tert-butyl 4-bromo-2,6-difluorobenzoate

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (17.9 mL, 0.12 mol) in anhydrous THF at −78° C. was added n-BuLi (45.5 mL, 0.11 mol, 2.5 M in hexane) dropwise, over period of 15 min and the resulting solution was stirred at −78° C. for 30 mins. To this was added 1-bromo-3,5-difluoro benzene (20.0 g, 0.10 mol) in THF (30 mL) dropwise and it was stirred for 1 h. Finally, Boc-anhydride (26.0 mL, 0.11 mol) was added to it and the reaction mixture was slowly allowed to come to room temperature over a period of 2 h. After completion of the reaction, it was diluted with water (100 mL) and extraction was carried out using diethyl ether (300×2). The combine organic layers were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude VII-5-IV (26 g) as a brown liquid, which was used for next step with out any purification. 1H NMR (DMSO-d6, 400 MHz) δ 1.42 (s, 9H), 7.63 (d, J=8.0 Hz, 2H). it was stirred for 1 h to come to room temperature over a period of 2 h After completion of the reaction, it The combine organic layers were washed with water (250 mL), brine (250 mL) dried over anhydrous Na2SO4 filtered concentrated under reduced pressure to provide crude VII-5-IV (26 g) as a brown liquid, which was used for next step with out any purification

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (17.9 mL, 0.12 mol) in anhydrous THF at −78° C. was added n-BuLi (45.5 mL, 0.11 mol, 2.5 M in hexane) dropwise, over period of 15 min and the resulting solution was stirred at −78° C. for 30 mins. To this was added 1-bromo-3,5-difluoro benzene (20.0 g, 0.10 mol) in THF (30 mL) dropwise and it was stirred for 1 h. Finally, Boc-anhydride (26.0 mL, 0.11 mol) was added to it and the reaction mixture was slowly allowed to come to room temperature over a period of 2 h. After completion of the reaction, it was diluted with water (100 mL) and extraction was carried out using diethyl ether (300×2). The combine organic layers were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude VII-5-IV (26 g) as a brown liquid, which was used for next step with out any purification. 1H NMR (DMSO-d6, 400 MHz) δ 1.42 (s, 9H), 7.63 (d, J=8.0 Hz, 2H). it was stirred for 1 h to come to room temperature over a period of 2 h After completion of the reaction, it The combine organic layers were washed with water (250 mL), brine (250 mL) dried over anhydrous Na2SO4 filtered concentrated under reduced pressure to provide crude VII-5-IV (26 g) as a brown liquid, which was used for next step with out any purification

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 35b, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) and 4-bromo-2,6-difluoro-benzoic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1 H) 7.23 (s, 1 H) 6.48 (d, J=8.84 Hz, 2 H) 3.89 (s, 3 H) 2.88 (s, 2 H) 1.59 (s, 9 H) 1.49 (s, 6 H); LCMS for C23H24F2O6 m/z 457.20 (M+Na)+.

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 35b, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) and 4-bromo-2,6-difluoro-benzoic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1 H) 7.23 (s, 1 H) 6.48 (d, J=8.84 Hz, 2 H) 3.89 (s, 3 H) 2.88 (s, 2 H) 1.59 (s, 9 H) 1.49 (s, 6 H); LCMS for C23H24F2O6 m/z 457.20 (M+Na)+.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (17.9 mL, 0.12 mol) in anhydrous THF at −78° C. was added n-BuLi (45.5 mL, 0.11 mol, 2.5 M in hexane) dropwise, over period of 15 min and the resulting solution was stirred at −78° C. for 30 mins. To this was added 1-bromo-3,5-difluoro benzene (20.0 g, 0.10 mol) in THF (30 mL) dropwise and it was stirred for 1 h. Finally, Boc-anhydride (26.0 mL, 0.11 mol) was added to it and the reaction mixture was slowly allowed to come to room temperature over a period of 2 h. After completion of the reaction, it was diluted with water (100 mL) and extraction was carried out using diethyl ether (300×2). The combine organic layers were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude VII-5-IV (26 g) as a brown liquid, which was used for next step with out any purification. 1H NMR (DMSO-d6, 400 MHz) δ 1.42 (s, 9H), 7.63 (d, J=8.0 Hz, 2H). it was stirred for 1 h to come to room temperature over a period of 2 h After completion of the reaction, it The combine organic layers were washed with water (250 mL), brine (250 mL) dried over anhydrous Na2SO4 filtered concentrated under reduced pressure to provide crude VII-5-IV (26 g) as a brown liquid, which was used for next step with out any purification