(2-chloro-6-methoxyphenyl)boronic acid

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Treatment of 2-bromochlorobenzene (15.5 g, 80.6 mmol) with 2-chloro-6-methoxybenzene boronic acid (5.0 g, 26.8 mmol) in DME-water (5:1, 250 mL) according to the procedure described for Example 69, Step 1 provided 5.0 g (74%) of 2.2′-dichloro-6-methoxybiphenyl as a colorless oil.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Treatment of 2-bromochlorobenzene (15.5 g, 80.6 mmol) with 2-chloro-6-methoxybenzene boronic acid (5.0 g, 26.8 mmol) in DME-water (5:1, 250 mL) according to the procedure described for Example 69, Step 1 provided 5.0 g (74%) of 2.2′-dichloro-6-methoxybiphenyl as a colorless oil.

反応条件: temp:82.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-bromotoluene (13.8 g, 80.6 mmol) and sodium carbonate (9.0 g, 84.9 mmol) in DME-water (5:1, 250 mL) was added 2-chloro-6-methoxybenzene boronic acid (5.0 g, 26.8 mmol) at 82° C., followed by tetrakis(triphenylphosphine)-palladium (0) (1.5 g, 1.4 mmol). The reaction mixture was heated at 82° C. overnight and cooled to room temperature. The resulting mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4) and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 5% ethyl acetate in hexanes provided 3.9 g (62%) of 2-chloro-6-methoxy-2′-methylbiphenyl as a colorless oil. cooled to room temperature The resulting mixture was extracted with ethyl acetate washed with water and saturated sodium chloride dried (Na2SO4) concentrated under reduced pressure Purification by ISCO

反応条件: temp:82.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-bromotoluene (13.8 g, 80.6 mmol) and sodium carbonate (9.0 g, 84.9 mmol) in DME-water (5:1, 250 mL) was added 2-chloro-6-methoxybenzene boronic acid (5.0 g, 26.8 mmol) at 82° C., followed by tetrakis(triphenylphosphine)-palladium (0) (1.5 g, 1.4 mmol). The reaction mixture was heated at 82° C. overnight and cooled to room temperature. The resulting mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4) and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 5% ethyl acetate in hexanes provided 3.9 g (62%) of 2-chloro-6-methoxy-2′-methylbiphenyl as a colorless oil. cooled to room temperature The resulting mixture was extracted with ethyl acetate washed with water and saturated sodium chloride dried (Na2SO4) concentrated under reduced pressure Purification by ISCO

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using Method G, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (600 mg) and 2-chloro-6-methoxy-phenylboronic acid (1051 mg) were reacted to afford the title compound (263 mg) as a off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.55(br, 1H), 7.94-7.88 (m, 1H), 7.79-7.65 (m, 2H), 7.37-7.29 (m, 1H), 7.15 (m, 1H), 6.94 (m, 1H), 3.65 (s, 3H), 3.44 (apparent quartet, J=7.0 Hz, 2H), 1.64 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=371 (M+H) HPLC 1.86 min. were reacted

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using Method G, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (600 mg) and 2-chloro-6-methoxy-phenylboronic acid (1051 mg) were reacted to afford the title compound (263 mg) as a off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.55(br, 1H), 7.94-7.88 (m, 1H), 7.79-7.65 (m, 2H), 7.37-7.29 (m, 1H), 7.15 (m, 1H), 6.94 (m, 1H), 3.65 (s, 3H), 3.44 (apparent quartet, J=7.0 Hz, 2H), 1.64 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=371 (M+H) HPLC 1.86 min. were reacted

