[(E)-2-cyclohexylethenyl]boronic acid

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

実験手順: In analogy to the procedure described in Example 14C], [1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone (Example 30A]) and trans-2-cyclohexylvinylboronic acid gave the title compound in 40% yield as brown gum. MS: 449.3 (MH+).

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

実験手順: Isopropanol (60 mL) was added to PEPPSI™-IPr catalyst (161 mg, 0.24 mmol) and tert-butoxy potassium (2.65 g, 23.6 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 15 min. To the reaction mixture were added trans-(2-cyclohexylvinyl)boronic acid (2.00 g, 13.0 mmol) and 4-bromo-2-fluoroaniline (2.24 g, 11.8 mmol) successively and the mixture was stirred at room temperature for 15 hr. Water was added thereto, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to afford 4-[(E)-2-cyclohexylethenyl]-2-fluoroaniline as a reddish brown oil (2.58 g). the mixture was stirred at room temperature for 15 hr the mixture was extracted with ethyl acetate the organic layer was washed with brine dried over anhydrous magnesium sulfate The desiccant was filtered off the filtrate was concentrated under reduced pressure

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

実験手順: Isopropanol (60 mL) was added to PEPPSI™-IPr catalyst (161 mg, 0.24 mmol) and tert-butoxy potassium (2.65 g, 23.6 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 15 min. To the reaction mixture were added trans-(2-cyclohexylvinyl)boronic acid (2.00 g, 13.0 mmol) and 4-bromo-2-fluoroaniline (2.24 g, 11.8 mmol) successively and the mixture was stirred at room temperature for 15 hr. Water was added thereto, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to afford 4-[(E)-2-cyclohexylethenyl]-2-fluoroaniline as a reddish brown oil (2.58 g). the mixture was stirred at room temperature for 15 hr the mixture was extracted with ethyl acetate the organic layer was washed with brine dried over anhydrous magnesium sulfate The desiccant was filtered off the filtrate was concentrated under reduced pressure

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

実験手順: Coupling of (E)-(2-cyclohexylvinyl)boronic acid with 5-bromonicotinaldehyde following the method used in Example 3 gave (E)-5-(2-cyclohexylvinyl)nicotinaldehyde as a yellow oil. Yield (0.8 g, 69%); 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.32 (s, 1H), 8.75 (s, 1H), 8.28 (s, 1H), 6.51-6.38 (m, 2H), 2.26-2.13 (m, 1H), 1.88-1.58 (m, 5H), 1.42-1.18 (m, 5H).

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

実験手順: Coupling of (E)-(2-cyclohexylvinyl)boronic acid with 5-bromonicotinaldehyde following the method used in Example 3 gave (E)-5-(2-cyclohexylvinyl)nicotinaldehyde as a yellow oil. Yield (0.8 g, 69%); 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.32 (s, 1H), 8.75 (s, 1H), 8.28 (s, 1H), 6.51-6.38 (m, 2H), 2.26-2.13 (m, 1H), 1.88-1.58 (m, 5H), 1.42-1.18 (m, 5H).

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate (0.203 g, 0.33 mmol), Na2CO3 (70 mg, 0.66 mmol) and trans-(2-cyclohexylvinyl)boronic acid (0.102 g, 0.66 mmol) in DME (1.5 mL) and water (0.5 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (27 mg, 0.033 mmol) was then added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 45 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were passed through a phase separator cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to afford (E)-tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylvinyl)thiazol-5-ylcarbamate as a brown gum (0.144 g, 68%). A solution of this gum (0.142 g, 0.22 mmol) in MeOH (5 mL) and acetic acid (0.5 mL) was passed through the H-Cube® (70 bar, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylethyl)thiazol-5-ylcarbamate as a clear gum (0.122 g, 99%). This gum (0.122 g, 0.188 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 2 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7N ammonia in MeOH to yield 281 as a pink solid (39 mg, 63%). 1H NMR (400 MHz, d4-MeOD) δ 7.43 (s, 1H), 3.71 (s, 3H), 3.21-3.06 (m, 4H), 2.86 (t, J=7.8 Hz, 2H), 2.62 (d, J=6.6 Hz, 2H), 1.87-1.59 (m, 9H), 1.58-1.45 (m, 1H), 1.43-1.15 (m, 6H), 0.99 (q, J=11.9 Hz, 2H). LCMS (ES+) m/z 446 (M+1) was then added the mixture degassed for a further 10 min The reaction mixture was diluted with water extracted with EtOAc concentrated under reduced pressure The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane)

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

実験手順: Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and trans-(2-cyclohexylvinyl)boronic acid gave 257 as an off-white solid (17 mg, 20% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.70 (s, 1H), 7.36 (s, 2H), 7.31 (s, 1H), 6.40 (dd, J=16.0, 1.3 Hz, 1H), 6.20 (dd, J=16.0, 6.7 Hz, 1H), 3.63 (s, 3H), 3.10-2.96 (m, 6H), 2.47 (d, J=5.9 Hz, 2H), 2.21-2.10 (m, 1H), 1.83-1.71 (m, 7H), 1.35-1.13 (m, 8H). LCMS (ES+) m/z 444 (M+1)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a dried and purged vessel were added N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.536 mmol, 1 eq.), [(E)-2-cyclohexylvinyl]boronic acid (0.090 g, 0.58 mmol, 1.1 eq.), Na2CO3 (0.119 g, 1.12 mmol, 2.1 eq.) and Tetrakis(triphenylphosphine)palladium (0.030 g, 0.027 mmol, 0.05 eq.). A mixture of solvent was added toluene/ethanol/water (4/1/1) was added and the vessel purged with argon and sealed. The reaction was heated to 90° C. for 6 hrs. After cooling, 10 ml of EtOAc were added and the solids were filtered through a “Celite” plug and washed with EtOAc. The organics were separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give N-({6-[(E)-2-cyclohexylvinyl]pyridin-2-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.155 g, 68% yield) as a colorless gum. In a dried purged vessel A mixture of solvent was added the vessel purged with argon sealed After cooling 10 ml of EtOAc were added the solids were filtered through a “Celite” plug washed with EtOAc The organics were separated dried over MgSO4 concentrated The residue was purified by chromatography on silica gel

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate (0.203 g, 0.33 mmol), Na2CO3 (70 mg, 0.66 mmol) and trans-(2-cyclohexylvinyl)boronic acid (0.102 g, 0.66 mmol) in DME (1.5 mL) and water (0.5 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (27 mg, 0.033 mmol) was then added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 45 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were passed through a phase separator cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to afford (E)-tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylvinyl)thiazol-5-ylcarbamate as a brown gum (0.144 g, 68%). A solution of this gum (0.142 g, 0.22 mmol) in MeOH (5 mL) and acetic acid (0.5 mL) was passed through the H-Cube® (70 bar, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylethyl)thiazol-5-ylcarbamate as a clear gum (0.122 g, 99%). This gum (0.122 g, 0.188 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 2 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7 N ammonia in MeOH to yield 281 as a pink solid (39 mg, 63%). 1H NMR (400 MHz, d4-MeOD) δ 7.43 (s, 1H), 3.71 (s, 3H), 3.21-3.06 (m, 4H), 2.86 (t, J=7.8 Hz, 2H), 2.62 (d, J=6.6 Hz, 2H), 1.87-1.59 (m, 9H), 1.58-1.45 (m, 1H), 1.43-1.15 (m, 6H), 0.99 (q, J=11.9 Hz, 2H). LCMS (ES+) m/z 446 (M+1) was then added the mixture degassed for a further 10 min The reaction mixture was diluted with water extracted with EtOAc concentrated under reduced pressure The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane)

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

実験手順: Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and trans-(2-cyclohexylvinyl)boronic acid gave 257 as an off-white solid (17 mg, 20% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.70 (s, 1H), 7.36 (s, 2H), 7.31 (s, 1H), 6.40 (dd, J=16.0, 1.3 Hz, 1H), 6.20 (dd, J=16.0, 6.7 Hz, 1H), 3.63 (s, 3H), 3.10-2.96 (m, 6H), 2.47 (d, J=5.9 Hz, 2H), 2.21-2.10 (m, 1H), 1.83-1.71 (m, 7H), 1.35-1.13 (m, 8H). LCMS (ES+) m/z 444 (M+1)

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

実験手順: In analogy to the procedure described in Example 14C], [1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone (Example 30A]) and trans-2-cyclohexylvinylboronic acid gave the title compound in 40% yield as brown gum. MS: 449.3 (MH+).

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

実験手順: Isopropanol (60 mL) was added to PEPPSI™-IPr catalyst (161 mg, 0.24 mmol) and tert-butoxy potassium (2.65 g, 23.6 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 15 min. To the reaction mixture were added trans-(2-cyclohexylvinyl)boronic acid (2.00 g, 13.0 mmol) and 4-bromo-2-fluoroaniline (2.24 g, 11.8 mmol) successively and the mixture was stirred at room temperature for 15 hr. Water was added thereto, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to afford 4-[(E)-2-cyclohexylethenyl]-2-fluoroaniline as a reddish brown oil (2.58 g). the mixture was stirred at room temperature for 15 hr the mixture was extracted with ethyl acetate the organic layer was washed with brine dried over anhydrous magnesium sulfate The desiccant was filtered off the filtrate was concentrated under reduced pressure