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Stage #1: 1-bromo-4-chloro-2-fluorobenzene With lithium diisopropyl amide In tetrahydrofuran at -50 - -20℃; for 1h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -50 - 0℃; |
1 Step-1 : Synthesis of 3-bromo-6-chloro-2-fluorobenzaldehyde 2
To a stirred solution of l-Bromo-4-chloro-2-fluorobenzene Al (200 g, 0.955 mol, 1.0 equiv.) in anhydrous THF (2.0 L) was added 2.0 M lithium diisopropylamide (LDA) in THF (620 mL, 1.24 mol, 1.3 equiv.) at -50 °C, the reaction mixture was allowed to -20 °C and stirred for 1 h. Then it was re-cooled to -50 °C and slowly added DMF (184.8 mL, 2.48 mol, 2.6 equiv.) at the same temperature. The mixture was allowed to 0 °C and stirred for 30-45 min. After completion of the reaction (monitored by TLC), it was quenched with the slow addition of ice cold water (2.0 L); then diluted with ethyl acetate (2.0 L) and stirred for 15 min at room temperature. The organic layer was separated and aqueous layer was extracted with ethyl acetate (2 x 1.0 L). The combined organic layers were washed with water (2 x 1 0 L); 1.0 N HC1 (1 0 L) and 1 % NaCl solution (2.0 L). The organic layer was dried over anhydrous Na2SC , concentrated under vacuum. The resultant crude solid was directly used for next step without further purification. Yield: 210.0 g, 93% (reported 78%). NMR (400 MHz, CDCb): δ 10.39 (d, J= 0.8 Hz, 1H), 7.69 (dd, Ji = 7.2 Hz, J2 = 8.8 Hz, 1H), 7.19 (dd, Ji = 1.2 Hz, J2 = 8.4 Hz, 1H). |
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Stage #1: 1-bromo-4-chloro-2-fluorobenzene With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -35 - -30℃; Large scale;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -35 - -30℃; Large scale; |
I.7
To a reactor was added tetrahydrofuran (THF, 275 kg) and diisopropyl amine (DIP A, 30 kg) and the mixture was cooled to about -35 °C. nButyl lithium (2.5 mol/L in hexanes, 74 kg) was charged slowly keeping the reaction temperature less than -30 °C. The mixture was agitated at-35 °C until the reaction was complete. 1 -brom o-4-chl oro-2-fluorobenzene (52 kg) was charged keeping reaction temperature less than 30 °C and the mixture was agitated at -35°C until reaction was complete. N,N-dimethylform amide (DMF, 36 kg) was charged keeping reaction temperature less than -30 °C and the mixture was agitated at about -35 °C until reaction was complete. Hydrochloric acid (HO, 18 mass% in water, 147 kg) was charged keeping reaction temperature less than -5 °C. The reaction was warmed to about 0 °C, water (312 kg) was added, and the reaction was extracted with methyl tert-butyl ether (MTBE, 770 kg). The organic was warmed to about 20 °C and washed with brine (NaCl, 23.5 mass% in water, 1404 kg). The mixture was distilled to about 3-4 volumes and heptane was charged (354 kg). The product was isolated by distillation to 3-4 volumes. The slurry was filtered and washed with heptane (141 kg) and dried to afford 6a. 1H NMR (400 MHz, DMSO-i/6) d 10.23 (d, J= 1.2 Hz, 1H), 8.00 (dd, j = 8.7, 1.4 Hz, 1H), 7.44 (dd, j= 8.7, 1.4 Hz, 1H). |
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Stage #1: 1-bromo-4-chloro-2-fluorobenzene With lithium diisopropyl amide In tetrahydrofuran at -50 - -20℃; for 1h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -50 - 0℃; |
1
Step-l: Synthesis of 3-bromo-6-chloro-2-fluorobenzaldehyde 2Reaction scheme: To a stirred solution of l-Bromo-4-chloro-2-fluorobenzene (200 g, 0.955 mol, 1.0 equiv.) in anhydrous THF (2.0 L) was added 2.0 M lithium diisopropylamide (LDA) in THF (620 mL, 1.24 mol, 1.3 equiv.) at -50 °C, the reaction mixture was allowed to -20 °C and stirred for 1 h. Then it was re-cooled to -50 °C and slowly added DMF (184.8 mL,2.48 mol, 2.6 equiv.) at the same temperature. The mixture was allowed to 0 °C and stirred for 30-45 min. After completion of the reaction (monitored by TLC), it was quenched with the slow addition of ice cold water (2.0 L); then diluted with ethyl acetate (2.0 L) and stirred for 15 min at room temperature. The organic layer was separated and aqueous layer was extracted with ethyl acetate (2 x 1.0 L). The combined organic layers were washed with water (2 x 1.0 L); 1.0 N HC1 (1.0 L) and.5% NaCl solution (2.0 L). The organic layer was dried over anhydrous NaiSOr. concentrated under vacuum. The resultant crude solid was directly used for next step without further purification. Yield: 210.0 g, 93% (reported 78%). NMR (400 MHz, CDCb): d 10.39 (d, J= 0.8 Hz, 1H), 7.69 (dd, Ji = 7.2 Hz, J2 = 8.8 Hz, 1H), 7.19 (dd, Ji = 1.2 Hz, J2 = 8.4 Hz, 1H). |
