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CAS No. : | 57381-39-2 | MDL No. : | MFCD00142875 |
Formula : | C7H3BrFN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MDHNVHCZDCSTMS-UHFFFAOYSA-N |
M.W : | 200.01 | Pubchem ID : | 93654 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 38.81 |
TPSA : | 23.79 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.79 cm/s |
Log Po/w (iLOGP) : | 1.89 |
Log Po/w (XLOGP3) : | 2.43 |
Log Po/w (WLOGP) : | 2.88 |
Log Po/w (MLOGP) : | 2.63 |
Log Po/w (SILICOS-IT) : | 2.9 |
Consensus Log Po/w : | 2.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.05 |
Solubility : | 0.176 mg/ml ; 0.000881 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.57 |
Solubility : | 0.535 mg/ml ; 0.00268 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.62 |
Solubility : | 0.0481 mg/ml ; 0.00024 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.67 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280 | UN#: | N/A |
Hazard Statements: | H302-H312-H332 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: for 4 h; Inert atmosphere; Reflux Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether at 20℃; |
33a 33bTo a solution of 2-bromo-5-fluoro-benzonitrile 33a (10 g, 50 mmol) in dry tetrahydrofuran (100 mL) under nitrogen was added methylmagnesium bromide (3.2 M in ether, 19 mL, 60.0 mmol), and the resulting mixture was heated to reflux for 4 hours. The RM was then cooled down to RT, poured into a 2 N HCl solution (100 mL) and then diluted with methanol (100 mL). The resulting green solution was concentrated on a steam bath for 1 h at which point the organic solvents had been removed and the crude product had precipitated. The reaction mixture was then extracted with ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by column chromatography using heptane and dichloromethane to give 4.88 g (45percent yield) of the desired product l-(2-bromo-5-fluorophenyl)ethanone 33b as a pink oil; m/z 218 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; dimethyl sulfoxide; at 90.0℃; for 18h; | A suspension of [2-BROMO-5-FLUOROBENZONITRILE] (30.0 g, 150 mmol), bis (pinacolato) diboron (41.9 g, 165 mmol) and potassium acetate (29.4 g, 300 mmol) in 1,4-dioxane (375 ml) and DMSO (30 ml) was degassed with nitrogen for 1 h. Dichloro [[L,] [1'-BIS] (diphenylphosphino) ferrocene]- palladium (II) dichloromethane adduct (3.7 g, 4.5 mmol) was added and the mixture heated at [90C] for [18] h. The mixture was allowed to cool to ambient temperature then diluted with diethyl ether (300 ml) and filtered through a glass microfibre filter paper. The solvent was evaporated and the residue was treated with ice-cold 2N sodium hydroxide solution (250 ml) and the mixture left to stir for 15 min. The aqueous phase was extracted with diethyl ether (200 ml). The pH of the aqueous was adjusted to 5 by the addition of concentrated hydrochloric acid. The aqueous phase was extracted with diethyl ether (2 x 200 ml), the organic phase was combined, washed with water (150 ml) and brine (150 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give 5-fluoro-2- (4,4, 5, [5-TETRAMETHYL- [1,] 3,2] dioxaborolan-2-yl) benzonitrile (36.5 g, [98%)] as a brown oil which crystallised on standing: [5H] (360 MHz, CDCl3) 1.38 (12H, s), 7.25-7.30 (1H, m), 7.40 (1H, dd, J 3 and 8), 7.91 (1H, dd, J 6 and 8). 5-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- benzonitrile (0.99 g, 4.0 mmol) and [1,] 3-dibromo-5-fluorobenzene (1.52 g, [6.] 0 mmol) were suspended in 1,2-dimethoxyethane (8 ml) and 2N sodium carbonate solution (4 [ML)] and degassed for 30 min before addition of tetrakis (triphenylphosphine) palladium [(0).] On complete addition the mixture was heated at [65C] for 20 h. The mixture was partitioned between ethyl acetate (100 ml) and water (50 ml), the organic layer separated and washed with brine (50 ml), dried over anhydrous sodium sulphate, filtered and evaporated onto silica. The product was purified by flash column chromatography on silica, eluting with isohexane on a gradient of diethyl ether (5-100%). Combination of the desired fractions and evaporation gave [3'-BROMO-4,] [5'-DIFLUOROBIPHENYL-2-CARBONITRILE] (110 mg, 9%) as a white solid: [SN] (500 MHz, [CD13)] 7.53-7. 55 [(1H,] m), 7.67 (1H, s), 7.69-7. 76 (3H, m), 8.03 [(1H,] dd, [J 9 AND] 2). [2- (8-FLUOROIMIDAZO [L,] 2-a] [PYRIDIN-7-YL)] propan-2-ol (58 mg, 0.3 mmol) and 3'-bromo-4, [5'-DIFLUOROBIPHENYL-2-CARBONITRILE] (106 mg, 0.36 mmol) were coupled following the procedure in Example 6 to afford 4,3'-difluoro- 5'- [8-fluoro-7- (l-hydroxy-l-methylethyl) imidazo [1, [2-A] PYRIDIN-3-YL]-] [BIPHENYL-2-CARBONITRILE] (25 mg, 20%) as a white solid: [SN] (500 MHz, [CD13)] 1.74 (6H, s), 2.07 [(1H,] s), 7.22-7. 