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CAS No. : | 51417-13-1 | MDL No. : | MFCD16658881 |
Formula : | C7H8BrNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UEHHXNZKBMALIY-UHFFFAOYSA-N |
M.W : | 202.05 | Pubchem ID : | 12272664 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.29 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 44.63 |
TPSA : | 22.0 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.7 cm/s |
Log Po/w (iLOGP) : | 2.19 |
Log Po/w (XLOGP3) : | 1.17 |
Log Po/w (WLOGP) : | 1.46 |
Log Po/w (MLOGP) : | 1.7 |
Log Po/w (SILICOS-IT) : | 2.02 |
Consensus Log Po/w : | 1.71 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.27 |
Solubility : | 1.08 mg/ml ; 0.00532 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.23 |
Solubility : | 12.0 mg/ml ; 0.0593 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.74 |
Solubility : | 0.369 mg/ml ; 0.00182 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.73 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P301+P312+P330 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.6% | With potassium carbonate In N,N-dimethyl-formamide for 16h; | Fragment 1 : 5-bromo-l,3-dimethylpyridin-2(lH)-one To a mixture containing 5-bromo-3-methylpyridin-2(lH)-one (1.3 g, 6.91 mmol) and K2CO3 (2.87 g, 20.74 mmol) in DMF (20 mL) was added dropwise Mel (0.865 mL, 13.83 mmol). The reaction mixture was stirred for 16 h and diluted with ethyl acetate (150 mL). The mixture was filtered through a pad of celite to remove the solids and the filtrate was washed with aqueous 10% LiCl solution (3 X 30 mL). The aqueous washes were combined and back extracted with additional ethyl acetate (2X25 mL). The organic extracts were combined and washed with saturated aqueous NaCl solution (50 mL), dried (Na2S04), filtered and concentrated to afford a mixture of O-methylated (minor) and N- methylated (major) products. The crude product was dissolved in a small amount of DCM and charged to a 24 g ISCO silica gel column which was eluted over a 15 min gradient with 10%-100% hexanes/ethyl acetate to afford 5-bromo-l,3-dimethylpyridin- 2(lH)-one (1 g, 4.95 mmol, 71.6 % yield). LCMS MH+: 202. HPLC Ret. Time 0.64 min. Method: Method B l . NMR: (400 MHz, CHLOROFORM-d) δ 7.32 (d, J=2.6 Hz, 1H), 7.30-7.25 (J=2.6 Hz, 1H), 3.55 (s, 3H), 2.17 (s, 3H). |
49% | Stage #1: 5-bromo-3-methylpyridin-2(1H)-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 20℃; for 16h; | Step-1: Initially 5-bromo-3-methyl-1H-pyridin-2-one (1.050 g, 5.58 mmol) was dissolved in DMF (17.22 mL) and cooled to 0°C before sodium hydride (268.03 mg, 11.17 mmol) was added in one portion and the mixture was stirred for 30 mins. Iodomethane (3.17 g, 22.34 mmol, 1.39 mL) was then added dropwise and the mixture was allowed to stir overnight at ambient temperature. The reaction was then quenched with ice water and the mixture was then extracted with ethyl acetate (3x 50 mL), the combined organic layers were dried with brine (1x 100 mL), Na2SO4, filtered and concentrated to a residue which was purified via flash column chromatography (hexanes:ethyl acetate 1:0 to 0:1) to afford 4-bromo-2,6-dimethoxy- benzaldehyde. Yield- 554 mg, 49%; LC-MS (ES+): m/z 201.9 [M+H]+. |
With potassium hydroxide In methanol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: (Ph3P)2PdCl2 / dimethylformamide 2: NBS; H2O / dimethylsulfoxide 3: aq. K2CO3 / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: (Ph3P)2PdCl2 / dimethylformamide 2: NBS; H2O / dimethylsulfoxide 3: aq. K2CO3 / dimethylformamide 4: ammonium formate; Pd/C / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: (Ph3P)2PdCl2 / dimethylformamide 2: NBS; H2O / dimethylsulfoxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: (Ph3P)2PdCl2 / dimethylformamide 2: NBS; H2O / dimethylsulfoxide 3: aq. K2CO3 / dimethylformamide 4: ammonium formate; Pd/C / ethanol 5: Ph3P; DEAD / benzene 6: PrNH2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: (Ph3P)2PdCl2 / dimethylformamide 2: NBS; H2O / dimethylsulfoxide 3: aq. K2CO3 / dimethylformamide 4: ammonium formate; Pd/C / ethanol 5: Ph3P; DEAD / benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: NaNO2; aq. H2SO4 / 0 - 50 °C 2: KOH / methanol / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: 5-bromo-1,3-dimethyl-1,2-dihydropyridin-2-one With TurboGrignard In tetrahydrofuran for 0.00833333h; Inert atmosphere; Stage #2: N-((3-bromo-4-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide In tetrahydrofuran Stage #3: With hydrogenchloride; methanol In tetrahydrofuran for 1h; | 21i 5-(3-Amino-1-(3-bromo-4-fluorophenyl)-4-fluoro-1H-isoindol-1-yl)-1,3-dimethylpyridin-2(1H)-one Example 21i 5-(3-Amino-1-(3-bromo-4-fluorophenyl)-4-fluoro-1H-isoindol-1-yl)-1,3-dimethylpyridin-2(1H)-one 5-Bromo-1,3-dimethylpyridin-2(1H)-one (1.069 g, 5.29 mmol, C. Morrow et al. J. Org. Chem., 1974, 39 (14), pp 2116-2118) was stirred under Ar (g) for 3 min and dissolved in THF (8 mL). Isopropylmagnesiumchloride lithiumchloride complex (1.3 M in THF) (3.74 mL, 4.87 mmol) was added dropwise and the mixture were stirred for 30 sec. N-((3-bromo-4-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (0.9 g, 2.12 mmol, WO 2010056196) in THF (4 mL) was added. The mixture was stirred overnight, HCl in MeOH (1.25 M, 8.46 mL, 10.58 mmol) was added and the mixture was stirred for 1 h. The reaction was quenched with NaHCO3 (aq.sat.) and extracted with EtOAc. The organic phases were pooled, dried over MgSO4, filtered and concentrated. Chromatography on a silica gel column eluted with a gradient of 0-3% (0.1 M NH3 in MeOH) in DCM gave the title compound (664 mg, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.93 (s, 3H), 3.35 (s, 3H), 6.61 (br. s., 2H), 7.21-7.32 (m, 4H), 7.35-7.40 (m, 1H), 7.50-7.56 (m, 2H), 7.58-7.62 (m, 1H);); MS (ES+) m/z 444, 446 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 0.08 h / -100 °C / Inert atmosphere 1.2: 1.5 h / -100 - 25 °C 1.3: 1 h / 20 - 25 °C 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide; water / 0.25 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 0.08 h / -100 °C / Inert atmosphere 1.2: 1.5 h / -100 - 25 °C 1.3: 1 h / 20 - 25 °C 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide; water / 0.25 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 0.08 h / -100 °C / Inert atmosphere 1.2: 1.5 h / -100 - 25 °C 1.3: 1 h / 20 - 25 °C 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide; water / 0.25 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 0.08 h / -100 °C / Inert atmosphere 1.2: 1.5 h / -100 - 25 °C 1.3: 1 h / 20 - 25 °C 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide; water / 0.25 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: TurboGrignard / tetrahydrofuran / 0.17 h / Inert atmosphere 1.2: 2 h 2.1: sodium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 0.67 h / 140 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 5-bromo-1,3-dimethyl-1,2-dihydropyridin-2-one With TurboGrignard In tetrahydrofuran for 0.166667h; Inert atmosphere; Stage #2: N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide In tetrahydrofuran for 2h; Stage #3: With hydrogenchloride; methanol In tetrahydrofuran | 10i.B Method B 5-Bromo-1,3-dimethylpyridin-2(1H)-one (143 mg, 0.71 mmol, C. Morrow et al. J. Org. Chem., 1974, 39 (14), pp 2116-2118) was stirred under Ar(g) for 3 min and dissolved in THF (2 mL). Isopropylmagnesiumchloride lithiumchloride complex (1.3 M in THF) (0.544 mL, 0.71 mmol) was added dropwise and the mixture were stirred for 10 min. N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (170 mg, 0.42 mmol, WO2010/056196) in THF (2 mL) was added. The mixture was stirred for 2 h. HCl in MeOH (1.25 M, 2.33 mL, 2.91 mmol) was added and the mixture were stirred another h. NaHCO3(aq. sat) was added and the mixture was extracted with EtOAc. The organic phases were pooled, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using a gradient of 0-4% MeOH(containing NH3) in DCM to give the title is compound (140 mg, 79% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.94 (s, 3H), 3.36 (s, 3 H), 6.71 (br. s., 2H), 7.23 (m, 1H), 7.29 (m, 2H), 7.40 (m, 1H), 7.46 (m, 1H), 7.56 (m, 1H), 7.65 (m, 1H), 8.30 (d, 1H); MS (ES+) m/z 427 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | Stage #1: 5-bromo-1,3-dimethyl-1,2-dihydropyridin-2-one With n-butyllithium In tetrahydrofuran at -100℃; for 0.0833333h; Inert atmosphere; Stage #2: N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide In tetrahydrofuran at -100 - 25℃; for 1.5h; Stage #3: With hydrogenchloride; methanol In tetrahydrofuran at 20 - 25℃; for 1h; | 9i.A 5-(3-Amino-1-(3-bromophenyl)-4-fluoro-1H-isoindol-1-yl)-1,3-dimethylpyridin-2(1H)-one Example 9i 5-(3-Amino-1-(3-bromophenyl)-4-fluoro-1H-isoindol-1-yl)-1,3-dimethylpyridin-2(1H)-one Method A: tert-Butyllithium (1.969 mL, 3.15 mmol) was added dropwise to a solution of 5-bromo-1,3-dimethylpyridin-2(1H)-one (333 mg, 1.65 mmol, C. Morrow et al. J. Org. Chem., 1974, 39 (14), pp 2116-2118) in THF (1.5 mL) at -100° C. under a nitrogen atmosphere. After 5 min a solution of N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (611 mg, 1.5 mmol, WO2010/056196) in THF (2 mL) was added. After 30 min on the thawing cooling bath and 1 h at rt hydrogen chloride-1.25 M methanol solution (4.80 mL, 6.00 mmol) was added and the resulting mixture was stirred at rt for 1 h. The mixture was concentrated and the resulting residue was dissolved in DCM and sat. aq. NaHCO3. The mixture was poured into a phase separator, the organic phase was concentrated and purified on a silica gel column eluted with a gradient of 0-8% 0.1M NH3 in MeOH in DCM to give the title compound (110 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.94 (s, 3H), 3.35 (s, 3H), 6.60 (br. s., 2H), 7.20-7.30 (m, 4H), 7.34 (dt, 1H), 7.43 (tt, 2H), 7.52 (td, 1H), 7.59 (d, 1H); MS (ES+) m/z 426, 428 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 141 To a suspension of NaH (60% dispersion in mineral oil, 1.02 g, 42.4 mmol) in THF (10 mL), a solution of <strong>[13466-38-1]5-bromopyridin-2-ol</strong> (2.0 g, 10.6 mmol) in THF (50 mL) was added, and the resulting mixture was stirred at RT for 1 h. To this mixture, iodomethane (7.5 g, 53.2 mmol) was added and the resulting mixture was stirred at RT overnight. The mixture was quenched with water and extracted with ethyl acetate (200 mL). The organic layer was washed with aqueous NH4Cl solution and dried over anhydrous MgSO4 and filtered. The filtrate was concentrated to dryness to afford 5-bromo-1,3-dimethylpyridin-2(1H)-one. The pinacol ester was prepared in analogous fashion to Example 140, except 5-bromo-1,3-dimethylpyridin-2(1H)-one was used in place of 5-bromo-1-ethylpyridin-2(1H)-one. Compound 231 was prepared from compound 8 in analogous fashion to Example 140, except 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one was used in place of 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. ESI-MS m/z: 504.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With iron(III)-acetylacetonate In tetrahydrofuran; toluene for 2h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium acetate; palladium diacetate; XPhos / 1,4-dioxane / 16 h / 100 °C / Inert atmosphere; Sealed tube 2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; ethanol; toluene / 16 h / 95 °C / Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium acetate; palladium diacetate; XPhos / 1,4-dioxane / 16 h / 100 °C / Inert atmosphere; Sealed tube 2.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; ethanol; toluene / 16 h / 95 °C / Sealed tube 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 °C 3.2: 16 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 |
---|---|---|
286 mg | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine In 1,4-dioxane at 120℃; for 6h; | 132 Example 132 4-(4-chlorophenyl)-1-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(methoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one Example 132 4-(4-chlorophenyl)-1-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(methoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one The title compound was prepared using an analogous procedure to that described in Example 23 but using 4-(4-chlorophenyl)-1-cyclopropyl-3-(methoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 130.4) and 5-bromo-1,3-dimethyl-2-pyridone. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 0.5-3.5%) to provide the title compound (286 mg) as a colorless solid. tR: 0.95 min (LC-MS 2); ESI-MS: 439.1 [M+H]+ (LC-MS 2); Rf=0.48 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.07 (m, 2H) 1.20-1.27 (m, 2H) 1.91 (s, 3H) 3.02 (s, 3H) 3.34 (s, 3H) 3.81-3.89 (m, 1H) 3.97 (d, J=12.51 Hz, 1H) 4.20 (d, J=12.51 Hz, 1H) 6.09 (s, 1H) 7.20-7.28 (m, 2H) 7.31-7.37 (m, 2H) 7.40-7.45 (m, 1H) 7.76 (d, J=2.74 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16.0h; | 5-Bromo-1,3-dimethyl-1H-pyridin-2-one B-1 To a suspension of <strong>[89488-30-2]5-bromo-2-hydroxy-3-methyl pyridine</strong> A1 (1.000 g; 5.053 mmol) and potassium carbonate (1.397 g; 10.105 mmol) in DMF (5.000 ml) is carefully added iodomethane (0.346 ml; 5.558 mmol). The reaction mixture is stirred overnight (16 h) at room temperature. The reaction mixture is then quenched with 10% ammonia solution (10 ml) and 30 ml water is added. It is extracted with 3*50 ml EtOAc. The combined organic layer is dried with Na2SO4, filtered and concentrated under reduced pressure to afford the product. Yield: 98% (1.0 g; 4.95 mmol) HPLC-MS: (M+H)+=202/204; tRet=0.65 min; method LCMS BAS1 |
98% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16.0h; | 5-Bromo- 1 ,3-dimethyl- 1H-pyridin-2-one B-i To a suspension of <strong>[89488-30-2]5-bromo-2-hydroxy-3-methyl pyridine</strong> Al (1.000 g; 5.053mmo 1) and potassium carbonate (1.397 g; 10.105 mmo 1) in DMF (5.000 ml) iscarefully added iodomethane (0.346 ml; 5.558 mmol). The reaction mixture is stirred overnight (1 6h) at room temperature. The reaction mixture is then quenched with 10% ammonia solution (10 ml) and 30 ml water is added. It is extracted with 3x50 ml EtOAc. The combined organic layer is dried with Na2SO4, filtered andconcentrated under reduced pressure to afford the product.Yield: 98% (1.0 g; 4.95 mmol)HPLC-MS: (M+H) = 202/204; tRet = 0.65 mm; method LCMS BAS1 |
98% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16.0h; | 5-Bromo- 1 ,3-dimethyl- lH-pyridin-2- ne B- 1 To a suspension of <strong>[89488-30-2]5-bromo-2-hydroxy-3-methyl pyridine</strong> Al (1.000 g; 5.053 mmol) and potassium carbonate (1.397 g; 10.105 mmol) in DMF (5.000 ml) is carefully added iodomethane (0.346 ml; 5.558 mmol). The reaction mixture is stirred overnight (16h) at room temperature. The reaction mixture is then quenched with 10% ammonia solution (10 ml) and 30 ml water is added. It is extracted with 3x50 ml EtOAc. The combined organic layer is dried with Na2S04, filtered and concentrated under reduced pressure to afford the product. Yield: 98% (1.0 g; 4.95 mmol) HPLC-MS: (M+H)+ = 202/204; tRet = 0.65 min; method LCMS BAS1 |
98% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | To a suspension of starting material A (1.00 g; 5.053 mmol) and potassium carbonate (1.397 g; 10.105 mmol) in DMF (5 ml_) is carefully added iodomethane (0.346 ml5.558 mmol). The reaction mixture is stirred overnight (16 h) at room temperature. The reaction mixture is then quenched with 10 % ammonia solution (10 ml_) and 30 ml_ water is added. It is extracted with 3 x 50 mL EtOAc. The combined organic layer is dried with Na2S04, filtered and concentrated under reduced pressure to afford the product. Yield: 98 % (1.0 g; 4.95 mmol) ( HPLC-MS: (M+H)+ = 202/204; tRet = 0.65 min; method LCMS BAS1 |
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16.0h; | 5-Bromo-1,3-dimethyl-1H-pyridin-2-one C-1 To a suspension of <strong>[89488-30-2]5-bromo-2-hydroxy-3-methyl pyridine</strong> B1 (1.000 g; 5.053 mmol) and potassium carbonate (1.397 g; 10.105 mmol) in DMF (5.0 mL) is carefully added iodomethane (0.346 mL; 5.558 mmol). The reaction mixture is stirred at RT overnight (16 h). The reaction mixture is then quenched with 10% ammonia solution (10.0 mL) and water (30.0 mL) is added. The mixture is extracted with EtOAc (3*50.0 mL). The combined organic layer is dried with Na2SO4, filtered and concentrated under reduced pressure to afford the product. HPLC-MS: (M+H)+=202/204; tRet=0.65 min; method M1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine / tetrahydrofuran / 5 h / 20 °C | ||
Multi-step reaction with 3 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: triethylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2.1: sodium hydroxide; methanol / 2 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.25 h / 0 °C 3.2: 1 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2.1: sodium hydroxide; methanol / 2 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.25 h / 0 °C 3.2: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine / tetrahydrofuran / 16 h / 20 °C 4: acetic acid / 10 h / 150 °C / Microwave irradiation | ||
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: triethylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran / 16 h / 20 °C 4: acetic acid / 10 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine / tetrahydrofuran / 16 h / 20 °C | ||
Multi-step reaction with 3 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: triethylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: N-ethyl-N,N-diisopropylamine; HATU / tetrahydrofuran / 1 h / 0 - 20 °C | ||
Multi-step reaction with 3 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / tetrahydrofuran / 1 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: N-ethyl-N,N-diisopropylamine; HATU / tetrahydrofuran / 1 h / 0 - 20 °C 4: 5 h / 170 °C / Microwave irradiation | ||
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / tetrahydrofuran / 1 h / 0 - 20 °C 4: acetic acid / 5 h / 170 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: N-ethyl-N,N-diisopropylamine; HATU / tetrahydrofuran / 1 h / 0 - 20 °C 4: 5 h / 170 °C / Microwave irradiation 5: hydrogenchloride / water / 1 h / 100 °C | ||
Multi-step reaction with 5 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / tetrahydrofuran / 1 h / 0 - 20 °C 4: acetic acid / 5 h / 170 °C / Microwave irradiation 5: hydrogenchloride / water / 1 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C | ||
Multi-step reaction with 2 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C | ||
Multi-step reaction with 2 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; water / methanol / 2 h / 100 °C |
Multi-step reaction with 2 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr / Inert atmosphere 2: sodium hydroxide; methanol / 2 h / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine / tetrahydrofuran / 5 h / 20 °C 4: acetic acid / 80 °C | ||
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: triethylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran / 5 h / 20 °C 4: acetic acid / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2.1: sodium hydroxide; methanol / 2 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.25 h / 0 °C 3.2: 1 h / 20 °C 4.1: 1 h / 150 °C / Microwave irradiation 5.1: hydrogenchloride / water / 3 h / 100 °C | ||
Multi-step reaction with 5 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2.1: sodium hydroxide; methanol / 2 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.25 h / 0 °C 3.2: 1 h / 20 °C 4.1: acetic acid / 1 h / 150 °C / Microwave irradiation 5.1: hydrogenchloride / water / 3 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2.1: sodium hydroxide; methanol / 2 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.25 h / 0 °C 3.2: 1 h / 20 °C 4.1: 1 h / 150 °C / Microwave irradiation | ||
Multi-step reaction with 4 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2.1: sodium hydroxide; methanol / 2 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.25 h / 0 °C 3.2: 1 h / 20 °C 4.1: acetic acid / 1 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: thionyl chloride / 2 h / 60 °C 4: triethylamine / dichloromethane / 1 h 5: acetic acid / 1 h / 150 °C / Microwave irradiation | ||
Multi-step reaction with 5 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: thionyl chloride / 2 h / 60 °C 4: triethylamine / dichloromethane / 1 h 5: acetic acid / 1 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: thionyl chloride / 2 h / 60 °C 4: triethylamine / dichloromethane / 1 h | ||
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: thionyl chloride / 2 h / 60 °C 4: triethylamine / dichloromethane / 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: thionyl chloride / 2 h / 60 °C 4: triethylamine / dichloromethane / 1 h 5: acetic acid / 1 h / 150 °C / Microwave irradiation | ||
Multi-step reaction with 5 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: thionyl chloride / 2 h / 60 °C 4: triethylamine / dichloromethane / 1 h 5: acetic acid / 1 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2.1: sodium hydroxide; methanol / 2 h / 100 °C 3.1: thionyl chloride / 2 h / 60 °C 4.1: triethylamine / dichloromethane / 1 h 5.1: acetic acid / 1 h / 150 °C / Microwave irradiation 6.1: sodium hydride / toluene / 0.25 h / 70 °C / Inert atmosphere 6.2: 2 h / 100 °C | ||
Multi-step reaction with 6 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2.1: sodium hydroxide; methanol / 2 h / 100 °C 3.1: thionyl chloride / 2 h / 60 °C 4.1: triethylamine / dichloromethane / 1 h 5.1: acetic acid / 1 h / 150 °C / Microwave irradiation 6.1: sodium hydride / toluene; mineral oil / 0.25 h / 70 °C / Inert atmosphere 6.2: 2 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine at 70℃; for 18h; | 1 ,5-Dimethyl-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid methyl ester C-i 1 ,5-Dimethyl-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid methyl ester C-i In the carbonylation reactor from Büchi Glas Uster, 5-Bromo-1,3-dimethyl-1H-pyridin-2-one B-i (3.300 g; 16.006 mmol) is dissolved in MeOH (80.000 ml) andTEA (5.399 ml; 40.015 mmol) is added. Then Pd(dppf)C12.CH2C12 (389.000 mg;0.476 mmol) is added and the reactor is closed and filled with carbon monoxide(8bar). The reactor is heated to 70°C and stirred overnight 18h. The reactionmixture is filtered through a small pad of silica and washed with ethyl acetate. Thefiltrate is concentrated under reduced pressure and the residue is purified on silicachromatography Combiflash (Column: Redisep Rf, 120 g; gradient: cHex/EtOAc = 100% / 0% to 50% / 50%; flow rate = 30 mllmin, 28 column volumes; detection wavelength: 254nm). The product containing fractions are combined and concentrated under reduce pressure.Yield: 90% (2.6 g; 14.35 mmol)HPLC-MS: (M+H) = 182; tRet = 0.49 mm; method LCMS BAS1 |
90% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine at 70℃; for 18h; | 1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester C-1 1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester C-1 In the carbonylation reactor from Büchi Glas Uster, 5-Bromo-1,3-dimethyl-1H-pyridin-2-one B-1 (3.300 g; 16.006 mmol) is dissolved in MeOH (80.000 ml) and TEA (5.399 ml; 40.015 mmol) is added. Then Pd(dppf)Cl2.CH2Cl2 (389.000 mg; 0.476 mmol) is added and the reactor is closed and filled with carbon monoxide (8 bar). The reactor is heated to 70° C. and stirred overnight 18 h. The reaction mixture is filtered through a small pad of silica and washed with ethyl acetate. The filtrate is concentrated under reduced pressure and the residue is purified on silica chromatography Combiflash (Column: Redisep Rf, 120 g; gradient: cHex/EtOAc=100%/0% to 50%/50%; flow rate=30 ml/min, 28 column volumes; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduce pressure. Yield: 90% (2.6 g; 14.35 mmol) HPLC-MS: (M+H)+=182; tRet=0.49 min; method LCMS BAS1 |
90% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine at 70℃; for 18h; | l,5-Dimethyl-6-oxo-l,6-dihydro- ridine-3-carboxylic acid methyl ester C-l l,5-Dimethyl-6-oxo-l,6-dihydro- ridine-3-carboxylic acid methyl ester C-l In the carbonylation reactor from Biichi Glas Uster, 5-Bromo-l,3-dimethyl-lH- pyridin-2-one B-l (3.300 g; 16.006 mmol) is dissolved in MeOH (80.000 ml) and TEA (5.399 ml; 40.015 mmol) is added. Then Pd(dppf)Cl2.CH2Cl2 (389.000 mg; 0.476 mmol) is added and the reactor is closed and filled with carbon monoxide (8bar). The reactor is heated to 70°C and stirred overnight 18h. The reaction mixture is filtered through a small pad of silica and washed with ethyl acetate. The filtrate is concentrated under reduced pressure and the residue is purified on silica chromatography Combiflash (Column: Redisep Rf, 120 g; gradient: cHex/EtOAc = 100% / 0% to 50% / 50%; flow rate = 30 ml/min, 28 column volumes; detection wavelength: 254nm). The product containing fractions are combined and concentrated under reduce pressure. Yield: 90% (2.6 g; 14.35 mmol) HPLC-MS: (M+H)+ = 182; tRet = 0.49 min; method LCMS BAS1 |
90% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine at 70℃; for 18h; Inert atmosphere; | Synthesis of intermediate C In the carbonylation reactor from BLICHI GLAS USTER, intermediate B (3.30 g; 16.006 mmol) is dissolved in MeOH (80.00 mL) and TEA (5.399 mL; 40.015 mmol) is added. Then Pd(dppf)Cl2.CH2Cl2 (389.00 mg; 0.476 mmol) is added and the reactor is closed and filled with carbon monoxide (8 bar). The reactor is heated to 70 °C and stirred overnight for 18 h. The reaction mixture is filtered through a small pad of silica and washed with ethyl acetate. The filtrate is concentrated under reduced pressure and the residue is purified on silica chromatography Combiflash (Column: Redisep Rf, 120 g; gradient: cHex/EtOAc = 100 %/0 % to 50 %/50 %; flow rate = 30 mL/min, 28 column volumes; detection wavelength: 254nm). The product containing fractions are combined and concentrated under reduce pressure. Yield: 90 % (2.6 g; 14.35 mmol) HPLC-MS: (M+H)+ = 182; tRet = 0.49 min; method LCMS BAS1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: thionyl chloride / 2 h / 60 °C 4: triethylamine / dichloromethane / 1 h | ||
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; methanol / 2 h / 100 °C 3: thionyl chloride / 2 h / 60 °C 4: triethylamine / dichloromethane / 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate In methanol; 1,2-dimethoxyethane at 80℃; for 18h; Inert atmosphere; | 4 N-[3-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-methanesulfonamide (I-31) N-[3-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-methanesulfonamide (I-31) 5-bromo-1,3-dimethyl-pyridin-2-one C-1 (100.0 mg; 0.495 mmol), [3-(methanesulfonamido)phenyl]boronic acid K-23 (127.7 mg; 0.594 mmol), bis(triphenylphosphine)palladium dichloride (17.4 mg; 0.025 mmol) and CsCO3 solution 2M (0.495 mL; 0.990 mmol) are dissolved in DME/MeOH (2.0 mL/0.5 mL) flushed with argon and stirred at 80° C. for 18 h. Solvent is removed and the residue is dissolved in DMSO, filtered and purified by RP HPLC (Waters Sunfire 19*50 mm, HCOOH). HPLC-MS: (M+H)+=293; tRet=0.68 min; method M1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; water / methanol / 2 h / 100 °C 3: N-ethyl-N,N-diisopropylamine; HATU / 1-methyl-pyrrolidin-2-one / 12 h / 20 °C 4: acetic acid / 1 h / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2: sodium hydroxide; water / methanol / 2 h / 100 °C 3: N-ethyl-N,N-diisopropylamine; HATU / 1-methyl-pyrrolidin-2-one / 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2.1: sodium hydroxide; water / methanol / 2 h / 100 °C 3.1: thionyl chloride / 15 h / 60 °C 3.2: 12 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr / Inert atmosphere 2.1: sodium hydroxide; methanol / 2 h / 100 °C / Inert atmosphere 3.1: thionyl chloride / 15 h / 60 °C / Inert atmosphere 3.2: acid chloride / 12 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr 2.1: sodium hydroxide; water / methanol / 2 h / 100 °C 3.1: thionyl chloride / 15 h / 60 °C 3.2: 12 h / 20 °C 4.1: acetic acid / 7 h / 120 °C | ||
Multi-step reaction with 4 steps 1.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 18 h / 70 °C / 6000.6 Torr / Inert atmosphere 2.1: sodium hydroxide; methanol / 2 h / 100 °C / Inert atmosphere 3.1: thionyl chloride / 15 h / 60 °C / Inert atmosphere 3.2: acid chloride / 12 h / 20 °C / Inert atmosphere 4.1: acetic acid / 7 h / 120 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere 3.1: sodium acetate; acetic acid / dichloromethane / 0.17 h / 0 °C 3.2: 0.5 h 3.3: 16 h / 20 - 25 °C 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 16 h / 20 - 25 °C | ||
Multi-step reaction with 3 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 3.5 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / water; N,N-dimethyl-formamide / 1 h / 80 °C / Inert atmosphere; Sealed tube 3: hydrogenchloride / 1,4-dioxane; dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / water; 1,4-dioxane / 12 h / 90 °C / Inert atmosphere 2: phosphorus tribromide / dichloromethane / 0 °C | ||
Multi-step reaction with 3 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 3.5 h / 90 °C / Inert atmosphere 2: sodium hydrogencarbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere; Sealed tube 3: phosphorus tribromide / dichloromethane / 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / water; 1,4-dioxane / 2 h / 90 °C | ||
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 3.5 h / 90 °C / Inert atmosphere 2: caesium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 2 h / 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / water; 1,4-dioxane / 12 h / 90 °C / Inert atmosphere 2: phosphorus tribromide / dichloromethane / 0 °C 3: methanol; dichloromethane / 12 h / 20 - 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / water; 1,4-dioxane / 2 h / 90 °C 3: hydrogen; ammonium hydroxide / methanol / 16 h / 20 - 25 °C / 2585.81 Torr | ||
Multi-step reaction with 3 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 3.5 h / 90 °C / Inert atmosphere 2: caesium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 2 h / 90 °C 3: hydrogen; ammonium hydroxide / methanol / 20 °C / 2585.81 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 3.5 h / 90 °C / Inert atmosphere 2: sodium hydrogencarbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere; Sealed tube | ||
Multi-step reaction with 2 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: caesium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 2 h / 80 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 5 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium acetate / water; N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere 3.1: sodium acetate; acetic acid / dichloromethane / 0.17 h / 0 °C 3.2: 0.5 h 3.3: 16 h / 20 - 25 °C | ||
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 3.5 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / water; N,N-dimethyl-formamide / 1 h / 80 °C / Inert atmosphere; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 - 25 °C 4: dichloromethane / 8 h / 20 - 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 - 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / N,N-dimethyl-formamide / 1 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In N,N-dimethyl-formamide at 100℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 90℃; for 2h; | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 90℃; for 2h; | 8 4-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-ethyl-6-methoxy-benzonitrile (I-41') 4-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-ethyl-6-methoxy-benzonitrile (I-41') To the solution of 2-ethyl-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile K-2 (570.0 mg; 1.985 mmol) and 5-bromo-1,3-dimethyl-pyridin-2-one C-1 (440.0 mg; 2.178 mmol) in dioxane (20.0 mL) and water (1.0 mL) is added Cs2CO3 (2.000 g; 6.154 mmol), then Pd(dppf)Cl2 (100.0 mg; 0.137 mmol). The mixture is heated to 90° C. for 2 h. The reaction is filtered over a pad of celite and the filtrate is concentrated. The residue is dissolved in EA, washed with brine. The combined organic layers are dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which is purified with prep-HPLC. HPLC-MS: (M+H)+=283; tRet=1.363 min; method M7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Stage #1: 5-bromo-1,3-dimethyl-1,2-dihydropyridin-2-one; (1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-5-(methoxycarbonyl)-3-methyl-1H-pyrazol-4-yl)boronic acid With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 85℃; for 18h; Stage #2: With lithium hydroxide In 1,4-dioxane; water at 90℃; for 0.75h; Microwave irradiation; | 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-1H-pyrazole-5-carboxylic acid A solution of 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-5- (methoxycarbonyl)-3-methyl-1H-pyrazol-4-ylboronic acid (50 mg, 0.10 mmol), 5-bromo-1,3- dimethylpyridin-2(1H)-one (25 mg, 0.12 mmol), Pd(PPh3)4 (12 mg, 0.10 mmol), Na2CO3 (54 mg, 0.51 mmol) in degassed 1,4-dioxane and H2O (4:1, 2.1 mL) was heated at 85 °C for 18 hours. LiOH (12.4 mg, 0.52 mmol) was added and the reaction was heated at 90 oC under microwave radiation for 45 minutes.1 N HCl (1 mL) was added, followed by water (5 mL) and the mixture was extracted with EtOAc (3x5 mL). The combined organic layers were dried with sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by semi-prep HPLC-MS (column X-Bridge 30x50) using a solution of MeCN in water (containing 10 mM of NH4CO2H) (35 to 55%). The product was lyophylised and afforded the title compound (12 mg, 0.022 mmol, 22%) as a pale yellow solid. [387] 1H NMR (500 MHz, DMSO) δ 8.19 (d, J = 2.1 Hz, 1H), 8.01 (dd, J = 8.5, 2.1 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.41-7.39 (m, 1H), 3.48 (s, 3H), 3.35 (hept, J = 6.7 Hz, 1H), 2.28 (s, 3H), 2.03 (s, 3H), 1.23 (d, J = 6.7 Hz, 6H); MS (m/z): 549.0 [M+H]+. |
22% | Stage #1: 5-bromo-1,3-dimethyl-1,2-dihydropyridin-2-one; (1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-5-(methoxycarbonyl)-3-methyl-1H-pyrazol-4-yl)boronic acid With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 85℃; for 18h; Stage #2: With lithium hydroxide In 1,4-dioxane; water at 90℃; for 0.75h; Microwave irradiation; | Compound 94: 1 -(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yI)-4-(1 ,5-dimethyl- 6-oxo-1 ,6-di hydropyridi n-3-yI)-3-methyl-1 H-pyrazole-5-carboxyl ic acid A solution of 1 -(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-5- (methoxycarbonyl)-3-methyl-1H-pyrazol-4-ylboronic acid (50 mg, 0.10 mmol), 5-bromo-1,3- dimethylpyridin-2(1H)-one (25 mg, 0.12 mmol), Pd(PPh3)4 (12 mg, 0.10 mmol), Na2003 (54 mg, 0.51 mmol) in degassed 1,4-dioxane and H20 (4:1, 2.1 mL) was heated at 85 C for 18 hours. LiOH (12.4 mg, 0.52 mmol) was added and the reaction was heated at 90 0 under |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane; water / 16 h / 85 °C / Inert atmosphere 2: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / tetrahydrofuran / 16 h / 90 °C / Sealed tube; Inert atmosphere 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / 85 °C / Inert atmosphere 4: lithium hydroxide / methanol; water; tetrahydrofuran / 0.25 h / 110 °C / Microwave irradiation | ||
Multi-step reaction with 4 steps 1: potassium acetate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / 1,4-dioxane / 16 h / 85 °C / Inert atmosphere 2: dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate / tetrahydrofuran / 16 h / 20 - 90 °C / Inert atmosphere; Sealed tube 3: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane; water / 16 h / 85 °C / Inert atmosphere 4: water; lithium hydroxide / methanol; tetrahydrofuran / 0.25 h / 110 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane; water / 16 h / 85 °C / Inert atmosphere 2: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / tetrahydrofuran / 16 h / 90 °C / Sealed tube; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: potassium acetate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / 1,4-dioxane / 16 h / 85 °C / Inert atmosphere 2: dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate / tetrahydrofuran / 16 h / 20 - 90 °C / Inert atmosphere; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane; water / 16 h / 85 °C / Inert atmosphere 2: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / tetrahydrofuran / 16 h / 90 °C / Sealed tube; Inert atmosphere 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 16 h / 85 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: potassium acetate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / 1,4-dioxane / 16 h / 85 °C / Inert atmosphere 2: dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate / tetrahydrofuran / 16 h / 20 - 90 °C / Inert atmosphere; Sealed tube 3: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane; water / 16 h / 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water Reflux; | 7 4-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-benzoic acid methyl ester I-37' 4-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-benzoic acid methyl ester I-37' To a solution of 5-bromo-1,3-dimethyl-1H-pyridin-2-one C-1 (10.0 g; 49.493 mmol) in dioxane/H2O (50.0 mL/50.0 mL) are added (4-methoxycarbonylphenyl) boronic acid K-25 (10.7 g, 59.456 mmol), Pd(PPh3)4 (0.500 g, 0.433 mmol) and Na2CO3 (17.1 g, 161.321 mmol). The reaction mixture is stirred at reflux overnight. The mixture is filtered over celite and concentrated in vacuo. The residue is purified by NP silica gel chromatography with PE/EA (1:1) to give desired compound. HPLC-MS: (M+H)+=258; tRet=0.745 min; method M6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 12h;Inert atmosphere; | 5-(3-Amino-4-methyl-phenyl)-1,3-dimethyl-1H-pyridin-2-one (I-42') 5-bromo-1,3-dimethyl-pyridin-2-one C-1 (7.000 g; 0.035 mol), (3-amino-4-methyl-phenyl)boronic acid K-20 (7.846 g; 0.052 mol), Cs2CO3 (33.883 g; 0.104 mol), Pd(dppf)2Cl2 (1.472 g; 0.002 mol) are dissolved in dioxane/H2O=3:1 (50.0 mL) under N2. The reaction mixture is heated to 90 C. for 12 h. After the reaction is completed, the solvent is removed and water is added to the mixture. The mixture is extracted with DCM and the organic layer is washed with water and brine. The combined organic layers are dried with Na2SO4, filtered and concentrated under reduced pressure. The product is then purified by HPLC. TLC Information (Silica, Eluent: PE:EA=1:2); Rf (product)=0.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31 mg | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In ethanol; toluene at 120℃; for 1h; Microwave irradiation; | 97 5-(l-benzyl-lH-imidazol-5-yl)-l,3-dimethylpyridin-2(lH)-one A mixture of 5-bromo-l,3-dimethylpyridin-2(lH)-one (100 mg, 0.495 mmol), l-benzyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-imidazole (commercially available from, for example, J & W PharmLab, 211 mg, 0.742 mmol), potassium carbonate (342 mg, 2.47 mmol) and bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.05 mmol) in EtOH (2 mL) and toluene (2 mL) was heated in a microwave at 120 °C for 1 h. The cooled reaction mixture was diluted with ethyl acetate (25 mL). The mixture was filtered and the solvent was evaporated from the filtrate. The residue was chromatographed [0-10% 2 M NH3/methanol in dichloromethane] to give the title compound as a colourless oil (31 mg). LCMS (System B): tRET = 0.71 min; MH+ 280. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Stage #1: 1-benzyl-4-fluoro-1H-imidazole With 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex In tetrahydrofuran; toluene at 0℃; for 0.5h; Inert atmosphere; Stage #2: With zinc(II) chloride In tetrahydrofuran; 2-methyltetrahydrofuran; toluene at 0℃; for 0.25h; Stage #3: 5-bromo-1,3-dimethyl-1,2-dihydropyridin-2-one With bis-triphenylphosphine-palladium(II) chloride In tetrahydrofuran; 2-methyltetrahydrofuran; toluene at 110℃; for 1h; Inert atmosphere; Microwave irradiation; | 62 5-(l-benzyl-4-fluoro-l y-imidazol-2-yl>l,3-dimethylpyridin-2(lffl-one A solution of TMPMgCI.LiCI (1 M in THF/toluene, 0.511 mL, 0.511 mmol) was added dropwise to a solution of l-benzyl-4-fluoro-lH-imidazole (for an example preparation, see Intermediate 22, 45 mg, 0.255 mmol) in THF (1 mL) at 0 °C in a dried vial under nitrogen. The reaction mixture was stirred at 0 °C for 30 min, then a solution of zinc chloride (1.9M in 2-methyltetrahydrofuran) (0.403 mL, 0.766 mmol) was added, and the reaction stirred at 0 °C for a further 15 min. The reaction was allowed to warm to RT and added via syringe to a dried and nitrogen-purged vial containing 5-bromo-l,3-dimethylpyridin-2(lH)-one (103 mg, 0.511 mmol) and bis(triphenylphosphine)palladium dichloride (14.34 mg, 0.020 mmol). The reaction mixture was then heated at 110 °C in a Biotage 160 microwave reactor for 60 min. The reaction was quenched by the addition of MeOH (1 mL) and the solvent removed in vacuo. The crude residue was dissolved in MeOH (1.8 mL), filtered through a pipette filter, and purified by MDAP (Method B) to afford the title compound as a colourless film (26 mg, 0.08 mmol, 33%). LCMS (System A): tRET = 0.88 min; MH+ 298. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis[tris( 1,1-dimethylethyl)phosphine]-palladium; caesium carbonate In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 90℃; for 1h; Inert atmosphere; Sealed tube; | 3 4-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-N-(1-methyl-piperidin-4-yl)-benzamide (I-30) 4-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-N-(1-methyl-piperidin-4-yl)-benzamide (I-30) [4-[(1-methyl-4-piperidyl)carbamoyl]phenyl]boronic acid K-7 (104.8 mg; 0.400 mmol), 5-bromo-1,3-dimethyl-pyridin-2-one C-1 (83.3 mg; 0.400 mmol), cesium carbonate (260.6 mg; 0.800 mmol) and bis(tri-tert-butylphosphine)palladium(0) (40.9 mg; 0.080 mmol) are suspended in THF/NMP (0.6 mL/0.3 mL). The reaction mixture is flushed with argon, sealed and stirred at 90° C. for 1 h. The reaction mixture is then filtered and purified with the basic (ammonia buffer) RP HPLC system (column: YMC TriaRT C-18 20*50 mm). The product containing fractions are concentrated under reduced pressure. The product is dissolved in acetonitrile/water 1:1 and freeze dried. HPLC-MS: (M+H)+=340; tRet=0.81 min; method M1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 90℃; for 2h; Inert atmosphere; | 2 N-[5-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-methyl-phenyl]-methanesulfonamide (I-23) N-[5-(1,5-Dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-methyl-phenyl]-methanesulfonamide (I-23) To a solution of 5-bromo-1,3-dimethyl-1H-pyridin-2-one C-1 (100.0 mg; 0.495 mmol) in dioxane (4.0 mL) and H2O (1.0 mL) is added successively [3-(methanesulfonamido)-4-methyl-phenyl]boronic acid K-6 (113.4 mg; 0.495 mmol), Cs2CO3 (322.5 mg; 0.990 mmol) and Pd(dppf)Cl2 (80.8 mg; 0.099 mmol), the reaction mixture is stirred at 90° C. under N2 for 2 h. The mixture is poured onto ice water, extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product which is purified by Prep-HPLC to yield the title product. HPLC-MS: (M+H)+=307.0; tRet=2.181 min; method M11 |
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; | 1 In a vial 5-bromo-1,3-dimethyl-1H-pyridin-2-one C-1 (138.3 mg; 0.685 mmol), [4-(1-pyrrolidin-1-ylethyl)phenyl]boronic acid K-8 (150.0 mg; 0.685 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (57.6 mg; 0.068 mmol) are weight in. N,N-Dimethylformamide (0.8 mL) and 2N sodium bicarbonate solution (0.856 mL; 1.711 mmol) are added. The vial is flushed with argon and sealed. The reaction mixture is heated at 100° C. for 1 h. To the reaction mixture one drop of water is added and the mixture is filtered and 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. A chiral separation is performed (JASCO SFC, column: Chiralpak AD 200×10 mm; 5 μm, mobile phase: MeOH/CO2=40/60). The product containing fractions are pooled and evaporated, then re-dissolved in acetonitrile/water 1:1 and freeze dried |
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; | 6 5-(4-Hydroxymethyl-3-methyl-phenyl)-1,3-dimethyl-1H-pyridin-2-one (I-33') 5-(4-Hydroxymethyl-3-methyl-phenyl)-1,3-dimethyl-1H-pyridin-2-one (I-33') In a vial 5-bromo-1,3-dimethyl-1H-pyridin-2-one C-1 (1.00 g; 5.78 mmol) [4-(1-pyrrolidin-1-ylethyl)phenyl]boronic acid K-24 (1.17 g; 5.78 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (472.3 mg; 0.578 mmol) are weight in. N,N-dimethylformamide (5.0 mL) and 2N sodium bicarbonate solution (7.23 mL; 14.5 mmol) are added. The vial is flushed with argon and sealed. The reaction mixture is heated at 100° C. for 1 h. The reaction mixture is diluted with water and extracted with DCM (3*30.0 mL). The combined organic layers are dried with Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified by silica gel chromatography Combiflash (Column Redisep Rf, 40 g; gradient: cyclohexane/EtOAc=100%/0% to 0%/100% over 41 column volumes; flow rate=40 mL/min; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduced pressure. HPLC-MS: (M+H)+=244; tRet=0.99 min; method M1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium phosphate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) In tetrahydrofuran; water at 65℃; for 2h; Inert atmosphere; | 2A Intermediate 2A: tert-butyl 4-(2-(l,5-dimethyl-6-oxo l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indol-5-yl)piperidine-l-carboxylate (2A) To a mixture containing tert-butyl 4-(3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indol-5-yl)piperidine-l -carboxylate (2434 mg, 5.20 mmol), 5- bromo-l ,3-dimethylpyridin-2(lH)-one (1000 mg, 4.95 mmol), and Xphos Pd G2 (97 mg, 0.124 mmol) in a screw cap vial was added THF (25 mL) followed by an aqueous solution of potassium phosphate, tribasic (4.95 mL, 14.85 mmol). The vial was fitted with a Teflon lined septum cap. The vial was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The evacuation procedure was repeated three times. The needle was removed and the vial was heated at 65 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaCl solution (10 mL), dried (Na2S04), filtered and concentrated to afford crude material. The crude product was dissolved in a small amount of DCM and charged to a 40 g ISCO silica gel column, which was eluted over a 15 min gradient with 5%-100% hexanes/ethyl acetate to afford tert-butyl 4-(2-(l,5-dimethyl-6-oxo-l ,6-dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl) piperidine-l -carboxylate, 2.1 g (90 %yield) m/e (464, M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 90℃; for 1h; | To a mixture of 5-bromo-l,3-dimethylpyridin-2(lH)-one (300 mg, 1.485 mmol) (Fl) and NBS (264 mg, 1.485 mmol) in CC (20 mL) was added AIBN (24.38 mg, 0.148 mmol). The reaction mixture was heated at 90 °C for 1 hour and then cooled to room temperature. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCC . The organic layer was dried with MgS04, filtered and concentrated to afford 5-bromo-3-(bromomethyl)-l-methylpyridin-2(lH)-one (420 mg, 1.4 mmol, 100% yield). NMR (400 MHz, CHLOROFORM-d) δ 7.58 (d, J=2.6 Hz, 1H), 7.46 (d, J=2.6 Hz, 1H), 4.43 (s, 2H), 3.59 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium phosphate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) In tetrahydrofuran; water at 70℃; for 20h; | 7.7G Intermediate 7G: tert-butyl 4-(6-(l ,5-dimethyl-6-oxo-l ,6-dihydropyridin-3-yl)-5-((2- (trimethylsi]yl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-y])piperidine-l-carboxylate To a mixture containing tert-butyl 4-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2~ yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)piperidine-l- carboxyate (400 mg, 0.72 mmol), 5-bromo-l,3-dimethylpyridin-2(lH)-one (145 mg, 0.72 mmol), and Xphos Pd G2 (14 mg, 0.018 mmol) in a screw cap vial was added THF (5 mL) followed by the addition of aqueous 3M solution of potassium phosphate, tribasic (0.72 mL, 2.15 mmol). The vial was fited with a Teflon lined septum cap. The system w'as evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 70 °C for 20 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with saturated aqueous NaCl solution (10 mL), dried (NaaSOr), filtered and concentrated. The crude product was dissolved in a small amount of DCM and charged to 12 g ISCO sili ca gel column and purified using the Teledyne ISCO CombiFlash Rf chromatography system. The compound was eluted over a 10 min gradient with 0%-5% MeOH/ DCM to afford tert- butyl 4-(6-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-5-((2-(trimethylsilyl)ethoxy) methyl)-5H-pyrrolo[3,2-d]pynmidin-2-yl)piperidine-l-carboxylate (330 mg, 0.596 mmol, 83 % yield), m/e (554, M+l). H NMR (400 MHz, CHLOROFORM-d) d 8.89-8.86 (m, i l l ). 7 72 (d, J= 2.3 Hz, 1H), 7.51 (dd, ./ 2.4. 1.2 Hz, l i t). 6.65 (s, l i t). 5.45 (s, 2H), 4.37- 4.20 (m, 21 1). 3.69-3.64 (m, 5H), 3.20-3 09 (m, 1H), 3.00-2.85 (m, 2H), 2.26 (s, 31 1). 2.09-2.02 (m, 2H), 2.00-1.88 (m, 2H), 1.50 (s, 9H), 1.03-0.95 (m, 2H), 0.02 (d, 7=0.7 Hz, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water; N,N-dimethyl-formamide Inert atmosphere; | 6.3 Step 3: Synthesis IId from IIc General procedure: R2-Hal, IIc, Pd(PPh3)4, Na2CO3, H2O, dioxane or DMF under argon atmosphere at elevated temperature for at least overnight (see: e.g., Martin, L. J., et al., J Med Chem. 2016; 59:4462-4475). Purification of IId was carried out by silica-gel chromatography or preparative HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: tert-butyl 4-(5-bromo-7-methyl-2H-indazol-2-yl)piperidine-1-carboxylate With tetrahydroxydiboron; methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); potassium acetate; XPhos In ethanol at 80℃; for 0.5h; Inert atmosphere; Microwave irradiation; Stage #2: 5-bromo-1,3-dimethyl-1,2-dihydropyridin-2-one With potassium carbonate In ethanol at 80℃; for 1h; Microwave irradiation; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | Initially cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (91.36 mg, 124.86 umol) , 4-bromo-2,6-dimethoxy-benzaldehyde (306 mg, 1.25 mmol) Bis(pinacolato) diboron (380.49 mg, 1.50 mmol) , Potassium Acetate (367.63 mg, 3.75 mmol, 234.16 uL) were charged into a MW vial (2-5 mL) and suspended under an argon atmosphere in 1,4-Dioxane (12.27 mL) and heated in a MW at 140C for 40 mins. The suspension then had 5-bromo-1,3-dimethyl- pyridin-2-one (252.28 mg, 1.25 mmol) added under argon along with Potassium Carbonate (2 M, 2 eq) and reheated at 120C for 30 mins before being checked by LCMS. Upon reaction completion the mixture was filtered through a Celite pad and washed with DCM/ethyl acetate. The filtrate was washed with water (10 mL) before being washed with brine (50 mL), Na2SO4, filtered and concentrated to a residue which was purified via flash column chromatography (hexanes:ethyl acetate 1:0 to 0:1) to afford 4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2,6- dimethoxybenzaldehyde. Yield- 62 mg, 17%; LC-MS (ES+): m/z 288.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.7% | With potassium dihydrogenphosphate; copper(l) iodide; (1R,2R)-1,2-diaminocyclohexane In N,N-dimethyl-formamide at 120℃; for 21h; Inert atmosphere; | 237 Example 237: 5-(5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3- yl)-6-methyl-1H-indazol-1-yl)-1,3-dimethylpyridin-2(1H)-one A suspension of 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin- 3-yl)-6-methyl-1H-indazole (52.0 mg, 94% Wt, 112 µmol), (1R,2R)-cyclohexane-1,2- diamine (14.3 mg, 15.0 µL, 125 µmol) (Intermediate AI), 5-bromo-1,3-dimethylpyridin- 2(1H)-one (51.0 mg, 252 µmol) and potassium phosphate (64.0 mg, 302 µmol) in DMF (2.00 mL) was sparged with N2 for 5 minutes before copper(I) iodide (12.0 mg, 63.0 µmol) was added. The reaction mixture was sparged with N2 for 5 minutes and then the reaction mixture was heated at 120 °C for 21 hours. The reaction mixture was allowed to cool to room temperature, diluted with 5% LiCl(aq) solution (10 mL) and extracted with EtOAc (4 x 5 mL). The combined organic phase was washed with 1:1 saturated brine (aq) /water (2 x 10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% formic acid in water), Acidic, Waters X-Select CSH C18 ODB prep column, 30-60% MeCN in Water) to afford 5-(5-(3-benzyl-1- ((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1,3- dimethylpyridin-2(1H)-one (Example 237) (32.3 mg, 56.8 µmol, 50.7 %) as a tan solid; Rt 1.97 min (Method 6); m/z 558.3 (M+H)+ (ES+). δH (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.09 - 8.04 (m, 2H), 7.66 (dd, J = 2.9, 1.3 Hz, 1H), 7.48 (s, 1H), 7.12 - 6.99 (m, 4H), 6.54 - 6.47 (m, 2H), 4.17 (s, 3H), 3.97 (d, J = 9.7 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.56 (s, 3H), 3.53 - 3.46 (m, 1H), 3.36 (d, J = 9.8 Hz, 1H), 3.01 (d, J = 13.4 Hz, 1H), 2.73 (d, J = 13.5 Hz, 1H), 2.45 - 2.37 (m, 4H), 2.13 - 2.01 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate / 1,4-dioxane; water monomer / 16 h / 80 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4: sodium tris(acetoxy)borohydride / dichloromethane / 16 h / 25 °C 5: trifluoroacetic acid / dichloromethane / 1 h / 20 °C | ||
Multi-step reaction with 5 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate / 1,4-dioxane; water monomer / 16 h / 80 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4: sodium tris(acetoxy)borohydride / dichloromethane / 16 h / 25 °C 5: trifluoroacetic acid / dichloromethane / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate / 1,4-dioxane; water monomer / 16 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate / 1,4-dioxane; water monomer / 16 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate / 1,4-dioxane; water monomer / 16 h / 80 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C | ||
Multi-step reaction with 3 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate / 1,4-dioxane; water monomer / 16 h / 80 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate / 1,4-dioxane; water monomer / 16 h / 80 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4: sodium tris(acetoxy)borohydride / dichloromethane / 16 h / 25 °C | ||
Multi-step reaction with 4 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate / 1,4-dioxane; water monomer / 16 h / 80 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4: sodium tris(acetoxy)borohydride / dichloromethane / 16 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.8% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate In 1,4-dioxane; water monomer at 80℃; for 2h; Inert atmosphere; | 1.1 Step 1: preparation of 5-(6-chloro-2-ethyl-3-pyridyl)-1,3-dimethyl-pyridin-2-one A mixture of 5-bromo-1,3-dimethylpyridin-2(1H)-one (238mg, 1.19 μmol, CAS No. 51417-13-1, vendor: ALDRICH, catalog JRD0890), 6-chloro-2-ethyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (Int-A2, 318 mg, 1.19 mmol) and K2CO3 (205 mg, 1.48 mmol) in a mixed solvent of dioxane (5 mL) and water (1 mL) was added PdCl2(DPPF)-CH2Cl2 adduct (72.4 mg, 99 μmol, CAS No. 95464-05-4, vendor: Accela ChemBio Inc, catalog SY002614) and the mixture was stirred at 80oC under N2 atmosphere for 2 hours. After the reaction was completed, the mixture was then concentrated in vacuo. The residue was then purified by flash column eluting with a gradient of MeOH/DCM (0% to 10%) to give 5-(6-chloro-2-ethyl-3- pyridyl)-1,3-dimethyl-pyridin-2-one (297 mg, 94.8 % yield) as light brown oil. MS: calc’d 263 (M+H+), measured 263 (M+H+). |
94.8% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate In 1,4-dioxane; water monomer at 80℃; for 2h; Inert atmosphere; | 1.1 Step 1: preparation of 5-(6-chloro-2-ethyl-3-pyridyl)-1,3-dimethyl-pyridin-2-one A mixture of 5-bromo-1,3-dimethylpyridin-2(1H)-one (238mg, 1.19 μmol, CAS No. 51417-13-1, vendor: ALDRICH, catalog JRD0890), 6-chloro-2-ethyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (Int-A2, 318 mg, 1.19 mmol) and K2CO3 (205 mg, 1.48 mmol) in a mixed solvent of dioxane (5 mL) and water (1 mL) was added PdCl2(DPPF)-CH2Cl2 adduct (72.4 mg, 99 μmol, CAS No. 95464-05-4, vendor: Accela ChemBio Inc, catalog SY002614) and the mixture was stirred at 80oC under N2 atmosphere for 2 hours. After the reaction was completed, the mixture was then concentrated in vacuo. The residue was then purified by flash column eluting with a gradient of MeOH/DCM (0% to 10%) to give 5-(6-chloro-2-ethyl-3- pyridyl)-1,3-dimethyl-pyridin-2-one (297 mg, 94.8 % yield) as light brown oil. MS: calc’d 263 (M+H+), measured 263 (M+H+). |
Tags: 51417-13-1 synthesis path| 51417-13-1 SDS| 51417-13-1 COA| 51417-13-1 purity| 51417-13-1 application| 51417-13-1 NMR| 51417-13-1 COA| 51417-13-1 structure
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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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