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Step 1: A reaction mixture of 34-1 (3.5 g, 18.2 mmol) and SOCl2 (2.17 g, 18.2 mmol) in CH3OH (50 mL) was stirred at 50C for 3 hrs. The solvent was evaporated and the resulting residue was purified by column chromatography (eluent: PE/EA = 10/1) to give 34- 2 as a colorless oil. LC-MS: m/z = 207.5 [M+H]+.
177.2
Step 2: A reaction mixture of 34-2 (1.1 g, 5.32 mmol) and cyclopropanamine (608 mg, 10.65 mmol) in DMSO (10 mL) was stirred at 70°C overnight. Water was added and the resulting mixture was extracted with EA (30 mL x 3). The combined organic layer was washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography (eluent: PE to PE/EA = 10/1) to give 34-3 as a colorless oil. JH NMR (300 MHz, CDCI3) Π.73 (dd, 7 = 1.9, 1.3 Hz, 1H), 7.58 (dd, 7 = 13.1, 1.9 Hz, 1H), 4.68 (s, 1H), 3.86 (s, 3H), 3.02-2.94 (m, 1H), 0.82-0.76 (m, 2H), 0.62-0.59 (m, 2H). LC-MS: m/z = 244.1 [M+H]+.
184.1
Step 1: A mixture of 34-2 (1.5 g, 7.26 mmol), l -methoxypropan-2-amine (1.29 g, 14.5 mmol) and DMSO (10 mL) was stirred at 70°C overnight. Water was added and the resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SC>4 and evaporated. The residue was purified by column chromatography (eluent: PE to PE/EA = 100/1) to give 34B-1 as a colorless oil. JH NMR (301 MHz, CDC13) δ 7.75-7.74 (m, 1H), 7.54 (dd, / = 13.6, 1.9 Hz, 1H), 4.59 (s, 1H), 4.13-4.08 (m, 1H), 3.84 (s, 3H), 3.45-3.35 (m, 5H), 1.23 (d, / = 6.5 Hz, 3H). LC-MS: m/z = 276.0 [M+H]+.
In methanol; diethyl ether; dichloromethane at 0 - 20℃; for 1h; Inert atmosphere;
1.2.9
To a solution of 3-chloro-4,5-difluorobenzoic acid (CAS150444-95-4; 1 g, 5.19 mmol, 1 eq) in 1/1 mixture of DCM/MeOH (20 mL) was added (diazomethyl)trimethylsilane (2M Et20 solution, 3.24 mL, 6.49 mmol, 1.25 eq) at 0°C under N2 atmosphere. The reaction mixture was stirred at room temperature for lh, quenched with AcOH and extracted with DCM. The combined organic layers were filtered on phase separator, concentrated under vacuum to afford the title intermediate.
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