26 (2H, m), 7.35 [(1H,] d, J 9), 7.39-7. 45 [(1H,] m), 7.51-7. 57 (3H, m), 7.76 [(1H,] s), 8.35 [(1H,] d, J 7) ; [RNLZ] (ES+) 408 (100%, [[MH] +).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium fluoride; tri-tert-butyl phosphine;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; hexane; water; at 20℃; for 18h; | A suspension of [2-BROMO-5-FLUOROBENZONITRILE] (10.0 g, 50 mmol), potassium fluoride (9.59 g, 165 mmol) and 2, [6-DIFLUOROPHENYLBORONIC] acid (9. 87 g, 62. 5 mmol) in tetrahydrofuran (120 ml) and water [(15] ml) was degassed with nitrogen for 30 min. Tris [(DIBENZYLIDINEACETONE)-] dipalladium (0) (916 mg, 1.0 mmol) and tri-tert-butylphosphine (10% w/w solution in hexane, 0.5 ml) were added and the mixture stirred at ambient temperature for 18 h. The black solution was washed with IN sodium hydroxide solution (2 x 100 ml), and the aqueous phase was re-extracted with diethyl ether (100 ml). The combined organic layer was washed with brine (50 [ML),] filtered through a glass microfibre filter paper then evaporated to give an orange solid. The solid was suspended in 2-propanol (120 ml) and heated to [70C] to aid dissolution. The solution was left to cool to ambient temperature then water (120 ml) added dropwise over 1 h. The solid was filtered and washed with [2-PROPANOL/WATER] (1: 1,30 ml) then dried under vacuum to give 4,2', [6'-TRIFLUOROBIPHENYL-2-CARBONITRILE] (9.92 g, 85%) as a grey solid: 8H (360 MHz, CDCl3) 7.06 (2H, t, [J 8),] 7. [38-7.] 52 (4H, m). To a slurry of 4, 2', [6'-TRIFLUOROBIPHENYL-2-CARBONITRILE] [(5.] 0 g, 21.4 mmol) and [1,] [3-DIBROMO-5,] 5-dimethylhydantoin (3. [37] g, 11.8 mmol) in acetonitrile (45 ml) was added concentrated sulphuric acid (3.15 g, 32.2 [MMOL).] The slurry was warmed to [70C] and the resulting solution stirred for 7 h then stood at ambient temperature for 18 h. Water (45 ml) was added dropwise to the solution over 15 min. The layers were allowed to settle and the product rapidly crystallised. The slurry was left to stir for 0.5 h then filtered, washed with 1: 1 acetonitrile/water (10 ml) and left to air-dry, which gave 3'-bromo-4,2', 6'-trifluorobiphenyl-2-carbonitrile (6.3 g, 94%) as a white solid: aH (360 MHz, [CDC13)] 6.97-7. 08 [(1H,] m), 7. [38-7.] 54 (2H, m), 7.62-7. 68 [(1H,] m). 2- (8-Fluoroimidazo [l, 2-a] pyridin-7-yl) propan-2-ol (194 mg, 1.0 mmol) and [3'-BROMO-4,] 2', [6'-TRIFLUOROBIPHENYL-2-CARBONITRILE] (343 mg, 1.1 mmol) were coupled following the procedure in Example 6 to afford [3'- [8-] fluoro-7- (1-hydroxy-1-methylethyl) imidazo [1, 2-a] [PYRIDIN-3-YL]-4,] 2', 6'- [TRIFLUOROBIPHENYL-2-CARBONITRILE] (155 mg, 36%) as a white solid: [8H] (360 MHz, [CD13)] 1.74 [(6H,] s), 2.07 [(1H,] s), 7.19-7. 26 (2H, m), 7.41-7. 49 [(1H,] m), 7.54-7. 65 (3H, m), 7.73 [(1H,] s), 7.93 [(1H,] dd, J 7 and 7); [M/Z] [(ES+)] 426 (100%, [MH] +). |
85% | With potassium fluoride;tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; In tetrahydrofuran; hexane; water; at 20℃; for 18h; | A suspension of <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (10.0 g, 50 mmol), potassium fluoride (9.59 g, 165 mmol) and 2,6-difluorophenylboronic acid (9.87 g, 62.5 mmol) in tetrahydrofuran (120 ml) and water (15 ml) was degassed with nitrogen for 30 min. Tris (dibenzylidineacetone)- dipalladium (0) (916 mg, 1.0 mmol) and tri-tert-butylphosphine (10% w/w solution in hexane, 0.5 ml) were added and the mixture stirred at ambient temperature for 18 h. The black solution was washed with IN sodium hydroxide solution (2 x 100 ml), and the aqueous phase was re-extracted with diethyl ether (100 ml). The organic layers were combined, washed with brine (50 ml), filtered through a glass microfibre filter paper then evaporated to give an orange solid. The solid was suspended in 2-propanol (120 ml) and heated to 70C to aid dissolution. The solution was left to cool to ambient temperature then water (120 ml) was added dropwise over 1 h. The resulting solid was collected by filtration, washed with 2-propanol/water (1: 1,30 ml) then dried under vacuum to give 4,2', 6'- trifluorobiphenyl-2-carbonitrile (9.92 g, 85%) as a grey solid: on (360 MHz, CDC1s) 7.06 (2H, t, J 7. 9), 7.38-7. 52 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 6 4,2'-Difluoro-5'-(5-methyl-4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)biphenyl-2-carbonitrile 2-Bromo-5-fluorobenzonitrile was converted to 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile as described in Example 2 to give a straw-coloured solid: deltaH (360 MHz, CDCl3) 1.38 (12H, s), 7.27 (1H, ddd, J 8, 8 and 2), 7.39 (1H, dd, J 9 and 2), 7.90 (1H, dd, J 8 and 6). 1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one was coupled to 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile, in the same way as in Example 1, to give 4,2'-difluoro-5'-(5-methyl-4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)biphenyl-2-carbonitrile as an off-white solid (360 mg, 55%): deltaH (400 MHz, d6-DMSO) 3.54 (3H, s), 6.67 (1H, d, J 7), 7.61 (1H, d, J 7), 7.69 (1H, t, J 9), 7.75-7.87 (4H, m), 8.09 (1H, dd, J 9 and 3), 8.38 (1H, s); m/z (ES+) 363 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium fluoride;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; 1,4-dioxane; water; | EXAMPLE 1 4,2'-Difluoro-5'-[3-(1-fluoro-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile A mixture of 2-bromo-5-fluorobenzonitrile (20 g, 100 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2] dioxaborolane (from Example B) (34.7 g, 130 mmol) and potassium fluoride (19.2 g, 330 mmol) in tetrahydrofuran (350 ml) and water (20 ml) was degassed with nitrogen for 30 min then treated with tris(dibenzylideneacetone)dipalladium(0) (1.83 g, 2 mmol) followed by tri-tert-butylphosphine (4 ml of a 0.2 M solution in 1,4-dioxane, 0.8 mmol). This mixture was stirred at ambient temperature for 30 min before heating at 50 C. for 18 h. The resulting dark suspension was cooled to ambient temperature, diluted with 0.5 M sodium hydroxide (2.5 l) and stirred at ambient temperature for 4 h. The solid was collected by filtration, washed with water and dried under suction to afford 4,2'-difluoro-5'-nitrobiphenyl-2-carbonitrile as a black solid (28.1 g, >100%) contaminated with dibenzylideneacetone: 1H NMR (360 MHz, CDCl3) delta 7.38-7.56 (4H, m), 8.33-8.40 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium;zinc(II) chloride; In tetrahydrofuran; | Step B. 4-(2-Cyano-4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester A solution of <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (8.1 g, 40.5 mmole) in THF (50 mL) was added rapidly to a solution of n-BuLi (20 mL, 2.5M, 50 mmole) in THF at -78 C. and the resulting solution is stirred for 5 minutes. To this solution was added ZnCl2, (0.5 M in THF, 89 mL, mmoles) and the solution was warmed to 0 C. Palladium tetrakistriphenylphosphine (1.5 g, 1.3 mmole) was added followed by trifluoromethanesulfonic acid [1-tert-butoxycarbonyl-(1,2,3,6-tetra-hydropyridin-4-yl)] ester from step A from above (9 g, 27.16 mmole). The reaction was heated to 40 C. for 30 minutes and then cooled to room temperature and poured into saturated aqueous sodium bicarbonate (1 L). The mixture was extracted with ethyl acetate (3*300 mL) and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica gel eluding with 15% to 30% ethyl acetate/hexanes to give the product. 1H NMR (CDCl3): delta6 7.4-7.25 (m, 3H), 5.95 (br s, 1H), 4.09 (br s, 2H), 3.65-3.60 (m, 2H), 2.50 (m, 2H), 1.50 (s, 9H). | |
With n-butyllithium;zinc(II) chloride; In tetrahydrofuran; | Step A. 4-(2-Cyano-4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester A solution of <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (8.1 g, 40.5 mmole) in THF (50 mL) was added rapidly to a solution of n-BuLi (20 mL, 2.5M, 50 mmole) in THF at -78 C. and the resulting solution is stirred for 5 minutes. To this solution was added ZnCl2, (0.5 M in THF, 89 mL, mmoles) and the solution was warmed to 0 C. Palladium tetrakistriphenylphosphine (1.5 g, 1.3 mmole) was added followed by trifluoromethanesulfonic acid [1-tert-butoxycarbonyl-(1,2,3,6-tetra-hydropyridin-4-yl)] ester from Example 7, step A below (9 g, 27.16 mmole). The reaction was heated to 40 C. for 30 minutes and then cooled to room temperature and poured into saturated aqueous sodium bicarbonate (1 L). The mixture was extracted with ethyl acetate (3*300 mL) and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica gel eluding with 15% to 30% ethyl acetate/hexanes to give the product. 1H NMR (CDCl3): delta 7.4-7.25 (m, 3H), 5.95 (br s, 1H), 4.09 (br s, 2H), 3.65-3.60 (m, 2H), 2.50 (m, 2H), 1.50 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N2;Pd(PPh3)4; In toluene; | EXAMPLE 5 2-Cyano-4-fluoro-4'-methylbiphenyl A solution of p-tolyltrimethyltin (1.26 g; 4.96 mmol) in dry toluene (8 mL) was degassed with a stream of N2 for ca. 5 min. To this solution under N2 was added <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (0.901 g; 4.51 mmol) and Pd(PPh3)4 (260 mg; 5 mol%). The reaction was stirred at reflux under N2 for 12 hr and then cooled to room temperature. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The product was purified by flash chromatography on a silica gel column, eluding with Hex/CH2 Cl2 to afford the title compound as a slightly yellow solid. 1 H-NMR (300 MHz, CDCl3): delta2.40 (s, 3H), 7.28 (d, 2H), 7.34 (dd, 1H), 7.40 (d, 2H), 7.44 (t, 1H), 7.46 (dd, 1H); MS (FAB) m/e 211 (M+, calcd for C14 H10 NF, 211). | |
0.606 g (64%) | With N2;Pd(PPh3)4; In toluene; | Step 1 2-cyano-4-fluoro-4'-methylbiphenyl A solution of p-tolyltrimethyltin (1.26 g; 4.96 mmol) in dry toluene (8 mL) was degassed with a stream of N2 for ca. 5 min. To this solution under N2 was added <strong>[57381-39-2]2-bromo-5-fluoro-benzonitrile</strong> (0.901 g; 4.51 mmol) and Pd(PPh3)4 (260 mg; 5 mol %). The reaction was stirred at reflux under N2 for 12 hr and then cooled to room temperature. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The product was purified by flash chromatography on a silica column eluding with Hex/CH2 Cl2 to afford 0.606 g (64%) of the title compound as a slightly yellow solid. 1 H-NMR (300 MHz, CDCl3) delta 2.40 (s, 3H), 7.28 (d, 2H), 7.34 (dd, 1H), 7.40 (d, 2H), 7.44 (t, 1H), 7.46 (dd, 1H); FAB mass spectrum, m/e 211 (m+, calcd for C14 H10 NF, 211). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride;tris(dibenzylideneacetone)dipalladium (0); In tetrahydrofuran; 2-Methylpentane; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate; | 5'-Acetyl-4,2'-difluorobiphenyl-2-carbonitrile To a degassed solution of 1-[4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]ethanone (12 g, 45.43 mmol), <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (9.09 g, 5.28 ml, 45.44 mmol), potassium fluoride (7.92 g, 136.31 mmol) and tris(dibenzylideneacetone)palladium(0) (0.834 g, 0.908 mmol) in THF (200 ml) and water (10 ml) was added tri-tert butylphosphine (10% weight solution) (0.368 g, 3.63 ml, 1.817 mmol). The reaction was heated at 70 C. for 14 h then allowed to cool to ambient temperature. The reaction was partitioned between water (200 ml) and ether (300 ml). The aqueous phase was extracted with ether (150 ml) and the combined organics washed with brine (200 ml), dried (MgSO4), filtered and evaporated to give a brown solid. The solid was dissolved in DCM and adsorbed onto silica. The crude product was chromatographed on silica (5-20% EtOAc in isohexane) to give the title product as a white solid (6.8 g): deltaH (400 MHz, CDCl3) 2.63 (3H, s), 7.31 (1H, t, J 9.0 Hz), 7.40-7.44 (1H, m), 7.50-7.53 (2H, m), 8.02-8.10 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100 - 110℃; for 1h; | Example 195: 4-Chloro-6-(5-fluoro-2-piperazin-l-yl-benzylamino)-2H-phthalazin-l- one; 4-(2-Cyano-4-fluoro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester; A mixture of piperazine-1-carboxylic acid tert-butyl ester (1.05 g , 5.65 mmol), 2- bromo-5-fluoro-benzonitrile (1.13 g, 5.65 mmol), Pd2(dba)3 (259 mg, 0.283 mmol), xanthphos (490 mg, 0.848 mmol), sodium tert-butoxide (1.63 g, 16.95 mmol) in anhydrous 1,4-dioxane (10 ml) was heated at 100-110 C in a sealed tube for Ih. After cooled to room temperature, the mixture was filtered through celite then concentrated before purified by chromatography (hexanes/EtOAc) to provide compound as indicated (1.31 g, 76%). m/z (M+l) 306.21. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In toluene; at 90℃; for 9h;Inert atmosphere; | Example 24; 5-chloro-1-[2-(ethylsulfonyl)-5-fluorobenzyl]-2-imino-1,2-dihydropyridine-3-carboxamide hydrochloride; (Step 1); A mixture of <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (5.0 g), sodium ethanethiolate (2.31 g), Pd2(dba)3 (114 mg), Xantphos (145 mg) and N,N-diisopropylethylamine (6.46 g) was stirred in toluene (100 ml) at 90 C. for 9 hr under a nitrogen atmosphere. The reaction mixture was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19) to give 2-(ethylsulfanyl)-5-fluorobenzonitrile (1.81 g) as a solid. 1H NMR (300 MHz, CDCl3) delta ppm 1.33 (3H, t, J=7.19 Hz), 3.01 (2H, q, J=7.19 Hz), 7.16-7.29 (1H, m), 7.31-7.42 (1H, m), 7.43-7.70 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | 33a 33bTo a solution of 2-bromo-5-fluoro-benzonitrile 33a (10 g, 50 mmol) in dry tetrahydrofuran (100 mL) under nitrogen was added methylmagnesium bromide (3.2 M in ether, 19 mL, 60.0 mmol), and the resulting mixture was heated to reflux for 4 hours. The RM was then cooled down to RT, poured into a 2 N HCl solution (100 mL) and then diluted with methanol (100 mL). The resulting green solution was concentrated on a steam bath for 1 h at which point the organic solvents had been removed and the crude product had precipitated. The reaction mixture was then extracted with ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by column chromatography using heptane and dichloromethane to give 4.88 g (45% yield) of the desired product l-(2-bromo-5-fluorophenyl)ethanone 33b as a pink oil; m/z 218 [M+H]+. | |
45% | In tetrahydrofuran; diethyl ether; for 4h;Inert atmosphere; Reflux; | To a solution of 2-bromo-5-fluorobenzonitrile (10.0 g, 48.5 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen was added methylmagnesium bromide (3.2M in ether, 19 mL, 60.0 mmol). The resulting mixture was heated to reflux for 4 h. The reaction mixture was then cooled, poured into 2N hydrochloric acid (100 mL), and diluted with methanol (100 mL). The organic solvents were removed and the crude product precipitated out. The reaction mixture was extracted with ethyl acetate, dried over MgS04, and concentrated. The residue was purified by column chromatography (heptane/dichloromethane) to give 4.88 g (21.9 mmol, 45percent) of compound 86 as a pink oil. |
45% | In tetrahydrofuran; diethyl ether; for 4h;Reflux; | To a solution of 2-bromo-5-fluorobenzonitrile (10.0 g, 48.5 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen was added methylmagnesium bromide (3.2M in ether,19 mL, 60.0 mmol). The resulting mixture was heated to reflux for 4 h. The reaction mixture was then cooled, poured into 2N hydrochloric acid (100 mL), and diluted with methanol (100 mL). The organic solvents were removed and the crude product precipitated out. The reaction mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated. The residue was purified by column chromatography (heptane/dichioromethane) to give 4.88 g (21.9 mmol, 45percent)of compound 86 as a pink oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Reagent 85-Fluoro-2-(tributylstannyl)benzonitrile<strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (1.5 g, 7.50 mmol) in ether (50 mL) was treated with n-BuLi (4.5 mL, 11.25 mmol) slowly at -75 C. After ten minutes, tributylchlorostannane (2.93 g, 9.00 mmol) was added and stirred at -75 C. for another forty-five minutes. The reaction was queched with a mixture of wet ether (50 mL)/saturated NH4Cl (50 mL), warmed to RT, diluted with ether (300 mL) and washed with half-saturated NH4Cl once. The organic layer was dried over MgSO4, filtered and evaporated to dryness. The crude material was added to a silica gel column and was eluted with 0-20% ethyl acetate in hexane to give a light-yellow oil (3.2 g, 104% yield, 70% purity) as the title compound.1H NMR (300 MHz, CHLOROFORM-d) delta ppm 7.51 (dd, J=8.22, 6.32 Hz, 1H) 7.37 (dd, J=8.85, 2.53 Hz, 1H) 7.21 (dd, J=8.64, 2.53 Hz, 1H) 1.10-1.60 (m, 18 H) 0.89 (t, J=7.3 Hz, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step A. N-(4- { ( 1 JZ)-I - [(J?)-(4-Bromo-3 -cyanophenrhoxy)(4-chlorophenyl)methyl]butyl } benzoyl)- beta-alamneTo a flask charged with potassium tert-butoxide (0.805 g, 7.18 mmol), 2-bromo- 5-fluorobenzonitrile (0.622 g, 3.11 mmol), and INTERMEDIATE 1 (1.00 g, 2.39 mmol) was added THF (16 mL), then the mixture was stirred at 70 0C for 16 hours. After cooling to RT, the mixture was diluted with NH4Cl (aq) then extracted with EtOAc. The organic layer was dried over MgSO4, filtered, then concentrated. The resulting residue was purified by PTLC to afford the title compound. LCl 1.24 min. (M+H)+ 569. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | <strong>[57381-39-2]2-Bromo-5-fluorobenzonitrile</strong> (6.00 g, 30.0 mmol) and triisopropyl borate (8.28 ml_, 36.0 mmol) were dissolved in a mixture of toluene (48 ml_) and tetrahydrofuran (12 ml_), and the solution was cooled in a dry ice/acetone bath. A solution of n-butyllithium in hexanes (2.5M, 14.4 ml_, 36.0 mmol) was added drop-wise over 1 hour, and the reaction was then allowed to warm to room temperature with stirring over 18 hours. The mixture was cooled in an ice bath and treated with a 2N aqueous hydrochloric acid solution until the pH reached 1 , then allowed to warm to room temperature, at which time the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-heptane to provide (2-cyano-4- fluorophenyl)boronic acid as a white solid. Yield: 2.20 g, 13.3 mmol, 44%. 1H NMR (400 MHz, CD3OD) delta 7.43 (ddd, J=8.6, 8.6, 2.5 Hz, 1 H), 7.55 (dd, J=8.8, 2.5 Hz, 1 H), 7.69 (br s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; In dimethyl sulfoxide; at 100℃;Sealed vial; | A mixture of <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (500 mg, 2.500 mmol), pyrrolidine (0.21 mL, 2.54 mmol), and K2CO3 (346 mg, 2.500 mmol) was taken up in DMSO (5 mL) in a 1 dram vial. The vial was sealed, and the reaction was heated at 100 0C (bath temp) for 16.5 showed. Water (15 mL) and EtOAc (10 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL) and concentrated. The crude product was purified by flash column chromatography to afford the title compound (411 mg, 66%). LC-MS m/z 251 (M)+, 1.16 min (ret time). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.5% | With sodium tetrahydroborate; trifluoroacetic acid; In tetrahydrofuran; at 20℃; for 16h; | To a solution of <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (3.0g, 15.00mmol) and NaBH4 (1.419 g, 37.5 mmol) in THF (30mL) was slowly added TFA (3.47 ml., 45.0 mmol) over a period of20 min. The resulting mixture was stirred at rt for 16 hours, then MeOH (10 mL) was added and the mixture wasstirred for another 30 min. It was then diluted with EtOAc(200 ml.), washed with water, dried over Na2S04 and evaporated.The residue was purified on an 80 g Thompson silicacartridge (3% to 100% B in Hexanes, 1200 ml., B: 10%MeOH in EtOAc). The desired product was obtained as acolorless oil (1.70 g, 8.33 mmol, 55.5% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃;Inert atmosphere; | General procedure: To a solution of the aryl bromide (5 mmol) in 15 mL of toluene/EtOH (1/1) was added 0.17 g (0.14 mmol) of Pd(PPh3)4, and the mixture was stirred under argon atmosphere. Then 2 N aqueous Na2CO3 (7.5 mL) and 0.80 g (6 mmol) of 2-tolylboronic acid were added. The mixture was refluxed at 80 C for 1-2 days until reaction was completed (TLC). After cooling to room temperature, the product was diluted with water and extracted with EtOAc. The organic layers were dried with MgSO4, filtered, and concentrated. Purification was performed by column chromatography using a mixture of CH/EtOAc (9:1). The compounds were used, without structure determination, directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 48h; | 2-bromo-5-(4-morpholinyl)-benzonitrile (Intermediate 10)(Intermediate 10)A mixture of <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (10 g, 50 mmol), morpholine (4.37 mL, 50 mmol), and potassium carbonate (6.91 g, 50 mmol), in DMSO (100 mL) was stirred at 100 C for 48 h. The reaction mixture was poured into water (200 mL) and was stirred for 1 h. The precipitate was filtered off and purified by column chromatography on silica gel (eluent gradient from 50/50 to 100/0 DCM/heptane). The desired fractions were collected and evaporated, yielding 4.1 g (30 %) of Intermediate 10, after drying overnight under vacuum at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With tetrakis(triphenylphosphine) palladium(0); potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 1.75h;Microwave irradiation; | In a 100 mL round-bottom flask were placed 2-methyl-4-(phenylsulfonylmethyl) thiazole or 2-methyl-4-(tosylmethyl)thiazole or 4-[(4-chlorophenylsulfonyl)methyl]-2-methylthiazole (1.5 equiv), 2-bromobenzaldehyde or 2-bromobenzonitrile (1 equiv), tetrakis(triphenylphosphine) palladium (0.05 equiv), potassium acetate(3 equiv) and dimethylacetamide (5 mL). The vessel was then placed in the synthesis multimode microwave oven cavity (ETHOS Synth Lab station) and reaction was carried out under microwave irradiation at 150 C at 300 W for an appropriate time. The disappearance of starting materials was monitored by TLC. After being cooled down, the mixture was poured into water and then extracted with EtOAc (5 * 15 mL). The organic layers were dried over anhydrous sodium sulfate and removed under vacuum. The residue was purified by chromatographic column, eluting with EtOAc/cyclohexane (5/5) for all compounds except 7 (chloroform/petroleum ether/ethyl ether (6/2/2)) and 8 (chloroform/EtOAc (9/1)). The residue was then recrystallized from i-PrOH to give the corresponding required product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With tetrakis(triphenylphosphine) palladium(0); potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 2.25h;Microwave irradiation; | General procedure: In a 100 mL round-bottom flask were placed 2-methyl-4-(phenylsulfonylmethyl) thiazole or 2-methyl-4-(tosylmethyl)thiazole or 4-[(4-chlorophenylsulfonyl)methyl]-2-methylthiazole (1.5 equiv), 2-bromobenzaldehyde or 2-bromobenzonitrile (1 equiv), tetrakis(triphenylphosphine) palladium (0.05 equiv), potassium acetate(3 equiv) and dimethylacetamide (5 mL). The vessel was then placed in the synthesis multimode microwave oven cavity (ETHOS Synth Lab station) and reaction was carried out under microwave irradiation at 150 C at 300 W for an appropriate time. The disappearance of starting materials was monitored by TLC. After being cooled down, the mixture was poured into water and then extracted with EtOAc (5 * 15 mL). The organic layers were dried over anhydrous sodium sulfate and removed under vacuum. The residue was purified by chromatographic column, eluting with EtOAc/cyclohexane (5/5) for all compounds except 7 (chloroform/petroleum ether/ethyl ether (6/2/2)) and 8 (chloroform/EtOAc (9/1)). The residue was then recrystallized from i-PrOH to give the corresponding required product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 1.5h;Microwave irradiation; | General procedure: In a 100 mL round-bottom flask were placed 2-methyl-4-(phenylsulfonylmethyl) thiazole or 2-methyl-4-(tosylmethyl)thiazole or 4-[(4-chlorophenylsulfonyl)methyl]-2-methylthiazole (1.5 equiv), 2-bromobenzaldehyde or 2-bromobenzonitrile (1 equiv), tetrakis(triphenylphosphine) palladium (0.05 equiv), potassium acetate(3 equiv) and dimethylacetamide (5 mL). The vessel was then placed in the synthesis multimode microwave oven cavity (ETHOS Synth Lab station) and reaction was carried out under microwave irradiation at 150 C at 300 W for an appropriate time. The disappearance of starting materials was monitored by TLC. After being cooled down, the mixture was poured into water and then extracted with EtOAc (5 * 15 mL). The organic layers were dried over anhydrous sodium sulfate and removed under vacuum. The residue was purified by chromatographic column, eluting with EtOAc/cyclohexane (5/5) for all compounds except 7 (chloroform/petroleum ether/ethyl ether (6/2/2)) and 8 (chloroform/EtOAc (9/1)). The residue was then recrystallized from i-PrOH to give the corresponding required product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.7% | With copper(l) iodide; diisopropylamine;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 70℃; for 2h;Inert atmosphere; Sealed; | Step A: 2-f(4a£5j -4a-Ethyl-5-hydroxy-l-phenyl-l ,414 ,5,6,7-hexaliydrocyclopenta[f)indazoI- 5 -yl } ethynyl 1-5 -fl uorobenzonitri le ( 10- 1 )Intermediate A (300 mg, 0.986 mmol), <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (296 mg, 1.48 mmol), Cul (4.69 mg, 0.025 mmol), diisopropylamine (0.147 ml, 1.035 mmol) were combined in THF (2 ml) and then nitrogen gas was bubbled through the mixture for 10 min. Added bis(triphenylphosphine)palladium(II) chloride (17.29 mg, 0.025 rranol) and then sealed the flask and stirred at 70C for 2 h. The reaction was allowed to cool to ambient temperature and then was diluted with Et20, filtered through a celite pad and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel ISCO 12 gram, eluting with hexanes to EtOAc to give 10-1 (220 mg, 52.7%) as an orange oil. MS (ESI): m/z = 423.9 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | To a stirred solution of <strong>[57381-39-2]2-bromo-5-fluoro-benzonitrile</strong> (1 g, 5 mmol) and Ti(Oi-Pr)4 (1.81 mL, 5.5 mmol) in ether (20 mL) was added EtMgBr (3.67 mL, 11 mmol) at -78 C. After stirring at -78 C for 10 min, the solution was warmed up to room temperature and stirred for 1 hour. BF3-Et20 (1.25 mL) was added before it was stirred for another 1 hour. After addition of 1 N aq. HCl (15 mL) and ether (30 mL), aq. NaOH (10%, 45 mL) solution was added to give two clear phases. The mixture was exacted with EtOAc (30 mL x 5). The combined organic layers were dried over anhy. Na2S04, filtered, and concentrated in vacuo to give a crude product, which was purified by column chromatography (PE:EA = 5: 1) to afford the title compound (800 mg, 70%>) as oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 130℃; for 0.5h;Microwave irradiation; Inert atmosphere; | A microwave vial was charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M, 0.125 g, 0.299 mmol), 2-bromo-5-methoxybenzonitrile (ASDI, 0.111 g, 0.524 mmol), Xantphos (0.035 g, 0.060 mmol), Pd2(dba)3 (0.027 g, 0.030 mmol) and sodium tert-butoxide (0.058 g, 0.599 mmol). The mixture was diluted with Toluene (2.00 ml), and purged with nitrogen, and heated at 130 C in the microwave for 30 minutes. After cooling to RT, trifluoroacetic acid (0.577 ml, 7.48 mmol) was added to the crude reaction mixture, and the reaction was stirred at RT for 2h (), after which the crude reaction was filtered over a plug of Celite (washing with minimal DCM to flush through the product). The reactions were then