* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium dithionite In water at 0 - 30℃; for 1 h;
1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one from previous step (50 g, 0.234 mol) was added to 2 liter round bottom flask. Water (1L) was added, and the yellow suspension was stirred at Rt. Sodium dithionite (225 g, 5.5 eq) was added in one portion and the reaction mixture was stirred and kept < 30 C until HPLC analysis indicated no starting material remained (typically less than 1 hour). Upon completion, the reaction mixture was cooled to 0 C and the tan solid product was collected by vacuum filtration. The wet product was dried at <50 C under house vacuum to afford 4-fluoro-2-methyl-1H-indol-5-ol (31.4 g, 81 percent yield) which was isolated as a tan crystalline powder. The material had an HPLC purity of >99.8. 1H NMR (CDC3, 400 MHz) δ 7.8 (s, 1H), 6.9-6.7 (m, 2H), 6.2 (s, 1H), 4.7 (s, 1H), 2.4 (s, 3H). 13 C NMR (CDCl3, 100 MHz) δ 145.7, 143.4, 137.5, 136.7, 134.4, 120.1, 112.7, 106.8, 95.4, 13.3
68%
With sodium dithionite; potassium carbonate In water at 25℃; for 2 h; Industry scale
Preparation of 4-fluoro-2 -methyl- lH-indol-5-ol (large scale)To a solution of potassium carbonate (79 kg) in water (800 kg) was added l-(2-fluoro-3- hydroxy-6-nitrophenyl)-propan-2-one (61 kg) and the mixture stirred to give a solution. To this solution at 250C was added a solution of sodium dithionite (298 kg) in water (750 kg).The mixture was held at 250C for 2 hours. The product was isolated by filtration, washing the filter cake with water (366 kg). The product was dried under reduced pressure (50 mbar) at350C. Yield: 34 kg, 72percent. The crude 4-fluoro-2-methyl-lH-indol-5-ol (33 kg) was dissolved in dichloromethane(880 1) and filtered through silica (33 kg). The filter was washed with dichloromethane (4401). The combined filtrates were distilled, removing 835 1 of distillate. This concentrate was EPO <DP n="43"/>added rapidly to σhexane (360 kg), resulting in a suspension. The batch was distilled, removing 436 1 of distillate. The batch was cooled to 00C, aged for 1 hour and then filtered. The filter cake was washed with /soehexane (73 kg). The product was dried under reduced pressure (50 mbar) at 35°C. Yield: 31 kg, 68percent based on l-(2-fluoro-3-hydroxy-6- s nitrophenyl)-propan-2-one.
17%
With hydrogen In ethanol at 20℃; for 8 h;
Step 3c: 4-Fluoro-2-methyl-1H-indol-5-ol (Compound 304) A mixture of 303 (900 mg, 4.2 mmol), Pd/C (90 mg) and ethanol (20 mL) was stirred under H2 at ambient temperature for 8 h. The solvent was removed and the residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1/15) to give the title compound 304 as a brown solid (120 mg, 17percent): LCMS: 166 [M+1]+; 1H NMR (DMSO-d6): δ 2.34 (s, 3H), 6.05 (s, 1H), 6.64 (t, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 8.70 (s, 1H), 10.84 (s, 1H).
Reference：
[1] Patent: WO2004/9542, 2004, A2, . Location in patent: Page 35
[2] Organic Process Research and Development, 2014, vol. 18, # 1, p. 89 - 102
[3] Patent: WO2008/53221, 2008, A2, . Location in patent: Page/Page column 41-42
[4] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 28
[5] Patent: WO2008/53221, 2008, A2, . Location in patent: Page/Page column 39-40
[6] Patent: WO2004/9542, 2004, A2, . Location in patent: Page 26
2
[ 288385-98-8 ]
[ 10035-10-6 ]
[ 649736-31-2 ]
Yield
Reaction Conditions
Operation in experiment
80%
With acetic anhydride In acetic acid at 20 - 100℃; for 0.5 h; Heating / reflux
To a solution of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (3. 03 g, 10 mmol) in acetic anhydride (5 mL) and acetic acid (5 mL) at room temperature was added hydrobromic acid (48 percent aqueous solution, 3 mL). After addition, the reaction was heated at 100 C for 30 min and then cooled to room temperature. To this mixture was added 10 [ml] of hexanes with stirring. The solution was decanted and concentrated. The residue was diluted with ethyl acetate (50 mL) and washed with brine (3 x 20 mL). The organic layer was dried and concentrated in vacuo to provide 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1.7 g, 80 percent) as a brown solid, which was used in the next step without further purification. LC/MS; (M+H)+ = 213.2
With sodium acetate In N,N-dimethyl-formamide at 100℃; for 12 h;
Step 3b: 1-(2-Fluoro-3-hydroxy-6-nitrophenyl)propan-2-one (Compound 303) A mixture of 302 (4.30 g, 0.02 mol), AcONa (1.72 g, 0.021 mol) and DMF (40 mL) was stirred at 100° C. for 12 h. The mixture was then filtered and the solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (100 mL). The organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1/1) to give compound 303 (2.3 g, 54percent) as a pale yellow solid: LCMS: 214 [M+1]+; 1H NMR (DMSO-d6): δ 2.30 (s, 3H), 4.26 (s, 2H), 7.67 (m, 1H), 8.05 (m, 1H).
Reference：
[1] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 27-28
[2] Organic Process Research and Development, 2014, vol. 18, # 1, p. 89 - 102
4
[ 288385-99-9 ]
[ 649736-31-2 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 20 - 180℃; for 1.25 h; Heating / reflux
A mixture of 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one from previous step (454 mg, 21 mmol) and pyridinium chloride (0.9 g, 7.8 mmol) was stirred at 180 C for 75 min. The reaction was cooled to room temperature, diluted with 1N HCl (3mL) and ethyl acetate (10 mL) and filtered. The filtrate was washed with brine (2x), dried and concentrated in vacuo to give 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (410 mg, 96 percent) as a grey solid, which was used without further purification for the next step. LC/MS; (M+H)+ = 214. 1H NMR (CDCl3): δ 2.37 (s, 3H), 4.22 (s, 2H), 6.95 (dd, 1H), 7.95 (d, 1H, J= 9.35 Hz)
Reference：
[1] Patent: WO2004/9542, 2004, A2, . Location in patent: Page 35
[2] Organic Process Research and Development, 2014, vol. 18, # 1, p. 89 - 102
5
[ 288385-98-8 ]
[ 649736-31-2 ]
Yield
Reaction Conditions
Operation in experiment
81%
at 20 - 180℃; for 1 h;
A mixture of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (65.0 g, 0.214 mol) and pyridinium chloride (60.74 g, 0.526 mol) was stirred at 180 C for 1 hr. The reaction mixture was cooled to room temperature, diluted with 3N HCl (100 mL) and ethyl acetate (500 mL) and filtered. The aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were washed with brine, dried MgSO4, s filtered through a pad of silica gel and concentrated in vacuo. The residue was decolorized with charcoal in methanol, filtered and concentrated in vacuo to afford 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (37 g, 81 percent) as a brown solid. LC/MS; (M+H)+ = 213.2
With sulfuric acid; acetic acid In water at 97℃; for 3.5 h;
Preparation of l-C2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-oneTo a mixture of acetic acid (57 ml) and water (68 ml) was added sulphuric acid (61 ml). The mixture was warmed to 970C and an aqueous solution containing ethyl 2-(2-fluoro-3- hydroxy-6-nitrophenyl)-3-oxobutanoate (31.6 g) added. The mixture was heated at 97°C for 3.5 hours, then cooled to 80°C and water (95 ml) added. The mixture was cooled to 400C and seeded with l-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (2 mg). The mixture was cooled to 00C and stirred overnight. The mixture was filtered and washed three times with water (58 ml). The product was dried in a vacuum oven to give l-(2-fluoro-3-hydroxy-6- nitrophenyl)-propan-2-one (8.42g, 35.7percent). Mass Spectrum [M-HV 212 IH NMR Spectrum (400 MHz, DMSO-J6) δ ppm 2.27 (s, 3 H) 4.18 (s, 2 H) 7.06 (t, J=8.94 Hz, 1 H) 7.92 (dd, J=9.21, 1.67 Hz, 1 H) 11.44 (br. s., 1 H)