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Stage #1: 1-bromo-4-chloro-2-fluorobenzene With lithium diisopropyl amide In tetrahydrofuran at -50 - -20℃; for 1h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -50 - 0℃; |
3-bromo-6-chloro-2-Jluorobenzaldehyde
To a stirred solution of l-bromo-4-chloro-2-fluorobenzene (200 g, 0.955 mol, 1.0 equiv.) in anhydrous THF (2.0 F) was added a solution of FDA in THF (2.0 M, 620 mF, 1.24 mol, 1.3 equiv.) at -50 °C. The reaction mixture was allowed to warm to -20 °C and was stirred for 1 h. The mixture was cooled to -50 °C and slowly to the mixture was added DMF (184.8 mF, 2.48 mol, 2.6 equiv.) maintaining a temperature of -50 °C. The mixture was allowed to warm to 0 °C and was stirred for 30-45 min at the same temperature (0 °C) The mixture was quenched via the slow addition of ice cold water (2.0 F). The reaction mixture was diluted with ethyl acetate (2.0 F) and stirred for 15 min at room temperature. The organic layer was separated and reserved; the aqueous layer was extracted with ethyl acetate (2 x 1.0 F). The combined organic layers were washed with water (2 x 1.0 F); 1.0 N HC1 (1.0 F) and then 15% NaCl solution (2.0 F). The organic solution was dried over NaiSCri: filtered; and then concentrated in vacuo. The resultant crude solid was used directly in the next step without further purification. Yield for the crude product: 210.0 g (93%). |
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Stage #1: 1-bromo-4-chloro-2-fluorobenzene With lithium diisopropyl amide In tetrahydrofuran at -50 - -20℃; for 1h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -50 - 0℃; |
Preparation of 3-bromo-6-chloro-2-fluorobenzaldehyde
To a stirred solution of 1-bromo-4-chloro-2-fluorobenzene (200 g, 0.955 mol, 1.0 equiv.) in anhydrous THF (2.0 L) was added a solution of LDA in THF (2.0 M, 620 mL, 1.24 mol, 1.3 equiv.) at -50 °C. The reaction mixture was allowed to warm to -20 °C and was stirred for 1 h. The mixture was cooled to -50 °C and slowly to the mixture was added DMF (184.8 mL, 2.48 mol, 2.6 equiv.) maintaining a temperature of -50 °C. The mixture was allowed to warm to 0 °C and was stirred for 30-45 min at the same temperature (0 °C). The mixture was quenched via the slow addition of ice-cold water (2.0 L). The reaction mixture was diluted with ethyl acetate (2.0 L) and stirred for 15 min at room tempreature. The organic layer was separated and reserved; the aqueous layer was extracted with ethyl acetate (2 x 1.0 L). The combined organic layers were washed with water (2 x 1.0 L); 1.0 N HCl (1.0 L) and then 15% NaCl solution (2.0 L). The organic solution was dried over Na2SO4; filtered; and then concentrated in vacuo. The resultant crude solid was used directly in the next step without further purification. Yield for the crude product: 210.0 g (93%). |
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Stage #1: 1-bromo-4-chloro-2-fluorobenzene With lithium diisopropyl amide In tetrahydrofuran at -50 - -20℃; for 1h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -50 - 0℃; |
Preparation of 3-bromo-6-chloro-2-fluorobenzaldehyde
To a stirred solution of l-bromo-4-chloro-2-fluorobenzene (200 g, 0.955 mol, 1.0 equiv.) in anhydrous THF (2.0 L) was added a solution of LDA in THF (2.0 M, 620 mL, 1.24 mol, 1.3 equiv.) at -50 °C. The reaction mixture was allowed to warm to -20 °C and was stirred for 1 h. The mixture was cooled to -50 °C and slowly to the mixture was added DMF (184.8 mL, 2.48 mol, 2.6 equiv.) maintaining a temperature of -50 °C. The mixture was allowed to warm to 0 °C and was stirred for 30-45 min at the same temperature (0 °C). The mixture was quenched via the slow addition of ice cold water (2.0 L). The reaction mixture was diluted with ethyl acetate (2.0 L) and stirred for 15 min at room tempreature. The organic layer was separated and reserved; the aqueous layer was extracted with ethyl acetate (2 x 1.0 L). The combined organic layers were washed with water (2 x 1.0 L); 1.0 N HC1 (1.0 L) and then l5% NaCl solution (2.0 L). The organic solution was dried over NaiSOr: filtered; and then concentrated in vacuo. The resultant crude solid was used directly in the next step without further purification. Yield for the crude product: 210.0 g (93%). |
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Stage #1: 1-bromo-4-chloro-2-fluorobenzene With lithium diisopropyl amide In tetrahydrofuran at -50 - -20℃; for 1h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -50 - 0℃; |
Preparation of 3-bromo-6-chloro-2-fluorobenzaldehyde
To a stirred solution of l-bromo-4-chloro-2-fluorobenzene (200 g, 0.955 mol, 1.0 equiv.) in anhydrous THF (2.0 F) was added a solution of FDA in THF (2.0 M, 620 mF, 1.24 mol, 1.3 equiv.) at -50 °C. The reaction mixture was allowed to warm to -20 °C and was stirred for 1 h. The mixture was cooled to -50 °C and slowly to the mixture was added DMF (184.8 mL, 2.48 mol, 2.6 equiv.) maintaining a temperature of -50 °C. The mixture was allowed to warm to 0 °C and was stirred for 30-45 min at the same temperature (0 °C). The mixture was quenched via the slow addition of ice cold water (2.0 L). The reaction mixture was diluted with ethyl acetate (2.0 L) and stirred for 15 min at room tempreature. The organic layer was separated and reserved; the aqueous layer was extracted with ethyl acetate (2 x 1.0 L). The combined organic layers were washed with water (2 x 1.0 L); 1.0 N HC1 (1.0 L) and then 15% NaCl solution (2.0 L). The organic solution was dried over NaiSOr: filtered; and then concentrated in vacuo. The resultant crude solid was used directly in the next step without further purification. Yield for the crude product: 210.0 g (93%). |
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Stage #1: 1-bromo-4-chloro-2-fluorobenzene With lithium diisopropyl amide In tetrahydrofuran at -50 - -20℃; for 1h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -50 - 0℃; |
Preparation of 3-bromo-6-chloro-2-fluorobenzaldehyde
To a stirred solution of l-bromo-4-chloro-2-fluorobenzene (200 g, 0.955 mol, 1.0 equiv.) in anhydrous THF (2.0 F) was added a solution of FDA in THF (2.0 M, 620 mF, 1.24 mol, 1.3 equiv.) at -50 °C. The reaction mixture was allowed to warm to -20 °C and was stirred for 1 h. The mixture was cooled to -50 °C and slowly to the mixture was added DMF (184.8 mL, 2.48 mol, 2.6 equiv.) maintaining a temperature of -50 °C. The mixture was allowed to warm to 0 °C and was stirred for 30-45 min at the same temperature (0 °C). The mixture was quenched via the slow addition of ice cold water (2.0 L). The reaction mixture was diluted with ethyl acetate (2.0 L) and stirred for 15 min at room tempreature. The organic layer was separated and reserved; the aqueous layer was extracted with ethyl acetate (2 x 1.0 L). The combined organic layers were washed with water (2 x 1.0 L); 1.0 N HC1 (1.0 L) and then 15% NaCl solution (2.0 L). The organic solution was dried over NaiSOr: filtered; and then concentrated in vacuo. The resultant crude solid was used directly in the next step without further purification. Yield for the crude product: 210.0 g (93%). |
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Stage #1: 1-bromo-4-chloro-2-fluorobenzene With lithium diisopropyl amide In tetrahydrofuran at -50 - -20℃; for 1h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -50 - 0℃; |
Preparation of 3-bromo-6-chloro-2-fluorobenzaldehyde
To a stirred solution of l-bromo-4-chloro-2-fluorobenzene (200 g, 0.955 mol, 1.0 equiv.) in anhydrous THF (2.0 L) was added a solution of LDA in THF (2.0 M, 620 mL, 1.24 mol, 1.3 equiv.) at -50 °C. The reaction mixture was allowed to warm to -20 °C and was stirred for 1 h. The mixture was cooled to -50 °C and slowly to the mixture was added DMF (184.8 mL, 2.48 mol, 2.6 equiv.) maintaining a temperature of -50 °C. The mixture was allowed to warm to 0 °C and was stirred for 30-45 min at the same temperature (0 °C). The mixture was quenched via the slow addition of ice cold water (2.0 L). The reaction mixture was diluted with ethyl acetate (2.0 L) and stirred for 15 min at room temperature. The organic layer was separated and reserved; the aqueous layer was extracted with ethyl acetate (2 x 1.0 L). The combined organic layers were washed with water (2 x 1.0 L); 1.0 N HCI (1.0 L) and then 15% NaCI solution (2.0 L). The organic solution was dried over Na2SC>4; filtered; and then concentrated in vacuo. The resultant crude solid was used directly in the next step without further purification. Yield for the crude product: 210.0 g (93%). |
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