* 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 acetate; pyridinium chlorochromate In dichloromethane at 20℃; for 2 h;
To a solution of (4-bromo-3-fluoro-phenyl)-methanol (7.9 g, 38.5 mmol) in dichloromethane (160.0 mL) was added sodium acetate (940 mg, 11.5 mmol) followed by pyridinium chlorochromate (10.8 g, 50.0 mmol) at room temperature. The reaction mixture was stirred at room temperature under light protection over a period of 2 h. The resulting reaction mixture was diluted with ethyl acetate (1.0 L) and filtered through celite pad. The filtrate obtained was washed with aqueous sodium bicarbonate (600 mL), water (600 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by column chromatography to give 4-bromo-2-fiuoro- benzaldehyde as white solid (5.0 g, 63percent).
63%
With sodium acetate; pyridinium chlorochromate In dichloromethane at 20℃; for 2 h; light protection
To a solution of (4-bromo-3-fluoro-phenyl)-methanol (7.9 g, 38.5 mmol) in dichloromethane (160.0 mL) was added sodium acetate (940 mg, 11.5 mmol) followed by pyridinium chlorochromate (10.8 g, 50.0 mmol) at room temperature. The reaction mixture was stirred at room temperature under light protection over a period of 2 h. The resulting reaction mixture was diluted with ethyl acetate (1.0 L) and filtered through celite pad. The filtrate obtained was washed with aqueous sodium bicarbonate (600 mL), water (600 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by column chromatography to give 4-bromo-2-fluoro-benzaldehyde as white solid (5.0 g, 63percent).
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 14, p. 2973 - 2984
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 10, p. 1257 - 1260
3
[ 153556-42-4 ]
[ 222978-01-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
With borane-THF In tetrahydrofuran at 25℃;
General procedure: BH3.THF (89 mL, 89.49 mmol) was added dropwise to a stirred solution of 4-bromo-3-fluorobenzoic acid (9.8 g, 44.75 mmol) in THF (200 mL) at 25°C, over a period of 10 minutes under nitrogen. The resulting solution was stirred at ambient temperaturefor 2 days. The reaction mixture was cautiously quenched with 2M Na2CO3 (200 mL),extracted with Et2O (2 x 500 mL), the organic extratcts were combined, washed with saturated brine (400 mL), dried over MgSO4, filtered and evaporated to afford a paleyellow oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 70percent EtOAc in heptane. Pure fractions were evaporated to dryness to afford (4-bromo-3-fluorophenyl)methanol (8.65 g, 94 percent) as a white solid.
93%
Stage #1: With borane In tetrahydrofuran at 0 - 70℃; Stage #2: With hydrogenchloride In methanol; water at 25℃; for 2 h;
To a solution of commercially available 4-bromo-3-fluoro-benzoic acid (SI-2) (11 g, 50 mmol) in THF (250 mL) was added BH3 (1.0 M in THF, 100 mL, 100 mmol) at 0 oC and then the solution was stirred at 70 oC overnight. Then, the mixture was quenched with MeOH and 1 N HCl, and stirred at room temperature for an additional 2 hours. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography to obtainSI-3 (9.5 g, 93percent) as a yellow oil.ESI-MS m/z 205 [M+H]+calc. forC7H6BrFO.This intermediate was used in the next step without further characterization.
91.6%
With dimethylsulfide borane complex In tetrahydrofuran; diethyl ether at 0 - 20℃; for 6 h;
Step 1 (MT-Si):Boranmethyl sulfide in ether (5.0 M; 38.3 mL, 191.8 mmol) was added to a solution of 4- bromo-3-fluorobenzoic acid (21.0 g, 95.9 mmol) in dry tetrahydrofuran (250 mL) at 0°C and the reaction mixture was stirred at room temperature for 6 h. The reaction was quenched with saturated sodium hydrogen carbonate solution, extracted with ethyl acetate, and the combined organic layers were washed with water, brine; dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under vacuum to afford 18 g (91 .6percent) of MTSi as a colorless liquid, further used without any purification.
87%
With borane-THF In tetrahydrofuran at 0 - 20℃; for 72 h;
Step A: (4-Bromo-3-fluorophenyl methanolA 0°C solution of 4-bromo-3-fluoro benzoic acid (2.3 g, 10.50 mmol) in dry THF (52.5 ml) is treated with borane tetrahydrofuran complex (15.75 ml of a 1 M solution in THF, 15.75 mmol) and the resulting mixture stirred at RT for 72 hours. The mixture is then quenched with IN HC1, stirred for 20 minutes, then extracted with DCM. Concentration and silica gel chromatography (10-50percent EtOAc/hexanes) yields the title compound 1.87 g (87 percent yield) as colorless needles. 1H NMR (500 MHz, CDC13) δ 7.55 (m, IH), 7.04 (d, J9.4 Hz, IH), 7.04 (d, J 8.3 Hz, IH), 4.70 (d, 2H).
87%
With borane-THF In tetrahydrofuran at 20℃; for 72 h;
A ooc solution of 4-bromo-3-fluoro benzoic acid (2.3 g, 10.50 mmol) in dry THF (52.5ml) is treated with borane tetrahydrofuran complex (15.75 ml of a 1M solution in THF, 15.75mmol) and the resulting mixture stirred at RT for 72 hours. The mixture is then quenched with20 IN HCl, stirred for 20 minutes, then extracted with DCM. Concentration and silica gelchromatography (10-50percent EtOAc/hexanes) yields the title compound 1.87 g (87percent yield) ascolorless needles. 1H NMR (500 MHz, CDCh) 8 7.55 (m, IH), 7.04 (d, J9.4 Hz, IH), 7.04 (d, J8.3 Hz, IH), 4.70 (d, 2H).
84%
Stage #1: With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 20℃; for 2 h; Stage #2: With methanol In tetrahydrofuran
To a suspension of sodium borohydride (10.4 g, 0.27 mol) in tetrahydrofuran (200 mL) was added boron trifluoride etherate (44.3 mL, 0.36 mol) followed by 4-bromo-3- fluoro-benzoic acid (10.0 g, 0.04 mol) in THF (200 mL) at ice temperature. The mixture was allowed to stir at room temperature over a period of 2 h. The resulting reaction mixture was quenched with methanol and methanol was removed under reduced pressure. The residue obtained upon evaporation of methanol was diluted with ethyl acetate (1.0 L), washed with water (700 mL), dried over sodium sulphate and concentrated to give (4- bromo-3-fluoro-phenyl)-methanol as off-white solid (7.9 g, 84percent)
84%
Stage #1: With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 20℃; for 2 h; Cooling with ice Stage #2: With water In ethyl acetate
To a suspension of sodium borohydride (10.4 g, 0.27 mol) in tetrahydrofuran (200 mL) was added boron trifluoride etherate (44.3 mL, 0.36 mol) followed by 4-bromo-3-fluoro-benzoic acid (10.0 g, 0.04 mol) in THF (200 mL) at ice temperature. The mixture was allowed to stir at room temperature over a period of 2 h. The resulting reaction mixture was quenched with methanol and methanol was removed under reduced pressure. The residue obtained upon evaporation of methanol was diluted with ethyl acetate (1.0 L), washed with water (700 mL), dried over sodium sulphate and concentrated to give (4-bromo-3-fluoro-phenyl)-methanol as off-white solid (7.9 g, 84percent).
73%
Stage #1: With sodium tetrahydroborate In tetrahydrofuran for 0.666667 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran at 20℃; for 14.5833 h; Cooling with ice
A suspension of 4-bromo-3-fluorobenzoic acid (84) (1.61 g, 7.35 mmol) in anhydrous THF (10 mL, then 4x 3 mL to rinse) under N2 was added drop- wise (over 40 min) to a suspension of sodium borohydride (400 mg, 10.6 mmol) in anhydrous TIIF (15 mL) under N2, and then the mixture was cooled in an ice bath. A solution of iodine (1.008 g, 3.97 mmol) in anhydrous THF (10 mL, then 2x 3 mL) was added drop- wise (over 35 min) to the stirred solution and then the mixture was stirred at room temperature for 14 h. The mixture was concentrated under reduced pressure and then treated successively with water (20 mL), 10percent HCl (3.4 mL) and water (20 mL), and extracted with CH2Cl2 (4x 50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel, eluting with 50percent CH2Cl2/petroleum ether, to give (4-bromo-3-fluorophenyl)methanol (85) (1.096 g, 73percent) as a white solid: mp (CH2Cl2/petroleum ether) 39-40 °C; 1H NMR (CDCl3) δ 7.52 (dd, J = 8.0, 7.2 Hz, 1 H), 7.16 (dd, J = 9.3, 1.8 Hz, 1 H), 7.02 (dd, J = 8.2, 1.8 Hz, 1 H), 4.67 (d, J = 5.9 Hz, 2 H), 1.75 (t, J = 5.9 Hz, 1 H); HREIMS calcd for C7H6BrFO mlz (M+) 205.9567, 203.9586, found 205.9566, 203.9580.
73%
Stage #1: With sodium tetrahydroborate In tetrahydrofuran for 0.666667 h; Inert atmosphere; Cooling with ice Stage #2: With iodine In tetrahydrofuran at 20℃; for 14.5833 h;
R. Synthesis of (6S)-6-[2-fluoro-4'-(trifluoromethoxy)[1,1'-biphenyl]-4-yl]methoxy}-2-nitro-6,7-dihydro-5H-imidazo[2,1-6][1,3]oxazine (15) by the method of Scheme 11 A suspension of 4-bromo-3-fluorobenzoic acid (84) (1.61 g, 7.35 mmol) in anhydrous THF (10 mL, then 4.x.3 mL to rinse) under N2 was added drop-wise (over 40 min) to a suspension of sodium borohydride (400 mg, 10.6 mmol) in anhydrous THF (15 mL) under N2, and then the mixture was cooled in an ice bath. A solution of iodine (1.008 g, 3.97 mmol) in anhydrous THF (10 mL, then 2.x.3 mL) was added drop-wise (over 35 min) to the stirred solution and then the mixture was stirred at room temperature for 14 h. The mixture was concentrated under reduced pressure and then treated successively with water (20 mL), 10percent HCl (3.4 mL) and water (20 mL), and extracted with CH2Cl2 (4.x.50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel, eluting with 50percent CH2Cl2/petroleum ether, to give (4-bromo-3-fluorophenyl)methanol (85) (1.096 g, 73percent) as a white solid: mp (CH2Cl2/petroleum ether) 39-40° C.; 1H NMR (CDCl3) δ 7.52 (dd, J=8.0, 7.2 Hz, 1H), 7.16 (dd, J=9.3, 1.8 Hz, 1H), 7.02 (dd, J=8.2, 1.8 Hz, 1H), 4.67 (d, J=5.9 Hz, 2H), 1.75 (t, J=5.9 Hz, 1H); HREIMS calcd for C7H6BrFO m/z (M+) 205.9567, 203.9586, found 205.9566, 203.9580.
Stage #1: With sodium tetrahydroborate In methanol at 0 - 20℃; for 2 h; Stage #2: With hydrogenchloride In methanol; water
Step i :Solid NaBH4 (603 mg, 15.9 mmol) is added to a solution of ketone 50a (4.11 g, 19.92 mmol) dissolved in MeOH (62 mL) at O0C. The reaction is warmed to RT and is allowed to stir for 2 h. The reaction is quenched with aqueous HCI (1 N, 20 mL), the MeOH is removed by concentration and the product extracted with EtOAc (2 x 50 <n="111"/>mL). The organic layer is washed with brine (50 ml_), dried over MgSO4, filtered and concentrated to afford alcohol 50b (4.1 g, 97percent yield). This material is used as is in the next step.
97%
With sodium tetrahydroborate In methanol at 0 - 25℃; for 2 h;
Solid NaBH4 (603 mg, 15.9 mmol) is added to a solution of aldehyde 48a (4.1 1 g,19.92 mmol) dissolved in MeOH (62 mL) at O0C. The reaction is warmed to RT and is allowed to stir for 2 h. The reaction is quenched with aqueous HCI (1 N, 20 mL), the MeOH is removed by concentration and the product extracted with EtOAc (2 x 50 mL). The organic layer is washed with brine (50 mL), dried over MgSO4, filtered and concentrated to afford alcohol 48b (4 1 g, 97percent yield). This material is used as is in the next step.
97%
With methanol; sodium tetrahydroborate In tetrahydrofuran
To a solution of 4-bromo-3-fluorobenzaldehyde (10 g, 49.3 mmol) and NaBH4 (3.73 g, 99 mmol) in THF (100 mL) was added MeOH (100 mL) dropwise at 20° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in DCM (200 mL) and washed with H2O (60 mL) and brine (60 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a white solid of (4-bromo-3-fluorophenyl)methanol (9.8 g, 47.7 mmol, 97.0percent yield): 1H NMR (400 MHz, CD3OD) δ 7.54 (t, J=7.8 Hz, 1H), 7.18 (d, J=9.6 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 4.56 (s, 2H); ES-LCMS m/z 188.9 (M-17).
97%
With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃;
To a solution of 4-bromo-3-fluorobenzaldehyde (10 g, 49.3 mmol) and NaBH4 (3.73 g, 99 mmol) in THF (100 mL) was added MeOH (100 inL) dropwise at 20 °C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in DCM (200 mL) and washed with H20 (60 mL) and brine (60 mL). The organic layer was dried over Na2S04, filtered and concentrated to yield a white solid of (4-bromo-3- fluorophenyl)methanol (9.8 g, 47.7 mmol, 97.0percent yield): lH NMR (400 MHz, CD3OD) δ 7.54 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 9.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 4.56 (s, 2H); ES-LCMS m/z 188.9 (M-17).
With diisobutylaluminium hydride In tetrahydrofuran at 20℃;
To a solution of 4-bromo-3-fluoro-benzoic acid methyl ester (5.3 g, 22.9 mmol) in dry THF (60 mL) was added diisobutylaluminum hydride (30 mL) dropwise, This mixture was stirred overnight at room temperature until the starting material had been consumed, quenched with saturated aqueous potassium tartrate solution and extracted with ethyl acetate (3.x.50 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to give white solid product (4.3 g, 92percent).
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7299 - 7317
[2] Patent: US2010/216806, 2010, A1, . Location in patent: Page/Page column 103
[3] Patent: WO2010/92043, 2010, A1, . Location in patent: Page/Page column 62
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 14, p. 2973 - 2984
13
[ 222978-01-0 ]
[ 133059-43-5 ]
Yield
Reaction Conditions
Operation in experiment
55%
With manganese(IV) oxide In chloroform at 20℃;
To a solution of (4-bromo-3-fluoro-phenyl)-methanol (4.3 g, 21 mmol) in CHCl3 (50 mL) was added manganese dioxide (18.7 g, 210 mmol), and the resulting mixture was stirred overnight at room temperature until the starting material had been consumed. After filtration, the filtrate was concentrated in vacuo to give product (2.3 g, 55percent).
With phosphorus tribromide In dichloromethane at 20℃;
To a solution of (4-bromo-3-fluorophenyl)methanol (5 g, 24.39 mmol) in DCM (100 mL) was added PBr3 (2.76 mL, 29.3 mmol) dropwise. The resulting mixture was stirred at 20° C. After LCMS analysis showed the starting material had disappeared, the mixture was adjusted to pH=8 by aq Na2CO3. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography (PE/EA=10/1) to yield a white solid of 1-bromo-4-(bromomethyl)-2-fluorobenzene (4.2 g, 14.89 mmol, 61.1percent yield): 1H NMR (400 MHz, CD3OD) δ 7.57 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.16 (d, J=6.4 Hz, 1H), 4.53 (s, 2H); ES-LCMS m/z 186.9 (M-79).
61.1%
With phosphorus tribromide In dichloromethane at 20℃;
To a solution of (4-bromo-3-fluorophenyl)methanol (5 g, 24.39 mmol) in DCM (100 mL) was added PBr3 (2.76 mL, 29.3 mmol) dropwise. The resulting mixture was stirred at 20 °C. After LCMS analysis showed the starting material had disappeared, the mixture was adjusted to pH = 8 by aqueous Na2CC>3. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography (PE/EA = 10/1) to yield a white solid of 1-bromo- 4-(bromomethyl)-2-fluorobenzene (4.2 g, 14.89 mmol, 61.1percent yield): l NMR (400 MHz, CD3OD) δ 7.57 (d, J= 7.6 Hz, 1H), 7.28 (d, J= 7.2 Hz, 1H), 7.16 (d, J= 6.4 Hz, 1H), 4.53 (s, 2H); ES-LCMS m/z 186.9 (M-79).
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h;
To a solution of <strong>[222978-01-0](4-bromo-3-fluoro-phenyl)-methanol</strong> (410 mg, 2.0 mmol) and imidazole (163 mg, 2.4 mmol) in DMF (10 mL) was added triisopropylsilyl chloride (0.472 mL, 2.2 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between ethyl acetate and water. The organic layer was isolated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-SPE, pentane) to provide the title compound as a colourless oil (643 mg, 89%). IH NMR (CDCl3, 400MHz) 7.48 (dd, J=8.1, 7.0 Hz, IH), 7.16 (d, J = 9.7 Hz, IH), 6.99 (d, J=8.7 Hz, IH), 4.78 (s, 2H), 1.04-1.24 (m, 21H).
Step 2: Preparation of (4-bromo-3-fluorophenyl) methanol; To a room temperature solution of 1-bromo-4- (bromomethyl)-2-fluorobenzene from Step 1 (11. 8 g) in DMF (150 mL) was added sodium acetate (10.8 g). The mixture was heated at 80 C for 16 hours. It was cooled to room temperature and poured into ice and saturated aqueous sodium bicarbonate (200 mL), and extracted with diethyl ether (2 X 100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The crude material was purified by chromatography on Si02 using ethyl acetate and hexanes (1: 25 to 1 : 10) to yield 4-bromo-3- fluorobenzyl acetate (containing about 15% of 4-bromo-3-fluorobenzaldehyde). The residue was dissolved in methanol (100 mL), cooled at 0 C and sodium methoxide (250 mg) was added. The reaction mixture was stirred at room temperature for 2 hours. It was cooled to 0 C and sodium borohydride was added (1.5 g). Stirred at 0 C for 1 hour and poured into ice and saturated aqueous ammonium chloride (200 mL). Extracted with ethyl acetate (2 X 100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on Si02 using ethyl acetate and hexanes (1: 5 to 1: 3) to yield the title compound. lH NMR (CD3COCD3) o 7.55-7. 65 (1H, m), 7.28 (1H, d), 7.15 (1H, d), 4.63 (2H, d), 4.50 (1H, t).
Step 4: Preparation of (4-bromo-3-fluorophenyl)methanol; To a room temperature solution of l-bromo-4-(bromomethyl)-2-fluorobenzene from Step 3 (1 1.8 g) in DMF (150 mL) was added sodium acetate (10.8 g). The mixture was heated at 80C for 16 hours. It was cooled to room temperature and poured into ice and saturated aqueous sodium bicarbonate (200 mL), and extracted with diethyl ether (2 x 100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The crude material was purified by cliromatography on SiO2 using ethyl acetate and hexanes (1:25 to 1: 10) to yield 4-bromo-3- fluorobenzyl acetate (containing about 15% of 4-bromo-3-fluorobenzaldehyde). The residue was dissolved in methanol (100 mL), cooled to 00C and sodium methoxide (250 mg) was added. The reaction mixture was stirred at room temperature for 2 hours. It was cooled to 00C and sodium borohydride was added (1.5 g). The mixture was stirred at 00C for 1 hour and poured into ice and saturated aqueous ammonium chloride (200 mL). The mixture was extracted with ethyl acetate (2 x 100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:5 to 1:3) to yield the title compound. EPO <DP n="31"/>1H NMR (CD3COCD3) delta 7.55-7.65 (1 H, m), 7.28 (1 H, d), 7.15 (1 H, d), 4.63 (2 H, d), 4.50 (1 H, t).
Step B Preparation of 4-bromo-3-fluorobenzyl Alcohol 4-Bromo-3-fluorobenzoic acid, as described above, (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10 C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) delta 7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
Step B Preparation of 4-bromo-3-fluorobenzyl Alcohol 4-Bromo-3-fluorobenzoic acid, as described above, (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) delta 7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
Step B Preparation of 4-bromo-3-fluorobenzyl Alcohol 4-Bromo-3-fluorobenzoic acid, as described above, (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10 C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) delta7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
Step B Preparation of 4-bromo-3-fluorobenzyl Alcohol 4-Bromo-3-fluorobenzoic acid, as described above, (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10 C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) delta 7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
(16-1) According to a method similar to Example (17-1), from (4-bromo-3-fluorophenyl) methanol which was synthesised according to the method described in literature (), (4-bromo-3-fluorophenyl)-acetonitrile was obtained as a colorless oil (1.60 g, yield: 75%).
79
Pd[(PPh3)]4[ No CAS ]
[ 222978-01-0 ]
[ 222978-02-1 ]
Yield
Reaction Conditions
Operation in experiment
In water; N,N-dimethyl-formamide;
Step C Preparation of 2-fluoro-4-hydroxymethylbenzonitrile 4-Bromo-3-fluorobenzyl alcohol (20 g, 0.097 mol) was dissolved in DMF (100 mL) and then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide (8 g, 0.068 mol) and the catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95 C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5. 1H NMR (CDCl3) delta 7.61 (t, 1H, J=8 Hz), 7.23-7.29 (m, 2H), 4.80 (d, 2H, J=6 Hz), 1.93 (t, 1H, J=6 Hz).
In water; N,N-dimethyl-formamide;
Step C Preparation of 2-fluoro-4-hydroxymethylbenzonitrile 4-Bromo-3-fluorobenzyl alcohol (20 g, 0.097 mol) was dissolved in DMF (100 mL) then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide (8 g, 0.068 mol) and the catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95 C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5). 1H NMR (CDCl3) delta7.61 (t, 1H, J=8 Hz), 7.23-7.29 (m, 2H), 4.80 (d, 2H, J=6 Hz), 1.93 (t, 1H, J=6 Hz).
In water; N,N-dimethyl-formamide;
Step C: Preparation of 2-fluoro-4-hydroxymethylbenzonitrile 4-Bromo-3-fluorobenzyl alcohol (20 g, 0.097 mol), prepared as described in Step B, was dissolved in DMF (100 mL) then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide (8 g, 0.068 mol) and the catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95 C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5). 1H NMR (CDCl3) delta7.61 (t, 1H, J=8 Hz), 7.23-7.29 (m, 2H), 4.80 (d, 2H, J=6 Hz), 1.93 (t, 1H, J=6 Hz).
In water; N,N-dimethyl-formamide;
Step C Preparation of 2-Fluoro-4-hydroxymethylbenzonitrile 4-Bromo-3-fluorobenzyl alcohol (20 g, 0.097 mol) was dissolved in DMF (100 mL) then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide (8 g, 0.068 mol) and the catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95 C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5). 1H NMR (CDCl3) delta 7.61 (t, lH, J=8 Hz), 7.23-7.29 (m, 2H), 4.80 (d, 2H, J=6Hz), 1.93 (t, 1H, J=6 Hz).
In water; N,N-dimethyl-formamide;
Step C: Preparation of 2-fluoro-4-hydroxymethylbenzonitrile 4-Bromo-3-fluorobenzyl alcohol(20 g, 0.097 mol) was dissolved in DMF (100 mL) and then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide (8 g, 0.068 mol) and the catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95 C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1 M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5). 1H NMR (CDCl3) d 7.61 (t, 1H, J=8 Hz), 7.23-7.29 (m, 2H), 4.80 (d, 2H, J=6 Hz), 1.93 (t, 1H, J=6 Hz).
In water; N,N-dimethyl-formamide;
Step C Preparation of 2-Fluoro-4-hydroxymethylbenzonitrile 4-Bromo-3-fluorobenzyl alcohol (20 g, 0.097 mol) was dissolved in DMF (100 mL) and then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide (8 g, 0.068 mol) and the catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95 C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5. 1H NMR (CDCl3) d 7.61 (t, 1H, J=8 Hz), 7.23-7.29 (m, 2H), 4.80 (d, 2H, J=6 Hz), 1.93 (t, 1H, J=6 Hz).
Step J Preparation of 4-Cyano-3-fluorobenzyl Alcohol To a degassed solution of the product from Step I (11.4 g, 55.6 mmol) in 100 mL of DMF was added Zn(CN)2 (3.92 g, 33.4 mmol) and Pd(PPh3)4 (5.1 g, 4.45 mmol). The reaction was stirred at 90 C. overnight, cooled to room temperature, and concentrated in vacuo. Purification of this material by silica gel chromatography (50% EtOAc/hexane) provided the titled product as a light yellow solid.
To a solution of <strong>[222978-01-0](4-bromo-3-fluoro-phenyl)-methanol</strong> (4.3 g, 21 mmol) in CHCl3 (50 mL) was added manganese dioxide (18.7 g, 210 mmol), and the resulting mixture was stirred overnight at room temperature until the starting material had been consumed. After filtration, the filtrate was concentrated in vacuo to give product (2.3 g, 55%).
With N-chloro-succinimide; cyfluthrin; tetrabutyl ammonium fluoride; sodium hydrogencarbonate; potassium carbonate; In dichloromethane;
Step A Preparation of 4-Bromo-3-fluorobenzaldehyde To a well-stirred mixture of <strong>[222978-01-0]4-bromo-3-fluorobenzyl alcohol</strong> (as described in Example 9, Step B) (10.25 g, 0.05 mol), TEMPO (0.781 g, 0.005 mol) and tetrabutylammonium fluoride (1.39 g, 0.005 mol) in CH2Cl2 (200 mL) and a solution of 0.5M NaHCO3/0.05M K2CO3 (200 mL) was added N-chlorosuccinimide (9.35 g, 0.07 mol). After 6 hrs, the layers were separated, the aqueous layer back-washed with CH2Cl2 (2*50 mL), the organics combined and dried (Na2SO4). The solution was filtered, concentrated to half its volume, then chromatographed (silica gel, CH2Cl2) to give the title compound. 1H NMR (CDCl3) delta 9.96 (s, 1H), 7.78 (dd, 1H, J=2, 8 Hz), 7.62 (dd, 1H, J=2, 8 Hz), 7.56 (dd, 1H, J=2, 8 Hz).
With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 10 - 30℃; for 12h;
Compound 21-d (501mg, 2.69mmol) was dissolved in tetrahydrofuran (20mL), followed by addition of triphenylphosphine (1.06g, 4.03mmol) and carbon tetrabromide (1.52g, 4.57mmol). The reaction solution was stirred at room temperature for 12 hours, then evaporated under reduced pressure. The residue was diluted with ethyl acetate (50mL), washed with saturated brine (20mL) and water (20mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 21-c (810mg, yield 99%). 1H NMR (400 MHz, CDCl3) delta: 7.54-7.50 (m, 1H), 7.18-7.16 (m, 1H), 7.07-7.05 (m, 1H), 4.41 (s, 2H) ppm.
61.1%
With phosphorus tribromide; In dichloromethane; at 20℃;
To a solution of <strong>[222978-01-0](4-bromo-3-fluorophenyl)methanol</strong> (5 g, 24.39 mmol) in DCM (100 mL) was added PBr3 (2.76 mL, 29.3 mmol) dropwise. The resulting mixture was stirred at 20 C. After LCMS analysis showed the starting material had disappeared, the mixture was adjusted to pH=8 by aq Na2CO3. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography (PE/EA=10/1) to yield a white solid of 1-bromo-4-(bromomethyl)-2-fluorobenzene (4.2 g, 14.89 mmol, 61.1% yield): 1H NMR (400 MHz, CD3OD) delta 7.57 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.16 (d, J=6.4 Hz, 1H), 4.53 (s, 2H); ES-LCMS m/z 186.9 (M-79).
61.1%
With phosphorus tribromide; In dichloromethane; at 20℃;
To a solution of <strong>[222978-01-0](4-bromo-3-fluorophenyl)methanol</strong> (5 g, 24.39 mmol) in DCM (100 mL) was added PBr3 (2.76 mL, 29.3 mmol) dropwise. The resulting mixture was stirred at 20 C. After LCMS analysis showed the starting material had disappeared, the mixture was adjusted to pH = 8 by aqueous Na2CC>3. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography (PE/EA = 10/1) to yield a white solid of 1-bromo- 4-(bromomethyl)-2-fluorobenzene (4.2 g, 14.89 mmol, 61.1% yield): l NMR (400 MHz, CD3OD) delta 7.57 (d, J= 7.6 Hz, 1H), 7.28 (d, J= 7.2 Hz, 1H), 7.16 (d, J= 6.4 Hz, 1H), 4.53 (s, 2H); ES-LCMS m/z 186.9 (M-79).
With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 5h;
To a solution of compound A26-1 (19 g, crude) in dry DCM (200 mL) at 0 C was added PBr3 (13.7 g, 50 mmol) dropwise. The reaction was stirred for 3 h, then warmed to 20 C and stirred for 2 h. Then the reaction was quenched with water, neutralized with saturated aqueous NaHCO3 to pH=7, and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2504, filtered andconcentrated in vacuo to afford crude compound A26-2, which was used in the next step without purification.
With N-chloro-succinimide; cyfluthrin; tetrabutyl ammonium fluoride; potassium carbonate; In dichloromethane;
Step A Preparation of 4-Bromo-3-fluorobenzaldehyde To a well-stirred mixture of <strong>[222978-01-0]4-bromo-3-fluorobenzyl alcohol</strong> (as described in Example 1, Step B) (10.25 g, 0.05 mol), TEMPO (0.781 g, 0.005 mol) and tetrabutylammonium fluoride (1.39 g, 0.005 mol) in CH2Cl2 (200 mL) and a solution of 0.5M NaHCO2/0.05M K2CO3(200 mL) was added N-chlorosuccinimide (9.35 g, 0.07 mol). After 6 hrs, the layers were separated, the aqueous layer back-washed with CH2Cl2 (2*50 mL), the organics combined and dried (Na2SO4). The solution was filtered, concentrated to half its volume, then chromatographed (silica gel, CH2Cl2) to give the title compound. 1H NMR (CDCl3) delta 9.96 (s, 1H), 7.78 (dd, 1H, J=2, 8 Hz), 7.62 (dd, 1H, J=2, 8 Hz), 7.56 (dd, 1H, J=2, 8 Hz).
With triethylamine; In dichloromethane; at 0 - 20℃;
A cooled (0 0C) solution of <strong>[222978-01-0](4-bromo-3-fluorophenyl)methanol</strong> (Intermediate 9; 299 mg; 1.46 mmol) and methanesulfonyl chloride (147 muL; 1.90 mmol) in DCM (3 mL) was treated slowly with a solution of triethylamine (305 muL; 2.19 mmol) in DCM (1.5 mL). The reaction mixture was allowed to warm to RT and stirred for 45 minutes before being quenched by addition of water. The organic phase was washed with HCI (0.1 N in water) and brine, dried over MgSO4, filtered and concentrated to dryness affording a residue, which was purified by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a colourless liquid.1H NMR (300MHz, DMSO-d6) delta [ppm] 7.77 (1 H, dd, J= 8.2, J= 7.5 Hz), 7.48 (1 H, dd, J= 9.7, J= 2.0 Hz), 7.26 (1 H, dd, J= 8.2, J= 2.0 Hz), 5.26 (2H, s), 3.27 (3H, s).
