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2.2 Step 2: Methyl 5-bromo-2-(methylthio)benzoate (Intermediate 203)
Potassium carbonate (83.0 g, 601 mmol, 7.0 eq.) and ethyl iodide (21.4 mL, 343 mmol, 4.0 eq.) were added 0° C. to a stirred solution of 5-bromo-2-mercaptobenzoic acid (202) (20 g, 85.8 mmol, 1 eq.) in DMF (600 mL) at RT. The reaction mixture was stirred at 80° C. for 4 h. The progress of the reaction was monitored by TLC (10% EtOAc in n-hexane) to ensure the completion of the reaction. DMW (500 mL) was added and the product was extracted with ethyl acetate (3*500 mL). The combined EtOAc extract was washed with brine (300 mL), dried over sodium sulfate, filtered and filtrate was concentrated under vacuum to get the crude compound. The crude product was purified by column chromatography on silica gel (230-400 mesh size) and gradient solvent (0-5% EtOAc in n-hexane) to afford intermediate 203 (20 g, 89.3%) as an off-white solid.
Stage #1: 5-bromo-2-mercaptobenzoic acid; methyl iodide With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: methyl iodide With sodium hydride In N,N-dimethyl-formamide at 70℃;
To a DMF (0.2 M) suspension of cesium carbonate (3 eq.) and 5-bromo-2-5 mercaptobenzoic acid (1 eq.) was added iodomethane (5 eq.). The resulting suspension was then stirred at RT for 1 h. The volatiles were removed before EtOAc and sat. aq. NH4Cl were added. The organic phase was separated, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to a pale yellow oil. This was taken up again in DMF (0.2 M) and added sequentially sodium hydride (3 eq.) and iodomethane (5 eq.). The reaction vessel was then sealed and heated to 7O0C for 16 h. After cooling to10 RT, EtOAc and sat. aq. NH4Cl were added to the crude reaction mixture. The organic phase was separated, dried over MgSO4, filtered and the filtrate concentrated in vacuo to a brown oil. Purification of the crude product thus obtained by way of flash chromatography (Siθ2, Hex, -> 3:2 (v/v) Hex : EtOAc) afforded the title compound as a light yellow solid.
Stage #1: 5-bromo-2-mercaptobenzoic acid; methyl iodide With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;
Stage #2: methyl iodide With sodium hydride In N,N-dimethyl-formamide at 70℃; for 16h; vessel sealed;
75.1
To a DMF (0.2 M) suspension of cesium carbonate (3 eq.) and 5-bromo-2- mercaptobenzoic acid (1 eq.) was added iodomethane (5 eq.). The resulting suspension was then stirred at RT for 1 h. The volatiles were removed before EtOAc and sat. aq. NH4Cl were added. The organic phase was separated, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to a pale yellow oil. This was taken up again in DMF (0.2 M) and added sequentially sodium hydride (3 eq.) and iodomethane (5 eq.). The reaction vessel was then sealed and heated to 7O0C for 16 h. After cooling to RT, EtOAc and sat. aq. NH4Cl were added to the crude reaction mixture. The organic phase was separated, dried over MgSO4, filtered and the filtrate concentrated in vacuo to a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex, -> 3:2 (v/v) Hex : EtOAc) afforded the title compound as a light yellow solid
Stage #1: methylallylether With 9-borabicyclo-[3.3.1]nonane dimer In tetrahydrofuran at 20℃;
Stage #2: methyl 5-bromo-2-(methylthio)benzoate With potassium phosphate In tetrahydrofuran; N,N-dimethyl-formamide at 80℃; for 16h;
To a THF (0.29 M) solution of 9-BBN (2 eq.) was added allyl methyl ether (2.1 eq.) dropwise and the resulting solution was stirred at RT until no more gaseous evolution was observed. The reaction mixture was then heated to 5O0C for 1 h. To this solution was subsequently added a DMF (0.34 M) solution of methyl 5-bromo-2-(methylthio)benzoate (1 eq.) from the previous step, potassium phosphate (2.5 eq.) and [l,r-bis(diphenylphosphino)ferrocene]dipalladium(II) dichloromethane complex20 (0.1 eq.). The resulting red suspension was heated at 8O0C for 16 h. After cooling to RT, the reaction was diluted with ether and water. The organic layer was separated and washed further with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9: 1 (v/v) Hex : EtOAc -> 7:3 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil.
Stage #1: methylallylether With 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran at 20 - 50℃; Inert atmosphere;
Stage #2: methyl 5-bromo-2-(methylthio)benzoate With potassium phosphate In tetrahydrofuran; N,N-dimethyl-formamide at 80℃; for 16h;
75.2
To a THF (0.29 M) solution of 9-BBN (2 eq.) was added allyl methyl ether (2.1 eq.) dropwise and the resulting solution was stirred at RT until no more gaseous evolution was observed. The reaction mixture was then heated to 5O0C for 1 h. To this solution was subsequently added a DMF (0.34 M) solution of methyl 5-bromo-2-(methylthio)benzoate (1 eq.) from the previous step, potassium phosphate (2.5 eq.) and [l,l'-bis(diphenylphosphino)- ferrocene]dipalladium(II) dichloromethane complex (0.1 eq.). The resulting red suspension was heated at 8O0C for 16 h. After cooling to RT, the reaction was diluted with ether and water. The organic layer was separated and washed further with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex : EtOAc -> 7:3 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil.
With Oxone In methanol; water at 0 - 50℃; for 16h;
2.3 Step 3: Methyl 5-bromo-2-(methylsulfonyl)benzoate (Intermediate 204)
A solution of oxone (40.8 g, 268 mmol, 5.0 eq.) in DMW (280 mL) was added to stirred a solution of methyl 5-bromo-2-(methylthio)benzoate (203) (14.0 g, 53.6 mmol, 1.0 eq.) in methanol (350 mL) at 0° C. The reaction mixture was stirred at 50° C. for 16 h. The progress of the reaction was monitored by TLC (30% EtOAc in n-hexane) to ensure completion of the reaction. The product was extracted with EtOAc (4*500 mL). The combined organic extract was washed with brine (2*300 mL), dried over sodium sulfate and concentrated under vacuum to get crude. The crude product was purified by column chromatography on silica gel (230-400 mesh size) and gradient solvent (5-20% EtOAc in n-hexane) to afford intermediate 204 (13.2 g, 84.0%) as an off-white solid. 1H NMR (300 MHz, DMSO): δ 8.08-7.98 ppm (m, 2H), 7.93 ppm (dd, J=7.9, 0.9 Hz, 1H), 3.87 ppm (s, 3H), 3.44-3.35 ppm (m, 3H). MS (ESI): m/z 292.8 (M-1).
51.4%
With Oxone In methanol; water at 0 - 20℃; for 16h;
20.1
Preparation 20: methyl 2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate; Step 1 : methyl 5-bromo-2-(methylsulfonyl)benzoate; Methyl 5-bromo-2-(methylthio)benzoate (1.44g, 5.53mmol) was dissolved in methanol (50 mL) cooled to 00C. To this was added a mixture of potassium peroxymonosulfate (10.4g, 16.6mmol) in water (50 mL). The reaction was warmed up to room temperature over 16 h. The mixture was poured into ethyl acetate and the layers were separated. The organic layer was dried over magnesium sulfate then concentrated to obtain the title compound (2.5 g, 51.4%) as a solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 3.36 (3 H, s), 3.87 (3 H, s), 7.93 (1 H, d, J=8.3 Hz), 8.05 (1 H, m), 8.03 (1 H, t, J=2.2 Hz).
Multi-step reaction with 2 steps
1.1: hydrogenchloride; sodium hydroxide; sodium nitrite / water / 0.5 h / 0 - 6 °C
1.2: 0.5 h / 90 °C
2.1: potassium carbonate / 4 h / 80 °C
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