[2-(tert-butylsulfamoyl)phenyl]boronic acid

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A reaction flask was charged with 155 mg (0.299 mmol) of 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-[2-chloro-5-(propionylamino)phenyl]-1H-pyrazole-5-carbonitrile (from Step H), 3.5 mL of toluene, 2.4 mL of ethanol, 615 μL (0.598 mmol) of a 250 mg/mL solution of 2-(N-t-butylsulfamoyl)phenylboronic acid (from Step I) in ethanol, 950 μL (1.20 mmol) of 1.25N NaOH, and 17 mg of tetrakis(triphenylphosphine)palladium(0). The mixture was stirred under N2 at 90° C. for 5 hours, then cooled and concentrated. The residue was partitioned between 30 mL of ethyl acetate and 25 mL of H2O. The organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo. The yellow residual oil was flash chromatographed on silica gel (elution with 3:1 and then 1:1 hexane-EtOAc) to give a 77% yield of the title compound as a slightly yellow, stiff foam; homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 650 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.92 (t, J=7.3 Hz, 3H), 100 (s, 9H), 1.21 (t, J=7.5 Hz, 3H), 1.38 (m, 2H), 1.65 (m, 2H), 2.39 (q, J=7.5 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 3.98 (s, 1H), 4.02 (s, 2H), 7.2-7.6 (m, 8H), 7.82 (d, J=2.5 Hz, 1H), 8.15 (dd, J=7.9, 1.4 Hz, 1H). cooled concentrated The residue was partitioned between 30 mL of ethyl acetate and 25 mL of H2O The organic layer was washed with brine dried (Na2SO4) filtered evaporated in vacuo chromatographed on silica gel ( elution with 3:1

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A reaction flask was charged with 155 mg (0.299 mmol) of 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-[2-chloro-5-(propionylamino)phenyl]-1H-pyrazole-5-carbonitrile (from Step H), 3.5 mL of toluene, 2.4 mL of ethanol, 615 μL (0.598 mmol) of a 250 mg/mL solution of 2-(N-t-butylsulfamoyl)phenylboronic acid (from Step I) in ethanol, 950 μL (1.20 mmol) of 1.25N NaOH, and 17 mg of tetrakis(triphenylphosphine)palladium(0). The mixture was stirred under N2 at 90° C. for 5 hours, then cooled and concentrated. The residue was partitioned between 30 mL of ethyl acetate and 25 mL of H2O. The organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo. The yellow residual oil was flash chromatographed on silica gel (elution with 3:1 and then 1:1 hexane-EtOAc) to give a 77% yield of the title compound as a slightly yellow, stiff foam; homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 650 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.92 (t, J=7.3 Hz, 3H), 100 (s, 9H), 1.21 (t, J=7.5 Hz, 3H), 1.38 (m, 2H), 1.65 (m, 2H), 2.39 (q, J=7.5 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 3.98 (s, 1H), 4.02 (s, 2H), 7.2-7.6 (m, 8H), 7.82 (d, J=2.5 Hz, 1H), 8.15 (dd, J=7.9, 1.4 Hz, 1H). cooled concentrated The residue was partitioned between 30 mL of ethyl acetate and 25 mL of H2O The organic layer was washed with brine dried (Na2SO4) filtered evaporated in vacuo chromatographed on silica gel ( elution with 3:1

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By the method described in Example 10, Step B, N-t-butylbenzenesulfonamide [G. Lombardino, J. Org. Chem., 36, 1843 (1971)] was deprotonated with n-butyllithium, and the resulting dianion was reacted with triisopropyl borate and worked up with acid to give the title compound, which was used directly in the next step without further purification.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By the method described in Example 10, Step B, N-t-butylbenzenesulfonamide [G. Lombardino, J. Org. Chem., 36, 1843 (1971)] was deprotonated with n-butyllithium, and the resulting dianion was reacted with triisopropyl borate and worked up with acid to give the title compound, which was used directly in the next step without further purification.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: From 0.16 g (0.29 mmol) of 1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole, using 0.12 g (0.47 mmol) of 2-(t-butylamino)sulfonylphenyl boronic acid, 0.12 g (0.86 mmol)potassium carbonate, 0.016 g (0.05 mmol) tetrabutylammonium bromide, 0.02 g (0.02 mmol) tetrakis(triphenylphosphine)palladium(0), with 1 mL of water and 2 mL of toluene as solvent, 0.08 g (40%) of the title compound was obtained following the procedure of Example 3, Part F, after purification by preparative TLC (silica gel; 20% acetone, 30% ethyl acetate, 50% hexane). 1H NMR (300 MHz, CDCl3): δ 0.97 (m, 12H, overlapping t-butyl singlet and methyl triplet); 1.32 (t, 3H, J=7.3 Hz); 1.72 (m, 2H); 2.63 (t, 2H, J=7.3 Hz); 2.83 (q, 2H, J=7.3 Hz); 3.57 (s, 1H); 5.06 (s, 2H); 5.58 (s,2H); 6.61 (t, 1H, J=8.1 Hz); 6.87-7.09 (m, 7H); 7.12 (d, 1H, J=8.1 Hz); 7.23-7.29 (m,5H); 7.51 (m, 2H); 8.15 (d, 1H, J=7.7 Hz). ##STR107##

