B-(6-Amino-3-pyridinyl)boronic acid

WX030 (0.05 g, 105.72 mumol, 1 eq), WX034-1 (29.17 mg, 211.45 mumol, 2 eq), caesium acetate (2.37 mg, 10.57 mumol, 0.1 eq), n-butyl-di(1-adamantyl)phosphine (3.79 mg, 10.57 mumol, 0.1 eq) and potassium carbonate (43.84 mg, 317.17 mumol, 3 eq) were added into a pre-dried thumb-bottle, then water (0.3 mL) and dioxane (3 mL) were added, followed by purging with nitrogen three times, and the mixture was reacted at 90 C. for 2 hours under the protection of nitrogen atmosphere. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to give a residue. The residue was dissolved in 5 ml of dichloromethane, diluted with 5 mL of water. The obtained solution was layered and then the organic phase was collected. The aqueous phase was washed with dichloromethane (3*5 mL). The organic phases were combined, then washed with saturated brine (2×3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which quickly passed through a short silica gel column (dichloromethane:methanol=3:1) and then separated and purified by flash preparative chromatography (column: Agela DuraShell 150 mm_25 mm_5 mum; mobile phase: [water (10 mM NH4HCO3)-ACN]; B %: 20%-45%, 12 min) to obtain WX034. 1H NMR (400 MHz, CHLOROFORM-d) delta 8.63 (s, 1H), 8.47 (d, J=7.03 Hz, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 8.11-8.16 (m, 1H), 8.07-8.11 (m, 1H), 7.98 (d, J=7.40 Hz, 1H), 7.87 (s, 1H), 7.34 (d, J=1.25 Hz, 1H), 7.04 (dd, J=2.38, 8.66 Hz, 1H), 6.70 (d, J=1.13 Hz, 1H), 6.44 (d, J=8.53 Hz, 1H), 5.51 (quin, J=6.78 Hz, 1H), 4.64 (s, 2H), 1.78-1.92 (m, 1H), 1.58 (d, J=6.65 Hz, 6H), 0.83-0.91 (m, 2H), 0.72-0.78 (m, 2H).A mixture of sodium [(benzyloxy)carbonyl]({2-[(benzyloxy)carbonyl]-3-bromo-1H-pyrrol-1- yl}sulfonyl)azanide (2.97 g, 5.76 mmol), 6-aminopyridine-3-boronic acid (872 mg, 6.32 mmol) and potassium phosphate tribasic (3.83 g, 18.0 mmol) in 1, 4-dioxane (40 mL) and water (10 mL) was degassed by bubbling nitrogen for 15 minutes followed by the addition of XPhos Pd G2 (474 mg, 0.60 mmol). The resulting mixture was heated to 45C under a nitrogen atmosphere for 6 hours. Additional 6-aminopyridine-3-boronic acid (249 mg, 1.81 mmol) was added followed by heating at 45C overnight. Additional 6-aminopyridine-3- boronic acid (249 mg, 1.81 mmol) and XPhos Pd G2 (474 mg, 0.60 mmol) were added before heating at 45C for a further 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with water (100 mL) and extracted into ethyl acetate (3 × 100 mL). The combined organic phases were dried over MgSO4, filtered and concentrated to dryness under reduced pressure. The residue was triturated with DCM (30 mL), isolated by filtration and purified by column chromatography (silica, DCM:1M ammonia in methanol, gradient elution from 100:0 to 80:20). The precipitated solid from clean column fractions was isolated by filtration to give the desired product as a white solid (980 mg, 34%). (0179) 1H NMR (500 MHz, DMSO-d6) d 13.34 (br s, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.88 (br s, 2H), 7.86 (br dd, J=2.2, 9.1 Hz, 1H), 7.4-7.5 (m, 2H), 7.35 (d, J=3.2 Hz, 1H), 7.2-7.3 (m, 8H), 6.88 (d, J=8.8 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H), 5.15 (s, 2H), 4.85 (s, 2H). (0180) LC-MS (Method A): RT = 2.64 min, m/z = 507.1 [M + H]+.A mixture of sodium [(benzyloxy)carbonyl]({2-[(benzyloxy)carbonyl]-3-bromo-1H-pyrrol-1- yl}sulfonyl)azanide (100 mg, 0.19 mmol), 6-aminopyridine-3-boronic acid (33 mg, 0.24 mmol) and sodium carbonate (64 mg, 0.60 mmol) in 1, 4-dioxane (1.0 mL) and water (0.5 mL) was degassed by bubbling nitrogen for 5 minutes followed by the addition of Pd(dppf)Cl2 (15 mg, 0.021 mmol). The resulting mixture was heated to 100C under microwave irradiation for 20 minutes. The reaction mixture was diluted with water (3 mL) and extracted into ethyl acetate (3 × 3 mL). The combined organic phases were washed with brine (3 mL), dried over MgSO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, DCM:methanol, gradient elution from 100:0 to 80:20) then triturated with diethyl ether to give the desired product as a tan solid (59 mg, 58%). (0172) 1H NMR (500 MHz, DMSO-d6) d 7.94 (d, J=1.89 Hz, 1H), 7.53 (dd, J=2.36, 8.67 Hz, 1H), 7.40-7.45 (m, J=3.00, 6.50 Hz, 2H), 7.25-7.35 (m, 9H), 6.63 (br s, 2H), 6.57 (d, J=8.83 Hz, 1H), 6.17 (d, J=3.15 Hz, 1H), 5.14 (s, 2H), 4.85 (s, 2H). (0173) LC-MS (Method A): RT = 2.68 min, m/z = 507.0 [M + H]+.To a solution of 1 -(bromomethyl)-3, 5-dichlorobenzene (0.480 g, 2.0 mmol), 5-(4, 4, 5, 5-tetramethyl-1 , 3-dioxolan-2-yl)pyridin-2-amine (0.534 g, 2.4 mmol) and potassium carbonate (0.553 g, 4.0 mmol) in 1 , 4-dioxane (9 ml_) and water (3 ml_) was added [1 , 1 '-b/s(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.147 g, 0.2 mmol) under nitrogen. The reaction mixture was stirred in the microwave at 100 C for 0.5 h. Water (50 ml_) was added and the mixture was extracted with ethyl acetate (80 ml_ x 3). The combined organic layers were dried with sodium sulfate, filtered and concentrated. Purification by column chromatography (silica gel, petroleum ether/ethyl acetate from 1 /1 to 1 /2) gives A/-(5-(3-methoxybenzyl)pyridin-2-yl)-1 -methyl-6-oxo-1 , 4, 5, 6-tetrahydropyridazine-3-carboxamide 5-(3, 5-dichlorobenzyl)pyridin-2-amine (0.458 g, 1 .8 mmol, 90%) as a brown solid. LCMS (ESI) m/z: 253.0 [M+H]+.To a solution of 1 -(bromomethyl)-3-methoxybenzene (0.362 g, 1 .8 mmol) and 5-(4, 4, 5, 5-tetramethyl-1 , 3-dioxolan-2-yl)pyridin-2-amine (0.480 g, 2.16 mmol) and potassium carbonate (0.498 g, 3.6 mmol) in 1 , 4-dioxane (9 ml_) and water (3 ml_) was added [1 , 1 '-b/'s(diphenylphosphino)ferrocene]dichloropalladium(ll) (132 mg, 0.18 mmol) under nitrogen. The reaction mixture was stirred in the microwave at 100 C for 30 minutes. After the reaction was completed, water (50 ml_) was added, the mixture was extracted with ethyl acetate (80 ml_ x 3). The organic layers were dried with sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column (petroleum ether/ethyl acetate from 1 /1 to 0/1 ) to give 5-(3-methoxybenzyl)pyridin-2-amine (0.285 g, 1 .33 mmol, 74%) as a brown solid. LCMS (ESI) m/z: 215.1 [M+H]+.

Molecular Weight:137.93
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:138.0600576
Monoisotopic Mass:138.0600576
Topological Polar Surface Area:79.4
Heavy Atom Count:10
Complexity:112
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes