* 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 tetrabutylammomium bromide In dichloromethane; water at 20℃; for 4 h;
2-bromo-4-(bromomethyl)-1-fluorobenzene (20.000 g, 74.649 mmol), potassium cyanide (14.583 g, 223.947 mmol) and tetra-n-butylammonium bromide (2.406 g, 7.465 mmol) was dissolved in a mixed solution of dichloromethane(80 mL)/water (80 mL) at room temperature and stirred at the same temperature for 4 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated sodium hydrogen carbonate aqueous solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified and purified by column chromatography (SiO2, 120 g cartridge; ethyl acetate / hexane = 0percent to 20percent) to give the title compound (14.200 g, 88.9percent) as a colorless liquid.
Reference：
[1] Patent: KR2017/43091, 2017, A, . Location in patent: Paragraph 1646-1649
2
[ 78239-71-1 ]
[ 143-33-9 ]
[ 501420-63-9 ]
Yield
Reaction Conditions
Operation in experiment
75%
for 18 h;
A solution of 2-bromo-4-(bromomethyl)-1 -fluorobenzene (5.0 g, 18.7 mmol) in DMSO (80 ml_) was treated with sodium cyanide (1.16 g, 22.4 mmol) and <n="100"/>stirred for 18 hours. The reaction was poured into ethyl acetate and washed 4x with 5percent sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to an oil. Purification by silica gel column chromatography provided the title compound as a light amber oil (3.6 g, 75percent). LC/MS: 10percent - 90percent CH3CN:H20 gradient over 5 minutes: 2.57 min. ,214, 216 (M+H); 1H NMR (400 MHz, CHLOROFORM-c/) δ ppm 3.73 (s, 2 H) 7.15 (t, J=8.40 Hz, 1 H) 7.20 - 7.32 (m, 1 H) 7.56 (dd, J=6.25, 2.35 Hz, 1 H).
A solution of 2-bromo-4-(bromomethyl)-1 -fluorobenzene (5.0 g, 18.7 mmol) in DMSO (80 ml_) was treated with sodium cyanide (1.16 g, 22.4 mmol) and <n="100"/>stirred for 18 hours. The reaction was poured into ethyl acetate and washed 4x with 5% sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to an oil. Purification by silica gel column chromatography provided the title compound as a light amber oil (3.6 g, 75%). LC/MS: 10% - 90% CH3CN:H20 gradient over 5 minutes: 2.57 min. ,214, 216 (M+H); 1H NMR (400 MHz, CHLOROFORM-c/) delta ppm 3.73 (s, 2 H) 7.15 (t, J=8.40 Hz, 1 H) 7.20 - 7.32 (m, 1 H) 7.56 (dd, J=6.25, 2.35 Hz, 1 H).
A solution of <strong>[501420-63-9]2-<strong>[501420-63-9](3-bromo-4-fluorophenyl)acetonitrile</strong></strong> (300 mg, 1.40 mmol) in DMSO (5 ml_) was treated with sodium hydride (120 mg, 3.0 mmol) and stirred for 1 hour. The reaction was then treated with 2-chloroethyl ether (409 mg, 0.335 ml_, 2.8 mmol) and stirred for 2 hours. The reaction was quenched with acetic acid, poured into water, and extracted 3x with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to an oil. Purification by silica gel column chromatography provided the title compound as a light amber oil (240 mg, 30%). 1H NMR (400 MHz, CHLOROFORM-c/) delta ppm 2.05 - 2.15 (m, 4 H) 3.86 - 3.94 (m, 2 H) 4.07 - 4.11 (m, 1 H) 4.10 - 4.15 (m, 1 H) 7.19 (dd, J=8.70, 8.11 Hz, 1 H) 7.43 (ddd, J=8.60, 4.30, 2.54 Hz, 1 H) 7.68 (dd, J=6.25, 2.54 Hz, 1 H).
To a stirred suspension of NaH (16.3 g, 406 mmol, 3 eq) in anhyd THF (100 mL) at 0 C was added dropwise a solution of <strong>[501420-63-9]2-<strong>[501420-63-9](3-bromo-4-fluorophenyl)acetonitrile</strong></strong> (29 g, 135 mmol) in anhyd THF (200 mL). After stirring lh, Mel (42.1 mL, 675 mmol, 5 eq) was added to the reaction mixture. After stirring 2h at 0 C, the reaction was allowed to warm to room temperature, quenched carefully with H20 and extracted with EtOAc. The combined extracts were washed with brine, dried over MgS04 and evaporated in vacuo to give 2-(3-bromo-4- fluorophenyl)-2-methylpropanenitrile (29 g, 88%). 1H NMR (400 MHz, CDC13) delta 7.66-7.64 (m, 1H), 7.44-7.40 (m, 1H), 7.15 (t, J=8.4 Hz, 1H), 1.72 (s, 6H).
88%
To a stirred suspension of NaH (16.3 g, 406 mmol, 3 eq) in anhyd THF (100 mL) at 0 0C was added dropwise a solution of <strong>[501420-63-9]2-<strong>[501420-63-9](3-bromo-4-fluorophenyl)acetonitrile</strong></strong> (29 g, 135 mmol) in anhyd THF (200 mL). After stirring Ih, MeI (42.1 mL, 675 mmol, 5 eq) was added to the reaction mixture. After stirring 2h at 0 0C, the reaction was allowed to warm to room temperature, quenched carefully with H2O and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4 and evaporated in vacuo to give 2-(3-bromo-4- fluorophenyl)-2-methylpropanenitrile (29 g, 88%). 1H NMR (400 MHz, CDCl3) delta 7.66-7.64 (m, IH), 7.44-7.40 (m, IH), 7.15 (t, J=8.4 Hz, IH), 1.72 (s, 6H).
To a stirred solution of 3-bromo-4-fluorobenzyl methanesulfonate (60 g, 0.212 mol) in DMF (300 mL) at 0 C was added NaCN (31.1 g, 0.635 mol, 3 eq) portionwise. After stirring at room temperature 4 h, the reaction mixture was partitioned in EtOAc and water. The organic layer was dried over MgS04 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc = 4: 1) to give 2-(3-bromo-4- fluorophenyl)acetonitrile (30 g, 3 step overall yield: 55%). 1H NMR (400 MHz, CDC13) delta 7.56-7.54 (m, 1H), 7.28-7.24 (m, 1H), 7.14 (t, J=4.4 Hz, 1H), 3.73 (s, 2H).
In N,N-dimethyl-formamide; at 0 - 20℃;
To a stirred solution of 3-bromo-4-fluorobenzyl methanesulfonate (60 g, 0.212 mol) in DMF (300 mL) at 0 0C was added NaCN (31.1 g, 0.635 mol, 3 eq) portionwise. After stirring at room temperature 4 h, the reaction mixture was partitioned in EtOAc and water. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc = 4:1) to give 2-(3-bromo-4- fluorophenyl)acetonitrile (30 g, 3 step overall yield: 55%). 1H NMR (400 MHz, CDCl3) delta 7.56-7.54 (m, IH), 7.28-7.24 (m, IH), 7.14 (t, J=4.4 Hz, IH), 3.73 (s, 2H).
With borane-THF; In tetrahydrofuran; methanol; at 0 - 20℃;Reflux;
a) 2- (3 -bromo-4-fluorophenyl)ethanamine To a stirred solution of <strong>[501420-63-9]2-(3-bromo-4-fluoro-phenyl)acetonitrile</strong> (5.0 g, 22.9 mmol, CAS501420-63-9) in THF (50 mL) was added borane-tetrahydronfuran complex 1.0 M in THF (45.8 mL, 45.8 mmol) at 0 C. The mixture was stirred at room temperature for 1 hour then heated to reflux overnight. The reaction mixture was then re-cooled to 0 C and MeOH (25 mL) was added. The mixture was heated to reflux for 90 min. The solvent was removed under vacuum and the residue was partitioned between EtOAc and aqueous 1.0 M HC1. The aqueous phase was made basic with aqueous 1.0 M NaOH then extracted with EtOAc. Organic layers were washed with saturated brine, dried (Na2S04) and concentrated in vacuo to afford the title compound (2.79 g, 56%) as viscous yellow oil which was used in the next step without further purification.
tert-butyl (11bR)-10-fluoro-9-[[2-(trifluoromethyl)pyridine-4-carbonyl]amino]-1,3,4,6,7,11b-hexahydropyrazino[2,1-a]isoquinoline-2-carboxylate[ No CAS ]
(3-bromo-4-fluorophenyl)-(6-difluoromethoxypyridazin-3-yl)acetonitrile[ No CAS ]
2-(3-bromo-4-fluorophenyl)-2-(6-chloropyridazin-3-yl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
Potassium hydroxide powder (603 mg, 10.75 mmol) was suspended in dry N,N-dimethylformamide (2 ml) in a glass vessel with stirrer bar and stirred at room temperature for 30 min. (3-Bromo-4-fluorophenyl)acetonitrile (1.0 g, 4.67 mmol), dissolved in N,N'-dimethylformamide (1.3 ml), was subsequently added dropwise. The reaction mixture was stirred at room temperature for a further 30 min. (5-Bromo-2,4-difluorophenyl)-(4-methoxyphenyl)methanol (506 mg, 2.80 mmol) was then added in portions to the reaction mixture and stirred at 50 C. for 2 h under an oxygen-free argon protective-gas atmosphere. The reaction mixture was added to a mixture of water (50 ml) and saturated sodium chloride solution (35 ml) and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness in a rotary evaporator. The residue was purified by means of RP column chromatography (gradient water/acetonitrile with 0.1% by vol. of formic acid, CombiFlash Rf 200). The suitable product fractions were combined, and the solvents were removed in a rotary evaporator, giving (3-bromo-4-fluorophenyl)-(6-difluoromethoxypyridazin-3-yl)acetonitrile (146 mg, 0.41 mmol, MS: 358.0/360.0[M+H+], 14% yield) as liquid. 2-(3-Bromo-4-fluorophenyl)-2-(6-chloropyridazin-3-yl)acetonitrile is formed as by-product.
Potassium hydroxide powder (603 mg, 10.75 mmol) was suspended in dry N,N-dimethylformamide (2 ml) in a glass vessel with stirrer bar and stirred at room temperature for 30 min. (3-Bromo-4-fluorophenyl)acetonitrile (1.0 g, 4.67 mmol), dissolved in N,N?-dimethylformamide (1.3 ml), was subsequently added dropwise. The reaction mixture was stirred at room temperature for a further 30 min. (5-Bromo-2,4-difluorophenyl)-(4-methoxyphenyl)methanol (506 mg, 2.80 mmol) was then added in portions to the reaction mixture and stirred at 50 C. for 2 h under an oxygen-free argon protective-gas atmosphere. The reaction mixture was added to a mixture of water (50 ml) and saturated sodium chloride solution (35 ml) and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness in a rotary evaporator. The residue was purified by means of RP column chromatography (gradient water/acetonitrile with 0.1% by vol. of formic acid, CombiFlash Rf 200). The suitable product fractions were combined, and the solvents were removed in a rotary evaporator, giving (3-bromo-4-fluorophenyl)-(6-difluoromethoxypyridazin-3-yl)acetonitrile (146 mg, 0.41 mmol, MS: 358.0/360.0[M+H+], 14% yield) as liquid. 2-(3-Bromo-4-fluorophenyl)-2-(6-chloropyridazin-3-yl)acetonitrile is formed as by-product.
[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In 1,4-dioxane; at 130℃; for 1.5h;Inert atmosphere;
(3-Bromo-4-fluorophenyl)acetonitrile (4.00 g, 18.32 mmol), bis(pinacolato)diboron (5.22 g, 20.15 mmol), potassium acetate (55.86 mmol) and bis(triphenylphosphine)palladium(II) chloride (15.2% of Pd) (393.53 mg, 0.55 mmol) were dissolved in oxygen-free 1,4-dioxane (40 ml, max. 0.005% of water) under argon. The reaction mixture was subsequently heated at a temperature of 130 C. for 90 min. When the reaction conversion was complete, the mixture was filtered through kieselguhr. The filtrate was diluted with dichloromethane (200 ml) and water (50 ml) and extracted. The organic phase was dried over sodium sulfate, subsequently filtered and evaporated to dryness in vacuo, giving [4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile as oil (7.59 g, purity 81%, MS: 262.2 [M+H+]), which was reacted further without further work-up.
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In 1,4-dioxane; at 130℃; for 1.5h;Inert atmosphere;
(3-bromo-4-fluorophenyl) acetonitrile (4.00 g, 18.32 mmol), bis (pinacolato) diboron (5.22 g, 20.15mmol), potassium acetate (55.86 mmol) and bis (triphenylphosphine ) palladium (II) chloride (15.2% of Pd) (393.53 mg, 0.55 mmol) oxygen was dissolved under argon in not including 1,4-dioxane (40 ml, water up to 0.005%). The reaction mixture was heated for 90 minutes at a temperature of 130 . When the reaction conversion is complete, the mixture was filtered through diatomaceous earth. The filtrate was diluted with dichloromethane (200 ml) and water (50 ml) and extracted. After drying the organic phase with sodium sulfate, filtered and evaporated under vacuum to dry, [4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile Five days (7.59 g, purity 81%, MS: 262.2 [M + H +]) which was obtained as and reacted further without further work-up.
1-(3-bromo-4-fluorophenyl)cyclobutane-1-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.6%
In step 1 Manufactured <strong>[501420-63-9]2-<strong>[501420-63-9](3-bromo-4-fluorophenyl)acetonitrile</strong></strong> (10.000 g, 46.720 mmol) in N,N-dimethylformamide (50 mL) at 0 C and sodium hydride (60.00%, 4.671 g, 116.801 mmol) was added and stirred at the same temperature for 30 minutes. To the reaction mixture 1,3-dibromopropane (4.764 mL, 46.720 mmol) was added and further stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The concentrate was purified by column chromatography (SiO2, 80 g cartridge, ethyl acetate / hexane = 0% to 30%) to give the title compound as a colorless oil. To give the title compound (6.958 g, 58.6%) as a colorless liquid.
With tetrabutylammomium bromide; In dichloromethane; water; at 20℃; for 4h;
2-bromo-4-(bromomethyl)-1-fluorobenzene (20.000 g, 74.649 mmol), potassium cyanide (14.583 g, 223.947 mmol) and tetra-n-butylammonium bromide (2.406 g, 7.465 mmol) was dissolved in a mixed solution of dichloromethane(80 mL)/water (80 mL) at room temperature and stirred at the same temperature for 4 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated sodium hydrogen carbonate aqueous solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified and purified by column chromatography (SiO2, 120 g cartridge; ethyl acetate / hexane = 0% to 20%) to give the title compound (14.200 g, 88.9%) as a colorless liquid.
methyl (2E)-3-(3,5-difluoropyridin-4-yl)acrylate[ No CAS ]
methyl 4-(3-bromo-4-fluorophenyl)-4-cyano-3-(3,5-difluoropyridin-4-yl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With potassium tert-butylate; In N,N-dimethyl-formamide; toluene; at 60℃; for 5h;Inert atmosphere;
1a) Preparation of methyl 4-(3-bromo-4-fluorophenyl)-4-cyano-3-(3,5-difluoropyridin-4-yl)butanoate Under protective gas (argon), 46 mg (0.41 mmol) of potassium tert-butoxide were added to 0.413 g (2.07 mmol) of methyl (2E)-3-(3,5-difluoropyridin-4-yl)acrylate and 0.443 g (2.07 mmol) of <strong>[501420-63-9](3-bromo-4-fluorophenyl)acetonitrile</strong> in 21.0 ml of toluene and 1 ml of DMF, and the mixture was stirred at 60 C. for 5 h. After removal of the solvent under reduced pressure, the residue was taken up in ethyl acetate and washed twice with in each case 50 ml of water. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. Chromatography of the residue over silica gel (ethyl acetate/heptane=15:85) gave 0.501 g (58% of theory) of the diastereomeric methyl 4-(3-bromo-4-fluorophenyl)-4-cyano-3-(3,5-difluoropyridin-4-yl)butanoates
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