With sodium hydrogencarbonate; triethylamine; In dichloromethane; water;
Reference Example 66 4-Bromo-3-fluorobenzyl methanesulfonate A solution of the compound (30.0 g) obtained in Reference Example 65 and triethylamine (22.4 mL) in dichloromethane (300 mL) was cooled to 0 C. Methanesulfonyl chloride (12.5 mL) was added dropwise thereto, and the mixture was stirred at the same temperature as above for 1.5 hours. The reaction mixture was washed with a mixed solution of a saturated aqueous solution of sodium bicarbonate and water (1:3) (300 mL) and saturated aqueous sodium chloride (300 mL), dried over anhydrous sodium sulfate, and then concentrated to obtain the title compound (40.7 g). 1H NMR (CDCl3, 400 MHz): delta (ppm) 7.57-7.62 (m, 1H), 7.18-7.22 (m, 1H), 7.07-7.11 (m, 1H), 5.18 (s, 2H), 3.00 (s, 3H)
With triethylamine; In dichloromethane; at -78 - 0℃; for 1h;
Step 5: Preparation of (4-bromo-3-fluorophenyl')acetonitrile; To a -78C solution of <strong>[222978-01-0](4-bromo-3-fluorophenyl)methanol</strong> from Step 4 (7.2 g) and triethylamine (5.9 mL) in dichloromethane (300 mL) was slowly added methanesulphonyl chloride (3.0 mL) The reaction mixture was stirred at 00C for 1 hour and then poured into ice and saturated aqueous ammonium chloride and partitioned. T he aqueous layer was extracted with dichloromethane (1 x 150 mL) The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was dissolved in DMF (150 mL) and sodium cyanide (5.1 g) was added. The reaction mixture was stirred at room temperature for 2 hours and poured into ice and water (100 mL) The aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1: 10 to 1:5) to yield the title compound.1H NMR (CD3COCD3) delta 7.70-7.78 (1 H, m), 7.39 (1 H, d), 7.28 (1 H, d), 4.09 (2 H, s).
With methanol; sodium tetrahydroborate; at 20℃; for 2h;
4-Bromo-3-fluorobenzaldehyde (500mg, 2.46mmol) was dissolved in methanol (10mL), followed by addition of sodium borohydride (465.9mg, 12.31mmol). The mixture was stirred at room temperature for 2 hours, then evaporated under reduced pressure. The residue was diluted with ethyl acetate (50mL), washed with saturated brine (20mL) and water (20mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give compound 21-d (501mg, yield 99%), which was directly used in the next step without further purification. 1H NMR (400 MHz, CDCl3) delta: 7.54-7.50 (m, 1H), 7.17-7.12 (m, 1H), 7.03-7.01 (m, 1H), 4.67 (s, 2H), 1.90 (br, 1H) ppm.
97%
Step i :Solid NaBH4 (603 mg, 15.9 mmol) is added to a solution of ketone 50a (4.11 g, 19.92 mmol) dissolved in MeOH (62 mL) at O0C. The reaction is warmed to RT and is allowed to stir for 2 h. The reaction is quenched with aqueous HCI (1 N, 20 mL), the MeOH is removed by concentration and the product extracted with EtOAc (2 x 50 <n="111"/>mL). The organic layer is washed with brine (50 ml_), dried over MgSO4, filtered and concentrated to afford alcohol 50b (4.1 g, 97% yield). This material is used as is in the next step.
97%
With sodium tetrahydroborate; In methanol; at 0 - 25℃; for 2h;
Solid NaBH4 (603 mg, 15.9 mmol) is added to a solution of aldehyde 48a (4.1 1 g,19.92 mmol) dissolved in MeOH (62 mL) at O0C. The reaction is warmed to RT and is allowed to stir for 2 h. The reaction is quenched with aqueous HCI (1 N, 20 mL), the MeOH is removed by concentration and the product extracted with EtOAc (2 x 50 mL). The organic layer is washed with brine (50 mL), dried over MgSO4, filtered and concentrated to afford alcohol 48b (4 1 g, 97% yield). This material is used as is in the next step.
97%
With methanol; sodium tetrahydroborate; In tetrahydrofuran;
To a solution of 4-bromo-3-fluorobenzaldehyde (10 g, 49.3 mmol) and NaBH4 (3.73 g, 99 mmol) in THF (100 mL) was added MeOH (100 mL) dropwise at 20 C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in DCM (200 mL) and washed with H2O (60 mL) and brine (60 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a white solid of (4-bromo-3-fluorophenyl)methanol (9.8 g, 47.7 mmol, 97.0% yield): 1H NMR (400 MHz, CD3OD) delta 7.54 (t, J=7.8 Hz, 1H), 7.18 (d, J=9.6 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 4.56 (s, 2H); ES-LCMS m/z 188.9 (M-17).
