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CAS No. : | 167415-27-2 | MDL No. : | MFCD00042184 |
Formula : | C6H2BrF2NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GJFYMYJYPARISZ-UHFFFAOYSA-N |
M.W : | 237.99 | Pubchem ID : | 2736286 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 42.88 |
TPSA : | 45.82 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.88 cm/s |
Log Po/w (iLOGP) : | 1.65 |
Log Po/w (XLOGP3) : | 2.64 |
Log Po/w (WLOGP) : | 3.48 |
Log Po/w (MLOGP) : | 2.49 |
Log Po/w (SILICOS-IT) : | 1.26 |
Consensus Log Po/w : | 2.3 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.28 |
Solubility : | 0.124 mg/ml ; 0.000522 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.25 |
Solubility : | 0.133 mg/ml ; 0.000559 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.19 |
Solubility : | 0.152 mg/ml ; 0.000638 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.04 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | 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 |
---|---|---|
93% | With sulfuric acid; nitric acid In dichloromethane at 20℃; for 3.5 h; Cooling with ice | Reference Example-50 Concentrated sulfuric acid (57 mL) was cooled in an ice bath, and 69percent nitric acid (25.5 g, 279 mmol) was added dropwise over 25 minutes, whereby a mixed acid was prepared. To this mixed acid, a solution of 2-bromo-1,4-difluorobenzene (50 g, 254 mmol) in dichloroethane (125 mL) was slowly added dropwise over 1.5 hours under ice-cooling. After the reaction was completed, the reaction solution was further stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was added little by little to ice water (500 g), and the resultant product was extracted with ether (300 mL*2). The organic layer was washed sequentially with water (300 mL), a saturated sodium hydrogencarbonate aqueous solution (300 mL), and a saturated saline solution (300 mL), and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (hexane:chloroform=4:1), whereby 1-bromo-2,5-difluoro-4-nitrobenzene (56 g, yield: 93percent) was obtained as a pale yellow solid. 1H-NMR (400 MHz, CDCl3): δ7.59 (dd, J=9.5 and 5.5 Hz, 1H), 7.89 (dd, J=7.3 and 6.5 Hz, 1H). 19F-NMR (376 MHz, CDCl3): δ-120.1 (d, J=15.2 Hz, 1F), -107.9 (d, J=15.2 Hz, 1F). |
93% | With sulfuric acid; nitric acid In 1,2-dichloro-ethane for 3.92 h; Cooling with ice | Concentrated sulfuric acid (57 mL) was cooled inan ice bath, and 69percent nitric acid (25.5 g, 279 mmol) was added dropwise over 25minutes to prepare a mixed acid. To this mixed acid, under ice-cooling, dichloroethane(125mL) solution of 2-bromo-1,4-difluoro-benzene (50g, 254mmol) was droppedslowly over a period of 1.5 hours. After completion of the dropwise addition,the reaction solution was further stirred for 2 hours at room temperature.After completion of the reaction, the reaction solution was added in portionsto ice-water (500 g), then extracted with ether (300mL × 2). The organic layerwas washed successively with water (300mL), saturated aqueous sodium hydrogencarbonate solution (300mL), saturated brine (300mL), and then dried overanhydrous magnesium sulfate, and the solvent was evaporated under reducedpressure. The resulting crude product was purified by silica gel chromatography(hexane: chloroform = 4/1) to give a pale yellow solid of 1-bromo-2,5-difluoro-4-nitrobenzene(56 g, yield: 93percent ). |
93% | at 20℃; for 3.5 h; Cooling with ice | Concentrated sulfuric acid (57 mL) was cooled in an ice bath, 69percent nitric acid (25.5 g, 279 mmol) was added dropwise over 25 minutes to prepare a mixed acid. In this mixed acid under ice-cooling 2-bromo-1,4-difluorobenzene (50g, 254mmol) was dropped slowly over a period of 1.5 hours of dichloroethane (125mL) solution . After completion of the dropwise addition, the reaction solution was further stirred for 2 hours at room temperature. After completion of the reaction, added little by little the reaction solution into ice water (500g), then ether (300mL ×And extracted with 2). The organic layer was washed with water (300mL), saturated aqueous sodium hydrogen carbonate solution (300mL), was washed successively with saturated brine (300mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography - (hexane: chloroform = 4/1) to give 1-bromo-2,5-difluoro-4-nitrobenzene as a pale yellow solid (56 g, yield: 93percent ) was obtained. |
80% | at 5 - 20℃; for 1.5 h; | Nitric acid (d 1.42) (26.2 g, 286.81 mmol) was slowly added dropwise to conc. sulfuric acid (102 g, 1042.96 mmol) over 1 hr under ice water, while the mixture was maintained at 10°C or below. Then, 2-bromo-1,4-difluorobenzene (50.32 g, 260.74 mmol) was slowly added thereto over 3 hr while the mixture was maintained at 10°C or below. The reaction mixture was stirred at 5°C for 30 min, and then at room temperature for 1 hr. The reaction mixture was poured into ice (about 600 g), and the mixture was extracted three times with a mixed solvent of Et2O/THF (3:1). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 20percent ethyl acetate/hexane) to give 1-bromo-2,5-difluoro-4-nitrobenzene (49.64 g, 209 mmol, 80percent) as a pale yellow solid. |
78.1% | at 0 - 20℃; for 16 h; | INTERMEDIATE 6 1-((3S,5S)-1 -Oxaspiror2.5loctan-5-ylmethyl)-5-fluoro-1 H-benzo[d]imidazole-6- carbonitrile1-Bromo-2,5-difluoro-4-nitrobenzene To a stirred solution of 2-bromo-1 ,4-difluoro-benzene (98.6 g, 510.88 mmol) in 1.2 L of concentrated H2S04 was added KN03 by portions at 0 °C. After this addition, the mixture was allowed to warm to RT and stirred for additional 16 h. The mixture was poured onto ice-cold water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2S04 and concentrated to give 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 78.1 percent yield) as a yellow solid. 1H NMR (400 MHz, CDCI3) δ 7.91-7.87 (dd, 1 H), 7.52-7.57 (dd, 1 H). |
78.1% | at 0 - 20℃; | 1-Bromo-2,5-difluoro-4-nitrobenzeneTo a stirred solution of 2-bromo-1 ,4-difluoro-benzene (98.6 g, 510.88 mmol) in 1.2 L of concentrated H2S04 was added KN03 by portions at 0 °C. After this addition, the mixture was allowed to warm to RT and stirred for additional 16 h. The mixture was poured onto ice-cold water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2S04 and concentrated to give 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 78.1 percent yield) as a yellow solid. H NMR (400 MHz, CDCI3) δ 7.91-7.87 (dd, 1 H), 7.52-7.57 (dd, 1 H). |
89% | With KNO3 In conc. H2 SO4 | 1-Bromo-2,5-difluoro-4-nitrobenzene: To a stirred solution of 1-bromo-2,5-difluorobenzene (1.000 g, 5.181 mmol, Aldrich, used as received) in conc. H2 SO4 (8.0 mL) at 0° C., KNO3 (0.525 g, 5.19 mmol) was added in one lot. The resulting yellow solution was allowed to warm to 28° C. and stirred at 28° C. overnight. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2 SO4, removed under vacuum, and the resulting white solid was dried further under vacuum to afford 1.102 g (89percent) of the title compound as a white powder; m.p. 58°-60° C.; 1 H NMR (CDCl3): δ7.591 (dd, 1H, J1 =9.6 Hz, J2 =5.4 Hz), 7.891 (t, 1H, J=6.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | at 160℃; for 7.5 h; Inert atmosphere | 2,5-Difluoro-4-nitrobenzonitrile A mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 399 mmol) and CuCN (71.8 g, 798 mmol) in NMP (700 ml.) was set to a pre-heated 160 °C oil-base and stirred at 160 °C under N2 over 450 min. The mixture was cooled to RT, charged with Na2S04 (300 g) and MTBE (1 L), and stirred for an additional 15 min. The resulting mixture was filtered and the filtrate was charged with 800 mL of water, then the separated aqueous layer was extracted with MTBE. The combined organic layers were washed with water and brine, dried over Na2S04 andconcentrated. The material was recrystallized from EtOH/water (2/1 ) to yield 2,5-Difluoro-4- nitro-benzonitrile (50 g, 68percent yield) as a pale brown solid. 1H NMR (400 MHz, CDCI3) δ 7.96- 7.95 (dd, 1 H), 7.67-7.64 (dd, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | at 160℃; for 7.5 h; Inert atmosphere | 2,5-Difluoro-4-nitrobenzonitrileA mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 399 mmol) and CuCN (71.8 g, 798 mmol) in NMP (700 mL) was set to a pre-heated 160 °C oil-base and stirred at 160 °C under N2 over 450 min. The mixture was cooled to RT, charged with Na2S04 (300 g) and MTBE (1 L), and stirred for an additional 15 min. The resulting mixture was filtered and the filtrate was charged with 800 mL of water, then the separated aqueous layer was extracted with MTBE. The combined organic layers were washed with water and brine, dried over Na2S04 andconcentrated. The material was recrystallized from EtOH/water (2/1 ) to yield 2,5-Difluoro-4- nitro-benzonitrile (50 g, 68percent yield) as a pale brown solid. H NMR (400 MHz, CDCI3) δ 7.96- 7.95 (dd, 1 H), 7.67-7.64 (dd, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With ammonium carbonate In N,N-dimethyl-formamide at 90℃; | Synthesis of 153-1. A solution of 153-0 (2.00 g, 8.4 mmol) and (NH4) 2CO3 (4.00 g, 42 mmol) in DMF (20 mL) was heated to 90 °C overnight. The mixture was cooled to room temperature and poured into water (100 mL). The precipitate was filtered off and washed with the mixture of diethyl ether (Et2O) and petroleum ether (PE; Et2O : PE = 1:1) to give 153-1 (1.50 g, 76 percent) as a yellow solid. |
73% | With ammonia In methanol at 60℃; for 18 h; Sealed tube | A solution of 1-bromo-2,5-difluoro-4-nitrobenzene (2 g, 8.43 mmol) inmethanolic ammonia (25 mL) was heated at 60°C in a sealed tube, for 18h. The reactionwas concentrated in vacuo, and the residue purified by column chromatography (Si02, 0-30 percent EtOAc/hexanes), yielding the title compound as a yellow solid (1.4 g, 73percent). 1HNMR (400 MHz, CDC13) 7.90 (d, 1H), 7.10 (d, 1H), 5.98 (bs, 2H). |
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