azetidin-1-yl-(2,4-difluorophenyl)methanone

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:0.00; pressure:0.00; stir:

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

Procedure: The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 7.48-7.56 (m, 1 H) 7.24 (s, 1 H) 7.20 (d, J=1.26 Hz, 1 H) 6.77 (dd, J=8.59, 2.53 Hz, 1 H) 6.66 (dd, J=11.24, 2.40 Hz, 1 H) 4.21 (t, J=7.83 Hz, 2 H) 4.11-4.17 (m, 2 H) 3.65-3.74 (m, 1 H) 3.55-3.63 (m, 1 H) 3.13 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.34 (dt, J=15.60, 7.74 Hz, 2 H) 1.89-1.97 (m, 1 H) 1.56 (s, 9 H) 1.44 (s, 3 H); LCMS for C25H28FNO6 m/z 458.20 (M+H)+.

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

Procedure: The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204d) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1 H) 7.54 (t, J=8.08 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.13 (s, 1 H) 7.08 (s, 1 H) 6.81 (dd, J=8.59, 2.27 Hz, 1 H) 6.78 (d, J=2.02 Hz, 1 H) 6.68 (dd, J=11.12, 2.27 Hz, 1 H) 5.00-5.08 (m, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.16 (t, J=7.71 Hz, 2 H) 3.81 (s, 3 H) 3.60 (d, J=5.05 Hz, 2 H) 3.43 (s, 3 H) 3.15 (dd, J=16.42, 9.60 Hz, 1 H) 2.92 (dd, J=16.42, 7.33 Hz, 1 H) 2.27-2.38 (m, 2 H); LCMS for C25H25FN4O5 m/z 481.00 (M+H)+.

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

Procedure: The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 1.57 (s, 9 H) 2.26-2.38 (m, 2 H) 3.06-3.17 (m, 1 H) 3.67-3.78 (m, 1 H) 3.81-3.90 (m, 1 H) 4.09-4.18 (m, 3 H) 4.18-4.25 (m, 2 H) 4.92-5.02 (m, 1 H) 6.63-6.68 (m, 1 H) 6.78 (dd, J=8.59, 2.27 Hz, 1 H) 7.21 (d, J=1.26 Hz, 1 H) 7.49-7.56 (m, 1 H) 8.02 (s, 1 H); LCMS for C24H24FNO6 m/z 444.00 (M+H)+.

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

Procedure: To a solution of 2,4-difluorobenzoyl chloride (1.14 g, 6.46 mmol) in CH2Cl2 was added azetidine hydrochloride (1.46 g, 15.6 mmol) and Et3N (2.70 mL, 19.4 mmol). The reaction mixture was stirred at room temperature for 1 hr, quenched with H2O (100 mL), and extracted with CH2Cl2 (2×100 mL). The organic layers were dried over MgSO4 and concentrated to give an off-white solid (896 mg, 76% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.52-7.59 (m, 1 H) 6.91-6.98 (m, 1 H) 6.81-6.87 (m, 1 H) 4.21 (t, J=7.71 Hz, 2 H) 4.11 (t, J=7.71 Hz, 2H) 2.30-2.38 (m, 2 H). quenched with H2O (100 mL) extracted with CH2Cl2 (2×100 mL) The organic layers were dried over MgSO4 concentrated

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a) (421 mg, 1.47 mmol) and Cs2CO3 (965 mg, 2.96 mmol) was added to a solution of azetidin-1-yl(2,4-difluorophenyl)methanone (33a) (292 mg, 1.48 mmol). The reaction mixture was heated to 160° C. for 2 hr in a microwave. The mixture was filtered and concentrated, The residue was purified by SFC chromatography to give 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (315 mg, 46% yield) and 4-[2-(azetidine-1-carbonyl)-5-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (34 mg, 5% yield) as white solid. The mixture was filtered concentrated The residue was purified by SFC chromatography

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

Procedure: The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 7.48-7.56 (m, 1 H) 7.24 (s, 1 H) 7.20 (d, J=1.26 Hz, 1 H) 6.77 (dd, J=8.59, 2.53 Hz, 1 H) 6.66 (dd, J=11.24, 2.40 Hz, 1 H) 4.21 (t, J=7.83 Hz, 2 H) 4.11-4.17 (m, 2 H) 3.65-3.74 (m, 1 H) 3.55-3.63 (m, 1 H) 3.13 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.34 (dt, J=15.60, 7.74 Hz, 2 H) 1.89-1.97 (m, 1 H) 1.56 (s, 9 H) 1.44 (s, 3 H); LCMS for C25H28FNO6 m/z 458.20 (M+H)+.

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

Procedure: The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204d) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1 H) 7.54 (t, J=8.08 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.13 (s, 1 H) 7.08 (s, 1 H) 6.81 (dd, J=8.59, 2.27 Hz, 1 H) 6.78 (d, J=2.02 Hz, 1 H) 6.68 (dd, J=11.12, 2.27 Hz, 1 H) 5.00-5.08 (m, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.16 (t, J=7.71 Hz, 2 H) 3.81 (s, 3 H) 3.60 (d, J=5.05 Hz, 2 H) 3.43 (s, 3 H) 3.15 (dd, J=16.42, 9.60 Hz, 1 H) 2.92 (dd, J=16.42, 7.33 Hz, 1 H) 2.27-2.38 (m, 2 H); LCMS for C25H25FN4O5 m/z 481.00 (M+H)+.