dried overnight in a hood and purified using reverse phase mass-directed HPLC. The column used was a Waters Xbridge CI 8 19 x 100 mm 10 micron column. The mobile phase was run under gradient conditions using Water and CH3CN with 0.1 % trifluoroacetic acid. 1H NMR (500 MHz, DMSO-d6) delta ppm 12.57 (br. s., 1 H) 7.55 (d, J=2.86 Hz, 1 H) 7.51 (d, J=8.94 Hz, 1 H) 7.37 (dd, J=8.94, 2.86 Hz, 1 H) 7.21 (d, J=4.47 Hz, 1 H) 7.16 (d, J=1.83 Hz, 1 H) 7.13 (dd, J=8.48, 1.95 Hz, 1 H) 6.78 (d, J=4.47 Hz, 1 H) 6.29 (d, J=8.59 Hz, 1 H) 4.31 - 4.37 (m, 2 H) 3.84 (s, 3 H) 3.68 - 3.73 (m, 2 H). m/z (ESI) 428.1 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 6h;Inert atmosphere; | A stirred solution of N-(( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)-4-(4,4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzenesulfonamide (1.6 g, 4.05 mmol), <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (2.03 g, 10.15 mmol), sodium carbonate (1.07 g, 10.1 mmol) in dioxane: water (30:3 mL) was degassed using argon for 10 mi [1,1-Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (0.296 g, 0.405 mmol) was added and the reaction mixture wasdegassed for another 10 mm and stirred at 110Cfor6 h. Solvent was evaporated under reduced pressure and the compound was extracted in ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The obtained residue was washed with hexane followed by n-pentane to afford the title compound as a white solid.Yield: 1.1 g, 70%.1H NMR (400 MHz, Chloroform-d) O 8.04 - 7.97 (m, 2 H), 7.71 - 7.64 (m, 2 H), 7.55 - 7.49(m, 2 H), 7.39 - 7.46 (m, 1 H), 4.46 (d, J=6.6 Hz, 1 H), 3.45 - 3.32 (m, 1 H), 1.92 - 1.82 (m,2 H), 1.65-1.35 (m, 6 H), 1.23 (5, 3H), 1.11 (brs, 1H).LCMS: mobile phase A: 5 mM ammonium formate in water + 0.1% ammonia, mobile phase B: acetonitrile + 5% mobile phase A + 0.1% ammonia; Column: YMC Triart, C18 (50X4.6 mm) 3uM; Flow rate: 1.4 mL/min. Run time: 5 mins - starting solvent 30:70 B:A is increased linearly to 95:5 B:A over the first 2.50 mins, held at 95:5 B:A for 1.5 mm,reduced linearly to 30:70 B:A over 0.5 mm and held at 30:70 B:A for the final 0.5 mm. Retention time 2.50 mm (ESI) m/z387[M-1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere; Sealed tube; | Synthesis of 5-fluoro-2-(2-((3-methoxy-4-(4-methyl-lH-imidazol-l-yl) phenyl) amino)-6, 7- dihydroSH-pyrimido [5, 4-b] [I, 4] oxazin-8-yl) benzonitrile [0496] A dry vial charged with Pd2(dba)3 (13 mg, 0.01 mmol) and Xantphos (25 mg, 0.04 mmol) in 1 , 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 C for 3 min. A mixture of N-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl) phenyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1 , 4] oxazin-2-amine (100 mg, 0.29 mmol), <strong>[57381-39-2]2-bromo-5-fluorobenzonitrile</strong> (53 mg, 0.26 mmol) and cesium carbonate (134 mg, 0.41 mmol) in 1 , 4-dioxane (0.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 C for 16 h in a sealed tube. After consumption of the starting materials (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH2C12 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 3-5% MeOH: CH2C12 to afford 5-fluoro-2-(2-((3-methoxy-4-(4-methyl-lH-imidazol-l-yl) phenyl) amino)- 6, 7-dihydro-8H-pyrimido [5, 4-b] [1 , 4] oxazin-8-yl) benzonitrile (60 mg, 44%>) as a pale yellow solid. 1H-NMR (DMSO-<, 400 MHz): delta 9.07 (s, 1H), 7.99 (d, 1H), 7.84 (s, 1H), 7.72 (d, 2H), 7.55 (s, 1H), 7.29 (s, 1H), 7.16 (d, 1H), 6.94 (d, 2H), 4.32-4.29 (m, 2H), 3.92-3.89 (m, 2H), 3.51 (s, 3H), 2.10 (s, 3H); Mass (ESI): 458.5 [M+1]; LCMS: 458.1 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 mupiiota); RT 2.19 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 95.0%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 muiotaeta); RT 1.47 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 10% MeOH/ CH2C12 (R 0.6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃; | General procedure: To a solution of 2-halobenzonitrile (4.0 mmol) in THF (1 mL) was added dropwise LiN(SiMe3)2 (4 mL, 1 M in anhydrous THF, 4.4 mmol) at r.t. The reaction mixture was stirred overnight at the same temperature until the disappearance of the reactants (monitored by TLC), and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc) to give the desired products 1. |
Tags: 57381-39-2 synthesis path| 57381-39-2 SDS| 57381-39-2 COA| 57381-39-2 purity| 57381-39-2 application| 57381-39-2 NMR| 57381-39-2 COA| 57381-39-2 structure
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P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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