chloromethyl 2-methylpropanoate

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(2,6-dimethylphenyl)-3-(2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)thiourea (75 mg, 0.143 mmol) in chloroform (CHCl3; 0.72 mL) was added chloromethyl isobutyrate (31.1 mg, 0.172 mmol). The mixture was heated at 100° C. for 1 h. The mixture was cooled to 25° C., and the residue was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound (17.3 mg, 19%) as a yellow oil: IR νmax 3332 (br), 3124, 2976, 2939, 1739, 1631, 1590, 1518, 1264, 1171, 986 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.2 Hz, 2H), 7.02 (d, J=7.5 Hz, 2H), 6.88 (t, J=7.5 Hz, 1H), 5.65 (br s, 2H), 2.88 (br s, 1H), 2.68-2.52 (m, 1H), 2.10 (s, 6H), 1.82-1.46 (m, 2H), 1.46-1.22 (m, 2H), 1.22-1.18 (m, 6H); ESIMS m/z 624 (M+H). The mixture was cooled to 25° C. the residue was purified by silica gel chromatography (EtOAc-hexanes gradient)

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.5 g, 1.02 mmol) and potassium hydroxide (115 mg, 2.04 mmol) in anhydrous DMF (4 mL) was added a solution of chloromethyl isobutyrate (37 mg, 0.25 mmol) in anhydrous DMF (1 mL) over 30 min at 10° C. The reaction was stirred at 10° C. for 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1 to 4/1) to afford the title compound as a white solid (0.39 g, 63.3%). The title compound was characterized by LC-MS and 1H NMR as shown below: filtered The filtrate was concentrated in vacuo the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1 to 4/1)

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.5 g, 1.02 mmol) and potassium hydroxide (115 mg, 2.04 mmol) in anhydrous DMF (4 mL) was added a solution of chloromethyl isobutyrate (37 mg, 0.25 mmol) in anhydrous DMF (1 mL) over 30 min at 10° C. The reaction was stirred at 10° C. for 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1 to 4/1) to afford the title compound as a white solid (0.39 g, 63.3%). The title compound was characterized by LC-MS and 1H NMR as shown below: filtered The filtrate was concentrated in vacuo the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1 to 4/1)

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

Procedure: To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (57 μL, 0.4 mmol) in DMF (1 mL) was added chloromethyl isobutyrate (34 mg, 0.25 mmol) at rt. The reaction was stirred at rt for 16 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1) to afford the title compound as a white solid (45 mg, 37.5%). The title compound was characterized by LC-MS and 1H NMR as shown below: concentrated in vacuo The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(2,6-dimethylphenyl)-3-(2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)thiourea (75 mg, 0.143 mmol) in chloroform (CHCl3; 0.72 mL) was added chloromethyl isobutyrate (31.1 mg, 0.172 mmol). The mixture was heated at 100° C. for 1 h. The mixture was cooled to 25° C., and the residue was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound (17.3 mg, 19%) as a yellow oil: IR νmax 3332 (br), 3124, 2976, 2939, 1739, 1631, 1590, 1518, 1264, 1171, 986 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.2 Hz, 2H), 7.02 (d, J=7.5 Hz, 2H), 6.88 (t, J=7.5 Hz, 1H), 5.65 (br s, 2H), 2.88 (br s, 1H), 2.68-2.52 (m, 1H), 2.10 (s, 6H), 1.82-1.46 (m, 2H), 1.46-1.22 (m, 2H), 1.22-1.18 (m, 6H); ESIMS m/z 624 (M+H). The mixture was cooled to 25° C. the residue was purified by silica gel chromatography (EtOAc-hexanes gradient)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(2,6-dimethylphenyl)-3-(2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)thiourea (75 mg, 0.143 mmol) in chloroform (CHCl3; 0.72 mL) was added chloromethyl isobutyrate (31.1 mg, 0.172 mmol). The mixture was heated at 100° C. for 1 h. The mixture was cooled to 25° C., and the residue was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound (17.3 mg, 19%) as a yellow oil: IR νmax 3332 (br), 3124, 2976, 2939, 1739, 1631, 1590, 1518, 1264, 1171, 986 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.2 Hz, 2H), 7.02 (d, J=7.5 Hz, 2H), 6.88 (t, J=7.5 Hz, 1H), 5.65 (br s, 2H), 2.88 (br s, 1H), 2.68-2.52 (m, 1H), 2.10 (s, 6H), 1.82-1.46 (m, 2H), 1.46-1.22 (m, 2H), 1.22-1.18 (m, 6H); ESIMS m/z 624 (M+H). The mixture was cooled to 25° C. the residue was purified by silica gel chromatography (EtOAc-hexanes gradient)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(2,6-dimethylphenyl)-3-(2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)thiourea (75 mg, 0.143 mmol) in chloroform (CHCl3; 0.72 mL) was added chloromethyl isobutyrate (31.1 mg, 0.172 mmol). The mixture was heated at 100° C. for 1 h. The mixture was cooled to 25° C., and the residue was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound (17.3 mg, 19%) as a yellow oil: IR νmax 3332 (br), 3124, 2976, 2939, 1739, 1631, 1590, 1518, 1264, 1171, 986 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.2 Hz, 2H), 7.02 (d, J=7.5 Hz, 2H), 6.88 (t, J=7.5 Hz, 1H), 5.65 (br s, 2H), 2.88 (br s, 1H), 2.68-2.52 (m, 1H), 2.10 (s, 6H), 1.82-1.46 (m, 2H), 1.46-1.22 (m, 2H), 1.22-1.18 (m, 6H); ESIMS m/z 624 (M+H). The mixture was cooled to 25° C. the residue was purified by silica gel chromatography (EtOAc-hexanes gradient)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-((3S,7R,8R,9S)-3-(3-hydroxy-4-methoxypicolinamido)-8-(isobutyryloxy)-9-methyl-2,6-dioxo-1,5-dioxonan-7-yl)ethyl benzoate (50 mg, 0.087 mmol), Na2CO3 (15 mg, 0.14 mmol) and NaI (3.09 mg, 0.021 mmol) in acetone (0.6 mL) was added chloromethyl isobutyrate (15.4 mg, 0.114 mmol) slowly at room temperature (about 22° C.). The resulting reaction mixture was warmed to 50° C. and stirred at 50° C. overnight. The solvent was evaporated and the crude residue was purified via flash chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (35 mg, 76%) as an off-white solid: mp 48-50° C.; 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=7.9 Hz, 1H), 8.26 (d, J=5.5 Hz, 1H), 8.04-7.87 (m, 2H), 7.55 (t, J=7.4 Hz, 1H), 7.43 (t, J=7.5 Hz, 2H), 6.95 (d, J=5.4 Hz, 1H), 5.85-5.62 (m, 2H), 5.41 (s, 1H), 5.26-5.06 (m, 2H), 4.94 (dd, J=9.8, 6.3 Hz, 1H), 4.42-4.19 (m, 2H), 3.92 (d, J=14.3 Hz, 3H), 3.65 (s, 1H), 2.76 (t, J=9.5 Hz, 1H), 2.62 (dt, J=10.8, 5.5 Hz, 1H), 2.58-2.47 (m, 1H), 2.30 (s, 1H), 1.82 (s, 1H), 1.29 (d, J=6.3 Hz, 3H), 1.21 (dd, J=7.0, 0.9 Hz, 6H), 1.13 (d, J=7.0 Hz, 6H); ESIMS m/z 673 ([M+H]+). The resulting reaction mixture The solvent was evaporated the crude residue was purified via flash chromatography (SiO2, hexanes/EtOAc gradient)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-((3S,7R,8R,9S)-7-(cyclopentylmethyl)-8-(cyclopropylmethoxy)-9-methyl-2-oxooxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (60 mg, 0.126 mmol) and K2CO3 (34.9 mg, 0.253 mmol) in acetone (1 mL) was added chloromethyl isobutyrate (34.5 mg, 0.253 mmol) and the reaction was heated to 60° C. After TLC analysis indicated full consumption of the picolinamide starting material, the mixture was concentrated under a stream of N2 and the residue purified by column chromatography on SiO2 (gradient, EtOAc/hexanes) to yield the title compound as a colorless semi-solid (60.4 mg, 83%): IR (thin film) 3381, 2942, 1745, 1678, 1506, 974 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=8.2 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H), 6.93 (d, J=5.4 Hz, 1H), 5.81-5.61 (m, 2H), 4.89 (dd, J=9.2, 6.3 Hz, 1H), 4.57 (dt, J=11.0, 7.5 Hz, 1H), 3.89 (s, 3H), 3.50 (dd, J=9.6, 7.0 Hz, 1H), 3.36 (dd, J=9.6, 6.9 Hz, 1H), 3.01 (t, J=9.0 Hz, 1H), 2.54 (p, J=7.0 Hz, 1H), 2.36 (dd, J=13.1, 6.8 Hz, 1H), 1.92-1.43 (m, 15H), 1.42 (d, J=6.5 Hz, 2H), 1.35-1.19 (m, 2H), 1.14 (d, J=7.0 Hz, 3H), 1.17-0.92 (m, 5H), 0.62-0.48 (m, 2H), 0.29-0.17 (m, 2H); HRMS-ESI (m/z) ([M]+) calcd for C31H46N2O8, 574.3254; found, 574.3262. consumption of the picolinamide starting material the mixture was concentrated under a stream of N2 the residue purified by column chromatography on SiO2 (gradient, EtOAc/hexanes)

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.5 g, 1.02 mmol) and potassium hydroxide (115 mg, 2.04 mmol) in anhydrous DMF (4 mL) was added a solution of chloromethyl isobutyrate (37 mg, 0.25 mmol) in anhydrous DMF (1 mL) over 30 min at 10° C. The reaction was stirred at 10° C. for 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1 to 4/1) to afford the title compound as a white solid (0.39 g, 63.3%). The title compound was characterized by LC-MS and 1H NMR as shown below: filtered The filtrate was concentrated in vacuo the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1 to 4/1)

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

Procedure: To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (57 μL, 0.4 mmol) in DMF (1 mL) was added chloromethyl isobutyrate (34 mg, 0.25 mmol) at rt. The reaction was stirred at rt for 16 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1) to afford the title compound as a white solid (45 mg, 37.5%). The title compound was characterized by LC-MS and 1H NMR as shown below: concentrated in vacuo The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(2,6-dimethylphenyl)-3-(2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)thiourea (75 mg, 0.143 mmol) in chloroform (CHCl3; 0.72 mL) was added chloromethyl isobutyrate (31.1 mg, 0.172 mmol). The mixture was heated at 100° C. for 1 h. The mixture was cooled to 25° C., and the residue was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound (17.3 mg, 19%) as a yellow oil: IR νmax 3332 (br), 3124, 2976, 2939, 1739, 1631, 1590, 1518, 1264, 1171, 986 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.2 Hz, 2H), 7.02 (d, J=7.5 Hz, 2H), 6.88 (t, J=7.5 Hz, 1H), 5.65 (br s, 2H), 2.88 (br s, 1H), 2.68-2.52 (m, 1H), 2.10 (s, 6H), 1.82-1.46 (m, 2H), 1.46-1.22 (m, 2H), 1.22-1.18 (m, 6H); ESIMS m/z 624 (M+H). The mixture was cooled to 25° C. the residue was purified by silica gel chromatography (EtOAc-hexanes gradient)