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CAS No. : | 1095708-32-9 | MDL No. : | MFCD12032217 |
Formula : | C16H25BN2O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SAAGMIHGVLKZBC-UHFFFAOYSA-N |
M.W : | 320.19 | Pubchem ID : | 49760449 |
Synonyms : |
|
Num. heavy atoms : | 23 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.62 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 90.96 |
TPSA : | 69.68 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.31 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.74 |
Log Po/w (WLOGP) : | 2.54 |
Log Po/w (MLOGP) : | 1.21 |
Log Po/w (SILICOS-IT) : | 1.29 |
Consensus Log Po/w : | 1.56 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.41 |
Solubility : | 0.123 mg/ml ; 0.000385 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.86 |
Solubility : | 0.0444 mg/ml ; 0.000139 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.55 |
Solubility : | 0.00894 mg/ml ; 0.0000279 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.46 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium acetate In dimethyl sulfoxide at 85℃; for 1.25 h; Inert atmosphere | Preparation 24terf-Butyl (4-bromopyhdin-2-yl)carbannate (0.494 g, 1 .81 mmol), bis(pinacolato)diboron (1 .4 g 5.51 mmol ) and potassium acetate (0.535 g , 5.45 mmol) were stirred in dimethylsulfoxide (8 ml_). The mixture was flushed with nitrogen for 10 minutes. [1 ,1 '- Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (0.150 g, 0.184 mmol) was added and the system flushed for a further 5 minutes with nitrogen before heating the reaction mixture to 85°C under nitrogen for 1 hour. The reaction mixture was diluted in ethyl acetate (15 ml_) and washed with aqueous hydrochloride solution (10 ml_, 0.2 M). Some of the product went into the aqueous layer and some stayed in the organic layer. The aqueous layer was treated with saturated aqueous sodium carbonate carefully until ~pH 6 was achieved then extracted with ethyl acetate (10 ml_). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to give title compound as a white solid (0.44 g, 76percent).1HNMR (de -DMSO): δ 1 .29 (s, 12H), 1 .45 (s, 9H), 7.15-7.17 (d, 1 H), 8.07 (s, 1 H), 8.24- 8.25 (d, 1 H), 9.77 (s, 1 H)LCMS Rt = 0.68 min MS m/z 183.1 [MH]+ |
56% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 80℃; for 5 h; | A solution of intermediate 20b (352 mg), potassium acetate (380 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (360 mg) and Pd(dppf)Cl2.CH2Cl2 (105 mg) in dry DMF (10 mL) was stirred at 80° C. for 5 h. The volatiles were removed under reduced pressure, the residue dissolved in EtOAc and the organic layer was washed with water, dried and the volatiles were removed under reduced pressure. The crude product was purified through washing with heptane to yield the desired compound (56percent yield). LC-MS (Method 1): m/z [M (boronic acid)+H]+=239.2 (MW (boronic acid) calc.=238.05); Rt=2.3 min. |
56% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 80℃; for 5 h; | Intermediate 20c) A solution of intermediate 20b (352 mg), potassium acetate (380 mg), 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'- bi(1 ,3,2-dioxaborolane) (360 mg) and Pd(dppf)CI2-CH2CI2 (105 mg) in dry DMF (10 mL) was stirred at 80 °C for 5 h. The volatiles were removed under reduced pressure, the residue dissolved in EtOAc and the organic layer was washed with water, dried and the volatiles were removed under reduced pressure. The crude product was purified through washing with heptane to yield the desired compound (56percent yield) LC- S (Method 1): m/z [M (boronic acid)+H]+ = 239.2 (MW (boronic acid) calc. = 238.05); R, = 2.3 min. |
53% | With potassium acetate In N,N-dimethyl-formamide at 80℃; for 2 h; Inert atmosphere | Step 6.1. tert-Butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate To a solution of 6.76 (24.8 mmol) of tert-butyl (4-bromopyrid-2-yl)carbamate (Deady, Leslie W.; Korytsky, Olga L.; Rowe, Jeffrey E.; Aust. J. Chem.; 35; 10; 1982; 2025-2034) in 150 mL of dimethylformamide are added 8.0 g (81 mmol) of potassium acetate predried at 130° C. and 6.9 g (27 mmol) of bis(pinacolato)diboron. A stream of argon is then sparged through for a few moments, and 1.2 g (1.5 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) are added. The mixture is stirred at 80° C. under argon for 2 hours and then poured into saturated aqueous ammonium chloride solution. The product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is stripped off under reduced pressure. The residue is triturated in 300 mL of refluxing diisopropyl ether and the insoluble matter is separated out by filtration. The filtrate is cooled and partially concentrated under reduced pressure. After adding 70 mL of hexane, the precipitate formed is isolated by filtration to give 4.2 g of an orange-colored solid after drying. Yield: 53percent m.p.: 188-193° C. 1H NMR (CDCl3) δ: 8.15 (m, 2H), 7.65 (broad s, 1H), 7.15 (d, 1H), 1.40 (s, 9H), 1.20 (s, 12H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | at 35℃; for 18 h; Inert atmosphere | 2-Ammopyndmc-4-boromc acid pinacol cstcr (2 0 g 9 1 rnmol) was siirrcd as asuspension in ret t-hutanol 30 mL) undei an aigon atinosphete The Boc anhydride (2 20g, 10.0 mmol) in tert-butanoi (20 mL) was added slowly, and the reaction stirred at 35 °Cfor 18 hours. Analysis by H N MR showed the pinacol ester starting material had beenconsumed. The reaction mixture was concentrated under reduced pressure, and the crudematerial stirred in water fur 5 minutes. The solid was collected by filtration and dried in vacuo at 50 °C. to afford tert-hutyl 4-(4,4,5,5-tetramethy1- i ,3,2-dioxaborolan-2- yi)pyridin-2-yl)carbamate (31) as a white solid (2.9 g, 98percent); mp 172— 178.0°C.(Lit. 188193 °C). 1H NMR (200 MHz, DMSO-d6) 8 9.75 (hr s, lEO, 8.26 (di 1 H, J 0.9, 4.8 Hz),808(ni lH).,7 l8dd 111 J07 4 8Hz), 147(s 911) 131 (s 1211) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 85℃; for 1.25h;Inert atmosphere; | Preparation 24terf-Butyl (4-bromopyhdin-2-yl)carbannate (0.494 g, 1 .81 mmol), bis(pinacolato)diboron (1 .4 g 5.51 mmol ) and potassium acetate (0.535 g , 5.45 mmol) were stirred in dimethylsulfoxide (8 ml_). The mixture was flushed with nitrogen for 10 minutes. [1 ,1 '- Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (0.150 g, 0.184 mmol) was added and the system flushed for a further 5 minutes with nitrogen before heating the reaction mixture to 85C under nitrogen for 1 hour. The reaction mixture was diluted in ethyl acetate (15 ml_) and washed with aqueous hydrochloride solution (10 ml_, 0.2 M). Some of the product went into the aqueous layer and some stayed in the organic layer. The aqueous layer was treated with saturated aqueous sodium carbonate carefully until ~pH 6 was achieved then extracted with ethyl acetate (10 ml_). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to give title compound as a white solid (0.44 g, 76%).1HNMR (de -DMSO): delta 1 .29 (s, 12H), 1 .45 (s, 9H), 7.15-7.17 (d, 1 H), 8.07 (s, 1 H), 8.24- 8.25 (d, 1 H), 9.77 (s, 1 H)LCMS Rt = 0.68 min MS m/z 183.1 [MH]+ |
56% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 5h; | A solution of intermediate 20b (352 mg), potassium acetate (380 mg), 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (360 mg) and Pd(dppf)Cl2.CH2Cl2 (105 mg) in dry DMF (10 mL) was stirred at 80 C. for 5 h. The volatiles were removed under reduced pressure, the residue dissolved in EtOAc and the organic layer was washed with water, dried and the volatiles were removed under reduced pressure. The crude product was purified through washing with heptane to yield the desired compound (56% yield). LC-MS (Method 1): m/z [M (boronic acid)+H]+=239.2 (MW (boronic acid) calc.=238.05); Rt=2.3 min. |
56% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 5h; | Intermediate 20c) A solution of intermediate 20b (352 mg), potassium acetate (380 mg), 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'- bi(1 ,3,2-dioxaborolane) (360 mg) and Pd(dppf)CI2-CH2CI2 (105 mg) in dry DMF (10 mL) was stirred at 80 C for 5 h. The volatiles were removed under reduced pressure, the residue dissolved in EtOAc and the organic layer was washed with water, dried and the volatiles were removed under reduced pressure. The crude product was purified through washing with heptane to yield the desired compound (56% yield) LC- S (Method 1): m/z [M (boronic acid)+H]+ = 239.2 (MW (boronic acid) calc. = 238.05); R, = 2.3 min. |
53% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; | Step 6.1. tert-Butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate To a solution of 6.76 (24.8 mmol) of <strong>[207799-10-8]tert-butyl (4-bromopyrid-2-yl)carbamate</strong> (Deady, Leslie W.; Korytsky, Olga L.; Rowe, Jeffrey E.; Aust. J. Chem.; 35; 10; 1982; 2025-2034) in 150 mL of dimethylformamide are added 8.0 g (81 mmol) of potassium acetate predried at 130 C. and 6.9 g (27 mmol) of bis(pinacolato)diboron. A stream of argon is then sparged through for a few moments, and 1.2 g (1.5 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) are added. The mixture is stirred at 80 C. under argon for 2 hours and then poured into saturated aqueous ammonium chloride solution. The product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is stripped off under reduced pressure. The residue is triturated in 300 mL of refluxing diisopropyl ether and the insoluble matter is separated out by filtration. The filtrate is cooled and partially concentrated under reduced pressure. After adding 70 mL of hexane, the precipitate formed is isolated by filtration to give 4.2 g of an orange-colored solid after drying. Yield: 53% m.p.: 188-193 C. 1H NMR (CDCl3) delta: 8.15 (m, 2H), 7.65 (broad s, 1H), 7.15 (d, 1H), 1.40 (s, 9H), 1.20 (s, 12H) ppm. |
46% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 3h;Inert atmosphere; | A 20 mL Biotage microwave vial loaded with <strong>[207799-10-8]tert-butyl (4-bromopyridin-2-yl)carbamate</strong> D-1 (1 g, 3.66 mmol), 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (1.3 g, 5.13 mmol), PdCl2(dppf) (215 mg, 0.293 mmol), and KOAc (1.15 g, 11.72 mmol) was capped, purged with argon, then injected with degassed dioxane (8.14 mL), and heated to 90 C. for 3 h in an oil bath. The reaction was cooled, diluted with EtOAC, poured into a separatory funnel containing EtOAc, saturated ammonium chloride solution, the mixture was shaken, and filtered through celite. After multiple extractions with EtOAc, the organics were washed with saturated ammonium chloride solution and brine. After concentration, the mixture was dissolved in Et2O and then heated/cooled repeatedly with Et2O, filtered, and washed with Et2O affording tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate D-2 White solid (540 mg, 1.686 mmol, 46% yield). 1H NMR (DMSO) delta: 9.76 (s, 1H), 8.27 (dd, J=4.7, 1.0 Hz, 1H), 8.09 (s, 1H), 7.19 (dd, J=4.8, 0.9 Hz, 1H), 1.49 (s, 9H), 1.33 (s, 12H). |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); at 80℃; for 2.16667h; | To a mixture of compound 1 (301 mg, 1.10 mmol), bis (pinacolato) diboron (309 mg, 1.22 mmol), potassium acetate (356 mg, 3.63 mmol) and [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium II (48.0 mg, 0.0656 mmol), degassed and sealed under nitrogen, was added dry dimethylformamide (7.5 mL). Following further nitrogen purging, the mixture was stirred at 80 C for 130 min. After cooling to room temperature, compound 2 (208 mg, 0.734 mmol), [1, 1'- bis (diphenylphosphino) ferrocene] dichloropalladium II (48. 2 mg, 0.0659 mmol) and 2M aqueous sodium carbonate (2.75 mL, 5.5 mmol) were added, and then the mixture was degassed, sealed under nitrogen, and stirred at 85 C for 4 h. After cooling to room temperature, the reaction mixture was added to aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (2x100 mL), 10% methanol in dichloromethane (3x100 mL), and then further ethyl acetate (3x100 mL). The combined extracts were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (gradient elution 100% dichloromethane to 2.5% methanol/dichloromethane) to provide (3) {4- [2- (3- Ethyl-ureido) -imidazo [1, 2-a] pyridin-7-yl]-pyridin-2-yl}-carbamic acid tert-butyl ester (122 mg). (MeOH/CH2CI2/hexane) LCMS (APCI+) 397.2 (100%, MH). | |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; | Step 5.1.: tert-Butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate A solution of 6.76 g (24.8 mmol) of <strong>[207799-10-8]tert-butyl (4-bromopyridin-2-yl)carbamate</strong> (Deady, Leslie W.; Korytsky, Olga L.; Rowe, Jeffrey E.; Aust. J. Chem.; 35; 10; 1982; 2025-2034) in 150 ml of dimethylformamide is admixed with 8.0 g (81 mmol) of potassium acetate, dried at 130 C. beforehand, and with 6.9 g (27 mmol) of bis(pinacolato)diboron. Subsequently a stream of argon is bubbled in for a few moments, and 1.2 g (1.5 mmol) of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) are added. The mixture is stirred at 80 C. under argon for 2 hours and then poured into saturated aqueous ammonium chloride solution. The product is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is stripped off under reduced pressure. The residue is triturated in 300 ml of diisopropyl ether at reflux and the insoluble matter is separated by filtration.The filtrate is cooled and partially concentrated under reduced pressure. Following addition of 70 ml of hexane, the precipitate formed is isolated by filtration, to give 4.2 g of an orange solid after drying.m.p.: 188-193 C.1H NMR (CDCl3) delta: 8.15 (m, 2H), 7.85 (broad s, 1H), 7.15 (d, 1H), 1.40 (s, 9H), 1.20 (s, 12H) ppm. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 85℃; for 1h;Inert atmosphere; Sealed tube; | fe/f-butyl (4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (i6): To a stirred suspension of ie f-butyl (4-bromopyridin-2-yl)carbamate (i5) (0.5 g, 1.8 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1 .4 g, 5.5 mmol), potassium acetate (0.541 g, 5.5 mmol) in DMSO (8 ml_), argon was purged for 15 min and PdCI2 (dppf) (0.15 g, 0.18 mmol) was added. The reaction was heated at 85C for 1 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ethyl acetate washed with 0.2 M HCI solution. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford ie f-butyl (4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-2-yl)carbamate (i6) (1 .5 g, crude), compound was used as such in the next reaction. | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere; | A mixture of ferf-butyl 4-bromopyridin-2-ylcarbamate (0.301 g, 1 .10 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (0.309 g, 1 .22 mmol), potassium acetate (0.356 g, 3.36 mmol) and [1 ,1 ,-b/s(diphenylphosphino)ferrocene]dichloropalladium(ll)-dichloromethane (0.048 g, 0.066 mmol) in dry A/,A/-dimethylformamide (7.5 ml_) was stirred at 80 C for 3 h under nitrogen. After being cooled to room temperature, 1 -(bromomethyl)-3-chlorobenzene (0.1 50 g, 0.73 mmol, [1 ,1 ,-b/s(diphenylphosphino)ferrocene]dichloropalladium(ll)-dichloromethane (0.048 g, 0.066 mmol), sodium carbonate (0.0583 g, 5.5 mmol) and water (2.5 ml_) were added. The mixture was stirred at 85 C for 2 h under nitrogen atmosphere. The reaction was concentrated, under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1 /1 ) to obtain ferf-butyl 4-(3-chlorobenzyl)pyridin-2-ylcarbamate (0.036 g, 0.1 1 mmol, 10.3% for 2 steps) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); water; at 85.0℃; for 4h; | To a mixture of compound 1 (301 mg, 1.10 mmol), bis (pinacolato) diboron (309 mg, 1.22 mmol), potassium acetate (356 mg, 3.63 mmol) and [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium II (48.0 mg, 0.0656 mmol), degassed and sealed under nitrogen, was added dry dimethylformamide (7.5 mL). Following further nitrogen purging, the mixture was stirred at 80 C for 130 min. After cooling to room temperature, compound 2 (208 mg, 0.734 mmol), [1, 1'- bis (diphenylphosphino) ferrocene] dichloropalladium II (48. 2 mg, 0.0659 mmol) and 2M aqueous sodium carbonate (2.75 mL, 5.5 mmol) were added, and then the mixture was degassed, sealed under nitrogen, and stirred at 85 C for 4 h. After cooling to room temperature, the reaction mixture was added to aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (2x100 mL), 10% methanol in dichloromethane (3x100 mL), and then further ethyl acetate (3x100 mL). The combined extracts were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (gradient elution 100% dichloromethane to 2.5% methanol/dichloromethane) to provide (3) {4- [2- (3- Ethyl-ureido) -imidazo [1, 2-a] pyridin-7-yl]-pyridin-2-yl}-carbamic acid tert-butyl ester (122 mg). (MeOH/CH2CI2/hexane) LCMS (APCI+) 397.2 (100%, MH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; for 18h;Reflux; Inert atmosphere; | Step 8.2. tert-Butyl {4-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}carbamate To a suspension of 3 g (7.31 mmol) of 6-chloro-2-(4-chlorophenyl)-3-iodoimidazo[1,2-b]pyridazine in 183 mL of a mixture of tetrahydrofuran and water (9:1) are added 7.1 g (22 mmol) of cesium carbonate and 2.90 g (8.8 mmol) of tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate. After sparging with a stream of argon for a few moments, 0.54 g (0.66 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) is added and the reaction mixture is refluxed under argon for 18 hours. After filtering through a Whatman filter and through Celite, the filtrate is then concentrated under reduced pressure to give 7.0 g of a brown residue. The residue is taken up in water, the product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off to give 3.5 g of a dark powder. The product is purified by chromatography on silica gel, eluding with a mixture of dichloromethane and ethyl acetate (100:0 to 80:20) to give 1.8 g of beige-colored crystals after crystallization from diisopropyl ether and drying under reduced pressure. m.p.: 212-214 C. 1H NMR (DMSO-d6) delta: 9.9 (s; 1H), 8.4 (d, 1H), 8.3 (d, 1H), 7.95 (s, 1H), 7.60 (d, 2H), 7.45 (m, 3H), 7.15 (d, 1H), 4.40 (s, 9H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; for 5h;Reflux; Inert atmosphere; | Step 6.4. tert-Butyl {4-[6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}carbamate To a solution of 3.60 g (6.34 mmol) of 6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-3-iodo-7,8-dimethylimidazo[1,2-b]pyridazine in 15 mL of a mixture of tetrahydrofuran and water (9:1) are added 6.2 g (19 mmol) of cesium carbonate and 2.4 g (7.6 mmol) of tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate. After sparging with a stream of argon for a few moments, 0.47 mg (0.57 mmol) of a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (PdCl2(dppf).CH2Cl2) is added and the reaction mixture is refluxed under argon for 5 hours. The mixture is then poured into 250 mL of water and the product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off to give a brown solid. The product is purified by chromatography on silica gel, eluding with a mixture of dichloromethane, methanol and aqueous ammonia (95:5:05) to give 2.91 g of a beige-colored solid. m.p.: 214-216 C. 1H NMR (CDCl3) delta: 8.70 (s, 1H), 8.20 (d; 1H), 7.92 (s, 1H), 7.7 (m, 2H), 7.3-7.4 (m, 4H), 7.1 (m, 3H), 3.70 (s, 2H), 3.35 (m, 4H), 3.0 (m, 4H), 2.70 (m, 4H), 2.70 (s, 3H), 2.35 (s+m, 3+2H), 1.55 (s, 9H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 110.0℃; for 1h;Inert atmosphere; Microwave irradiation; | A mixture of bromide lnt-13b (55 mg, 0.10 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate (39 mg, 0.12 mmol) and sodium carbonate (33 mg, 0.31 mmol) in ethano. (1 ml_), toluene (1 mL) and water (0.5 mL) at r.t. was purged with nitrogen gas for 5 min in a microwave vial. Tetrakistriphenylphosphorous palladium (12 mg, 0.010 mmol) was added. The mixture was heated in a microwave reactor at 110 C for 1 h. Water and ethyl acetate were added and the layers were separated. The separated aqueous layer was extracted with ethyl acetate. The separated organic layer was dried ( gS04) and filtered. The solvents were removed in vacuo and chromatographic purification (ethyl acetate - hexane) of the residue gave aminopyridine lnt-13c (27 mg, 41%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 110.0℃; for 1h;Inert atmosphere; Microwave irradiation; | A mixture of bromide lnt-12a (65 mg, 0.10 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate (27 mg, 0.12 mmol) and sodium carbonate (32 mg, 0.30 mmol) in ethanol (1 rriL), toluene (1 rnl_) and water (0.5 mL) at r.t. was purged with nitrogen gas for 5 min in a microwave vial. Tetrakistriphenylphosphorous palladium (12 mg, 0.010 mmol) was added. The mixture was heated in a microwave reactor at 1 10 C for 1 h. Water and ethyl acetate were added, and the layers were separated. The separated aqueous layer was extracted with ethyl acetate. The separated organic layer was dried ( gS04) and filtered. The solvents were removed in vacuo and chromatographic purification (ethyl acetate - hexane) of the residue gave aminopyridine lnt-12b (46 mg, 69%) as a colorless oil. LCMS m/e ( + H+) - 658.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; for 3h;Inert atmosphere; Reflux; | Step 5.2. tert-Butyl [4-(6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl]carbamate A mixture of 3.19 g (10.9 mmol) of 6-chloro-3-iodo-2-methylimidazo[1,2-b]pyridazine, 4.18 g (13.0 mmol) of tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]-carbamate and 10.6 g (32.6 mmol) of caesium carbonate in 250 ml of a mixture of tetrahydrofuran and water (90/10) is purged with argon. Then 0.80 g (0.98 mmol) of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (PdCl2 (dppf)) is added. The reaction is heated for 3 hours at reflux and then the solvent is evaporated under reduced pressure. The residue is taken up with chloroform and the organic phase is washed with saturated aqueous ammonium chloride solution. The organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure. The solid residue is purified on 110 g of silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (97/3/0.3), to give 3.6 g of a dark beige solid. The solid is triturated in diethyl ether to give 3.0 g of white solid after filtration and drying.m.p.: 260 C.1H NMR (CDCl3) delta: 8.50 (d, 1H), 8.45 (s, 1H), 7.90 (d, 1H), 7.85 (broad s, 1H), 7.45 (d, 1H), 7.10 (d, 1H), 2.70 (s, 3H), 1.55 (s, 9H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | 1,4-Dioxane and aqueous 2M sodium carbonate solution are degassed by bubbling a flow of argon through the solutions for 10 min. 2.06 g 4-iodo-l-isopropyl-3-(3-thienyl)-lH-pyrazole (6.15 mmol) are weighed into a 100 mL three-necked round bottom flask equipped with a reflux condenser and an internal thermometer. 36.8 mL degassed 1,4-dioxane, 2.36 g tert-butyl [4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (7.38 mmol), 454 m g o f bis(tricyclohexylphosphine)palladium(II) dichloride (0.62 mmol) and 12.3 mL degassed 2M sodium carbonate solution are added quickly. The reaction mixture is degassed by a flow of argon again for 1 min, then heated to reflux under argon for 3 h. After cooling to room temperature, the mixture was concentrated to half of its original volume and filtered through a short pad of silica with ethyl acetate. The filtrate is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. The residue is dissolved in tert-butanol (10 mL) and dichloromethane (10 mL) and treated with 1.34 g di-tert-butyl dicarbonate (6.15 mmol) at room temperature for 2 d. The reaction mixture is evaporated under vacuum and purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 1.69 g (72%) of the intermediate tert-butyl {4-[l - isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-yl}carbamate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; at 150.0℃; for 0.2h;Inert atmosphere; Sealed tube; Microwave irradiation; | General procedure: 4-[2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl]pyridin-2-amine [II-l]3- bromo-2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole (700mg, 2.5mmol) and tert-butyl [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (727mg, 2.27mmol, l . l eq) are dissolved in lOmL 1,4-dioxan. To this mixture is added Bis(tricyclohexylphosphine)palladium(II)-dichloride (168mg, 0.22mmol, 0.1 eq) and 5.4mL sodium carbonate solution (2 molar). The reaction mixture is flushed with argon for 5 mins and then sealed. Next the mixture is heated for 12 mins at 150C in the microwave (Biotage). After cooling, insoluble components are filtered off over Celite and the residue washed with 1,4-dioxan. The organic phase is evaporated and the crude product purified by column chromatography over silica gel using dichloromethane / methanol (95:5) as eluent. After evaporation of the solvents 530mg (72%) of 4-[2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl]pyridin-2-amine are obtained as a colourless solid.¾-NMR (400 MHz, CD3CN): delta = 7.84-7.82 (d, 1H), 7.49-7.44 (m, 2H), 7.11-7.05 (m, 2H), 6.40-6.38 (dd, 1H), 6.34 (s, 1H), 4.75 (s, 2H), 4.14 (t, 2H), 3.00 (t, 2H), 2.66-2.59 (m, 2H) ppmlogP (pH 2.7): 1.02MS (ESI): 295.2 ([M+H]+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4%; 44% | With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; at 120.0℃; for 3.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | Production of intermediates of the formula [Il-a] by route (V4):4-(2-Phenylpyrazolo[l,5-a]pyrimidin-3-yl)pyridin-2-amine [II-a-1] and tert-butyl [4-(2-phenylpyrazolo[l,5-a]pyrimidin-3-yl)pyridin-2-yl]carbamate [I-i-2]3-Bromo-2-phenylpyrazolo[l,5-a]pyrimidine (1.0 g, 3.65 mmol) and tert-butyl [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.29 g, 4.01 mmol, l . leq) are dissolved in lOmL 1,4-dioxan. To this mixture bis(tricyclohexylphosphine)palladium(II)-dichloride (269 mg, 0.37 mmol, O. l eq) and 9.1 mL sodium carbonate solution (2 molar) are added. The reaction mixture is flushed with argon for 5 mins and then sealed. Next the mixture is heated for 90min at 120C in the microwave (Biotage). Tert-butyl [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (214 mg, 1.4 mmol, 0.37eq) and bis(tricyclohexylphosphine)palladium(II)-dichloride (269 mg, 0.37 mmol, O. leq) are then added and the mixture is heated for 2h at 120C. The reaction mixture is then poured in water and extracted with ethyl acetate (3 x 50 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel in heptane and ethyl acetate (1 :0 to 1 :1) as eluent and 0.48 g (44%) of 4-(2-phenylpyrazolo[l,5-a]pyrimidin-3-yl)pyridin-2-amine are obtained as a white solid.'H-NMR (300MHZ, DMSO): delta = 9.21 (dd, 1H), 8.64 (dd, 1H), 7.85 (d, 1H), 7.62-7.60 (m, 2H), 7.46-7.45 (m, 3H), 7.17 (dd, 1H), 6.70 (s, 1H), 6.43 (dd, 1H), 5.89 (bs, 2H) ppmlogP (pH 2.7): 0.98MS (ESI): 288 ([M+H]+)56 mg (4%>) of tert-butyl [4-(2-phenylpyrazolo[l,5-a]pyrimidin-3-yl)pyridin-2-yl]carbamate is also isolated as a yellow solid.¾-NMR (300MHz, DMSO): delta = 9.68 (s, 1H), 9.25 (dd, 1H), 8.68 (dd, 1H), 8.17 (d, 1H), 8.06 (bs, 1H), 7.59-7.57 (m, 2H), 7.46-7.45 (m, 3H), 7.21 (dd, 1H), 7.00 (dd, 1H), 1.43 (s, 9H) ppmlogP (pH 2.7): 2.32MS (ESI): 388 ([M+H]+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; at 150.0℃; for 0.2h;Inert atmosphere; Sealed tube; Microwave irradiation; | General procedure: Production of intermediates of the formula [II] by route (V4): 4-(2-phenyl-6,7-dihydro-5H-pyrazolo[5,l-b] [l,3]oxazin-3-yl)pyridin-2-amine [II-l]3- bromo-2-phenyl-6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazine (700mg, 2.25mmol) and tert-butyl [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl] carbamate (792mg, 2.47mmol, 1 . 1 eq) are dissolved in lOmL 1,4-dioxan. To this mixture Bis(tricyclohexylphosphine)palladium(II)-dichloride (166mg, 0.22mmol, 0.1 eq) and 5.4mL sodium carbonate solution (2 molar) are added. The reaction mixture is flushed with argon for 5 mins and then sealed. Next the mixture is heated for 12 mins at 150C in the microwave (Biotage). The procedure is repeated 7x using the same scale and all crude reaction mixtures are combined thereafter. After cooling, insoluble components are filtered off over Celite and the residue washed with 1,4-dioxan. The organic phase is evaporated and the crude product purified by column chromatography over silica gel using dichloromethane / methanole as eluent. After evaporation of the solvents 2.10g (41%) of 4-(2-phenyl-6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazin-3-yl)pyridin-2-amine are obtained as a colourless solid.'H-NMR (400 MHz, de-DMSO): delta = 7.72 (d, 1H), 7.40-7.25 (m, 5H), 6.36 (s, 1H), 6.18-6.15 (dd, 1H), 5.76 (s, 2H), 4.38 (t, 2H), 4.16 (t, 2H), 2.25 (m, 2H) ppmlogP (pH 2.7): 0.87MS (ESI): 293.1 ([M+H]+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 95.0℃; for 20h; | A solution of intermediate 20a (200 mg), intermediate 20c (156 mg), cesium carbonate (312 mg) and tetrakis(triphenylphosphine)palladium (55 mg) in dioxane (12 mL) and water (5 drops) was stirred at 95 C. for 20 h. The volatiles were removed under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (SiO2, 65 g, Cy/EtOAc) to yield the desired compound (61% yield). LC-MS (Method 1): m/z [M+H]+=520.3 (MW calc.=519.54); Rt=3.9 min. |
61% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 95.0℃; for 20h; | Intermediate 20d) A solution of intermediate 20a (200 mg), intermediate 20c (156 mg), cesium carbonate (312 mg) and tetrakis(triphenylphosphine)palladium (55 mg) in dioxane (12 mL) and water (5 drops) was stirred at 95 C for 20 h. The volatiles were removed under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si02, 65 g, Cy / EtOAc) to yield the desired compound (61 % yield). LC-MS (Method 1): m/z [M+H]+ = 520.3 (MW calc. = 519.54); R, = 3.9 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; ethanol; water; at 110.0℃; for 2h;Sealed tube; Inert atmosphere; | To a solution of teu-hutyl (4-(4,4 S 5-tciramctl 1-1 3 2-diox ihorolan-2-yl)pyridin-2- sliccu bamate (30) (2 9 g 8 9 mmob 3-toimy lhiphenvl-4-yl tnfluoiomethanesulfonate (14) (2.7 g, 8,lmmoi) and sodium carbonate (1.7 g, 16.2 mmoi) in degasseddioxane/ethanol/H20 mixture (5:1:1, 75 niL) was added tetrakis(triphenslphosphine)palladium(0) (467 mg 0 40 mmol) The reaction was heated at 1 10 C fur 2 hours in a sealed tube . Analysis by H NMR indicated the triflate had been consumed. The reaction was concentrated, then taken up in 13CM and poured into water. The layers were separated and the aqueous phase extracted further with DCM(2x), The combined organic extracts were washed with water (xi) and brine then dried and concentrated to appro 20- 30 ml. olume The solution was hlteted thiough a short column of silica cluting w ith 13CM to afford ten-buty I (4-(3-folm3 [-[1 1 ?-hiphcn I]- 4-yl)pyridin-2-yl)earhamate (31) as a ye low solid (1 .5 g, 48%); nip 168.8 - 171 .5 C. ?HNMR (200 MHz, DMSO-d6) 710.00 (overlap s, 1 H), 9.98 (overlap, hr s, iN), 6.35 (dd,IN, .10.7, 5.1 hz), 8.20 (d, I H. .1 1.9 Hz), 8.10 (cM, 1 H, J 2.1, 8.0 Hz), 7.88 (m, 111), 7.79(m. 2H), 7.63 (d, 1FF .18.0 Hz), 7.59 7.40 (in, 3H), 7.16 (dd. IH, .1 1.6, 5.1 Hz), 1.47 (s,9Ff). ?CNMR.(50M[1z, DMSO-4)oe 191.4.152.8,152.6,147.8,146.8, 141.2, 140.7,1384, 1q36 1320 1312 1292 1283 1268 1261 1194 1128 797 280 ElMSm Found: M? 374.1611, C23H2203N requires 374.1625, ElMS: .?th 374 7%), 57(100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In tert-butyl alcohol; at 35.0℃; for 18h;Inert atmosphere; | 2-Ammopyndmc-4-boromc acid pinacol cstcr (2 0 g 9 1 rnmol) was siirrcd as asuspension in ret t-hutanol 30 mL) undei an aigon atinosphete The Boc anhydride (2 20g, 10.0 mmol) in tert-butanoi (20 mL) was added slowly, and the reaction stirred at 35 Cfor 18 hours. Analysis by H N MR showed the pinacol ester starting material had beenconsumed. The reaction mixture was concentrated under reduced pressure, and the crudematerial stirred in water fur 5 minutes. The solid was collected by filtration and dried in vacuo at 50 C. to afford tert-hutyl 4-(4,4,5,5-tetramethy1- i ,3,2-dioxaborolan-2- yi)pyridin-2-yl)carbamate (31) as a white solid (2.9 g, 98%); mp 172- 178.0C.(Lit. 188193 C). 1H NMR (200 MHz, DMSO-d6) 8 9.75 (hr s, lEO, 8.26 (di 1 H, J 0.9, 4.8 Hz),808(ni lH).,7 l8dd 111 J07 4 8Hz), 147(s 911) 131 (s 1211) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80.0℃; for 3h;Inert atmosphere; | a) Preparation of Int. 176 To a solution of N-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridinyl]- carbamic acid, 1,1-dimethylethyl ester (34 g; 90.258 mmol) in dioxane(200 ml) was added 2 chloro-5-bromo pyrimidine (9.699 g; 50.143 mmol). PdCl2(dppf)( 1.101 g; 1.504 mmol) and 20 ml 2 M aq. Na2C03 were added under N2 atmosphere. The reaction mixture was stirred at 80 C for 3 h. The mixture was filtered and evaporated. DCM was added and the organic layer was washed with water and brine and dried. The solution was filtered and evaporated. The residue was stirred in tert-butyl methyl ether and the solid was filtered off and dried. Yield: 11 g of Int. 176 (60.7 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In tetrahydrofuran; water; at 100.0℃; for 16h;Inert atmosphere; Sealed tube; | 4-(9/-/-pyrrolo[2, 3-b:4, 5-c]dipyridin-2-yl)pyridin-2-amine (Example 16): To a stirred suspension of 2-chloro-9/-/-pyrrolo [2,3-b: 4,5-c'] dipyridine (i2) (0.15 g, 0.73 mmol) in THF (13.5 mL) and water (1.5 ml_), ie/f-butyl (4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-2-yl)carbamate (i6) (0.945 g, 2.9 mmol), ) and Cs2C03 (0.72 g, 2.2 mmol) were added and argon was purged through the reaction mixture for 15 min.PdCI2(dppf) (0.06 g, 0.07 mmol) was then added and argon was purged through the reaction mixture for further 15 min. The reaction was heated at 100C for 16h in a sealed tube. The progress of the reaction was monitored by TLC and LCMS. After 16 h of heating, LCMS showed mass corresponding to Boc deprotected compound. At this point, the reaction was diluted with 10% methanol in dichloromethane and washed with water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford 4-(9H-pyrrolo[2, 3-6:4, 5-c]dipyridin-2-yl)pyridin-2-amine as a bisformate salt (0.013 g, Yield 7%). 1H NMR (400 MHz, DMSO-d6) delta 6.06 (brs, 2H) 7.19 - 7.26 (m, 2H) 7.50 (d, J=5.73 Hz, 1 H) 7.86 (d, J=7.94 Hz, 1 H) 8.04 (d, J=5.29 Hz, 1 H), 8.38 (s, 2H bisformate), 8.50 (d, J=5.7 Hz, 1 H) 8.72 (d, J=7.94 Hz, 1 H) 9.39 (s, 1 H), 12.4 (brs, 1 H). MS (ESI) m/e (M+1 )+: 262 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In tetrahydrofuran; water; at 65.0℃;Inert atmosphere; | The compound obtained in Step 2 (0.681 g, 1.45 mmol) and tert- vXy N-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.1 eq) were dissolved in THF/water (3: 1, 20 ml) under N2. Potassium carbonate (3 eq) and Pd(dtbpf)Cl2 (10% wt) were added and the resulting mixture was degassed under N2 for 5 minutes. The reaction mixture was heated at 65 C overnight under N2, cooled to room temperature and diluted with water (10 mL) and DCM (50 mL). The organic layer was separated, washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified via flash chromatography using EtOAc and isohexane as eluent to give the desired coupled compound. The compound was dissolved in 2 M HC1 solution in MeOH (4 mL) and heated at 90 C on a CEM microwave reactor for 1 hour. The reaction mixture was concentrated in vacuo and diluted with 10% IPA in DCM (20 ml), washed with sat. aq. NaHC03, dried over MgS04 and concentrated in vacuo. The residue was purified via flash chromatography using MeOH and DCM as eluent to give, after trituration with diethyl ether, the product (99 mg, 0.26 mmol, 26%) as a white solid. 1H NMR (399 MHz, DMSO-d6) delta 12.39 (s, 1H), 7.74 (s, 1H), 7.58 (d, 1H), 7.36 (d, 1H), 7.27 (d, 1H), 7.19 (dd, 1H), 6.07 (t, 1H), 6.00 (dd, 1H), 5.68 (s, 2H), 2.72 (s, 3H). LC/MS (method B): RT = 0.96 min; m/z = 382 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2 g | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120.0℃; for 16h;Inert atmosphere; Sealed tube; | To a stirred solution of N- [ [5-bromo-2- [[3- [ [tert-butyl(dimethyl)silyl] oxymethyl] -2- pyridyl] sulfanyl] -3-chloro-phenyl] methyl] -2-methyl-propane-2- sulfinamide (2. Og, 3.46mmol) in 1,4-dioxane (20mL) were added tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-pyridyl] carbamate (1 .44g, 4. Smmol), Na2CO3 (11mg, 0.1 mmol), water (10 mL) and reaction mass was purged with argon for 15 mm. Then Pd(PPh3)4 (0.2g, 0.l7mmol) wasadded and reaction mass was heated to 120C in a sealed tube for 16h. Reaction mass was filtered through celite pad and the filtrate was evaporated under reduced pressure to get N-[[5-(2- amino-4-pyridyl)-2- [[3- [[tert-butyl(dimethyl) silyl] oxymethyl] -2-pyridyl] sulfanyl] -3-chloro- phenyl] methyl]-2-methyl-propane-2-sulfinamide (2g) as brown resin. LC-MS: 590.7 [M+H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; for 18h;Reflux; | [0108] 1-(2-Bromo-5-methoxypyridin-4-yl)ethanone (XIX) (1 g, 4.34 mmol) obtained in Example 3-4 and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid-tert-butyl ester (1.16g, 3.62mmol) were dissolved in ethylene glycol dimethyl ester/distilled water (10 ml / 2 ml) solution. To the resulting solution were added sodium carbonate (1.15 g, 10.86 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (125.6 mg, 0.109 mmol) and the solution was stirred with reflux for 18 hrs. After completion of the reaction by addition of water, the solution was extracted with ethylacetate, washed with distilled water, and dried over magnesium sulfate (MgSO4) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (hexane/ethylacetate = 1/1) to give the brown title compound (317.2 mg, 30.0 %). 1H NMR (400 MHz, CDCl3) delta 8.55 (s, 1H), 8.43 (s, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.80 (dd, J= 8.0, 7.6 Hz, 1H), 7.34 (d, J= 7.6 Hz, 1H), 4.10 (s, 3H), 2.70 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.0% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; for 18h;Reflux; | [0112] 2,4-Dichloro-5-methoxypyrimidine (XXIX) (800 mg, 4.34 mmol) and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid-tert-butyl ester (XXIV) (1.16 g, 3.62 mmol) were dissolved in ethylene glycol dimethylester/distilled water (10 ml / 2 ml) solution. Sodium carbonate (1.15 g, 10.86 mmol) and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (125.6 mg, 0.109 mmol) were added to the resulting solution and then the solution was stirredwith reflux for 18 hrs. After completion of the reaction by addition of water, the solution was extracted with ethylacetate,washed with distilled water, and dried over magnesium sulfate (MgSO4) to concentrate. The resulting residue wasisolated and purified by silica gel column chromatography (hexane/ethylacetate = 1/1) to give the brown title compound(302.1 mg, 28.0 %).1H NMR (400 MHz, CDCl3) delta 8.43 (s, 1H), 8.01 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H),1.48 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; ethanol; water; at 85.0℃; for 2h;Inert atmosphere; | A round bottom flask fitted with a reflux condenser and under nitrogen atmosphere was charged with 1 ,3-diethyl 2-(((2- trifluoromethyl)sulfonyl)oxo)-5-(pyrimidin-5-yl)benzyl)propanedioate (0.400 g, 0.840 mmol), (1 , 1-dimethylethoxy)(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2- ylamino)methanone (0.296 g, 0.924 mmol), potassium carbonate (0.232 g 1.68 mmol), 1 ,4- dioxane (3.2 mL), ethanol (0.8 mL) and water (0.8 mL). The reaction mixture was degassed by bubbling nitrogen through for 2 min then palladium tetrakis(triphenylphosphine) (0.097 g, 0.084 mmol) was added and the reaction mixture stirred at 85 C for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 mL) and water (15 mL). The mixture was transferred to a separatory funnel, the aqueous phase was separated and further extracted with ethyl acetate (25 mL). The organics were combined, washed with brine (10 mL), dried (magnesium sulfate), filtered and concentrated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound as yellow solid (0.316 g, 72%). LCMS [M+H]+ = 521.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80.0℃; for 2h; | Compound 92 (1.3 g, 6.25 mmol) was dissolved in 1,4-dioxane (50 mL) in a 100mL single neck flask, then 3-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (2 g, 6.25 mmol), tetrakis(triphenylphosphine)palladium (360 mg, 0.31 mmol),sodium carbonate (1.3 g, 12.5 mmol), and water (15 ml) were added, and the temperature was increased to 80 C toreact for 2 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate for 3 times, driedover sodium sulfate, and spin-dried to obtain crude product 93a. Then aqueous hydrochloric acid solution (50 mL) wasadded to the crude product 93a, and the temperature was raised to 50 C to react for 2h. The mixture was first extractedwith ethyl acetate for 2 times, and the organic phase was poured off. Then NaOH was used to adjust the pH of theaqueous phase to 9. Subsequently, the mixture was extracted with ethyl acetate for 3 times, dried, concentrated, andsubjected to column chromatography to obtain compound 94a (300 mg, 1.34 mmol). MS (ESI) (m/z): [M+H]+ 225.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80.0℃; for 2h; | Compound 92 (1.3 g, 4.06 mmol) was dissolved in 1,4-dioxane (50 mL) in a 100mL single neck flask, then 3-iodo-1-methyl-1H-pyrazolo[4,3-b]pyridine (400 mg, 1.54 mmol), tetrakis(triphenylphosphine)palladium (178 mg, 0.308mmol), sodium carbonate (408 mg, 3.85 mmol) and water (15 ml) were added, and the temperature was increased to80 C to react for 2 hours. Water was added to quench the reaction. The mixture was extracted with ethyl acetate for 3times, dried over sodium sulfate, and concentrated to obtain crude product 93c. Then aqueous hydrochloric acid solution(50ml) was added to the crude product, and the temperature was raised to 50 C to react for 2 h. The mixture was firstextracted with ethyl acetate for 2 times, and the organic layer was poured off. Then NaOH was used to adjust the pH ofthe aqueous phase to 9. Subsequently, the mixture was extracted with ethyl acetate for 3 times, dried, concentrated,and subjected to column chromatography to obtain product 94c (350 mg, 1.56 mmol). MS (ESI) (m/z): [M+H]+ 226.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.035 g | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 110.0℃;Inert atmosphere; | To a solution of compound 25 (0.1 15 gm, 0.366 mmol, 1 eq) in dioxane (5 ml_) of 2M K2CO3 (0.150 g, 1 .05 mmol, 3 eqs.) was added followed by addition of compound 26 (0.149 mg, 0.475 mmol, 1 .3 eqs.). After that Pd(PP i3)4 (0.020 g, 0.017 mmol, 0.05 eq) was added and reaction was heated under inert condition at 1 10C for overnight. The progress of the reaction was monitored by tic taking 25 as a limiting reactant. After completion of reaction, reaction mixture was filtered by using filter paper and the filtrate was washed with ethyl acetate and water mixture. The organic layer was extracted and dried over anhyd. Na2S04 and concentrated to get crude product. The crude product was purified via column chromatography using 10 % mixture of ethyl acetate in hexane as eluent to obtain 27 as pure compound (0.035 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70 mg | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 100.0℃; for 4h; | To a solution of compound 32 (0.1 gm, 0.319 mmol, eq) in dioxane (5 ml.) 2M solution of K2CO3 (0.132 gm, 0.956 mmol, 3 eqs.) was added followed by addition of compound 26 (0.205mg, 0.638 mmol, 2 eqs.). After that Pd(PP i3)4 (0.018 g, 0.015 mmol, 0.05eq) was added and reaction was heated under inert conditions at 100 C for 4 hrs. The progress of the reaction was monitored by tic taking 32 as a limiting reactant. After completion of reaction, reaction mixture was filtered by using filter paper and the filtrate was washed with ethyl acetate and water mixture. The organic layer was extracted and dried over anhydrous Na2S04 and concentrated to get crude product. The crude product was purified via column chromatography using 5 % mixture of ethyl acetate in hexane as eluent to obtain 33 as pure compound (70mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81 mg | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 120.0℃; for 6h;Inert atmosphere; | To a solution of compound 4 (0.1 g, 0.367 mmol, 1 eq.) in dioxane (10 mL) was added successively compound 7 (0.176 g, 0.551 mmol, 1 .5 eqs.) and 2 (M) solution of K2CO3 (0.152 g, 1 .101 mmol, 3 eqs.). Degassing was done for 15min, and then Pd(PP i3)4 (0.021 g, 0.018 mmol, 0.05 eqs.) was added under inert atmosphere. The reaction mixture was heated at 120 C for 6 hrs. Excess of solvent was removed under vacuum and the reaction mass was diluted with water and extracted with ethyl acetate (3 x 30 mL). Combined organic layers were washed with water (30 mL) followed by brine solution (30 mL). The organic layer thus obtained was dried over anhyd. Na2S04 and concentrated to get crude product. The crude product was purified via column chromatography using 35 % mixture of ethyl acetate in hexane as eluent to obtain 8 as pure compound (81 mg) as a brownish solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver trifluoroacetate; In methanol; at 60.0℃; for 12h; | Dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (8.2 mg, 0.01289 mmol), silver trifluoroacetate (0.569 g, 2.58 mmol), tert-butyl 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2- yl)pyridin-2-ylcarbamate (0.434 g, 1.29 mmol), and tert-butyl 2-[2-[[4-[3-[(tert- butoxycarbonylamino)methyl]phenyl] -1 -pyrimidin-2-yl-indol-6-yl]methoxy]phenyl] acetate(0.400 g, 0.644 mmol) were dissolved in methanol (3.2 mL) and the reaction was heated at60C for 12 h. After cooling to rt, the reaction was filtered through celite using isopropyl acetate. The filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (silica, 0% to 100% isopropyl acetate - heptane) to give tert-butyl 2-[2- [[4- [3- [(tert-butoxycarbonylamino)methyl]phenyl] -2-[2-(tert-butoxycarbonylamino)-4-pyridyl] -1 -pyrimidin-2-yl-indol-6-yl]methoxy]phenyl] acetate (0.270 g, 0.332 mmol, 52% Yield). ?H NMR (400 MHz, Chloroform-d) oe 8.74 (d, J= 4.8 Hz, 2H), 8.32 (s, 1H), 8.21 (s, 1H), 7.98 - 7.91 (m, 2H), 7.61 - 7.51 (m, 2H), 7.46 (t, J= 7.8 Hz,1H), 7.41 - 7.31 (m, 2H), 7.26 - 7.17 (m, 3H), 7.12 (s, 1H), 7.01 - 6.89 (m, 2H), 6.83 - 6.77(m, 1H), 5.25 (s, 2H), 5.05 (dd, J= 12.0, 7.5 Hz, 1H), 4.41 (d, J= 5.8 Hz, 2H), 3.61 (s, 2H),1.46 (s, 9H), 1.44 (s, 9H), 1.27 (s, 9H). LCMS mlz= + 813.3 (M+Naj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.036 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 85.0℃; for 2h;Inert atmosphere; | A mixture of ferf-butyl 4-bromopyridin-2-ylcarbamate (0.301 g, 1 .10 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (0.309 g, 1 .22 mmol), potassium acetate (0.356 g, 3.36 mmol) and [1 ,1 ,-b/s(diphenylphosphino)ferrocene]dichloropalladium(ll)-dichloromethane (0.048 g, 0.066 mmol) in dry A/,A/-dimethylformamide (7.5 ml_) was stirred at 80 C for 3 h under nitrogen. After being cooled to room temperature, 1 -(bromomethyl)-3-chlorobenzene (0.1 50 g, 0.73 mmol, [1 ,1 ,-b/s(diphenylphosphino)ferrocene]dichloropalladium(ll)-dichloromethane (0.048 g, 0.066 mmol), sodium carbonate (0.0583 g, 5.5 mmol) and water (2.5 ml_) were added. The mixture was stirred at 85 C for 2 h under nitrogen atmosphere. The reaction was concentrated, under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1 /1 ) to obtain ferf-butyl 4-(3-chlorobenzyl)pyridin-2-ylcarbamate (0.036 g, 0.1 1 mmol, 10.3% for 2 steps) as a white solid. LCMS (ESI) m/z: 319.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 140.0℃; for 0.833333h;Inert atmosphere; Microwave irradiation; | A 2-5 mL Biotage microwave vial loaded with 4-((5-(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)thiophen-2-yl)methyl)morpholine 114-A (100 mg, 0.239 mmol), <strong>[1095708-32-9]tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate</strong> D-2 (84 mg, 0.263 mmol), Pd(PPh3)4 (16.57 mg, 0.014 mmol), and NaHCO3, (80 mg, 0.956 mmol), was capped, purged with argon, then injected with degassed dioxane: H2O (1.66 mL: 0.33 mL, 5:1 v/v), and heated to 140 C. for 50 min in a Biotage Microwave Reactor. The reaction was cooled, 37% conc. HCl (0.7 mL) was added, stirred for 1 h and basified with 10% NaOH. The mixture was extracted with DCM, washed with 10% NaOH, H2O, brine, and the organic layer was dried over Na2SO4, concentrated, dryloaded onto silica gel and purified on a 12 g silica gel column (DCM/MeOH, 0-10%), affording 4-(3-(5-(morpholinomethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-amine 114 as a green semi-solid (7 mg, 0.018 mmol, 7% yield, 10% MeOH in DCM). 1H NMR (CDCl3) delta: 8.63 (d, J=7.4 Hz, 1H), 8.45 (s, 1H), 8.16 (d, J=6.2 Hz, 1H), 7.62 (d, J=3.7 Hz, 1H), 7.44-7.38 (m, 2H), 7.21 (d, J=7.4 Hz, 1H), 7.03 (dt, J=3.7, 0.9 Hz, 1H), 4.58 (s, 2H), 3.92-3.60 (m, 6H), 2.66-2.54 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 125.0℃; for 0.916667h;Inert atmosphere; | A 20 mL Biotage microwave vial loaded with 5-chloro-3-(4-chloro-3-fluorophenyl)-2-methyl-3H-imidazo[4,5-b]pyridine 181-B (700 mg, 2.364 mmol), <strong>[1095708-32-9]tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate</strong> D-2 (833 mg, 2.6 mmol), PdCl2(dppf) (191 mg, 0.26 mmol), and K3PO4, (1154 mg, 5.44 mmol) was capped, purged with argon, then injected with degassed dioxane: H2O (7.564 mL: 1.891 mL, 4:1 v/v), and heated to 125 C. for 55 min in an oil bath. The reaction was cooled, diluted with DCM, filtered through celite, concentrated, dryloaded onto silica gel and purified on a 40 g silica gel column (DCM/MeOH, 0-5%), affording tert-butyl (4-(3-(4-chloro-3-fluorophenyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)carbamate 181-C as a white solid (165 mg, 0.364 mmol, 36% yield, 5% MeOH in DCM). 1H NMR (CDCl3) delta: 8.94 (s, 1H), 8.56 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.63 (t, J=8.2 Hz, 1H), 7.57 (d, J=5.3 Hz, 1H), 7.37 (dd, J=9.2, 2.4 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 2.60 (s, 3H), 1.54 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydrogencarbonate; In 1,4-dioxane; water; at 140.0℃; for 0.833333h;Inert atmosphere; Microwave irradiation; | A 2-5 mL Biotage microwave vial loaded with 2-chloro-5-methoxypyrimidine (12.3 mg, 0.085 mmol), <strong>[1095708-32-9]tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate</strong> D-2 (30 mg, 0.094 mmol), Pd(PPh3)4 (7.87 mg, 0.00681 mmol), and NaHCO3 (28.6 mg, 0.341 mmol), was capped, purged with argon, then injected with degassed dioxane: H2O (0.89 mL: 0.177 mL, 5:1 v/v), and heated to 140 for 50 min in a Biotage Microwave Reactor. The reaction was cooled, 37% conc. HCl (0.3 mL) was added, stirred for 1 h and basified with 10% NaOH. The mixture was extracted with DCM, washed with 10% NaOH, H2O, brine, and the organic layer was dried over Na2SO4, concentrated, dryloaded onto silica gel and purified on a 12 g silica gel column (DCM/MeOH, 0-11%), affording 4-(5-methoxypyrimidin-2-yl)pyridin-2-amine 69 as a white semi-solid (12 mg, 0.059 mmol, 70% yield, 11% MeOH in DCM). 1H NMR (CDCl3) delta: 8.51 (s, 2H), 8.21 (d, J=5.3 Hz, 1H), 7.59 (dd, J=5.4, 1.5 Hz, 1H), 7.48 (s, 1H), 4.55 (s, 2H), 4.00 (s, 3H). 13C NMR (CDCl3) delta: 159.13, 155.91, 152.79, 148.78, 146.38, 143.36, 112.37, 106.58, 56.06, 29.70. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 125.0℃; for 1.25h;Inert atmosphere; | A 20 mL Biotage microwave vial loaded with N-(6-bromo-2-chloropyridin-3-yl)acetamide C-2 (748 mg, 3 mmol), <strong>[1095708-32-9]tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate</strong> D-2 (1.057 g, 3.3 mmol), PdCl2(dppf) (220 mg, 0.300 mmol), and K3PO4, (1.4 g, 6.6 mmol) was capped, purged with argon, then injected with degassed dioxane: H2O (9.6 mL: 2.4 mL, 4:1 v/v), and heated to 125 C. for 75 min in an oil bath. The reaction was cooled, diluted with DCM, filtered through celite, concentrated, dryloaded onto silica gel and purified on a 40 g silica gel column (DCM/MeOH, 0-6%), affording N-(2?-amino-6-chloro-[2,4?-bipyridin]-5-yl)acetamide D-3 as a beige solid (392 mg, 1.492 mmol, 50% yield). 1H NMR (DMSO) delta: 9.76 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.02 (d, J=5.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.10 (s, 1H), 7.06 (dd, J=5.4, 1.6 Hz, 1H), 6.11 (s, 2H), 2.18 (s, 3H). 13C NMR (DMSO) delta: 169.78, 161.09, 150.47, 149.14, 144.97, 142.59, 134.54, 132.51, 120.45, 109.30, 104.94, 24.03. The product tert-butyl (5-acetamido-6-chloro-[2,4?-bipyridin]-2?-yl)carbamate D-4 was also afforded, white solid (370 mg, 1.020 mmol, 34% yield, 5% MeOH). 1H NMR (CDCl3) delta: 8.86 (d, J=8.5 Hz, 1H), 8.49 (s, 1H), 8.37 (d, J=5.3 Hz, 1H), 7.95 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.75 (bs, 1H), 7.62 (dd, J=5.3, 1.6 Hz, 1H), 2.33 (s, 3H), 1.59 (s, 9H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 120.0℃; for 1h;Inert atmosphere; | A 5 mL Biotage microwave vial loaded with 5-chloro-3-(indolin-5-yl)-2-methyl-3H-imidazo[4,5-b]pyridine 174-C (243 mg, 0.852 mmol), <strong>[1095708-32-9]tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate</strong> D-2 (300 mg, 0.937 mmol), PdCl2(dppf) (68.7 mg, 0.094 mmol), and K3PO4, (416 mg, 1.959 mmol) was capped, purged with argon, then injected with degassed dioxane: H2O (2.72 mL: 0.68 mL, 4:1 v/v), and heated to 120 C. for 1 h in an oil bath. The reaction was cooled, diluted with DCM, filtered through celite, concentrated, dryloaded onto silica gel and purified on a 12 g silica gel column (DCM/MeOH, 0-6%), affording tert-butyl (4-(3-(indolin-5-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)carbamate 174-D as a white solid (111 mg, 0.251 mmol, 29% yield, 6% MeOH in DCM). 1H NMR (CDCl3) delta: 8.56 (d, J=6.4 Hz, 2H), 8.32 (d, J=5.4 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.66 (dd, J=5.3, 1.6 Hz, 1H), 7.20 (s, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 4.03 (s, 1H), 3.71 (t, J=8.4 Hz, 2H), 3.19 (t, J=8.4 Hz, 2H), 2.60 (s, 3H), 1.58 (s, 9H). 13C NMR (CDCl3) delta: 155.25, 152.87, 152.66, 152.13, 149.45, 149.25, 148.75, 148.07, 135.15, 130.55, 126.59, 126.52, 125.00, 123.85, 116.43, 116.39, 109.69, 109.02, 80.75, 47.65, 29.67, 28.37, 15.30. |
Tags: 1095708-32-9 synthesis path| 1095708-32-9 SDS| 1095708-32-9 COA| 1095708-32-9 purity| 1095708-32-9 application| 1095708-32-9 NMR| 1095708-32-9 COA| 1095708-32-9 structure
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P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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