4-Amino-3-fluorophenylboronic acid, pinacol ester

2.1: 2-fluoro-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline 4-Bromo-2-fluoroaniline (45.00 g, 236.8 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl- 2, 2Route B (Pd-catalyzed borylation) Step 1 570 mg 4-bromo-2-fluoroaniline (3 mmol, 1 eq.), 1.14 g bis(pinacolato)diboron (4.5 mmol, 1.5 eq.), 883 mg KOAc (9 mmol, 3 eq.) and 245 mg PdClRoute A (Pd-catalyzed borylation)Step 1570 mg 4-bromo-2-fluoroaniline (3 mmol, 1 eq.), 1.14 g bis(pinacolato)diboron (4.5 mmol, 1.5 eq.), 883 mg KOAc (9 mmol, 3 eq.) and 245 mg PdClTo a solution of 4-bromo-2-fluoroaniline (40 g 211 mmol) 4 4 4′ 4′ 5 5 5′ 5′-octamethyl-2 2′-bi (1 3 2-dioxaborolane) (64.1 g 253 mmol) and KOAc (41.3 g 421 mmol) in 1 4-dioxane (500 mL) stirred under NStep 4 Step 4 A solution of the BOC-derivative from step 3 (3.6 g, 10.6 mmol) in 35 ml_ DCM and 10 mL of 5N HCl in dioxane was stirred at 30 EXAMPLE 56; N-[4-(2-dimethylaminomethyl-phenyl)-2-fluorophenyl]-2-(2-fluororhohenyl)-2-(4- chlorophenylaminocarbonylamino)-acetamide; A. Preparation of 4-(2-dimethylaminomethyl-phenyl)-2-fluoro-phenylamine; [0377] To a solution of 2-dimethylaminomethyl-bromobenzene (1.93 g, 9.02 mmol) and 4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)aniline (4.42 g, 18.6 mmol) in toluene (40 mL) and n-BuOH (10 mL), Cs2CO3 (8.80 g, 27.0 mmol) in H2O (20 mL) was added, followed by addition OfPd(Ph3P)4 (0.556 g, 0.480 mmol). The mixture was then heated at reflux overnight. EtOAc and H2O were added. The organic layer was separated, filtered, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel flash column using 50% EtOAc / hexanes (containing 1% TEA) as eluent to give an oil (0.537 g). MS 245.1 (M+H).A solution of 3-tert-butyl-l-(4-methylphenyl)-lH-pyrazol-5-amine (300 mg, 1.18 mmol, 1.0 eq) and DIEA (641 mg, 4.7 mmol, 4.0 eq) in DCM (lmL) was added dropwise to a solution of triphosgene (69 mg, 0.22 mmol, 0.6 eq) in DCM (5 mL) maintained at 0C and under nitrogen atmosphere. The reaction mixture was stirred for 20 min at 0C and added to a solution of 2-fluoro-4-(tetramethyl-l , 3, 2-dioxaborolan-2-yl)aniline (323 mg, 1.3 mmol, 1.1 eq) in DCM (3 mL). The resulting reaction mixture was stirred for 3h at RT, washed with a saturated solution of NH4CI (2x 10 mL) and brine (1x10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH; 3: 1) afforded the title compound as a brown solid (180 mg, 20%). LC/MS: 493.0 [M+H]A solution of 4-nitrophenyl chloro formate (440 mg, 2.07 mmol, 1.0 eq), dichloromethane (5 mL), pyridine (235 mg, 2.91 mmol, 1.4 eq) and 3-tert-butyl-l -[4-(propan-2- yl)phenyl]-lH-pyrazol-5-amine (prepared as described in Molecules, 2014, Volumel9, Issue2, 2004-2028, 520 mg, 1.92 mmol, 0.93 eq) in DCM (5 mL) maintained under nitrogen atmosphere was stirred at 5C for 2h before the addition of 2-fluoro-4-(tetramethyl-l , 3, 2-dioxaborolan-2- yl)aniline (470 mg, 1.88 mmol, 0.9 eq) and DIEA (520 mg, 3.94 mmol, 1.9 eq). The resulting reaction mixture was stirred for an additional 3h at RT . The solvent was removed under reduced pressure and the crude was purified by flash chromatography on silica (EtOAc:PE; 1 :l) to afford the title compound as a yellow solid (300 mg, 19%).To a solution of 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanoic acid INTB37 (0.75 g, 2.58 mmol) in DCM (15 ml_) was added 1-chloro-N, N, 2-trimethylprop-1-en-1 -amine (0.63 ml_, 5.17 mmol). The reaction mixture was stirred at RT for 1 hr. The reaction mixture was concentrated to dryness and the resulting brown residue was redissolved in DCM (15 ml_). 2- fluoro-4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)aniline (0.67 g, 2.84 mmol) and pyridine (1.67 ml.) were added to the reaction mixture. The reaction mixture was stirred at RT for 18 hrs. The reaction mixture was diluted with NH4CI (sat. aq, 10 ml.) and further DCM (10 ml_). The phases were separated and the aqueous was extracted with further DCM (2 x 20 ml_). The combined organics were dried (phase separator) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc/iso-hexane) to afford a mixture of 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(4, 4, 5, 5-tetramethyl-1 , 3, 2- dioxaborolan-2-yl)phenyl)-2-methylpropanamide (730 mg, 1.06 mmol, 41 % yield) as an orange gum Rt 2.30 min (HPLC acidic); m/z 51 1 (M+H)+ (ES+)., contaminated with boronic acid hydrolysis product; Rt 1.47 min (HPLC acidic); m/z 428 (M+H)+ (ES+).

Molecular Weight:237.08
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:237.1336371
Monoisotopic Mass:237.1336371
Topological Polar Surface Area:44.5
Heavy Atom Count:17
Complexity:282
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes