4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile

General procedure: to a dioxane solution (3.0 mL) of tert-butyl N-[(3S)-l-[3-bromo-5-(4-methyl-lH-l, 3-benzodiazol-2-yl)pyridin-4-yl]pyrrolidin- 3-yl]carbamate (1.0 equiv, 0.24 mmol, 112 mg) was added Pd(Amphos)Cl2(0.1 equiv, 0.024 mmol, 16 mg), 3-cyano-5-fluorophenyl boronic acid (3.0 equiv, 0.72 mmol, 120 mg) and K2C03(3.0 equiv, 0.72 mmol, 100 mg). N2was bubbled through the reaction solution for 5 min and 0.3 mL water was added. The resulting mixture was heated at 100 C for 0.5 h and LCMS analysis showed complete consumption of starting material. The reaction solution was concentrated and the residue obtained was purified by silica gel chromatography eluting with ethylacetate/dichloromethane (0-100%) to give 92 mg of the title compound. MS (M+H)+= 513.4.3-bromo-4-(2, 6-difluoro-4-nitrophenoxy)-1 -{[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrrolo[2, 3- b]pyridine (1 .20 g, 2.40 mmol, intermediate 16), 4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)pyridine-2-carbonitrile (CAS No. [741709-62-6]) (662 mg, 2.88 mmol), tetrakis(triphenylphosphin)palladium(0) (222 mg, 192 muetaetaomicronIota), and aq. sodium carbonate (2.6 ml_, 2.0 M, 5.3 mmol) were combined in 1 , 4-dioxane (42 ml_), degassed and flushed with argon. The mixture was heated up to 100C for 16h, diluted with ethyl acetated and filtered. To the filtrate was added water and the phases were separated. The aqueous phase was washed with ethyl acetate, and the combined organic phases were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (50g SNAP KP-Sil, hexane/ 0-35 % ethyl acetate) to give the title compound (320 mg, 23 % yield). LC-MS (Method 2): Rt = 1 .57 min; MS (ESIpos): m/z = 524 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.08 (s, 9 H) 0.80 - 0.89 (m, 2 H) 3.57 - 3.70 (m, 2 H) 5.73 (s, 2 H) 6.73 - 6.79 (m, 1 H) 7.98 - 8.03 (m, 1 H) 8.27 - 8.32 (m, 2 H) 8.40 - 8.49 (m, 3 H) 8.69 - 8.75 (m, 1 H).To a solution of 2-bromo-4-fluoro-6-isopropylaniline (3.6 g, 15.51 mmol, 1 eq) and 4- (4, 4, 5, 5-tetramethyl-i, 3, 2-dioxaborolan-2-yl)picolinonitrile (3.60 g, 15.67 mmol, 1.01 eq) in dioxane (90 mL) and H20 (9 mL) was added Na2C03 (4.11 g, 38.78 mmol, 2.5 eq). Then Pd(dppf)Cl2 (1.13 g, 1.55 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere. The resulting mixture was stirred at 80 C for 2 hours under nitrogen. Then the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (Si02, petroleum ether: ethyl acetate, 20:1 to 5:1) and then triturated with petroleum ether (10 mL) to give the title compound (2.65 g, 65 % yield, 97 % purity on LCMS) as a yellow solid. (0666) FontWeight='Bold' FontSize='10' HNMR (CDC13) delta 8.79 (d, 1 H), 7.86 (d, 1 H), 7.65 (dd, 1 H), 6.99 (dd, 1 H), 6.70 (dd, 1 H), 3.63 (br s, 2 H), 2.98-2.87 (m, 1 H) and 1.30 (d, 6 H). (0667) LCMS: m/z 256.2 (M+H)+ (ES+).To a solution of 2-bromo-4-fluoro-6-isopropylanthne (3.6 g, 15.51 mmol, 1 eq) and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)picolinonitrile (3.60 g, 15.67 mmol, 1.01 eq) in dioxane (90 mL) and H20 ( mL) was added Na2CO3 (4.11 g, 38.78 mmol, 2.5 eq). Then Pd(dppf)C12 (1.13 g, 1.55 mmol, 0.1 eq) was added under N2 atmosphere. The resulting mixture was stirred at 80 C for 2 hours under nitrogen and thenconcentrated in vacuo. The residue was purified by column chromatography (Si02, PE:EtOAc = 20:1 to 5:1) and then triturated with PE (10 mL) to give the title compound(2.65 g, 6 % yield, 97 % purity on LCMS) as a yellow solid.1HNMR (CDC13): 6 8.79 (d, 1 H), 7.86 (d, 1 H), 7.65 (dd, 1 H), 6.99 (dd, 1 H), 6.70 (dd, 1H), 3.63 (br 5, 2 H), 2.98-2.87 (m, 1 H) and 1.30 (d, 6 H).LCMS: m/z 256.2 (M+H)÷ (ESI.General procedure: 5-Bromo-2, 3-dihydro-iH-inden-4-amine (280 mg, 1.320 mmol) was dissolved in dioxane (5 mL). A solution of potassium carbonate (600 mg, 4.34 mmol) in water (1 mL) and (2-methoxypyridin-4-yl)boronic acid (250 mg, 1.635 mmol) were added. The mixture was degassed with nitrogen for 15 minutes before Pd(dppf)Cl2.DCM (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80 C (bath temperature) for 2 hours. Then the mixture was cooled to room temperature and partitioned between DCM (30 mL) and water (20 mL). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to give a brown oil. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc/isohexane) to afford the title compound (0.29 g, 87 %) as a pale yellow crystalline solid. (0646) NMR (CDC13) delta 8.26 (d, J = 54 Hz, lH), 7.11 (d, J = 5-0 Hz, lH), 7.01 (d, J = 7-7 Hz, - Ill - lH), 6.97 (s, lH), 6.80 (d, J = 7-6 Hz, lH), 4.06 (s, 3H), 2.98 (t, J = 7.6 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 2.19 (p, J = 7.5 Hz, 2H). Two exchangeable protons not observed. LCMS: m/z 241.3 (M+H)+ (ES+)To a solution of tert-butyl (5-(3-iodo-1-tosyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)pyridin-3-yl)carbamate from step 3 (500 mg, 0.85 mmol) in 1, 4-dioxane (7 mL) and water (3 mL) was added 2-cyanopyridine-4-boronic acid, pinacol ester (195 mg, 0.85 mmol), potassium carbonate (352 mg, 2.5 mmol) and [1, 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).DCM (35 mg, 0.042 mmol) and the solution was treated with microwave radiation at 120 C. for one hour. After cooling the resulting solution was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide tert-butyl (5-(3-(2-cyanopyridin-4-yl)-1-tosyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)pyridin-3-yl)carbamate (51 mg, 11% yield): MS (ES) m/z 567 (M+H).To a mixture 4-bromo-3 -[4-( 1 -methylpyrazol-4-yl)phenyl]pyrazolo[ 1, 5 -a]pyridine (48, 34 mg, 0.096 mmol), Step b. To a mixture of tert-butyl 4-(5-bromopyridin-2-yl)hexahydropyrrolo[3, 4-b] [l, 4]oxazine- 6(2H)-carboxylate (0.230 g, 0.60 mmol) and 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)picolinonitrile (CAS Number 741709-62-6; 0.207 g, 0.90 mmol) in DMF-water (5: 1.5; 6.5 mL) was added NaHC03 (0.151 g, 1.802 mmol) at rt. The reaction mixture was degassed by purging nitrogen through the reaction solution for 15 min before addition of PdCl2(dppf) (0.044 g, 0.06 mmol). The reaction mixture was heated to 100C for 1.5 h. The reaction was cooled to rt, diluted with water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (60% EtOAc in hexane) to provide tert-butyl 4-(2'-cyano- [3, 4'-bipyridin]-6-yl)hexahydropyrrolo[3, 4-b][l, 4]oxazine-6(2H)-carboxylate (0.190 g, 0.47 mmol). LCMS: Method C, 2.069 min, MS: ES+ 352.22 (M-56).

A pyridylborane derivative evaluated for its kinase inhibitory activity.

Molecular Weight:230.07
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:230.1226579
Monoisotopic Mass:230.1226579
Topological Polar Surface Area:55.1
Heavy Atom Count:17
Complexity:332
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes