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CAS No. : | 64248-63-1 | MDL No. : | MFCD00010311 |
Formula : | C7H3F2N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CQXZSEXZQVKCHW-UHFFFAOYSA-N |
M.W : | 139.10 | Pubchem ID : | 587204 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 31.07 |
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) : | -5.84 cm/s |
Log Po/w (iLOGP) : | 1.67 |
Log Po/w (XLOGP3) : | 1.84 |
Log Po/w (WLOGP) : | 2.68 |
Log Po/w (MLOGP) : | 2.32 |
Log Po/w (SILICOS-IT) : | 2.64 |
Consensus Log Po/w : | 2.23 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.31 |
Solubility : | 0.688 mg/ml ; 0.00495 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.96 |
Solubility : | 1.52 mg/ml ; 0.011 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.01 |
Solubility : | 0.135 mg/ml ; 0.000971 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.5 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-H315-H319-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 |
---|---|---|
82% | Stage #1: With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at -15℃; for 0.25 h; Stage #2: With N,N-dimethyl-formamide In tetrahydrofuran at 0℃; for 2 h; Stage #3: With ammonia; iodine In tetrahydrofuran; water at 20℃; for 2 h; |
General procedure: To a flask containing dried LiCl (0.35 g, 8.24 mmol) was added iPrMgCl (2 M in THF, 4.1 mL) and THF (5 mL) at 15° C. After beingstirred for 15 min, 3-bromo-1-benzonitrile (1.46 g, 8.03 mmol) inTHF (1 mL) was added to the reaction mixture and the obtainedmixture was stirred for 15 min. Then, DMF (1.3 mL, 12 mmol) wasadded at 0° C and the mixture was stirred for 2 h. Then, aq NH3 (7 mL, 28-30percent) and I2 (4.06 g, 16 mmol) were added to the reaction mixture. After being stirred for 2 h at room temperature, the reactionmixture was poured into satd aq Na2SO3 solution and was extracted with CHCl3 (3∗30 mL). The organic layer was dried over Na2SO4 and filtered. After removal of the solvent, the residue waspurified by short column chromatography on silica gel (eluent:hexane/ethyl acetate=9:1, v/v) to provide pure 1,3-dicyanobenzene (0.73 g) in 71percent yield. Most nitriles mentioned in this work are commercially availableand were identified by comparison with the authentic samples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With copper (II) trifluoroacetate hydrate; palladium diacetate In dimethyl sulfoxide at 130℃; for 8 h; Sealed tube; Inert atmosphere | General procedure: Aryl iodide (0.7 mmol, 1 equiv), tert-butyl isocyanide (2.1 mmol, 237 μL, 3 equiv), Pd(OAc)2 (0.035 mmol, 8 mg, 5 mol percent), Cu(TFA)2*xH2O (1.4 mmol, 405 mg, 2 equiv) and DMSO (2.5 mL) were added to a 15 mL sealed tube, and stirred at 130 °C for 4-12 h under nitrogen. After completion of the reaction indicated by TLC, the mixture was extracted with Et2O (510 mL). The combined organic phases was dried over Na2SO4, and concentrated under vacuum. Then the residue was purified by column chromatography on silica gel using petroleum ether (30-60 °C)/Et2O as eluant to provide the pure target product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With ammonia In methanol; ethyl acetate | A: 3,5-Difluorobenzylamine A solution of 3,5-difluorobenzonitrile (4 g, 28.8 mmole) in methanol saturated with ammonia (100 ml) was added to a slurry of methanol washed Raney nickel. The mixture was shaken under 50 psi hydrogen for 1.5 hours, filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate and extracted with 3N HCl. The acidic solution was basified with 50percent sodium hydroxide and was extracted into ethyl acetate. The organic extract was dried (Na2 SO4) and concentrated to give 3.0 g (74percent) of title compound as a yellow oil which was stored under nitrogen. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.3% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.75 h; Stage #2: for 0.416667 h; Cooling with ice |
To a cooled (-78 °C) clear, colorless solution of 3,5-difluorobenzonitrile (1 g, 7.19 mmol) in THF (28.8 mL) was added dropwise 1.6M n-butyllithium in hexane (4.49 ml, 7.19 mmol) to give a red- orange solution. After 45 min, carbon dioxide (sublimation of dry ice passing through a drierite tower) was bubbled through the reaction to eventually give a thick off-white suspension. After 25 min, the reaction was quenched with 1M HC1 (aq) and the reaction was allowed to warm to RT. The reaction was extracted with EtOAc(2x). The organic layers were combined, washed with brine, dried over a2S04, filtered and concentrated to a white residue. The crude residue was partitioned between EtOAc and 1M NaOH (aq) and the layers were separated. The organic layer was extracted with IN NaOH (aq) (2x). The aqueous layers were combined and then washed with EtOAc (2x). The aqueous layer was then acidified to pH ~2 to give a cloudy white suspension. The aqueous layer was then extracted with EtOAc (2x). The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated to a give 922.5mg (65.3 percent) of Intermediate 29A as a white solid. MS (ESI) m/z: 184.0 (M+H)+. |
55.6% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -75 - -70℃; for 1 h; Stage #2: at 20℃; Stage #3: With hydrogenchloride In water |
To a solution of 3, 5-difluorobenzonitrile (3.48 g, 25 mmol, Fluorochem) in THF (35 ml) was added slowly butyl lithium (1.6M in hexanes) (15.63 ml, 25.00 mmol) at -75°C. The resulting solution was stirred for 1 hr at -70-75°C. Then this solution was poured on freshly crushed dry ice C02 (44.0 g, 1000 mmol). The contents were stirred at room temperature until dry ice disappearance. The solvent was evaporated off under HV. Then residual organic layer was suspended in water and extracted with ethyl acetate (3x 50ml). The product containing aqueous layer was acidified with aqueous HCI solution and the product was re-extracted in the organic layer with Ethylacetate (4x50ml). The combined organic layers were washed with brine, dried over MgS04, filtered and evaporated to give a white crystalline solid (2.5731 g, 13.91 mmol, 55.6 percent yield)1 H NMR (400 MHz, DMSO-c/6) δ ppm 14.32 (br. S., 1 H), 7.78 - 8.01 (m, 2 H). The product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: With acetic acid In tetrahydrofuran for 0.5 h; |
ft-BuLi (2.5 M, 4.4 mL) was added to a stirred solution of DIPEA (1.1, 11 mmol) in dry THF (100 mL) at -78°C under a nitrogen atmosphere then warmed to at 0°C and stirred for 1 h. The solution was cooled to -78°C and 3,5-difluorobenzonitrile (1.39 g, 10 mmol) was added. The mixture was stirred at -78°C for 1 h then DMF (877 mg, 12 mmol) was added and the reaction continued for a further 0.5 h before addition of 10percent v/v aqueous acetic acid (20 mL). The mixture was warmed to room temperature, extracted with ethyl acetate and then concentrated in vacuo to afford 3,5-difluoro-4-formylbenzonitrile (1.29 g, 77percent) as a yellow solid |
31.25% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Stage #2: for 0.75 h; |
Step a: Synthesis of 3,5-difluoro-4-formylbenzonitrileTo a solution of 3,5-difluorobenzonitrile (1 gm, 7.1 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.769 gm, 7.1 mmol) was added at -78 °C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.62 g, 8.5 mmol) was added dropwise to the reaction mixture and stirring was continued for about 45 minutes. Acetic acid (1 .5 mL) and water (40 mL) were added to the cold solution of reaction mixture. The aquoeus phase was extracted with diethyl ether (4x50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using hexane and ethyl acetate as gradient system to afford pure 3,5-difluoro-4-formylbenzonitrile (0.5 gm, 31 .25percent ).1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1 H), 7.91 -8.04 (m, 2H). |
31.25% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran for 1 h; Stage #2: for 45 h; |
To a solution of 3,5-difluorobenzonitrile (1 gm, 7.1 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.769 gm, 7.1 mmol) was added at -78° C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.62 g, 8.5 mmol) was added dropwise to the reaction mixture and stirring was continued for about 45 minutes. Acetic acid (1.5 mL) and water (40 mL) were added to the cold solution of reaction mixture. The aquoeus phase was extracted with diethyl ether (4*50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using hexane and ethyl acetate as gradient system to afford pure 3,5-difluoro-4-formylbenzonitrile (0.5 gm, 31.25percent). 1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 7.91-8.04 (m, 2H). |
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