97%
With sodium tetrahydroborate; In tetrahydrofuran; methanol; at 20℃;
To a solution of 4-bromo-3-fluorobenzaldehyde (10 g, 49.3 mmol) and NaBH4 (3.73 g, 99 mmol) in THF (100 mL) was added MeOH (100 inL) dropwise at 20 C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in DCM (200 mL) and washed with H20 (60 mL) and brine (60 mL). The organic layer was dried over Na2S04, filtered and concentrated to yield a white solid of (4-bromo-3- fluorophenyl)methanol (9.8 g, 47.7 mmol, 97.0% yield): lH NMR (400 MHz, CD3OD) delta 7.54 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 9.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 4.56 (s, 2H); ES-LCMS m/z 188.9 (M-17).
With methanol; sodium tetrahydroborate; at 20℃; for 2h;
To a solution of 4-bromo-3-fluoro-benzaldehyde (10.1 g, 49.8 mmol, 1.0 eq) in MeOH (100 mL) was added NaB (3.8 g, 99.6 mmol, 2.0 eq). The mixture was stirred at rt for 2 h. The reaction mixture was extracted with ethyl acetate, washed with brine and water. The organic layer was dried over Na2S04 and evaporated to give the crude product (4-bromo-3-fluoro-ph -methanol (10.3 g, 100%).
With methanol; sodium tetrahydroborate; at 0℃; for 3h;
To a solution of 4-bromo-3-fluoro- benzaldehyde (20 g, 99.5 mmol) in MeOH (200 mL) at 0 C was added NaBH4 (5.7g, 150 mmol) portion wise, and the reaction was stirred for 3 h. Then the mixture was quenched with water, and extracted with EtOAc three times. The combined organic layers were concentrated to afford crude compound A26- 1, which was used in the next step without purification.
With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; for 2h;
Step 2:To a cold solution (O0C) of 50b (3.96 g, 19.31 mmol) in DCM (12 mL) is added diethylamino sulfur trifluoride (2.78 mL, 21.25 mmol). The reaction is warmed to RT and is allowed to stir for 2 h. The reaction is quenched with aqueous NaHCO3 and extracted with DCM. The organic layer is dried with MgSO4, filtered and evaporated to dryness. The product is purified by CombiFlash Companion to afford 50c (2.1 g, 52% yield) as a colorless oil.
52%
With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 25℃; for 2h;
To a cold solution (O0C) of 48b (3 96 g, 19 31 mmol) in DCM (12 mL) is added diethylamino sulfur trifluoride (2 78 mL, 21 25 mmol) The reaction is warmed to RT and is allowed to stir for 2 h The reaction is quenched with aqueous NaHCO3 and extracted with DCM The organic layer is dried with MgSO4, filtered and evaporated to dryness The product is purified by CombiFlash Companion to afford 48c (2 1 g, 52% yield) as a colorless oil
Step 3: Preparation of (4-bromo-3-fluorophenyl) acetonitrile; To a-78 C solution of <strong>[222978-01-0](4-bromo-3-fluorophenyl) methanol</strong> from Step 2 (7.2 g) and triethylamine (5.9 mL) in dichloromethane (300 mL) was slowly added methanesulphonyl chloride (3.0 mL). The reaction mixture was stirred at 0 C for 1 hour. Then poured into ice and saturated aqueous ammonium chloride and partitioned. The aqueous layer was extracted with dichloromethane (1 X 150 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was dissolved in DMF (150 mL) and sodium cyanide (5.1 g) was added. The reaction mixture was stirred at room temperature for 2 hours and poured into ice and water (100 mL). Extracted with ethyl acetate (2 X 100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on Si02 using ethyl acetate and hexanes (1: 10 to 1: 5) to yield the title compound. 'H NMR (CD3COCD3) 8 7.70-7. 78 (1H, m), 7.39 (1H, d), 7.28 (1H, d), 4.09 (2H, s).
With diisobutylaluminium hydride; In tetrahydrofuran; at 20℃;
To a solution of 4-bromo-3-fluoro-benzoic acid methyl ester (5.3 g, 22.9 mmol) in dry THF (60 mL) was added diisobutylaluminum hydride (30 mL) dropwise, This mixture was stirred overnight at room temperature until the starting material had been consumed, quenched with saturated aqueous potassium tartrate solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to give white solid product (4.3 g, 92%).
A cooled (0 0C) suspension of lithium aluminum hydride (88 mg; 2.3 mmol) in anhydrous THF (10 mL) was treated dropwise with a solution of methyl 4-bromo-3-fluorobenzoate (Combi-Blocks; 300 mg; 1.29 mmol) dissolved in anhydrous Et2O (10 mL), and the reaction mixture was stirred at RT for 2 days. The reaction mixture was treated with a saturated aqueous solution of sodium thiosulfate. The organic phase was separated, dried over MgSO4, filtered and concentrated to dryness affording the title compound as a yellow liquid (247 mg, 94%). 1H NMR (300MHz, DMSO-d6) delta [ppm] 7.64 (1 H, dd, J= 8.1 , J= 7.5 Hz), 7.28 (1 H, m), 7.11 (1 H, m), 5.40 (1 H, t, J= 5.8 Hz), 4.48 (2H, d, J= 5.8 Hz). HPLC (Condition A): Rt 2.78 min (HPLC purity 90.2%).
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