With acetic anhydride; In acetic acid; at 20 - 100℃; for 0.5h;Heating / reflux;
To a solution of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (3. 03 g, 10 mmol) in acetic anhydride (5 mL) and acetic acid (5 mL) at room temperature was added hydrobromic acid (48 percent aqueous solution, 3 mL). After addition, the reaction was heated at 100 C for 30 min and then cooled to room temperature. To this mixture was added 10 [ml] of hexanes with stirring. The solution was decanted and concentrated. The residue was diluted with ethyl acetate (50 mL) and washed with brine (3 x 20 mL). The organic layer was dried and concentrated in vacuo to provide 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1.7 g, 80 percent) as a brown solid, which was used in the next step without further purification. LC/MS; (M+H)+ = 213.2
With pyridine hydrochloride; at 20 - 180℃; for 1.0h;
A mixture of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (65.0 g, 0.214 mol) and pyridinium chloride (60.74 g, 0.526 mol) was stirred at 180 C for 1 hr. The reaction mixture was cooled to room temperature, diluted with 3N HCl (100 mL) and ethyl acetate (500 mL) and filtered. The aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were washed with brine, dried MgSO4, s filtered through a pad of silica gel and concentrated in vacuo. The residue was decolorized with charcoal in methanol, filtered and concentrated in vacuo to afford 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (37 g, 81 percent) as a brown solid. LC/MS; (M+H)+ = 213.2
With pyridine hydrochloride; at 20 - 180℃; for 1.25h;Heating / reflux;
A mixture of 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one from previous step (454 mg, 21 mmol) and pyridinium chloride (0.9 g, 7.8 mmol) was stirred at 180 C for 75 min. The reaction was cooled to room temperature, diluted with 1N HCl (3mL) and ethyl acetate (10 mL) and filtered. The filtrate was washed with brine (2x), dried and concentrated in vacuo to give 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (410 mg, 96 %) as a grey solid, which was used without further purification for the next step. LC/MS; (M+H)+ = 214. 1H NMR (CDCl3): delta 2.37 (s, 3H), 4.22 (s, 2H), 6.95 (dd, 1H), 7.95 (d, 1H, J= 9.35 Hz)
With sodium dithionite; In water; at 0 - 30℃; for 1h;
1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one from previous step (50 g, 0.234 mol) was added to 2 liter round bottom flask. Water (1L) was added, and the yellow suspension was stirred at Rt. Sodium dithionite (225 g, 5.5 eq) was added in one portion and the reaction mixture was stirred and kept < 30 C until HPLC analysis indicated no starting material remained (typically less than 1 hour). Upon completion, the reaction mixture was cooled to 0 C and the tan solid product was collected by vacuum filtration. The wet product was dried at <50 C under house vacuum to afford 4-fluoro-2-methyl-1H-indol-5-ol (31.4 g, 81 % yield) which was isolated as a tan crystalline powder. The material had an HPLC purity of >99.8. 1H NMR (CDC3, 400 MHz) delta 7.8 (s, 1H), 6.9-6.7 (m, 2H), 6.2 (s, 1H), 4.7 (s, 1H), 2.4 (s, 3H). 13 C NMR (CDCl3, 100 MHz) delta 145.7, 143.4, 137.5, 136.7, 134.4, 120.1, 112.7, 106.8, 95.4, 13.3
68%
With sodium dithionite; potassium carbonate; In water; at 25℃; for 2h;Industry scale;Product distribution / selectivity;
Preparation of 4-fluoro-2 -methyl- lH-indol-5-ol (large scale)To a solution of potassium carbonate (79 kg) in water (800 kg) was added l-(2-fluoro-3- hydroxy-6-nitrophenyl)-propan-2-one (61 kg) and the mixture stirred to give a solution. To this solution at 250C was added a solution of sodium dithionite (298 kg) in water (750 kg).The mixture was held at 250C for 2 hours. The product was isolated by filtration, washing the filter cake with water (366 kg). The product was dried under reduced pressure (50 mbar) at350C. Yield: 34 kg, 72%. The crude 4-fluoro-2-methyl-lH-indol-5-ol (33 kg) was dissolved in dichloromethane(880 1) and filtered through silica (33 kg). The filter was washed with dichloromethane (4401). The combined filtrates were distilled, removing 835 1 of distillate. This concentrate was EPO <DP n="43"/>added rapidly to ?hexane (360 kg), resulting in a suspension. The batch was distilled, removing 436 1 of distillate. The batch was cooled to 00C, aged for 1 hour and then filtered. The filter cake was washed with /s°hexane (73 kg). The product was dried under reduced pressure (50 mbar) at 35C. Yield: 31 kg, 68% based on l-(2-fluoro-3-hydroxy-6- s nitrophenyl)-propan-2-one.
17%
With hydrogen;palladium on activated charcoal; In ethanol; at 20℃; for 8h;
Step 3c: 4-Fluoro-2-methyl-1H-indol-5-ol (Compound 304) A mixture of 303 (900 mg, 4.2 mmol), Pd/C (90 mg) and ethanol (20 mL) was stirred under H2 at ambient temperature for 8 h. The solvent was removed and the residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1/15) to give the title compound 304 as a brown solid (120 mg, 17%): LCMS: 166 [M+1]+; 1H NMR (DMSO-d6): delta 2.34 (s, 3H), 6.05 (s, 1H), 6.64 (t, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 8.70 (s, 1H), 10.84 (s, 1H).
With sodium dithionite; potassium carbonate; In water; for 1.5h;Product distribution / selectivity;
Preparation of 4-fluoro-2 -methyl- lH-indol-5-ol (small scale) l-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1 g) was dissolved in a solution of potassium carbonate (1.3g) in water (13 ml). A solution of sodium dithionite (5.24g) in water (12.3 ml) was added dropwise. The mixture was stirred for 1.5 hours, then left to stand overnight. The solid was filtered and washed with water (6 ml). The solid was dried at 35C in a vacuum oven to give crude 4-fluoro-2-methyl-lH-indol-5-ol (0.5 g, 64.5%). EPO <DP n="41"/>The crude solid (250 mg) was dissolved in dichloromethane (6.75 ml) and filtered through a pad of silica (250 mg). The filter pad was washed with dichloromethane (3.4 ml).The combined filtrates were distilled, removing 6 ml of dsitillate. The concentrate was then added dropwise to ohexane (4.25 ml) and the mixture concentrated, removing 3 ml of distillate. The mixture was cooled in an ice-bath and the precipitate filtered and washed with wohexane (0.9 ml). The solid was dried in a vacuum oven at 350C to give 4-fluoro-2-methyl- lH-indol-5-ol (180 mg, 72%)Mass Spectrum [M+eta]+ 166IH NMR Spectrum (400 MHz, DMSO-J6) delta ppm 2.33 (s, 3 H) 6.02 - 6.05 (m, 1 H) 6.64 (t, J=8.41 Hz, 1 H) 6.87 (d, J=8.51 Hz, 1 H) 8.68 (s, 1 H) 10.81 (br. s., 1 H)
Preparation of l-(3-H"7-(benzyloxy)-6-methoxyquinazolin-4-ylloxyl-2-fluoro-6- nitrophenvDacetone l-(2-Fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (4.286 g) was suspended in acetonitrile(16 ml) and cooled to -5C. To the slurry was added aqueous sodium hydroxide (0.93 ml of io 46.9%w/w solution). A line wash of acetonitrile (16 ml) was applied.This cold solution was added to a solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (4.26 g) in anisole (28.8 ml) at 80C over 15 minutes. A line wash of acetonitrile (16 ml) was applied. The mixture was heated at 8O0C for 21 hours. The stirrer was stopped and the lower aqueous layer separated. The upper organic layer was washed further with water (6 ml) at is 8O0C.The batch was cooled to 200C and concentrated under reduced pressure (130 mbar), allowing the batch temperature to reach 1000C, collecting 24 ml of distillate. The batch temperature was adjusted to 65C and a solution of water (4 ml) in methanol (28 ml) added. The mixture was cooled to 200C and the product filtered. The filter cake was washed with methanol (2 x20 12 ml) and dried in a vacuum oven at overnight to give l-(3-[7-(benzyloxy)-6- methoxyquinazolin-4-yl]oxy}-2-fluoro-6-nitrophenyl)acetone (4.543 g, 67% of theory). IH NMR Spectrum (400 MHz, DMSO-J6) delta ppm 2.29 (s, 3 H) 4.00 (s, 3 H) 4.27 (s, 2 H) 5.37 (s, 2 H) 7.38 (m, 1 H) 7.44 (m, 2 H) 7.53 (m, 2 H) 7.56 (s, 1 H) 7.62 (s, 1 H) 7.77 (dd, J=9.1, 7.8 Hz, IH) 8.12 (dd, J=9.05, 0.81 Hz, 1 H) 8.59 (s, 1 H)25 Mass Spectrum [M+H]+
With sulfuric acid; acetic acid; In water; at 90℃; for 4.0h;Product distribution / selectivity;
Preparation of l-f2-fluoro-3-hvdroxy-6-nitrophenylVpropan-2-one Water (17.7 ml) was added to acetic acid (15.6 ml) followed by sulphuric acid (16.6 ml). To this solution was added an aqueous solution containing methyl 2-(2-fluoro-3-hydiOxy-6- nitrophenyl)-3-oxobutanoate (8.195 g) and the mixture heated at 9O0C for 4 hours. The mixture was cooled to 80C and water (24.6 ml) added. The mxture was cooled to 400C and a seed of l-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (2 mg) added. The mixture was cooled to O0C and left to stir overnight. The solid was filtered, washed three times with water (15 ml) and dried under vacuum at 400C to give l-(2-fluoro-3-hydroxy-6-nitrophenyl)- propan-2-one (320 mg, ) Mass Spectrum [M-Hp 214 IH NMR Spectrum (400 MHz, DMS(W6) delta ppm 1.75 (s, 3 H enol) 3.59 (s, 3 H enol) 6.56 (t, J=9.27 Hz, 1 H enol) 7.86 (dd, J=9.43, 1.24 Hz, 1 H enol) 12.72 (br. s., 1 H enol)
With sulfuric acid; acetic acid; In water; at 97℃; for 3.5h;Product distribution / selectivity;
Preparation of l-C2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-oneTo a mixture of acetic acid (57 ml) and water (68 ml) was added sulphuric acid (61 ml). The mixture was warmed to 970C and an aqueous solution containing ethyl 2-(2-fluoro-3- hydroxy-6-nitrophenyl)-3-oxobutanoate (31.6 g) added. The mixture was heated at 97C for 3.5 hours, then cooled to 80C and water (95 ml) added. The mixture was cooled to 400C and seeded with l-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (2 mg). The mixture was cooled to 00C and stirred overnight. The mixture was filtered and washed three times with water (58 ml). The product was dried in a vacuum oven to give l-(2-fluoro-3-hydroxy-6- nitrophenyl)-propan-2-one (8.42g, 35.7%). Mass Spectrum [M-HV 212 IH NMR Spectrum (400 MHz, DMSO-J6) delta ppm 2.27 (s, 3 H) 4.18 (s, 2 H) 7.06 (t, J=8.94 Hz, 1 H) 7.92 (dd, J=9.21, 1.67 Hz, 1 H) 11.44 (br. s., 1 H)
Preparation of l-(2-fluoro-3-hydroxy-6-nitrophengammalVpropan-2-one (small scale) To a solution of tert-butyl 2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate (7.89 g) in dichloromethane was added trifluoroacetic acid (11.2g) and the mixture stirred at ambient temperature for 20 hours. The mixture was concentrated to a thick paste and toluene (14 ml) added and the mixture distilled on a rotary evaporator (77 mbar, bath 4O0C). Further toluene (14 ml) was added and the mixture distilled. Sodium hydroxide (7.4% w/w, 20 ml) was added and the lower aqueous layer separated and washed with toluene (18 ml). The aqueous layer was diluted with water (20 ml) and warmed to 40C. Acetic acid (13 ml) was added followed by sulphuric acid (20% w/w, 20 ml). The mixture was cooled to O0C and further water (43 ml) added. The mixture was cooled to -50C and left overnight. The solid was filtered and washed with water (24 ml). The solid was dried in a vacuum oven to give l-(2-fluoro-3- hydroxy-6-nitrophenyl)-propan-2-one (1.65g, 30.7%). Mass Spectrum FM-H]' 214 IH NMR Spectrum (400 MHz, OMSO-d6) delta ppm 2.27 (s, 3 H) 4.18 (d, J=I.62 Hz, 2 H) 7.06 (t, J=9.00 Hz, 1 H) 7.92 (dd, J=9.16, 1.72 Hz, 1 H) 11.43 (br. s., 1 H)
Preparation of l-(2-fluoro-3-hvdroxy-6-nitrophenyl)-propan-2-one (large scale)To tert-butyl 2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate in dichloromethane from above was added further dichloromethane (123 1) followed by trifluoroacetic acid (158 kg) whilst maintaining the temperature at 25C. The reaction was stirred for 20 hours. The mixture was distilled, removing 283 kg of distillate. Toluene (176 1) was added and the mixture distilled, removing 208 kg of distillate. Further toluene (176 1) was added and the mixture distilled, removing 133 kg of distillate. To the residue was added 7.4%w/w aqueous sodium hydroxide (-705 kg) until the mixture was pH 10.5. The aqueous layer was separated and washed with toluene (250 1). The aqueous layer was diluted with water (250 1), heated to 4O0C and acetic acid (191.4 kg) added, reducing the pH from 10.1 to 3.8. The pH was then adjusted to 1 with 20% w/w sulphuric acid (~315 kg). The mixture was cooled to O0C and seeded with l-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one. Further water (600 kg) was added and the solid isolated by filtration. The filter cake was washed with water (300 1). The product was dried under vacuum (50 mbar) at 4O0C. Yield: 56.0 kg, 74% based on 1,2,3- trifluoro-4-nitrobenzene.
With sodium acetate; In N,N-dimethyl-formamide; at 100℃; for 12.0h;
Step 3b: 1-(2-Fluoro-3-hydroxy-6-nitrophenyl)propan-2-one (Compound 303) A mixture of 302 (4.30 g, 0.02 mol), AcONa (1.72 g, 0.021 mol) and DMF (40 mL) was stirred at 100 C. for 12 h. The mixture was then filtered and the solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (100 mL). The organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1/1) to give compound 303 (2.3 g, 54%) as a pale yellow solid: LCMS: 214 [M+1]+; 1H NMR (DMSO-d6): delta 2.30 (s, 3H), 4.26 (s, 2H), 7.67 (m, 1H), 8.05 (m, 1H).
With 1,4-diaza-bicyclo[2.2.2]octane; In 1-methyl-pyrrolidin-2-one; at 100℃;
7-Benzyloxy-4-chloro-6-methoxyquinoline 1 (29.98 g, 100 mmol) was added to a three-neck flask.1-(2-Fluoro-3-hydroxy-6-nitrophenyl)propyl-2-one 2 (21.32 g, 100 mmol)And N-methylpyrrolidone (150 mL), DABCO (11.22 g, 100 mmol),After stirring uniformly, the mixture was heated to 100 C to react overnight.At the end of the reaction, water (600 mL) was added to precipitate a large amount of solid and filtered.The crude product was recrystallized from isopropyl alcohol and water to give Compound 3 (40.02 g, 84%).
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