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Treatment of 1-bromo-2-chlorobenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (15.6 g, 80.64 mol) generally according to the procedure described for Intermediate 37 afforded 5.0 g (73%) of 6-chloro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (60 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (1.05 g, 26.35 mmol) and allyl bromide (3.19 g, 26.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol (2.8 g, 10.03 mmol) with m-chloroperoxybenzoic acid (4.6 g, 15.0 mmol, 77%) and potassium carbonate (1.6 g, 12.0 mmol) generally according to the procedure described for Intermediate 9 afforded 2.2 g (74%) of (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.6 g, 5.42 mmol) with p-toluenesulfonyl chloride (1.55 g, 8.13 mmol) generally according to the procedure described for Intermediate 10 gave 2.1 g (86%) of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.44 mmol) with sodium azide (0.2 g, 3.08 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.43 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.3 g, 1.14 mmol) generally according to the procedure described for Example 154 provided 0.036 g (24%) of (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 221-223° C.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Treatment of 1-bromo-2-methylbenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (13.8 g, 80.6 mol) generally according to the procedure described for Intermediate 37 afforded 3.85 g (62%) of 6-chloro-2′-methylbiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (100 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded brown oil. The oil was reacted with sodium hydride (0.61 g, 25.38 mmol) and allyl bromide (3.07 g, 25.38 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol (4.38 g, 16.92 mmol) with m-chloroperoxybenzoic acid (4.38 g, 25.38 mmol, 77%) and potassium carbonate (2.81 g, 20.30 mmol) generally according to the procedure described for Intermediate 9 afforded 2.4 g (52%) of (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (2.4 g, 8.73 mmol) with p-toluenesulfonyl chloride (2.50 g, 13.1 mmol) generally according to the procedure described for Intermediate 10 gave 3.2 g (85%) of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) with sodium azide (0.35 g, 5.38 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.468 mmol) in tetrahydrofuran (10 m]L) with polymer-supported triphenylphosphine (0.24 g, 0.936 mmol) generally according to the procedure described for Example 154 provided 0.028 g (18%) of (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 204-206° C.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted 2-chloro-6-methoxyphenylboronic acid (available from Aldrich Chemical Company, Inc.; 93 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-6′-methoxy-biphenyl-2-carboxylic acid (5 mg, 4%). 1H NMR (300 MHz, DMSO-d6), δ 12.87 (br s, 1H), 8.53 (d, J=1.7 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.4, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.32-7.41 (m, 2H), 7.10 (dd, J=18.2, 8.0 Hz, 2H), 3.67 (s, 3H). the acid was purified

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 6-Bromo-3-(3-hydroxy-propionyl)-3H-quinazolin-4-one (11.6 mg, 0.039 mmol) dissolved in 1 ml N,N-dimethylacetamide in a 20 ml vial, 2-chloro-6-methoxy-phenylboronic acid (14.55 mg, 0.078 mmol) dissolved in 0.5 ml ethanol and potassium carbonate (5.92 mg, 0.043 mmol) dissolved in 0.5 ml water were added. Triphenylphosphine (1 mg, 3.8 umol) and tris(dibenzylideneacetone)dipalladium (0) (0.7 mg, 0.78 umol) were added to the mixture which refluxed overnight. The crude product was poured into 5 ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 3.4 mg product was obtained. Yield: 24.3%; 1H NMR (500 MHz, DMSO-d6): δ 2.75538–2.78226(t, J=6.835 Hz, 2H), 3.70334(s, 3H), 4.15877–4.18594 (t, J=6.785 Hz, 2H), 7.13724–7.15535 (dd, J1=8.68 Hz, J2=0.75 Hz, 1H), 7.18337–7.20169 (dd, J1=8.375 Hz, J2=0.885 Hz, 1H), 7.41001–7.44275 (dd, J1=8.215 Hz, J2=8.185 Hz, 1H), 7.66453–7.68523 (dd, J1=8.38 Hz, J2=2.0 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.96 (d, J=1.9 Hz, 1H), 8.41 (s, 1H); ESI-MS: m/z 359 (M++1) were added refluxed overnight to extract the product Solvent in the organic phase was removed under vacuum The resulted residue was purified by preparative HPLC