohexane/EtOAc=100%/0% to 0%/100% over 16 column volumes; flow rate=200 mL/min; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduced pressure. The remaining catalyst is filtered off and washed with ethyl acetate. The filtrate is concentrated under reduced pressure to give the desired product as an oil, which crystallizes upon standing. HPLC-MS: (M+H)+=250; tRet=0.96 min; method M1 |
With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium acetate; In 1,4-dioxane; at 85℃; for 16.0h;Inert atmosphere; | Nitrogene was passed through dioxane and this solution (2.0 mL) was thenadded to a mixture of the 5-bromo-1 ,3-dimethylpyridin-2(1 H)-one (75 mg, 0.37 mmol), bis(pinacolato)diboron (113mg, 0.445 mmol) and KOAc (109 mg, 1.11 mmol) followed by the addition of the catalyst Pd012(dppf).0H2012 (30 mg, 0.037 mmol). The reaction mixture was heated at 85 00 for 16 hours then diluted with EtOAc and and filtered on a pad of Celite. The filtrate was concentrated under vacuum, resulting in the crude title compound (169 mg, 0.678 mmol, quantitative yield) as brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 75℃; for 1.0h;Sealed tube; Inert atmosphere; | Example 323 5-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one A mixture of 1-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylbenzene (450 mg, 1.2 mmol), <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (300 mg, 1.2 mmol), Pd(dppf)Cl2 (88 mg) and K3PO4 (654 mg, 3 mmol) in dioxane (8 mL) and water (800 uL) was purged with nitrogen for 7 min, capped, and heated to 75 C. for 1 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of EtOAc (5 to 100%) in DCM to afford the title compound (416 mg, 83%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 2.05-2.14 (s, 3H) 3.25-3.28 (s, 3H) 3.49-3.57 (s, 3H) 3.74-3.81 (s, 3H) 5.12-5.22 (s, 2H) 6.93-7.03 (m, 2H) 7.34-7.47 (m, 3H) 7.52-7.59 (m, 1H) 7.64-7.72 (m, 1H) 7.82-7.90 (m, 1H) 8.14-8.22 (m, 1H). LCMS (M+H)+=414. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 75℃; for 1.0h;Inert atmosphere; Sealed tube; | A mixture of N-[3-bromo-5-(2,4-difluorophenoxy)phenyl]ethanesulfonamide (70 mg, 0.17 mmol), <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (44 mg, 0.18 mmol), Pd(dppf)Cl2 (12 mg) and K3PO4 (92 mg, 0.42 mmol) in dioxane (1 mL) and water (133 uL) was purged with nitrogen, capped, and heated to 75 C. for 1 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of MeOH (0 to 10%) in DCM to afford the title compound (69 mg, 94%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.13-1.22 (m, 3H) 2.07 (s, 3H) 3.08-3.20 (m, 2H) 3.50 (s, 3H) 6.65-6.70 (m, 1H) 6.92-6.96 (m, 1H) 7.05-7.10 (m, 1H) 7.12-7.19 (m, 1H) 7.28-7.37 (m, 1H) 7.47-7.55 (m, 1H) 7.56-7.59 (m, 1H) 7.87-7.95 (m, 1H) 9.76-9.94 (m, 1H). LCMS (M+H)+=435. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With palladium diacetate; sodium carbonate; triphenylphosphine; In tetrahydrofuran; at 80℃; for 3.0h;Inert atmosphere; Sealed tube; | A mixture of 2,4,6-trichloropyrimidine (275 mg, 1.5 mmol), <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (246 mg, 1 mmol), Pd(OAc)2 (20 mg), triphenylphosphine (16 mg), and 2M Na2CO3 (1 mL, 2 mmol) in THF (6.7 mL) was purged with nitrogen for 5 min, capped, and heated to 80 C. for 3 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient (0 to 100%) EtOAc in DCM to afford the title compound (150 mg, 55%) as a white solid. LCMS (M+H)+=271. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 75℃; for 2.0h;Inert atmosphere; Sealed tube; | A mixture of N-(3-bromo-5-phenylmethoxyphenyl)ethanesulfonamide (60 mg, 0.16 mmol), <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (40 mg, 0.16 mmol), Pd(dppf)Cl2 (12 mg) and K3PO4 (88 mg, 0.40 mmol) in dioxane (1.5 mL) and water (150 uL) was purged with nitrogen, capped, and heated to 75 C. for 2 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of MeOH (0 to 10%) in DCM to afford the title compound (69 mg, 94%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.15-1.24 (m, 3H) 2.04-2.13 (m, 3H) 3.04-3.17 (m, 2H) 3.48-3.54 (m, 3H) 5.08-5.17 (m, 2H) 6.74-6.80 (m, 1H) 6.90-6.98 (m, 2H) 7.33-7.49 (m, 5H) 7.59-7.63 (m, 1H) 7.90-7.95 (m, 1H) 9.57-10.01 (b.s., 1H). LCMS (M+H)+=413. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.4% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 70℃; for 12.0h;Inert atmosphere; | A mixture of the title compound from step 3 (100 mg, 0.31 mmol), <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (93 mg, 0.37 mmol), Pd(dppf)Cl2 (23 mg, 0.31 mmol) and K3PO4 (199 mg, 0.94 mmol) in dioxane/water (3 mL/0.5 mL) was N2 purged and heated at 70 C. for 12 h. Concentration under vacuum and silica gel chromatography (PE:EA=3:10:1) followed by prep-HPLC gave the title compound (45 mg, 35.4%). 1H NMR (CDCl3, 400 MHz) delta 8.57 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.25-7.24 (m, 1H), 7.12-7.07 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 3.68 (s, 3H), 3.38 (s, 3H), 2.25 (s, 3H). LCMS: 407.9 (M+1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; cesium fluoride; In methanol; 1,2-dimethoxyethane; at 80℃; for 18.0h;Inert atmosphere; | A mixture of <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (2.50 g, 10.0 mmol), 2-bromo-1-fluoro-4-methylsulfonylbenzene (2.54 g, 10.0 mmol), CsF (3.8 g, 25.0 mmol), Pd(dppf)Cl2 (0.73 g, 1.0 mmol) in DME (50 mL) and MeOH (25 ml) was stirred at 80 C. for 18 hrs under N2. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA=2:1-0:1) to give the title compound (1.8 g, 61%) as a red solid. LCMS: 295.9 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1.0h;Inert atmosphere; | To a solution of the title compound from Step 3 (500 mg, 1.3 mmol) and <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (380 mg, 1.5 mmol) in 10 mL of DMF was added K2CO3 (50 mg, 3.8 mmol), water (2 mL) and Pd(dppf)Cl2 (30 mg) under N2. The reaction mixture was heated to 100 C. for 1 h. The resulting mixture was poured into 100 mL of water and extracted with DCM (100 mL*2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc to give the title compound (230 mg, 47% yield) as a white solid. 1H NMR (CDCl3, 400 MHz): delta 7.81 (d, J=3.6 Hz, 1H), 7.67-7.66 (m, 1H), 7.26 (t, J=1.2 Hz, 1H), 7.12 (d, J=3.2 Hz, 1H), 6.54 (br, 1H), 6.36 (d, J=0.8 Hz, 1H), 3.67 (s, 3H), 3.14-3.06 (m, 2H), 2.25 (s, 3H), 2.11-2.00 (m, 1H), 1.38-1.43 (m, 3H), 1.09-0.92 (m, 4H). LCMS: 387 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.42% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere; | To a stirred solution of 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (430 mg, 1 .73 mmol, 1 .0 equiv) and <strong>[1354050-38-6]4-bromo-2,6-dimethoxybenzaldehyde</strong> (634.52 mg, 2.59 mmol, 1 .50 equiv) in 1 ,4-dioxane(25 mLyPEO (5 ml_), was added Pd(dppf)Cl2 (126.3 mg, 0.17 mmol, 0.10 equiv) and CS2CO3 (1 124.78 mg, 3.45 mmol, 2.0 equiv). The resulting solution was stirred at 90 degrees C for 2 h under nitrogen atmosphere. Then the mixture was allowed to cool down to room temperature, the mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 25 ml_). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The residue was purified by silica gel column chromatography, eluted with ChEC /MeOH (20:1 ) to afford 4-(1 ,5- dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxybenzaldehyde (313 mg, 51 .42%) as an off-white solid. LCMS (ESI) m/z: [M+H]+ = 288 |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; Sealed tube; | 4-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2,6-dimethoxy-benzaldehyde (I-205') In a vial <strong>[1354050-38-6]4-bromo-2,6-dimethoxybenzaldehyde</strong> L-100 (517.8 mg; 2.007 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one J-1 (500.0 mg; 2.007 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane (169.0 mg; 0.201 mmol) are introduced. DMF (4 mL) and a 2N aqueous solution of sodium bicarbonate (2.5 mL) are added. The vial is flushed with argon and sealed. The reaction mixture is heated at 100 C. for 1 h. Water (a drop) is added to the reaction mixture and the mixture is filtered. The filtrate is purified with the basic (ammonia buffer) RP HPLC system (column: X-Bridge C-18 30*50 mm). The product containing fractions are concentrated under reduced pressure. HPLC/MS: (M+H)+=288; tRet=0.84 min; method M1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 2.0h; | A mixture of the title compound from step 3 (41 mg, 0.104 mmol), 1,3-dimethyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (31 mg, 0.125 mmol), K2CO3 (43 mg, 0.312 mmol) and Pd(dppf)Cl2 (7.6 mg, 0.010 mmol) in dioxane/H20 (6 mL/ 2 mL) was heated to 90C for 2 hr. It was then cooled to RT and filtered. The filtrate was diluted with water (15 mL) and extracted with DCM (25 mL). The organic layer was dried over Na2S04> filtered and concentrated under reduced pressure. The residue was purified with preparative TLC (PE/EtOAc 1:1) to give the title compound (26 mg, 57%) as a white solid. H NMR (400 MHz, CDCI3) delta 7.73 (s, 1H), 7.49 (s, 1H), 7.40-7.35 (m, 5H), 7.31-7.28 (m, 2H), 7.00 (s, 1H), 5.84 (s, 2H), 3.62 (s, 3H), 3.25 (q, / = 7.2 Hz, 2H), 2.22 (s, 3H), 1.43 (t, / = 7.2 Hz, 3H). LCMS: 438 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 1.0h; | A mixture of the title compound of Example 29, step 5 (40 mg, 0.11 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (33 mg, 0.13 mmol), K2C03 (46 mg, 0.33 mmol) and Pd(dppf)Cl2 (8 mg, 0.01 mmol) in dioxane (6 mL) and H20 (2 mL) was heated at 85C for 1 hr, cooled, diluted with H20 (20 mL),and extracted with DCM (35 mL x 2). The combined organic layers were dried over Na2S04, filtered, concentrated, and the residue was purified using prep-TLC (PE/EtOAc 1:1) to give the title compound (21 mg, 46%) as a white solid. FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-d6): delta 7.76 (s, IH), 7.74 (s, IH), 7.55 (s, IH), 7.36 (s, IH), 4.12 (s, 3H), 4.02 (d, / = 7.2 Hz, 2H), 3.51 (s, 3H), 3.33 (s, 3H), 2.06 (s, 3H), 1.29-1.24 (m, IH), 0.61-0.56 (m, 2H), 0.39-0.35 (m, 2H). LCMS: 402 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 25 - 90℃; for 12.0h;Inert atmosphere; | To a mixture of the title compound from step 1 (100 mg, 301 umol) and 1,3- dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (90 mg, 361umol) in 1,4- dioxane (5 mL) and H20 (0.5 mL) at 25C was added K3P04 (127 mg, 602 umol) and Pd(dppf)Cl2 (11 mg, 15 umol) in one portion under N2. The mixture was stirred at 90C for 12 hr. After cooling to RT, the reaction contents were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 3:1-1:1) followed by preparative HPLC to afford the title compound (50 mg, 44% yield) as a yellow solid. H NMR (CDC13, 400 MHz) delta 8.67 (s, 1 H ), 8.20 (s, 1 H), 7.60 (s, 1 H), 7.47(m, 2 H), 7.21-7.35(m, 5 H), 5.73(s, 2 H), 3.67(s, 3 H), 2.26(s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 80℃; for 3.0h;Inert atmosphere; Sealed tube; | A mixture of 7-chloro-2-cyclopropyl-5-nitro-l,3-benzoxazole (91 mg, 0.38 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (108 mg, 0.44 mmol), K3P04 (247 mg, 1.1 mmol), Pd2(dba)3 (17 mg, 5 %) and S-Phos (16 mg, 10%) in dioxane (2.4 mL) and 0 (120 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 80C for 180 min. After the reaction mixture was filtered through a short plug of celite, the celite plug was washed with EtOAc (35 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100%) in DCM to afford the title compound (71 mg, 57%) as a tan solid. LCMS (M+H)+ = 326. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 70℃; for 12.0h;Inert atmosphere; Sealed tube; | A mixture of N-(7-bromo-2-cyclopropyl-3-methylbenzimidazol-5- yl)ethanesulfonamide (60 mg, 0.17 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-one (41 mg, 0.17 mmol), K3P04 (91 mg, 0.42 mmol), Pd(dppf)Cl2 (12 mg, 10 %) in dioxane/S^O (1 mL/120 mu) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 70 C for 12 hr. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over Na2S04, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HPLC to afford the title compound (30 mg, 44%) as a white solid. LCMS (M+H)+ = 401. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 70℃; for 12.0h;Inert atmosphere; Sealed tube; | A mixture of 7-bromo-2-cyclopropyl-5-(methylsulfonylmethyl)- 1 ,3-benzoxazole (30 mg, 0.1 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (22 mg, 0.1 mmol), K3P04 (50 mg, 0.25 mmol), Pd(dppf)Cl2 (7 mg, 10 %) in dioxane/H20 (600 muIota750 uL) was bubbled with nitrogen for 7 min. The sealed vial was stirred at 70C for 12 hr. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by silica gel column chromatography using a gradient of MeOH (0 to 5%) in DCM to afford the title compound (26 mg, 72 %) as an off-white solid. H NMR (400 MHz, DMSO-ife) delta ppm 0.78 - 0.94 (m, 4 H) 2.12 (s, 3 H) 2.29 - 2.41 (m, 1 H) 2.91 (s, 3 H) 3.57 (s, 3 H) 4.52 - 4.63 (m, 2 H) 7.51 - 7.58 (m, 2 H) 7.80 - 7.85 (m, 1 H) 8.13 - 8.18 (m, 1 H). LCMS (M+H)+ = 373. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 90℃; for 12.0h;Inert atmosphere; | To a mixture of the title compound from step 2 (110 mg, 300 muiotaetaomicron) and l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (97 mg, 390 umol) in 1,4-dioxane (5 mL) and H20 (0.5 mL) was added K3PO4 (127 mg, 600 muiotaetaomicron) and Pd(dppf)Cl2 (11 mg, 15 muetaiotaomicron) in one portion under N2. The mixture was stirred at 90C for 12 nr. After cooling to RT, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA=20:1) to afford the title compound (110 mg, 90% yield) as a yellow solid. LCMS: 411 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 3.0h;Inert atmosphere; | The title compound form step 4 (100 mg, 0.26 mmol), l,3-dimethyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (90 mg, 0.36 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(dppf)Cl2 (40 mg, 0.054 mmol) in a DMF/H20 mixture (10 mL/1 mL) under N2 was heated to 100C for 3 hr. After cooling to RT, addition of water, and EtOAc extractive work up (50 mL x 3), the combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (EtOAc/MeOH, 15:1) to give the title compound (55 mg, 50%). H NMR (300 MHz, CDCI3): delta 7.92 (s, 1H), 7.46-7.41 (m, 3H), 7.36-7.26 (m, 3H), 7.08-7.05 (m, 2H), 5.41 (s, 2H), 3.62 (s, 3H), 3.51 (s, 3H), 2.65 (s, 3H), 2.22 (s, 3H). LCMS: 422 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 80℃; for 12.0h;Inert atmosphere; | A mixture of the title compound of step 6 (40 mg, 0.137 mmol), l,3-dimethyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (41 mg, 0.164 mmol), Pd(dppf)Cl2 (10 mg, 0.014 mmol) and K3PO4 (73 mg, 0.343 mmol) in dioxane/H20 (4/0.4 mL) was stirred at 80C for 12 hr under N2. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EA =2: 1) to give a yellow solid which was further purified by prep-HPLC to afford the title compound (20.2 mg, 44 %).1H NMR (CDC13, 400 MHz): delta 7.64 (s, 1 H), 7.40-7.38 (m, 2 H), 6.87 (s, 1 H), 4.34 (s, 2 H), 3.92 (s, 3 H), 3.61 (s, 3 H), 2.96 (s, 3 H), 2.21 (s, 3 H). LCMS: 335.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 3.0h;Inert atmosphere; | The title compound of step 4 (75 mg, 0.19 mmol), l,3-dimethyl-5-(4,4,5,5-tetra- methyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (58 mg, 0.23 mmol), K2CO3 (79 mg, 0.57 mmol) and Pd(dppf)Cl2 (15 mg, 0.019 mmol) in dioxane/H20 (9 mL/ 3 mL) under N2 were heated at 85 C for 3 hr. The mixture was cooled and filtered, and the filtrate was diluted with water and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2S04, filtered, and concentrated to give a residue which was triturated with EA/ether (3ml/20ml). The white solid that remained was dried to give the title compound (48 mg, 58%). H NMR (400 MHz, DMSO-ife): delta 9.36 (s, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 7.13 (s, 1H), 4.57 (q, / = 6.4 Hz, 2H), 3.92 (d, / = 6.4 Hz, 2H), 3.54 (s, 3H), 3.26 (s, 3H), 2.10 (s, 3H), 1.43 (t, / = 6.8 Hz, 3H), 1.31-1.28 (m, 1H), 0.51-0.42 (m, 4H). LCMS: 431 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 3.0h;Inert atmosphere; | The title compound of step 1 (130 mg, 0.35 mmol), l,3-dimethyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (104 mg, 0.41 mmol), K2C03 (145 mg, 1.05 mmol) and Pd(dppf)Cl2 (26 mg, 0.035 mmol) in dioxane/H20 (12 mL/ 4 mL) under N2 were heated at 85 C for 3 hr. The mixture was cooled and filtered, and the filtrate was diluted with water and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2S04, filtered, and concentrated to give a residue which was triturated with EA (5ml). The white solid that remained was dried to give the title compound (69 mg, 48%).1H NMR (400 MHz, DMSO-d6): delta 9.38 (s, 1H), 7.91 (s, 1H), 7.73 (s, 1H), 7.49 (s, 1H), 7.14 (s, 1H), 4.15 (s, 3H), 3.92 (d, / = 7.2 Hz, 2H), 3.54 (s, 3H), 3.26 (s, 3H), 2.10 (s, 3H), 1.30- 1.29 (m, 1H), 0.50-0.41 (m, 4H). LCMS: 417 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 3.0h;Inert atmosphere; | The title compound of step 1 (80 mg, 0.22 mmol), l,3-dimethyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (64 mg, 0.26 mmol), K2C03 (89 mg, 0.65 mmol) and Pd(dppf)Cl2 (16 mg, 0.022 mmol) in dioxane/H20 (9 mL/ 3 mL) under N2 were heated at 85 C for 3 hr. The mixture was cooled and filtered, and the filtrate was diluted with water and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2S04, filtered, and concentrated to give a residue which was purified by prep-TLQ, (DCM:MeOH:20: l) to give the title compound (23 mg, 25%) as a yellow solid. H NMR (400 MHz, DMSO-ifc): delta 9.36 (s, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 7.13 (s, 1H), 4.57 (q, / = 6.4 Hz, 2H), 3.92 (d, / = 6.4 Hz, 2H), 3.54 (s, 3H), 3.26 (s, 3H), 2.10 (s, 3H), 1.43 (t, / = 6.8 Hz, 3H), 1.31-1.28 (m, 1H), 0.51-0.42 (m, 4H) LCMS: 415 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium acetate; In N,N-dimethyl-formamide; at 100℃; for 3.0h;Inert atmosphere; | To a mixture of the title compound from step 3 (30 mg, 0.09 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (27 mg, 0.11 mmol) and KOAc (27 mg, 0.28 mmol) in DMF (3 mL) was added dichloro[l,l'-bis(di-i<?ri-butylphos- phino)ferrocene] palladiumll (3 mg) under N2. The reaction was heated at 100C for 3 hr. Water (30 mL) was added and the resulting mixture was filtered. The cake was purified by preparative TLC (ethyl acetate/petroleum ether = 2:1) to give the title compound (15 1^, 41%). ^ NMR (CD3OD, 400 MHz): delta 8.25 (d, / = 1.2 Hz, 1H), 8.02 (s, 1H), 7.94-7.92 (m, 2H), 7.54-7.51 (m, 3H), 7.45-7.43 (d, / = 7.2 Hz, 1H), 7.33-7.32 (d, / = 2.4 Hz, 1H), 7.29 (s, 1H), 3.77 (s, 3H), 3.01 (s, 3H), 2.29 (s, 3H). LCMS: 409(M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 3.0h;Inert atmosphere; | The title compound of step 1 (130 mg, 0.32 mmol), l,3-dimethyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (94 mg, 0.38 mmol), K2CO3 (133 mg, 0.96 mmol) and Pd(dppf)Cl2 (24 mg, 0.032 mmol) in dioxane/H20 (12 mL/ 4 mL) under N2 were heated at 85 C for 3 hr. After cooling to RT, the mixture was filtered, rinsing with EtOAC. The combined filtrate/rinse was diluted with water. After extraction with EtOAc (50 mL x 3), the combined extracts were dried over Na2S04, filtered, concentrated, and the residue was purified by prep-TLC (EtOAc) to give the title compound (74 mg, 51%) as a white solid. H NMR (400 MHz, DMSO-d6): delta 9.99 (s, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.79 (s, 1H), 7.41 (s, 1H), 4.36 (d, J = 6.8 Hz, 2H), 3.56 (s, 3H), 3.28 (s, 3H), 2.12 (s, 3H), 1.31-1.28 (m, 1H), 0.56-0.52 (m, 4H). LCMS: 455 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 3.0h;Inert atmosphere; | The title compound of step 4 (100 mg, 0.28 mmol), l ,3-dimethyl-5-(4,4,5,5- tetramethyl- l ,3,2-dioxaborolan-2-yl)pyridin-2-one (83 mg, 0.33 mmol), K2CO3 (115 mg, 0.84 mmol) and Pd(dppf)Cl2 (21 mg, 0.028 mmol) in dioxane/H20 (9 mL/3 mL) under N2 were heated at 85 C for 3 hr. After cooling to RT, the mixture was filtered, diluted with water (20 mL), and extracted with EtOAc (30 mL x 3). The combined extracts were dried over Na2S04, filtered, concentrated, and the residue was purified by prep-TLC (DCM:MeOH = 20: 1) to give the title compound (45 mg, 40%) as a white solid. H NMR (400 MHz, DMSO-d6): delta 9.53 (s, 1H), 7.91 (d, / = 2.8 Hz, 1H), 7.73 (s, 1H), 7.49 (d, / = 0.8 Hz, 1H), 7.19 (d, J = 1.2 Hz, 1H), 4.23-4.19 (m, 2H), 3.54 (s, 3H), 3.19 (s, 3H), 2.57 (s, 3H), 2.11 (s, 3H), 1.74-1.69 (m, 2H), 1.36-1.30 (m, 2H), 0.91 (t, / = 7.2 Hz, 3H). LCMS: 403 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 3.0h;Inert atmosphere; | A mixture of the title compound from step 3 (100 mg, 0.28 mmol), 1,3-dimethyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (83 mg, 0.33 mmol), K2CO3 (116 mg, 0.84 mmol) and Pd(dppf)Cl2 (21 mg, 0.028 mmol) in dioxane/H20 (9 mL/3 mL) under N2 was heated to 85 C for 3 hr. The reaction mixture was cooled to RT and filtered. The filtrate was diluted with water and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by preparative TLC (EtOAc) to give the title compound (42 mg, 38%) as a solid. lH NMR (300 MHz, DMSO-<i6): delta 9.94 (s, 1H), 8.97 (s, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 7.17 (s, 1H), 3.75 (d, / = 6.9 Hz, 2H), 3.53 (s, 3H), 3.14 (s, 3H), 2.10 (s, 3H), 1.34-1.31 (m, 1H), 0.54-0.45 (m, 4H). LCMS: 404 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In N,N-dimethyl acetamide; at 145℃; for 3.0h;Inert atmosphere; | A mixture of the title compound from step 2 (100 mg, 0.27 mmol), 1,3-dimethyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (88 mg, 0.35 mmol), K2CO3 (75 mg, 0.54 mmol) and Pd-118 (17 mg, 0.027 mmol) in DMA (10 mL) under N2 was heated to 145C for 3 hr. The reaction was cooled to RT and filtered. The filtrate was diluted with water, adjusted to pH 3-4 by addition a 2M HC1 solution, and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified with preparative TLC (DCM: MeOH = 20:1) to give the title compound (36 mg, 29%) as a solid. FontWeight="Bold" FontSize="10" H NMR (300 MHz, DMSO-d6): delta 8.51 (d, / = 2.1 Hz, 1H), 8.20 (d, / = 2.1 Hz, 1H), 7.34-7.31 (m, 2H), 7.22-7.19 (m, 2H), 5.51 (s, 2H), 3.58 (s, 3H), 3.55 (s, 3H), 2.48 (s, 3H), 2.10 (s, 3H). LCMS: 457 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In tetrahydrofuran; at 90℃; for 16.0h;Sealed tube; Inert atmosphere; | In a 5 mL glass microwave vial equipped with a magnetic stirring bar and nitrogen flow at room temperature was placed the methyl 4-bromo-1-(4-bromo-5- (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (100 mg, 0.220 mmol), the <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (110 mg, 0.440 mmol), K2CO3 (152 mg, 1.10 mmol) and THF (2 mL). Nitrogen was bubbled in the solvent for 10 minutes followed by the addition of the catalyst Pd(dtbpf)Cl2 (11 mg, 0.022 mmol). The vial was capped and placed in an oil bath at 90 C for 16 h. The solvent was evaporated under vacuum and the crude product was purified by flash chromatography (dry packing) on silica gel using a gradient 0 to 10% EtOAc in hexanes to give the title compound (42 mg, 0.084 mmol, 38%) as a brown oil. |
42 mg | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In tetrahydrofuran; at 20 - 90℃; for 16.0h;Inert atmosphere; Sealed tube; | In a 5 mL glass microwave vial equipped with a magnetic stirring bar and nitrogen flow at room temperature was placed the methyl 4-bromo-1-(4-bromo-5- (isopropylthio)thiazol-2-yl)-3-methyl- 1 H-pyrazole-5-carboxylate (100 mg, 0.220 mmol), the 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (110 mg, 0.440 mmol), K2003 (152 mg, 1.10 mmol) and THF (2 mL). Nitrogen was bubbled in the solvent for 10 minutes followed by the addition of the catalyst Pd(dtbpf)C12 (11 mg, 0.022 mmol). The vial was capped and placed in an oil bath at 90 00 for 16 h. The solvent was evaporated under vacuum and the crude product was purified by flash chromatography (dry packing) on silica gel using a gradient 0 to 10% EtOAc in hexanes to give the title compound (42 mg, 0.084 mmol, 38%) as a brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 20.0h; | Pd(PPh3)4 (51 mg, 0.044 mmol) was added to a degassed solution of 6-bromo-3,4-dihydro-1 H- quinolin-2-one (50 mg, 0.221 mmol), 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-2-one (prepared using described procedure in US20130053362, 82 mg, 0.332 mmol), and Cs2C03 (144 mg, 0.442 mmol) in DME (3 mL) and water (0.3 mL). The resulting mixture was heated to 80 C for 20 h and then cooled to rt. The mixture was diluted with saturated NaHC03 (20 mL) and EtOAc (20 mL), and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over MgS04, filtered, and concentrated under reduced pressure. The material was purified by flash chromatography on silica using a mixture of EtOAc in hexane as eluent to provide Intermediate 2 (25 mg, 42%). 1H NMR (500 MHz, CDCI3) delta 8.03 (s, 1 H), 7.46 (dd, J = 2.6, 1.2 Hz, 1 H), 7.33 (d, J = 2.3 Hz, 1 H), 7.23 - 7.19 (m, 2H), 6.80 (d, J = 8.7 Hz, 1 H), 3.63 (s, 3H), 3.04 - 2.99 (m, 2H), 2.67 (dd, J = 8.3, 6.8 Hz, 2H), 2.23 (s, 3H). MS (ESI) [M+Hf 269.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 5.0h; | Pd(PPh3)4 (102 mg, 0.088 mmol) was added to a degassed solution of 7-bromo-3,4-dihydro-1H- quinolin-2-one (100 mg, 0.442 mmol), 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-2-one (prepared using described procedure in U520130053362, 165 mg, 0.664 mmol), and C52CO3 (288 mg, 0.885 mmol) in DME (5 mL) and water (0.5 mL). The resulting mixture washeated to 80 C for 5 h and then cooled to rt. The mixture was diluted with saturated NaHCO3 (20 mL) and EtOAc (20 mL), and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over Mg504, filtered, and evaporated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of DCM and MeOH as eluent to provide Intermediate 3 (56 mg, 47%). 1H NMR (500 MHz, MeOD) O 7.78(d, J = 2.5 Hz, 1H), 7.70 (dd, J = 2.5, 1.1 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.15 (dd, J = 7.8, 1.9 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 3.65 (5, 3H), 3.01 -2.94 (m, 2H), 2.62-2.56 (m, 2H), 2.22- 2.17 (m, 3H). MS (ESI) [M+H] 269.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; at 80℃; for 12.0h;Inert atmosphere; | To a solution of 4-benzyl-7-bromo-1,4-benzoxazin-3-one (Intermediate 4, 169 mg, 0.531 mmol) in dioxane (1 mL) was added C52CO3 (432.8 mg, 1.33 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared using described procedure in US20 130053362,317.6 mg, 1.27 mmol), Pd(PPh3)4 (61.6 mg, 0.053 mmol) and water (0.1 ml). The reaction mixture was degassed by bubbling N2 and then heated at 80 C for 12 h. The mixture was cooled to ii and evaporated under reduced pressure. To the residue, EtOAc (5 mL) was added and the organic layer was washed with water (5 mL). The organic phase was dried over Na2SO4, filtered andevaporated under reduced pressure. The material was purified by flash chromatography on silicagel using a mixture of EtOAc in hexane as eluent, and followed by preparative HPLC to affordCompound 16(57mg, 30%). 1H NMR (500 MHz, CDCI3) O 7.41 (dd, J = 2.5, 1.1 Hz, 1H), 7.39-7.24 (m, 6H), 7.04 (d, J = 1.9 Hz, 1H), 6.92 (dt, J = 16.6, 8.4 Hz, 2H), 5.19 (5, 2H), 4.76 (5, 2H),3.60 (5, 3H), 2.20 (5, 3H). MS (ESI) [M+H] 361 .2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 80℃; for 12.0h;Inert atmosphere; | To a solution of 6-bromo-4-(2-pyridylmethyl)-1,4-benzoxazin-3-one (120 mg, 0.38 mmol) in dioxane (1 mL) was added C52CO3 (306.3 mg, 0.94 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared using described procedure in U520 130053362,140.5 mg, 0.56 mmol), Pd(PPh3)4 (43.6 mg, 0.038 mmol) and water (0.1 mL). The reactionmixture was degassed by bubbling N2 and then heated at 80 C for 12 h. The reaction mixturewas cooled to ii and then concentrated under reduced pressure. To the residue, EtOAc (5 mL)was added and the organic layer was then washed with water (5 ml). The organic phase wasdried over Na2504, filtered and evaporated under reduced pressure. The material was purified byflash chromatography on silica gel using a mixture of EtOAc in hexane as eluent, and followed bypreparative HPLC to afford Compound 18 (36.3 mg, 26%). 1H NMR (500 MHz, CDCI3) 0 8.60(ddd, J = 4.9, 1.7, 0.9 Hz, 1H), 7.66 (td, J = 7.7, 1.8 Hz, 1H), 7.36-7.29 (m, 2H), 7.25-7.17 (m,3H), 7.05 - 6.89 (m, 2H), 5.32 (5, 2H), 4.74 (5, 2H), 3.59 (5, 3H), 2.20 (5, 3H). MS (ESI) [M+H]+362.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 5.0h; | Pd(PPh3)4 (90 mg, 0.078 mmol) was added to a degassed solution of 6-bromo-7-methoxy-3,4- dihydro-1H-quinolin-2-one (prepared using described procedure in J. Med.Chem. 2012, 55(16), 7080-7089, 100 mg, 0.390 mmol), 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-2-one (prepared using described procedure in US20130053362, 145 mg, 0.586 mmol),and C52CO3 (254 mg, 0.781 mmol) in DME (5 mL) and water (0.5 mL). The resulting mixture was heated to 80 C for 5 h and then cooled to rt. The mixture was diluted with saturated NaHCO3 (20 mL) and EtOAc (20 mL), and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over MgSO4, filtered and evaporated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture ofMeOH in DCM as eluent to provide Intermediate 1 (87 mg, 75 %). 1H NMR (500 MHz, CDCI3) O7.79 (5, 1H), 7.39 (dd, J = 2.5, 1.2 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.01 (5, 1H), 6.34 (5, 1H),3.81 (5, 3H), 3.60 (5, 3H), 2.96-2.90 (m, 2H), 2.65 (dd, J = 8.3, 6.8 Hz, 2H), 2.22-2.18(m, 3H).MS (ESI) [M+H] 299.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 4.0h;Inert atmosphere; | To a stirred solution of 1-benzyl-6-bromo-8-methyl-3,4-dihydro quinolin-2(1H)-one (0.3 g, 0.91mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (0.34 g,1.36 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen for 20 mm followed by addition of solution of sodium carbonate (0.29 g, 2.733 mmol) in water (1 mL) and was again purged with nitrogen for 20 mm. After 20 mi Pd(PPh3)4 (0.05 g, 0.045 mmol) was added and the reaction mixture was heated at 100 C for 4 h. The mixture was diluted with water (100 mL) and extractedwith EtOAc (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and evaporated under vacuum. The material was purified by flash chromatography on silica gel using a mixture of 1.8% MeOH in DCM and followed by Et20 trituration to afford Compound 21(0.22 g, 65%) as solid. 1H NMR (400 MHz, DMSO) Oppm 7.49 (d, J= 1.2 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.28-7.18 (m, 3H), 7.15 (d, J = 1.6 Hz, 1H), 7.13 (5, 1H), 7.06 (5, 2H),5.16 (5, 2H), 3.65 (d, J= 7.2 Hz, 3H), 2.84-2.81 (m, 2H), 2.66-2.62 (m, 2H), 2.40 (5, 3H), 2.23(s3H). MS (ESI) [M+H] 373.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 4.0h;Inert atmosphere; | To a stirred solution of 1-benzyl-6-bromo-8-chloro-3,4-dihydro quinolin-2(1H)-one (0.3 g, 0.86 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (0.32 g, 1.29 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen for 20 mm followed by addition ofsolution of Na2CO3 (0.27 g, 2.58 mmol) in water (1 mL) and the reaction mixture was again purged with nitrogen for 20 mm. After 20 mi Pd(PPh3)4 (0.05 g, 0.043 mmol) was added and reaction mixture was heated at 100 C for 4 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layer were washed with brine (50 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The material was purified by columnchromatography by silica gel using a mixture of 1.8% MeOH in DCM as eluent and followed byEt20 trituration to afford Compound 22 (0.1 g, 30 %) as solid. 1H NMR (400 MHz, DMSO) O ppm7.44 (d, J = 1.2 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.26 (d, J =2.4 Hz, 1H), 7.29-7.17 (m, 5H), 7. 10(d, J = 3.5 Hz, 1H), 5.47(s, 2H), 3.63 (5, 3H), 2.86-2.83 (m, 2H), 2.68-2.65 (m, 2H), 2.23 (5, 3H).MS (ESI) [M+H] 393.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 5.0h;Inert atmosphere; | A stirred solution of 6-bromo-2-(tetrahydro-2H-pyran-4-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1 H- benzo[d]imidazole (0.14 g, 0.34 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2(1 H)-one (0.11 g, 0.44 mmol) in 1 ,4-dioxane (5 mL) was purged with nitrogen for 10 minutes followed by the addition of Na2C03 (0.11 g, 1.03 mmol) in water (0.5 mL). The reaction mixture was again purged with nitrogen for 10 minutes. Pd(PPh3) (0.02 g, 0.01 mmol) was added and the reaction mixture was heated to 90C for 5h. The solvent was then evaporated under reduced pressure and the residue was extracted with EtOAc (20 mL X 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2S0 , filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 1.5% MeOH in DCM as eluent. The fractions were combined and concentrated to afford a semi-purified product, which was further purified by preparative HPLC using 35-45 % MeCN in water to afford Compound 41 (0.07 g, 45%) as a solid. 1H NMR (400 MHz, DMSO) delta ppm 7.97 (d, J = 2.4 Hz, 1 H), 7.80 (s, 1 H), 7.74 (d, J = 1.2 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.34 (dd, J1.6 and 8.4 Hz, 1 H), 4.53 (t, J = 4.8 Hz, 2H), 4.09- 3.91 (m, 6H), 3.54 (s, 3H), 3.50-3.34 (m, 2H), 3.31-3.28 (m, 1 H), 2.1 1 (s, 3H), 1.91-1.77 (m, 4H). [M+H]+ 450.35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 5.0h;Inert atmosphere; | A stirred solution of 6-bromo-1-(2-methoxyethyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1 H- benzo[d]imidazole (0.18 g, 0.51 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2(1 H)-one (0.16 g, 0.66 mmol) in 1 ,4-dioxane (5 mL) was purged with nitrogen for 10 minutes, followed by the addition of Na2C03 (0.16 g, 1.53 mmol) in water (0.5 mL). The reaction mixture was again purged with nitrogen for 10 minutes. Pd(PPh3)4 (0.03 g, 0.05 mmol) was added and the reaction mixture was heated to 90C for 5h. The solvent was evaporated under reduced pressure and the residue was extracted using EtOAc (20 mL X 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2S0 , filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 1.3% MeOH in DCM as eluent to afford Compound 42 (0.07 g, 34%) as a solid. 1H NMR (400 MHz, DMSO) delta ppm 7.97 (d, J = 2.4 Hz, 1 H), 7.80 (s, 1 H), 7.69 (s, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.34 (dd, J = 1.6 and 8.4 Hz, 1 H), 4.41 (t, J = 5.2 Hz, 2H), 3.84 (dd, J = 2.4 and 11.2 Hz, 2H), 3.65 (t, J = 5.2 Hz, 2H), 3.53 (s, 3H), 3.34-3.31 (m, 2H), 3.19 (s, 3H), 2.81 (d, J = 6.8 Hz, 2H), 2.23-2.18 (m, 1 H), 2.10 (s, 3H), 1.68-1.65 (m, 2H), 1.37- 1.27 (m, 2H). [M+H]+ 395.50. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 5.0h;Inert atmosphere; | A stirred solution of 6-bromo-2-(4,4-difluorocyclohexyl)-1-(2-methoxyethyl)-1 H- benzo[d]imidazole (0.2 g, 0.53 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2(1 H)-one (0.17 g, 0.69 mmol) in 1 ,4-dioxane (5 mL) was purged with nitrogen for 10 minutes, followed by the addition of Na2C03 (0.17 g, 1.60 mmol) in water (0.5 mL). The reaction mixture was purged again with nitrogen for 10 minutes. Pd(PPh3) (0.03 g, 0.02 mmol) was added and the reaction mixture was heated to 90C for 5h. The solvent was then evaporated under reduced pressure and the residue was extracted with EtOAc (20 mL X 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography using 1.5% MeOH in DCM as eluent to afford Compound 44 (0.06 g, 27%) as a solid. 1H NMR (400 MHz, DMSO) delta ppm 7.97 (d, J = 2 Hz, 1 H), 7.81 (s, 1 H), 7.72 (s, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.36 (dd, J = 1.2 and 8.4 Hz, 1 H), 4.47 (t, J = 5 Hz, 2H), 3.67 (t, J = 5 Hz, 2H), 3.54 (s, 3H), 3.21 (s, 4H), 2.19-1.88 (m, 11 H). [M+H]+ 415.48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 16.0h;Inert atmosphere; | A stirred solution of (R)-5-bromo-N-(1-ethoxypropan-2-yl)-2-nitroaniline (0.5 g, 1.65 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (0.49 g, 1.98 mmol) in DME (10 mL) was purged with nitrogen for 15 minutes at rt, followed by the addition of Cs2C03 (1.34 g, 4.12 mmol) in water (2 mL) and purging with nitrogen for another 15 minutes. Pd(PPh3) (0.19 g, 0.16 mmol) was added and the reaction mixture was heated to 80 C for 16 h. The resulting mixture was then filtered through Celite and washed with EtOAc (15 mL X 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 1-2% MeOH in DCM as eluent. Product fractions were combined and evaporated to dryness to give the title compound (0.5 g, 88%) as a solid, [M+H]+ 346.29 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 16.0h;Inert atmosphere; | stirred solution of (S)-5-bromo (0.65 g, 2.14 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (0.64 g, 2.57 mmol) in DME (13 mL) was purged with nitrogen for 15 minutes at rt, followed by the addition of Cs2C03 (1.75 g, 5.36 mmol) in water (2 mL) and purging with nitrogen for another 15 minutes. Pd(PPh3) (0.19 g, 0.16 mmol) was added and the reaction mixture was heated to 80C for 16 h. The resulting mixture was then filtered through Celite and washed with EtOAc (15 mL X 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S0 , filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 2% MeOH in DCM as eluent. Product fractions were combined and evaporated to dryness to give the title compound (0.7 g, 94%) as a solid, [M+H]+ 346.29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 6.0h;Inert atmosphere; | A stirred solution of 5-bromo-N-(2-isopropoxyethyl)-2-nitroaniline (Example 44, Step 1 , 0.65 g, 2.14 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (0.801 g, 3.22 mmol) in 1 ,4-dioxane (5 ml_) was purged at rt with nitrogen for 15 minutes, followed by the addition of Na2C03(0.682 g, 6.43 mmol) in water (1 ml_) and purging with nitrogen for another 15 minutes. Pd(PPh3)4(0.124 g, 0.12 mmol) was added and the reaction mixture was heated at 100C for 6 h. The resulting mixture was then concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 3-5% MeOH in DCM as eluent. Product fractions were combined and concentrated in vacuo to afford the title compound (0.8 g, 90%) as a semisolid, [M+H]+346.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 16.0h;Inert atmosphere; | A stirred solution of 6-bromo-1-(2-isopropoxyethyl)-2-(tetrahydro-2H-pyran-4-yl)-1 H- benzo[d]imidazole (0.27 g, 0.74 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2(1 H)-one (0.24 g, 0.97 mmol) in 1 ,4-dioxane (4 mL) was purged with nitrogen for 20 min, followed by the addition of NaHC03 (0.29 g, 2.24 mmol) in water (0.3 mL) and purging with nitrogen for another 20 min. Pd(PPh3)4 (0.025 g, 0.022 mmol) was added at rt and the reaction mixture was heated at 90C for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography using 2-3% MeOH in DCM as eluent. Fractions were combined and concentrated to give 0.13 g, which was further purified by preparative HPLC using 20-60% MeCN in water to afford Compound 49 (0.075 g, 25%) as a solid. 1H NMR (400 MHz, DMSO) 7.97 (s, 1 H), 7.81 (s, 1 H), 7.71 (s, 1 H), 7.57 (d, J = 8 Hz, 1 H), 7.35 (d, J = 8 Hz, 1 H), 4.43 (s, 2H), 3.97 (d, J = 10 Hz, 2H), 3.69 (s, 2H), 3.53 (s, 3H), 3.51- 3.42 (m, 3H), 3.35-3.32 (m, 1 H), 2.10 (s, 3H), 1.94-1.80 (m, 4H), 0.95 (d, J = 6 Hz, 6H). [M+H]+ 410.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 20.0h;Inert atmosphere; | Pd(PPh3)4(194 mg, 0.167 mmol) was added to a degassed solution of 5-bromo-N-[(1 R)-2- methoxy-1-methyl-ethyl]-2-nitro-aniline (484 mg, 1.674 mmol), 1 ,3-dimethyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared using described procedure in US20130053362, 542 mg, 2.18 mmol), and Cs2C03(1.36 g, 4.19 mmol) in mixture of DME (20 mL) and water (2 mL) under N2and the resulting mixture was heated to 80 C for 20 h. The mixture was cooled to rt and saturated NaHC03(50 mL) and EtOAc (50 mL) were added, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na2S04, filtered through Celite and concentrated under reduced pressure. The product was purified by flash chromatography on silica gel using a mixture of EtOAc in hexane as eluent to provide title compound (561 mg, 99%).1H NMR (500 MHz, CDCI3) delta 8.29 (d, J = 7.6 Hz, 1 H), 8.20 (d, J = 8.9 Hz, 1 H), 7.71 - 7.63 (m, 1 H), 7.48 - 7.46 (m, 1 H), 6.87 (d, J = 1.8 Hz, 1 H), 6.66 (dd, J = 8.9, 1.9 Hz, 1 H), 4.02 - 3.94 (m, 1 H), 3.65 (s, 3H), 3.57 - 3.48 (m, 2H), 3.43 (d, J = 4.5 Hz, 3H), 2.24 (t, J = 0.8 Hz, 3H), 1.37 (d, J = 6.5 Hz, 3H). MS (ESI) [M+H]+332.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; at 80℃; for 18.0h;Inert atmosphere; | Pd(PPh3)4(186 mg, 0.161 mmol) was added to a degassed solution of 5-bromo-N-[(1S)-2- methoxy-1-methyl-ethyl]-2-nitro-aniline (466 mg, 1.61 mmol), 1 ,3-dimethyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared using the procedure described in US20130053362, 522 mg, 2.09 mmol), and Cs2C03(1.31 g, 4.03 mmol) in DME (20 mL) and water (2 mL) under N2. The reaction mixture was heated to 80 C for 18 h and then cooled to rt. The mixture was diluted with saturated NaHC03(50 mL) and EtOAc (50 mL), and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na2S04, filtered through Celite and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of EtOAc in hexane as eluent to provide the title compound (603 mg, 99%) as a solid.1H NMR (500 MHz, CDCI3) delta 8.29 (d, J = 7.6 Hz, 1 H), 8.20 (d, J = 8.9 Hz, 1 H), 7.47 (d, J = 0.8 Hz, 2H), 6.87 (d, J = 1.8 Hz, 1 H), 6.66 (dd, J = 8.9, 1.9 Hz, 1 H), 4.03 - 3.92 (m, 1 H), 3.65 (s, 3H), 3.57 - 3.48 (m, 2H), 3.43 (s, 3H), 2.24 (t, J = 0.8 Hz, 3H), 1.37 (d, J = 6.5 Hz, 3H). MS (ESI) [M+H]+332.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 80℃; for 5.0h;Inert atmosphere; | A stirred solution of (R)-6-bromo-2-(4,4-difluorocyclohexyl)-1-(1-methoxypropan-2-yl)-1 H- benzo[d]imidazole (0.38 g, 0.984 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2(1 H)-one (0.29 g, 1.18 mmol) in 1 ,4-Dioxan (8 mL) was purged with nitrogen for 15 minutes at rt followed by the addition of Cs2C03 (0.96 g, 2.95 mmol) in water (0.8 mL) and purging with nitrogen for another 15 minutes. Pd(PPh3)4 (0.1 g, 0.098 mmol) was added and the reaction mixture was heated at 80C for 5 h. The resulting mixture was filtered through Celite and washed with EtOAc (30 mL X 3). The organic layer was washed with brine (60 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 3% MeOH in DCM as eluent. Product fractions were combined and concentrated in vacuo to afford Compound 57 (0.1 1 g, 26%) as a solid. 1H NMR (400 MHz, DMSO) delta ppm 7.96 (d, J = 2.4 Hz, 1 H), 7.79 (d, J = 1.6 Hz, 1 H), 7.73 (d, J = 1.2 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.34 (dd, J = 1.6 and 8.4 Hz, 1 H), 4.90 (m, 1 H), 4.01 (t, J = 10 Hz, 1 H), 3.73 (dd, J = 4.8 and 10.4 Hz, 1 H), 3.54 (s, 3H), 3.21-3.18 (m, 4H), 2.14-1.86 (m, 11 H), 1.60 (d, J = 7.2 Hz, 3H). [M+H]+ 430.40. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3.0h;Inert atmosphere; | A stirred solution of 6-bromo-1-(2-ethoxyethyl)-2-(tetrahydro-2H-pyran-4-yl)-1 H-benzo[d] imidazole (0.21 g, 0.60 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridin-2(1 H)-one (0.2 g, 0.77 mmol) in 1 ,4-dioxane (4 mL) was purged with nitrogen for 10 minutes, followed by the addition of Na2C03(0.19 g, 1.8 mmol) in water (0.5 mL) and purging with nitrogen for another 10 min. Pd(PPh3) (0.035 g, 0.03 mmol) was then added and the reaction mixture was heated at 100 C for 3 h. The resulting mixture was diluted with EtOAc (100 mL), washed with water (40 mL X 2) and brine (30 mL), dried over anhydrous Na2S0 , filtered and concentrated under reduced pressure. The crude material was purified using flash chromatography using 1.5-2% MeOH in DCM as eluent. Product fractions were combined and evaporated to dryness to afford Compound 60 (0.09 g, 39%) as a solid.1H NMR (400 MHz, DMSO) delta ppm 7.97 (d, J = 2 Hz, 1 H), 7.80 (s, 1 H), 7.72 (s, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.37 (dd, J = 1.6 and 8.4 Hz, 1 H), 4.46 (t, J = 4.8 Hz, 2H), 3.99 (d, J = 10.5 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H), 3.54-3.46 (m, 5H), 3.40-3.32 (m, 3H), 2.1 1 (s, 3H), 1.95-1.80 (m, 4H), 1.01 (t, J = 7.2 Hz, 3H). MH+396.43. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3.0h;Inert atmosphere; | A stirred solution of 6-bromo-2-(4,4-difluorocyclohexyl)-1-(2-ethoxyethyl)-1 H-benzo[d]imidazole (0.13 g, 0.34 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin- 2(1 H)-one (0.11 g, 0.44 mmol) in 1 ,4-dioxane (4 mL) was purged for 10 minutes with nitrogen, followed by the addition of Na2C03(0.1 1 g, 1.02 mmol) in water (0.5 mL) and purging with nitrogen for another 10 min. Pd(PPh3) (0.02 g, 0.02 mmol) was added and the reaction mixture was heated at 100C for 3 h. The resulting mixture was then diluted with EtOAc (60 mL), washed with water (40 mL X 2) and brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material obtained was purified by flash chromatography using 1.5-1.8% MeOH in DCM as eluent. Product fractions were combined and concentrated to dryness to afford afford Compound 61 (0.088 g, 61 %) as a solid.1H NMR (400 MHz, DMSO) delta 7.97 (d, J = 2 Hz, 1 H), 7.80 (s, 1 H), 7.72 (s, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1 H), 4.48 (t, J = 4.4 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H), 3.54 (s, 3H), 3.40-3.35 (m, 2H), 3.28-2.25 (m, 1 H), 2.19-2.17 (m, 2H), 2.1 1 (s, 3H), 2.02-2.00 (m, 3H), 1.95-1.86 (m, 3H), 1.02 (t, J = 7.2 Hz, 3H). [M+H]+430.40 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 16.0h;Inert atmosphere; | A stirred solution of (R)-5-bromo-N-(1-isopropoxypropan-2-yl)-2-nitroaniline (0.14 g, 0.44 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (0.14 g, 0.57 mmol) in DME (5 mL) was purged with nitrogen for 20 min, followed by the addition of Cs2C03(0.42 g, 1.32 mmol) in water (0.3 mL) and purging with nitrogen for another 20 min. Pd(PPh3) (0.025 g, 0.022 mmol) was then added at rt and the reaction mixture was heated at 90C for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 3-5% MeOH in DCM as eluent. Product fractions were combined and evaporated to dryness to afford the title compound (0.16 g, 91 %) as a solid. [M+H]+360.31 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 16.0h;Inert atmosphere; | A stirred solution of (S)-5-bromo-N-(2-isopropoxypropyl)-2-nitroaniline (0.24 g, 0.75 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (0.24 g, 0.98 mmol) in DME (4 mL) was purged with nitrogen for 20 min, followed by the addition of Cs2C03(0.73 g, 2.27 mmol) in water (0.4 mL) and purging with nitrogen for another 20 min. Pd(PPh3) (0.045 g, 0.037 mmol) was then added and the reaction mixture was heated at 90C for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S0 , filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 3-5% MeOH in DCM as eluent. Product fractions were combined and evaporated to dryness to give the title compound (0.16 g, 48%) as a solid. [M+H]+360.31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 18.0h;Inert atmosphere; | A solution of 5-bromo-2-nitro-N-[2-(trifluoromethoxy)ethyl]aniline (Intermediate 1 , step 1 ; 320 mg, 1.16 mmol), 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared as in US20130053362, 348 mg, 1.40 mmol) in DME (8 mL) and water (0.4 mL) was degassed by bubbling for 10 min. Cs2C03(0.80 g, 2.44 mmol) and Pd(PPh3)4(134 mg, 0.116 mmol) were then added and the mixture was degassed by bubbling N2for 10 more min. The resulting mixture was heated to 85 C for 18 h and then cooled to rt. The mixture was diluted with saturated NaHC03(10 mL) and EtOAc (50 mL), and then the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over MgS04, filtered, and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of EtOAc in hexane as eluent to provide title compound (340 mg, 92%). MS (ESI) [M+H]+372.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 18.0h;Inert atmosphere; Sealed tube; | To a suspension of 5-bromo-N-(2-methoxypropyl)-2-nitro-aniline (450 mg, 1.56 mmol) in DME (4 ml) was added 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared using the procedure described in US20130053362, 465 mg, 1.87 mmol), Cs2C03(1.27 g, 3.89 mmol), Pd(PPh3)4(180 mg, 0.16 mmol) and water (0.5 ml) and the reaction mixture was degassed by bubbling N2for 5 min then heated in a sealed tube to 90 C for 18 h. The mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). The organic phase was collected, dried over Na2S04, filtered and concentrated under reduced pressure. The resulting solid (466 mg, 90%) was triturated with Et20 and to afford title compound, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) delta 8.32 (t, J = 5.0 Hz, 1 H), 8.23 (d, J = 2.6 Hz, 1 H), 8.09 (d, J = 9.0 Hz, 1 H), 7.93 - 7.80 (m, 1 H), 7.13 (d, J = 1.9 Hz, 1 H), 6.95 (dd, J = 9.1 , 1.9 Hz, 1 H), 3.67 (dddd, J = 13.2, 9.5, 7.8, 5.1 Hz, 2H), 3.54 (d, J = 3.9 Hz, 3H), 3.39 (ddd, J = 13.2, 6.6, 4.6 Hz, 1 H), 3.34 (s, 3H), 2.10 (s, 3H), 1.22 (d, J = 6.1 Hz, 3H). MS (ESI) [M+H]+332.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 1.0h; | To a solution of 4-bromo-2-fluoro-1 -nitrobenzene (2.0 g, 9.09 mmol) in DME (20 mL) was added 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared as in US20130053362, 4.53 g, 18.18 mmol), Cs2C03(2.96 g, 9.09 mmol), Pd(PPh3) (1.05 g, 0.909 mmol) and water (2 mL). The reaction mixture was degassed for 5 min and then heated to 80 C for 1 h. The mixture was cooled to rt. The solid was collected by filtration and washed with water. The title compound (2.2 g, 92%) was dried under reduced pressure and used in the next step without further purification.1H NMR (500 MHz, DMSO) delta 8.36 (d, J = 2.7 Hz, 1 H), 8.19 (t, J = 8.5 Hz, 1 H), 7.92 (dd, J = 2.7, 1.1 Hz, 1 H), 7.86 (dd, J = 13.6, 2.0 Hz, 1 H), 7.69 (dd, J = 8.7, 1.8 Hz, 1 H), 3.54 (s, 3H), 2.09 (s, 3H). MS (ESI) [M+H]+263.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 3.0h;Inert atmosphere; | 6-Bromo-2-tetrahydropyran-4-yl-1-[2-(trifluoromethoxy)ethyl]benzimidazole (70 mg, 0.18 mmol), 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared using the procedure described in US20130053362, 53 mg, 0.21 mmol), and Cs2C03(122 mg, 0.37 mmol) in a mixture of DME (2 mL) and water (0.2 mL) were degassed by bubbling N2for 10 min. Pd(PPh3)4(21 mg, 0.018 mmol) was then added and the reaction mixture was degassed by bubbling N2for 10 min. The resulting mixture was heated to 85 C for 3 h and then cooled to rt. The mixture was diluted with saturated NaHC03(10 mL) and EtOAc (30 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 15 mL). The combined organic phases were washed with brine, dried over Na2S04and evaporated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of EtOAc in hexane as eluent, and followed by preparative HPLC to provide Compound 1 (23 mg, 30%).1H NMR (500 MHz, CDCI3) delta 7.81 (d, J = 8.3 Hz, 1 H), 7.56 (dd, J = 2.6, 1.1 Hz, 1 H), 7.41 (d, J = 2.5 Hz, 1 H), 7.34 (dd, J = 8.3, 1.7 Hz, 1 H), 7.29 - 7.28 (m, 1 H), (4.54 (t, J = 5.4 Hz, 2H), 4.35 (t, J = 5.3 Hz, 2H), 4.17 (dd, J = 1 1.7, 2.6 Hz, 2H), 3.67 (s, 3H), 3.60 (td, J = 11.9, 1.9 Hz, 2H), 3.21 - 3.00 (m, 1 H), 2.28 (s, 3H), 2.38 - 2.16 (m, 2H), 1.87 (d, J = 1 1.4 Hz, 2H). MS (ESI) [M+H]+436.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 3.0h;Inert atmosphere; | A solution of 6-bromo-2-cyclopropyl-1-[2-(trifluoromethoxy)ethyl]benzimidazole (88 mg, 0.252 mmol), 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared as in US20130053362, 63 mg, 0.252 mmol) in DME (2 mL) and water (0.1 mL) was degassed by bubbling N2for 10 min. To the mixture, Cs2C03(172 mg, 0.529 mmol) and Pd(PPh3)4(29 mg, 0.025 mmol) were then added and then degassed by bubbling N2for 10 min. The resulting mixture was heated to 85 C for 3 h and then cooled to rt. The mixture was diluted with saturated NaHC03(10 mL) and EtOAc (10 mL), and the aqueous phase was extracted with EtOAc (3 x 10 ml_). The combined organic phases were dried over MgS04, filtered, and evaporated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of EtOAc in hexane as eluent, and followed by preparative HPLC to provide Compound 2 (56 mg, 57%).1H NMR (500 MHz, CDCI3) delta 7.66 (d, J = 8.2 Hz, 1 H), 7.55 - 7.48 (m, 1 H), 7.37 (d, J = 2.5 Hz, 1 H), 7.29 - 7.25 (m, 1 H), 7.25 - 7.23 (m, 1 H), 4.59 (t, J = 5.5 Hz, 2H), 4.34 (t, J = 5.5 Hz, 2H), 3.62 (s, 3H), 2.23 (s, 3H), 2.07 - 1.90 (m, 1 H), 1.33 - 1.22 (m, 2H), 1.17 - 1.09 (m, 2H). [M+H]+392.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 3.0h;Inert atmosphere; | A solution of 6-bromo-1-[2-(trifluoromethoxy)ethyl]benzimidazole (50 mg, 0.162 mmol), 1 ,3- dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared using described procedure in US20130053362, 48 mg, 0.194 mmol) in DME (2 mL) and water (0.1 mL) was degassed by bubbling N2for 10 min. Cs2C03(111 mg, 0.340 mmol) and Pd(PPh3)4(19 mg, 0.016 mmol) were then added and the mixture was degassed by bubbling N2for 10 min. The resulting mixture was heated to 85 C for 3h and then cooled to rt. The mixture was diluted with saturated NaHC03(10 mL) and EtOAc (30 mL), and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over Na2S04, filtered, and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of EtOAc in hexane as eluent and then MeOH in DCM, and followed by preparative HPLC to provide Compound 3 (56 mg, 38%).1H NMR (500 MHz, CDCI3) delta 7.95 (s, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.57 - 7.52 (m, 1 H), 7.41 (d, J = 2.5 Hz, 1 H), 7.38 - 7.37 (m, 1 H), 7.35 (dd, J = 8.4, 1.7 Hz, 1 H), 4.52 (t, J = 5.2 Hz, 2H), 4.34 (t, J = 5.2 Hz, 2H), 3.65 (s, 3H), 2.25 (s, 3H). MS (ESI) [M+H]+352.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 3.0h;Inert atmosphere; | o a solution of 6-bromo-2-cyclobutyl-1-[2-(trifluoromethoxy)ethyl]benzimidazole (50 mg, 0.162 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared using described procedure in US20130053362, 48 mg, 0.194 mmol) in DME (2 ml_) and water (0.1 ml_) was degassed by bubbling N2for 10 min. Cs2C03(11 1 mg, 0.340 mmol) and Pd(PPh3) (19 mg, 0.016 mmol) were then added and the mixture was degassed by bubbling N2for 10 more min. The resulting mixture was heated to 85 C for 3 h and then cooled to rt. To the mixture, saturated aqueous NaHC03(10 ml_) and EtOAc (30 ml_) were added, and the aqueous phase was extracted with EtOAc (3 x 10 ml_). The combined organic phases were dried over Na2S04, filtered, and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of EtOAc in hexane and then MeOH in DCM as eluent. The mixture was further purified with preparative HPLC to afford Compound 6 (56 mg, 38%).1H NMR (500 MHz, CDCI3) delta 7.82 - 7.78 (m, 1 H), 7.60 - 7.51 (m, 1 H), 7.40 (d, J = 2.3 Hz, 1 H), 7.31 (dd, J = 8.3, 1.7 Hz, 1 H), 7.27 - 7.22 (m, 1 H), 4.40 (t, J = 5.5 Hz, 2H), 4.26 (t, J = 5.5 Hz, 2H), 3.81 - 3.70 (m, 1 H), 3.65 (s, 3H), 2.74 - 2.52 (m, 2H), 2.52 - 2.34 (m, 2H), 2.24 (s, 3H), 2.22 - 1.94 (m, 2H). MS (ESI) [M+H]+406.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; at 85℃; for 18.0h;Inert atmosphere; | To a solution of 5-bromo-N-(2-methoxyethyl)-2-nitroaniline (320 mg, 1.16 mmol) and 1 ,3- dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared using the procedure described in US20130053362, 348 mg, 1.396 mmol) in DME (8 mL) and water (0.4 mL) was degassed by bubbling N2for 10 min. Cs2C03(0.796 g, 2.44 mmol) and Pd(PPh3)4(134 mg, 0.12 mmol) were then added and the mixture was degassed by bubbling N2for 10 more min. The resulting mixture was heated to 85 C for 18 h overnight and then cooled to rt. To the mixture, saturated NaHC03(10 mL) and EtOAc (50 mL) were added and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over MgS04, filtered, and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of EtOAc in hexane as eluent to provide title compound (340 mg, 92%).1H NMR (500 MHz, CDCI3) delta 8.35 (bs, 1 H), 8.23 (d, J = 8.9 Hz, 1 H), 7.50 (dd, J = 12.9, 2.0 Hz, 2H), 6.85 (d, J = 1.9 Hz, 1 H), 6.72 (dd, J = 8.9, 1.9 Hz, 1 H), 3.74 (t, J = 5.4 Hz, 2H), 3.67 (s, 3H), 3.58 (dd, J = 10.6, 5.2 Hz, 2H), 3.48 (s, 3H), 2.26 (s, 3H). MS (ESI) [M+H]+318.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 5.0h;Inert atmosphere; | A stirred solution of 2-benzyl-6-bromo-1-(2-methoxyethyl)-1 H-benzo[c]imidazole (0.15 g, 0.43 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (0.14 g, 0.56 mmol) in 1 ,4-dioxane (5 mL) was purged with nitrogen for 10 minutes, followed by the addition of Na2C03 (0.14 g, 1.30 mmol) in water (0.5 mL). The resulting mixture was purged again with nitrogen for 10 minutes. Pd(PPh3)4 (0.025 g, 0.02 mmol) was added and the reaction mixture was heated at 90C for 5h. The solvent was then evaporated under reduced pressure and the residue was extracted with EtOAc (20 mL X 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude material was purified by flash chromatography using 1.5% MeOH in DCM as eluent. Fractions were combined and concentrated to dryness to afford Compound 37 (0.08 g, 38%) as a solid. 1H NMR (400 MHz, DMSO) delta ppm 7.97 (d, J = 2 Hz, 1 H), 7.80 (s, 1 H), 7.70 (s, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.38-7.24 (m, 6H), 4.38 (t, J = 5 Hz, 2H), 4.31 (s, 2H), 3.53-3.51 (m, 5H), 3.16 (s, 3H), 2.10 (s, 3H). [M+H]+ 387.48 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 14.0h;Inert atmosphere; | A stirred solution of 6-bromo-2-cyclohexyl-1-(2-methoxyethyl)-1 H-benzo[c]imidazole (0.16 g, 0.47 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (0.15 g, 0.62 mmol) in 1 ,4-dioxane (5 mL) was purged with nitrogen for 10 minutes, followed by the addition of Na2C03 (0.15 g, 1.42 mmol) in water (0.5 mL). The resulting mixture was purged again with nitrogen for 10 minutes. Pd(PPh3) (0.028 g, 0.02 mmol) was added and the reaction mixture was heated at 90C for 14h. The solvent was evaporated under reduced pressure and the residue was extracted using EtOAc (20 mL X 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S0 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 1.3 % MeOH in DCM as eluent. Product fractions were combined and concentrated to dryness to afford Compound 38 (0.1 g, 56%) as a solid. 1H NMR (400 MHz, DMSO) delta 7.97 (d, J = 2.4 Hz, 1 H), 7.80 (s, 1 H), 7.69 (d, J = 1.2 Hz, 1 H),7.54 (d, J = 8.4 Hz, 1 H), 7.34 (dd, J J2 = 1.6 Hz, 1 H), 4.43 (t, J= 5 Hz, 2H), 3.65 (t, J = 5 Hz, 2H), 3.54 (s, 3H), 3.20 (s, 3H), 3.01-2.95 (m, 1 H), 2.11 (s, 3H), 1.90-1.83 (m, 4H), 1.80-1.59 (m, 3H), 1.46-1.26 (m, 3H).[M+H]+ 380. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 16.0h;Inert atmosphere; | A stirred solution of (S)-5-bromo-N-(2-ethoxypropyl)-2-nitroaniline (Example 35, Step 1 , 0.5 g, 1.65 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (0.49 g, 1.98 mmol) in DME (10 mL) was purged at rt with nitrogen for 15 minutes followed by the addition of Cs2C03 (1.34 g, 4.12 mmol) in water (3 mL) and purging with nitrogen for another 15 minutes. Pd(PPh3)4 (0.19 g, 0.16 mmol) was then added and the reaction mixture was heated to 80C for 16 h. The resulting mixture was filtered through Celite and washed with EtOAc (15 mL X 3). The organic layer was washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 1-2% MeOH in DCM as eluent. Product fractions were combined and evaporated to dryness to give the title compound (0.5 g, 88%) as a solid, [M+H]+ 346.29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 16.0h;Inert atmosphere; | A stirred solution of 5-bromo-2-nitro-N-(2-(2,2,2-trifluoroethoxy)ethyl)aniline (Example 36, Step 1 , 0.3 g, 0.87 mmol) and 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin- 2(1 H)-one (0.26 g, 1.04 mmol) in 1 ,4-dioxane (5 mL) was purged with nitrogen for 10 minutes followed by the addition of Cs2C03 (0.71 g, 2.18 mmol) in water (0.5 mL). The mixture was again purged with nitrogen for 10 minutes. Pd(PPh3) (0.10 g, 0.08 mmol) was added and the reaction mixture was heated to 90C for 16h. The solvent was then evaporated under vacuum and the residue was extracted with EtOAc (20 mL X 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 1.0% MeOH in DCM as eluent. The product fractions were combined and concentrated to dryness to afford the title compound (0.25 g, 74%) as a solid. [M+H]+ 386.54. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 18.0h;Sealed tube; Inert atmosphere; | To a solution of 6-bromo-3-[(4,4-difluoro-1-piperidyl)methyl]imidazo[1,2-a]pyridine (46 mg, 0.14 mmol) in DME (5 ml) and water (0.5 ml) was added <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (prepared using the procedure described in US20130053362, 65 mg, 0.167 mmol), Cs2CO3 (113.5 mg, 0.35 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol). The resulting mixture was degassed for 5 min with N2 and then heated in a sealed tube at 90C for 18 h. The mixture was cooled to rt, diluted with EtOAc (10 ml) and water (5 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of MeOH in DCM as eluent, followed by preparative HPLC purification to afford Compound 20 (14.6 mg, 28%) as a solid. 1H NMR (500 MHz, CDCl3) delta 8.27 (s, 1H), 7.66 (d, J=9.1 Hz, 1H), 7.55 (s, 1H), 7.43 (dd, J=2.5, 1.1 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.32-7.24 (m, 2H), 3.89 (s, 1H), 3.66 (s, 3H), 2.60 (d, J=5.4 Hz, 4H), 2.26 (s, 3H), 2.05-1.89 (m, 4H). MS (ESI) [M+H]+ 373.1; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 18.0h;Inert atmosphere; Sealed tube; | To a solution of (6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-phenyl-methanone (prepared using the procedure described in WO2015086498, 279 mg, 0.88 mmol) in DME (3 mL) and water (0.3 mL) was added <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (prepared using the procedure described in US20130053362, 264 mg, 1.06 mmol), Cs2CO3 (721 mg, 2.21 mmol) and Pd(PPh3)4 (102 mg, 0.089 mmol). The reaction mixture was degassed for 5 min and then heated in a sealed tube at 80C for 18 h. The mixture was cooled to rt, diluted with EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of MeOH in DCM as eluent to afford the title compound (200 mg, 63%) as a solid. 1H NMR (500 MHz, CDCl3) delta 9.47 (dd, J=1.8, 0.8 Hz, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.81 (ddd, J=10.0, 9.3, 1.3 Hz, 2H), 7.74-7.61 (m, 4H), 7.57 (t, J=7.5 Hz, 2H), 3.53 (s, 3H), 2.10 (s, 3H), 2.04 (s, 3H). MS (ESI) [M+H]+ 358.2; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 6.0h;Inert atmosphere; | A stirred solution of 6-bromo-N-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine-3-sulfonarnide (0.2 g, 0.5552 mmol) and <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (0.208 g, 0.8328 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen for 20 min, followed by the addition of sodium carbonate (0.177 g, 1.6656 mmol) in water (0.5 mL). The reaction mixture was purged again with nitrogen for 20 min. Pd(PPh3)4 (0.032 g, 0.0277 mmol) was then added and the reaction mixture was heated at 100C for 6 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel chromatography using 2-3% methanol in DCM as eluent. Fractions were combined and concentrated to afford Compound 42 (0.060 g, 27%) as a solid. 1H NMR (400 MHz, DMSO) delta 8.67 (s, 1H), 8.61 (d, J=7.6 Hz, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.9 (d, J=9.6 Hz, 1H), 7.83 (dd, J=1.6 and 9.6 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 3.69-3.66 (m, 2H), 3.56 (s, 3H), 3.22-3.16 (m, 3H), 2.14 (s, 3H), 1.39-1.27 (m, 4H). MH+ 403.29; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 18.0h;Inert atmosphere; | To a solution of (6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(2-pyridyl)methanone (327.0 mg, 1.034 mmol) in a mixture of DME (3 mL) and water (0.3 mL) were added <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (prepared as in US20130053362, 309.2 mg, 1.24 mmol), Cs2CO3 (842.5 mg, 2.59 mmol) and Pd(PPh3)4 (1 19.9 mg, 0.103 mmol). The reaction mixture was degassed with N2 for 5 min and then heated to 100C for 18 h. The mixture was cooled to rt and diluted with EtOAc (10 mL) and water (10 mL). The phases were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a gradient (0-20%) of MeOH in DCM as eluent to afford the title compound (213 mg, 57%) as a solid. 1H NMR (500 MHz, CDCl3) delta 9.66 (dd, J=1.9, 0.9 Hz, 1H), 8.72 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 7.94 (td, J=7.7, 1.7 Hz, 1H), 7.81 (dt, J=7.8, 1.1 Hz, 1H), 7.69 (dd, J=9.2, 0.9 Hz, 1H), 7.59-7.42 (m, 4H), 3.64 (s, 3H), 2.24 (s, 3H), 2.15 (s, 3H). MS (ESI) [M+H]+ 359.3; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 18.0h;Inert atmosphere; | To a solution of (6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(3-pyridyl) methanone (138 mg, 0.436 mmol) in a mixture of DME (5 mL) and water (0.5 mL) were added <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (prepared as in US20130053362, 130.5 mg, 0.524 mmol), Cs2CO3 (355 mg, 1.09 mmol) and Pd(PPh3)4 (50.62 mg, 0.044 mmol). The reaction mixture was degassed with N2 for 5 min and then heated in a sealed tube at 100C for 18 h. The mixture was cooled to rt, and then diluted with EtOAc (10 mL) and water (10 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The material was triturated with Et2O to afford the title compound (129 mg, 83%), which was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) delta 9.67 (dd, J=1.9, 0.9 Hz, 1H), 8.87 (ddd, J=6.6, 3.5, 1.2 Hz, 2H), 8.05-7.98 (m, 1H), 7.76-7.69 (m, 1H), 7.61 (dd, J=9.2, 1.9 Hz, 1H), 7.54-7.45 (m, 3H), 3.66 (s, 3H), 2.25 (d, J=14.2 Hz, 6H). MS (ESI) [M+H]+ 359.3; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 18.0h;Inert atmosphere; | To a solution of (6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(4-pyridyl)methanone (150 mg, 0.474 mmol) in a mixture of DME (5 mL) and water (0.5 mL) were added <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (prepared as in US20130053362, 141.8 mg, 0.569 mmol), Cs2CO3 (386.5 mg, 1.19 mmol) and Pd(PPh3)4 (54.8 mg, 0.047 mmol). The reaction mixture was degassed with N2 for 5 min and then heated in a sealed tube at 100C for 18 h. The mixture was cooled to rt and diluted with EtOAc (10 ml) and water (10 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The material was triturated with a mixture of EtOAc and hexane to afford the title compound (166 mg, 98%) as a solid. 1H NMR (500 MHz, CDCl3) delta 9.74 (dd, J=1.8, 0.8 Hz, 1H), 8.86 (d, J=4.8 Hz, 2H), 7.75 (dd, J=9.2, 0.8 Hz, 1H), 7.65 (dd, J=9.2, 1.9 Hz, 1H), 7.56-7.48 (m, 4H), 3.68 (s, 3H), 3.51 (d, J=5.5 Hz, 2H), 2.28 (s, 3H), 2.19 (s, 3H). MS (ESI) [M+H]+ 359.3; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 90.0℃; for 18.0h;Sealed tube; Inert atmosphere; | To a suspension of <strong>[64064-71-7]6-bromo-3-nitro-imidazo[1,2-a]pyridine</strong> (535 mg, 2.21 mmol) in DME (5 ml) was added 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared using the procedure described in US20130053362, 661 mg, 2.65 mmol), Cs2CO3 (1.8 g, 5.53 mmol), Pd(PPh3)4 (256 mg, 0.22 mmol) and water (1 ml). The reaction mixture was degassed with N2 and then heated in a sealed tube at 90C for 18 h. The mixture was cooled to rt and the resulting solid was collected by filtration, washed with water and dried under vacuum to afford the title compound (472 mg, 75%), which was used directly in the next step without further purification. 1H NMR (500 MHz, DMSO) delta 9.39 (s, 1H), 8.78 (s, 1H), 8.17 (d, J=2.5 Hz, 1H), 8.06-7.98 (m, 2H), 7.78 (d, J=1.4 Hz, 1H), 3.55 (s, 3H), 2.11 (s, 3H); MS (ESI) [M+H]+ 285.2; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 2.0h;Inert atmosphere; | A solution of N-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]aniline (10 mg, 0.033 mmol) and <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one</strong> (prepared using the procedure described in US20130053362, 10.7 mg, 0.043 mmol) in DME (2 mL) and water (0.1 mL) was degassed by bubbling N2 for 10 min. Cs2CO3 (23 mg, 0.069 mmol) and Pd(PPh3)4 (4 mg, 0.003 mmol) were then added and the mixture was degassed for another 10 min. The resulting mixture was heated to 85C for 2 h and then cooled to rt. To the mixture, saturated NaHCO3 (10 mL) and EtOAc (30 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of EtOAc in hexane as eluent, followed by preparative HPLC to provide Compound 10 (5 mg, 44%). 1H NMR (500 MHz, CDCl3) delta 8.10 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.65 (s, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.32-7.25 (m, 4H), 6.84 (t, J=7.4 Hz, 1H), 6.78 (d, J=7.7 Hz, 2H), 4.65 (s, 2H), 3.75 (s, 1H), 3.61 (s, 3H), 2.21 (s, 3H). MS (ESI) [M+H]+ 345.2; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3.0h;Inert atmosphere; | A stirred solution of 6-bromo-N-cyclopentylimidazo[1,2-a]pyridine-3-sulfonamide (0.15 g, 0.44 mmol) and <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (prepared using the procedure described in US20130053362, 0.13 g, 0.52 mmol) in 1,4-dioxane (3 mL) was purged with N2 for 10 min followed by the addition of a solution of Na2CO3 (0.14 g, 1.31 mmol) in water (1 mL), which was again purged with nitrogen for another 10 min. After 10 min, Pd(PPh3)4 (25 mg, 0.022 mmol) was added and the resulting mixture was heated at 100C for 3 h. The mixture was diluted with water and the aqueous layer was extracted using EtOAc (3 x 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and then evaporated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of 2% MeOH in DCM as eluent to afford Compound 16 (0.11 g, 65%) as a solid. 1H NMR (400 MHz, DMSO) delta ppm 8.67 (s, 1H), 8.44 (d, J=7.2 Hz, 1H), 8.10 (d, J=2.8 Hz, 1H), 8.09 (s, 1H), 7.90 (d, J=9.6 Hz, 1H), 7.82 (dd, J=1.6 and 9.6 Hz, 1H), 7.77 (s, 1H), 3.55 (s, 3H), 3.44-3.39 (m, 1H), 2.13 (s, 3H), 1.49 (s, 4H), 1.39-1.33 (m, 2H), 1.19-1.16 (m, 2H). MS (ESI) [M+H]+ 387.5; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3.0h;Inert atmosphere; | A stirred solution of 6-bromo-N-cyclohexylimidazo[1,2-a]pyridine-3-sulfonamide (40 mg, 0.11 mmol) and <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (prepared using the procedure described in US20130053362, 0.033 g, 0.13 mmol) in 1,4-dioxane (1 mL) was purged with N2 for 10 min. This was followed by the addition of a solution of Na2CO3 (43 mg, 0.33 mmol) in water (0.5 mL) and the reaction mixture was again purged with N2 for 10 min. After 10 min, Pd(PPh3)4 (8 mg g, 0.006 mmol) was added and the resulting mixture was heated at 100C for 3 h. The mixture was diluted with water and the aqueous layer was extracted using EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and then evaporated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of 2-3% MeOH in DCM as eluent to afford Example 18 (20 mg, 44%) as a solid. 1H NMR (400 MHz, DMSO) delta ppm 8.67 (s, 1H), 8.45 (d, J=7.6 Hz, 1H), 8.09 (d, J=2.4 Hz, 1H), 8.08 (s, 1H), 7.89 (d, J=9.6 Hz, 1H), 7.82 (dd, J=1.6 and 9.2 Hz, 1H), 7.78 (s, 1H), 3.55 (s, 3H), 2.96-2.93 (m, 1H), 2.13 (s, 3H), 1.54-1.52 (m, 2H), 1.41-1.39 (m, 3H), 1.11-1.01 (m, 5H). MS (ESI) [M+H]+ 401.4; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3.0h;Inert atmosphere; | A stirred solution of 6-bromo-3-(pyrrolidin-1-ylsulfonyl)imidazo[1,2-a]pyridine (0.15 g, 0.45 mmol) and <strong>[1425045-01-7]1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (prepared using the procedure described in US20130053362, 0.136 g, 0.54 mmol) in 1,4-dioxane (3 mL) was purged with N2 for 10 min. A solution of Na2CO3 (0.145 g, 1.36 mmol) in water (1 mL) was added and the resulting mixture was purged with N2 for another 10 min. After 10 min, Pd(PPh3)4 (26 mg, 0.02 mmol) was added and the mixture was heated at 100C for 3 h. The solvent was evaporated under vacuum and the aqueous layer was extracted using EtOAc (3 x 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and then evaporated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of 2% MeOH in DCM as eluent to afford Compound 19 (0.11 g, 41%) as a solid. 1H NMR (400 MHz, DMSO) delta ppm 8.80 (s, 1H), 8.21 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.90 (d, J=9.6 Hz, 1H), 7.79 (dd, J=1.6 and 2 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 3.54 (s, 3H), 3.25 (t, J=6.8 Hz, 4H), 2.11 (s, 3H), 1.75-1.71 (m, 4H). MS (ESI) [M+H]+ 373.5; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere; | A stirred solution of <strong>[372198-69-1]ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate</strong> (1 g, 3.71 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (prepared as in US20130053362, 1.11 g, 4.46 mmol) in 1,4-dioxane (20 mL) was purged with N2 for 10 min followed by addition of a solution of Na2CO3 (1.2 g, 11.15 mmol) in water (4.2 mL) and was again purged with N2 for 10 min. After 10 min, Pd(PPh3)4 (0.22 g, 0.19 mmol) was added and the reaction mixture was heated at 100C for 3 h. The solvent was evaporated under vacuum, water (100 mL) was added and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of 2% methanol in DCM as eluent to afford the title compound (1 g, 86%) as a solid. 1H NMR (400 MHz, DMSO) delta ppm 9.31 (s, 1H), 8.29 (s, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.80 (dd, J=2 and 1.6 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H), 4.37 (q, J=7.2 Hz, 2H), 3.54 (s, 3H), 2.10 (s, 3H), 1.36 (t, 3H); MS (ESI) [M+H]+ 312.3; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 12.0h;Inert atmosphere; Sealed tube; | To a suspension 3-benzyl-6-bromo-[1 ,2,4]triazolo[4, 3-a]pyridine (Intermediate 1; 100 mg, 0.35 mmol) in DME (2 mL) and water (0.2 mL) was added 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridin-2-one (prepared using described procedure in U520130053362; 104 mg, 0.42 mmol), 052003 (283 mg, 0.878 mmol) and Pd(PPh3)4 (40 mg, 0.035 mmol) and the reaction mixture wasdegassed with N2 for 5 mm then heated in a sealed tube at 90 00 for 12 h . The mixture was cooled to rt, diluted with EtOAc (10 mL) and water (10 mL). The phase was separated and the organic layer was dried over Mg504, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica using a mixture of MeOH in DCM as eluent then followed by preparative HPLC purification to afford Compound 1 (60 mg, 52%) as a solid. 1H NMR (500 MHz, ODd3) O 7.78(dd, J = 9.5, 0.8 Hz, 1 H), 7.65-7.60 (m, 1 H), 7.35 (ddd, J = 7.5, 6.2, 1.4 Hz, 2H), 7.32 -7.27 (m, 4H),7.20 (d, J = 0.7 Hz, 2H), 4.59 (5, 2H), 3.59 (5, 3H), 2.20 (5, 3H). MS (ESI) [M+H] 331.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 55℃; for 2h;Inert atmosphere; Sealed tube; | A mixture of <strong>[98027-84-0]2,6-dichloro-4-iodopyridine</strong> (400 mg, 1.45 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (364 mg, 1.45 mmol) and Pd(dppf)Cl2 (106 mg, 10%) in 1,4 dioxane (10 mL) and 3.75M aqueous K3PO4 (973 muL, 3.6 mmol) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 55 C. for 2 h. After cooling, the mixture was evaporated to dryness. The resulting residue was purified by flash column chromatography eluting with a gradient of EtOAc [0 to 20% (15 min), 20 to 100% (3 min)] in DCM. The fractions were collected and concentrated under reduced pressure to afford the title compound (255 mg, 65%) as an orange solid. LCMS (M+H)+270 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 75℃; for 1.5h;Inert atmosphere; Sealed tube; | A mixture of 4,6-Dichloro-2-(2,4-difluoro-benzyl)-pyrimidine (900 mg, 3.3 mmol), 1,3-Dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (815 mg, 3.3 mmol), and Pd(dppf)Cl2 (240 mg, 0.33 mmol) was diluted with 1,4 dioxane (10 mL) and 3.75M aqueous K3PO4 (2.2 mL, 8.3 mmol). The mixture was purged with nitrogen for 3 min, sealed and heated to 75 C. for 90 min. After cooling to room temperature, the mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was diluted with Et2O (10 mL); the resulting suspension was filtered. The filter cake was dried to give the title compound (700 mg, 54%) as a yellow solid. 1H NMR (300 MHz, CDCl3) delta 8.20 (s, 1H), 7.71 (s, 1H), 7.33-7.23 (m, 2H), 6.87-6.79 (m, 2H), 4.25 (s, 2H), 3.64 (s, 3H), 2.22 (s, 3H). LCMS (M+H)+362 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 2h; | A mixture of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (249 mg, 1 mmol), <strong>[3740-92-9]4,6-dichloro-2-phenylpyrimidine</strong> (171 mg, 1.0 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), aqueous sodium carbonate (2.0 M, 1 mL, 2 mmol) in dioxane (5 mL) was stirred and heated at 100° C. for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (3*). The extracts were combined, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (EA:Hex, 0-80percent) to provide the 173 mg (67percent) of the desired product as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 2.13 (s, 3 H) 3.61 (s, 3H) 7.51-7.66 (m, 4H) 8.01 (s, 1H) 8.29 (s, 1H) 8.49 (dd, J=7.83, 1.77 Hz, 2H) 8.87 (d, J=2.27 Hz, 1H). LCMS (M+H)+312. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | To a degassed solution of 2-bromo-lH-imidazole (21.0 g, 143 mmol), l,3-dimethyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (commercially available from, for example, Milestone PharmaTech, 38.0 g, 152 mmol) and potassium carbonate (57.4 g, 415 mmol) in 1,4-dioxane (200 mL) and water (60 mL) stirred under nitrogen at RT was added solid Tetrakis(triphenylphosphine)palladium(0) (8.00 g, 6.92 mmol) in one charge. The reaction mixture was stirred at 100 C for 16 h. The reaction mixture was filtered through a Celite pad and the filterate was separated. The aqueous layer was re- extracted with 10% MeOH in DCM (2x100 mL). The combined organic layers were washed with brine solution (100 mL), dried over sodium sulphate, filtered and evaporated in vacuo to give the crude product as a brown gum. The crude product was triturated with 10% DCM in diethyl ether (2x50 mL). The resultant solid was filtered and dried under reduced pressure to afford crude compound as cream solid. This compound was triturated with diethylether and filtered through a Celite pad and dried under reduced pressure to afford the title compound (23.0 g, 121.7 mmol, 85%) as cream colored solid. LCMS (System D): tRET = 2.14 min; MH+ 190. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1h;Microwave irradiation; Inert atmosphere; Sealed tube; | l,3-Dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (1.385 g, 5.56 mmol), 2-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-4-carbonitrile (for an example preparation, see Intermediate 16, 1.12 g, 3.71 mmol), and potassium carbonate (1.536 g, 11.12 mmol) were added to a microwave vial. 1,4-Dioxane (15 mL) and water (5 mL) were added to the vial, which was purged with nitrogen for 5 min prior to the addition of tetrakis(triphenylphosphine)palladium(0) (0.128 g, 0.111 mmol). After a further 5 min purge with nitrogen, the vial was capped and heated in the microwave at 110 C for 1 h. The solvent was removed by evaporation under reduced pressure. The residue was redissolved in ethyl acetate and filtered through Celite, the solvent again removed under reduced pressure. The sample was loaded in DCM and purified by column chromatography using a silica cartridge (80 g) with an ethyl acetate-cyclohexane solvent system [0-50%, 10CV; 50%, 15CV; 50-100%, 10CV; 100%, 5CV]. The appropriate fractions were combined and the solvent removed in vacuo to afford the title compound as a white solid, (933 mg, 2.71 mmol, 73%). LCMS (System A): tRET = 1.11 min; MH+ 345. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; Sealed tube; | 4-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-methoxy-benzoic acid (I-173') In a vial <strong>[56256-14-5]4-bromo-3-methoxy-benzoic acid</strong> L-91 (92.6 mg; 0.401 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one J-1 (100.0 mg; 0.401 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), dichloromethane (32.7 mg; 0.040 mmol) are introduced. N,N-dimethylformamide (800 muL) and 2N sodium bicarbonate solution (0.5 mL; 1.003 mmol) are then added. The vial is flushed with argon and sealed. The reaction mixture is heated at 100 C. for 1 h. To the reaction mixture, water is added and the crude product is filtered off. HPLC-MS: (M+H)+=274; tRet=0.392 min; method M4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; | 4-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-trifluoromethoxy-benzoic acid (I-177') 1,3-Dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one J-1 (150.0 mg; 0.457 mmol), 4-bromo-2-trifluoromethoxy-benzoic acid L-95 (159.6 mg; 0.549 mmol), tetrakis(triphenylphosphine)palladium(0) (105.7 mg; 0.091 mmol) and an 2N aqueous solution of sodium bicarbonate (0.572 mL; 1.143 mmol) are suspended in DMF (1.0 mL), the flask is purged for 5 min with argon. The reaction is heated to 100 C. for 1 h. The reaction is then concentrated under reduced pressure and the residue is purified on SP chromatography (DCM/MeOH 0 to 15%) to afford the product. HPLC-MS: (M+H)+=328; tRet=0.48 min; method M4 |
Tags: 1425045-01-7 synthesis path| 1425045-01-7 SDS| 1425045-01-7 COA| 1425045-01-7 purity| 1425045-01-7 application| 1425045-01-7 NMR| 1425045-01-7 COA| 1425045-01-7 structure
[ 1002309-52-5 ]
1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one
Similarity: 0.90
[ 1160790-84-0 ]
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one
Similarity: 0.82
[ 935660-75-6 ]
N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide
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[ 1256358-90-3 ]
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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