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: From 0.16 g (0.29 mmol) of 1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole, using 0.12 g (0.47 mmol) of 2-(t-butylamino)sulfonylphenyl boronic acid, 0.12 g (0.86 mmol)potassium carbonate, 0.016 g (0.05 mmol) tetrabutylammonium bromide, 0.02 g (0.02 mmol) tetrakis(triphenylphosphine)palladium(0), with 1 mL of water and 2 mL of toluene as solvent, 0.08 g (40%) of the title compound was obtained following the procedure of Example 3, Part F, after purification by preparative TLC (silica gel; 20% acetone, 30% ethyl acetate, 50% hexane). 1H NMR (300 MHz, CDCl3): δ 0.97 (m, 12H, overlapping t-butyl singlet and methyl triplet); 1.32 (t, 3H, J=7.3 Hz); 1.72 (m, 2H); 2.63 (t, 2H, J=7.3 Hz); 2.83 (q, 2H, J=7.3 Hz); 3.57 (s, 1H); 5.06 (s, 2H); 5.58 (s,2H); 6.61 (t, 1H, J=8.1 Hz); 6.87-7.09 (m, 7H); 7.12 (d, 1H, J=8.1 Hz); 7.23-7.29 (m,5H); 7.51 (m, 2H); 8.15 (d, 1H, J=7.7 Hz). ##STR107##

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(2-fluoro-4-iodobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-phenoxyphenethyl ketone (2.35 g, 3.90 mmol), 2-(t-butylamino)sulfonylphenyl boronic acid (1.52 g, 5.85 mmol), and soduim carbonate (10 mL of 2M aqueous solution), and tetrabutylammonium bromide (65 mg, o.20 mmol) were added together with 50 mL of toluene. Tetrakis(triphenylphosphine) palladium(O) (0.23 g, 0.20 mmol) was added. The mixture was refluxed under N2 overnight. The solvent was removed in vacuo and the residue was partitioned between H2O and CH2Cl2. The aqueous layer was extracted with CH2Cl2, and the combined organic solution was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by flash column chromatography (silica gel, 30% EtOAc/hexane) to give 1.92 g of light yellow foam (72%). MS m/e 682.5, [M+H]+ ; 1H NMR (300 MHz, CDCl3): δ 0.96 (t, 3H, CH3), 0.98 (t, 9H, CH3), 1.27 (t, 3H, CH3), 1.69 (m, 2H, CH2), 2.60 (t, 2H, CH2), 2.85 (q, 2H, CH2), 2.97 (m, 2H, CH2), 3.13 (m, 2H, CH2), 3.58 (s, 1H, NH), 5.57 (s, 2H, CH2Ar), 6.60 (t, 1H, ArH), 6.86 (d, 1H, ArH), 6.92 (d, 2H, ArH), 7.05 (d, 2H, ArH), 7.16 (m, 2H, ArH), 7.26 (m,5H, ArH), 7.55 (m, 2H, ArH), 8.16 (m, 1H, ArH). ##STR67## The mixture was refluxed under N2 overnight The solvent was removed in vacuo the residue was partitioned between H2O and CH2Cl2 The aqueous layer was extracted with CH2Cl2 the combined organic solution was washed with brine dried over MgSO4 concentrated The crude product was purified by flash column chromatography (silica gel, 30% EtOAc/hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.44 g (20 mmol) of 4-bromoaniline and 5.14 g (20 mmol) of 2-(t-butylaminosulfonyl)phenylboronic acid, 1.16 g of tetrakis(triphenylphosphine) palladium(0) (1 mmol), 0.32 g of tetrabutylammonium bromide (1 mmol) and 20 mL of 2M aqueous sodium carbonate were refluxed with 180 mL of benzene under N2 for 5.5 hours. After cooling, the mixture was diluted with methylene chloride and water. The two phases were separated and the organic phase was washed with water, dried with MgSO4 and concentrated in vacuo. The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane to afford 2.52 g (41%) of the title compound. 1H NMR (CDCl3) δ: 8.14 (d, 1H) ; 7.53 (t, 1H) ; 7.43 (t, 1H); 7.33 (d, 2H); 7.27 (d, 1H); 6.76 (d, 2H); 3.7 (br s, 1H); 0.99 (s, 9H). After cooling The two phases were separated the organic phase was washed with water dried with MgSO4 concentrated in vacuo The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane