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CAS No. : | 330156-50-8 | MDL No. : | MFCD09863794 |
Formula : | C8H7Cl2FO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JAOYKRSASYNDGH-SCSAIBSYSA-N |
M.W : | 209.05 | Pubchem ID : | 11344814 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.35 |
TPSA : | 20.23 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) : | -5.59 cm/s |
Log Po/w (iLOGP) : | 2.22 |
Log Po/w (XLOGP3) : | 2.79 |
Log Po/w (WLOGP) : | 3.28 |
Log Po/w (MLOGP) : | 3.44 |
Log Po/w (SILICOS-IT) : | 3.53 |
Consensus Log Po/w : | 3.05 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.2 |
Solubility : | 0.133 mg/ml ; 0.000634 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.87 |
Solubility : | 0.281 mg/ml ; 0.00135 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.78 |
Solubility : | 0.035 mg/ml ; 0.000167 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.14 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
76.7% | at 40℃; for 5.25 h; Inert atmosphere | (1) primary crystals(2,6-dichloro-3-fluorophenyl into an (R) -1-; 30g Compound (2) was added 105mL of petroleum ether obtained in Preparation Example 1 embodiment taken, heated and stirred under argon for 40 , dissolve yl) ethanol seed, after 45min, a seed crystal was smaller; after 1 hour, the disappearance of seed; 3.5h, the precipitated white solid (precipitated to the bottom); 10H, no further solid separated; dry filtration dry, weighing 22g, yield 73.3percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 62.5percent.(2) secondary crystalsTake a crystalline compound obtained 30g, was added 105mL of petroleum ether, heated and stirred under argon for 45 , dissolved; into an (R) -1- (2,6- dichloro-3-fluorophenyl) ethanol seed , after 45min, a seed crystal was smaller; after 1 hour, the disappearance of seed; 3.5h, the precipitated white solid (precipitated to the bottom); 10H, no further solid separated; dry suction filtration, weighed 22g a yield of 73.3percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 95.0percent.3) three times crystallizedTaking a second resultant crystalline compound 30g, was added 105mL of petroleum ether, heated and stirred under argon for 40 , dissolved; into an (R) -1- (2,6- dichloro-3-fluorophenyl) ethanol crystal species, after 45min, a seed crystal was smaller; after 1 hour, the disappearance of seed; 3.5h, the precipitated white solid (precipitated to the bottom); 10H, no further solid separated; dry suction filtration, weighed 23g, yield 76.7percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 99.6percent. |
51.1% | With dmap; N-(tert-butoxycarbonyl)-D-proline; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,2-dichloro-ethane at 0 - 20℃; | To a solution of A5 (219g, 1.05mol) in 1,2-dichloroethane (3500mL) was added Boc-D-Pro (141g, 0.65mol) followed by EDCI (163g, 0.85mol) and DMAP (21.57g, 0.18mol) at 0 °C. The resulting mixture was stirred at r.t. overnight and then water (3500mL) was added and separated, the water phase was extracted withDCM(1500mLx3), dried over MgS04, concentrated and purified by column chromatography to (PE:EA=30:1) to give Bl (55.96g, yield: 51.1percent) |
51.1% | With dmap; N-(tert-butoxycarbonyl)-D-proline; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,2-dichloro-ethane at 0 - 20℃; | To a solution of A5 (219g, 1.05mol) in 1,2-dichloroethane (3500mL) was added Boc-D-Pro (141g, 0.65mol) followed by EDCI (163g, 0.85mol) and DMAP (21.57g, 0.18mol) at 0 °C. The resulting mixture was stirred at r.t. overnight and then water (3500mL) was added and separated, the water phase was extracted withDCM(1500mLx3), dried over MgS04, concentrated and purified by column chromatography to (PE:EA=30:1) to give Bl (55.96g, yield: 51.1percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 2.5 h; Stage #2: at 0 - 20℃; for 3.3 h; |
Step 1) (R)-3-(l-(2.6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine [0168] To a solution of (R)-l-(2,6-dichloro-3-fluorophenyl)ethanol (10 g, 47.84 mmol) in THF (150 mL) was added NaH (2.3 g, 57.41 mmol, 60percent dispersion in mineral oil) in portions at 0°C in 30 min. The mixture was stirred at rt for 2 h, followed by the dropwise addition of a solution of 3-fluoro-2-nitropyridine (8.2 g, 57.41 mmol) in THF (80 mL) at 0°C over 20 min. The reaction was stirredat rtfor 3 h, then quenched with iced water (10 mL) and concentrated in vacuo. The residue was diluted with EtOAc (150 mL) and H20 (150 mL), and the seperated aqueous phase was extracted with EtOAc (150 mL x 2). The combined organic phases were washed with saturated aqueous aHC03 (400 mL) followed by brine (400 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a white solid (13.4 g, 84.6percent). LC-MS (ESI, pos. ion) m/z: 331 [M + H]+. |
84.8% | Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2.5 h; Stage #2: at 0 - 20℃; for 3.33333 h; |
To a solution of (R)-1-(2,6-dichloro-3-fluorophenyl)ethanol (10 g, 47.81 mmol, Zhenjiang Radiant Pharma, Ltd. China) in THF (150 mL) was added NaH (1.40 g, 57.42 mmol) in portions at 0°C in 30 minutes. The mixture was then stirred at room temperature for 2h. A solution of 3-fluoro-2-nitropyridine(8.2 g, 57.43 mmol, Shanghai Link Chem, Ltd. China) in THF (80 mL) was added to the reaction dropwise over 20 mm at 0°C. The reaction was then warmed up to rt and stirred further for 3 h. The reaction was quenched with 1 0mL of iced water, and the resulted solution was concentrated in vacuo. The residue was diluted with 150 mL of water, and the resulted aqueous mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with saturated NaHCO3 (400 mL), brine (400 mL), dried over Na2504 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc = 6/1 to 4/1) to provide the title compound as a white solid (13.4 g, 84.8percent). LC-MS (ESI, pos. ion) m/z: 331 [M + H]+. |
84.6% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 2.5 h; Stage #2: at 0 - 20℃; for 2.33333 h; |
To a solution of (R)-l-(2,6-dichloro-3-fluorophenyl)ethanol (10 g, 47.84 mmol) in THF (150 mL) was added NaH (2.3 g, 57.41 mmol, 60percent dispersion in mineral oil) in portions at 0 °C over 30 min. The mixture was stirred at rt for 2 h, followed by the addition of a solution of 3-fluoro-2-nitropyridine (8.2 g, 57.41 mmol) in THF (80 mL) at 0 °C over 20 min. The reaction was stirred at rt for 3 h, then quenched with iced water (10 mL) and concentrated in vacuo. The residue was diluted with H20 (150 mL), and extracted with EtOAc (150 mL x 3). The combined organic phases were washed with saturated aqueous NaHCC^ (400 mL), by brine (400 mL), dried over anhydrous a2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a white solid (13.4 g, 84.6percent). MS (ESI, pos. ion) m/z: 331 [M + H]+. |
84.8% | Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2.83333 h; Stage #2: at 20℃; for 3 h; |
The (R)-1-(2,6-dichloro-3-fluoro phenyl) ethanol (10g, 47.81mmol) dissolved in tetrahydrofuran (10 ml) in, cooling to 0 °C, in 30 minutes, the batch by adding sodium hydride (1.4g, 57 . 42mmol). Stirring the mixture at room temperature for 2 hours, to cool again to 0 °C, in 20 minutes, adding dropwisely the reaction system 3-fluoro-2-nitro-pyridine (8.2g, 57 . 43mmol) tetrahydrofuran (80 ml) solution. Restored to the room temperature, to continue stirring 3 hours. the response finishes, ice water (10 ml) quenching the reaction, and concentrated under reduced pressure. Residue water (150 ml) is diluted, and using ethyl acetate (150mLx3) extraction. Combined organic phase with saturated NaHCO 3 (400 ml) washing, saturated salt water (400 ml) washing, anhydrous Na 2 SO 4 drying. Concentrated under reduced pressure, the resulting residue by a silica gel column chromatography (PE/EtOAc (v/v) = 6:1 to 4:1) purification, to obtain the title compound as white solid (13.4g, 84.8percent). |
84.6% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1.83333 h; Stage #2: at 20℃; for 3 h; |
(R) -1- (2,6-dichloro-3-fluorophenyl) ethanol (10 g, 47.84 mmol)Was dissolved in tetrahydrofuran (150 mL)The solution was cooled to 0 ° C,Within 30 minutes,To this was added sodium hydride (2.3 g, 57.41 mmol, 60percent dispersion in mineral oil).The mixture was stirred at room temperature for 2 hours,Again cooled to 0 ° C,And in 20 minutes,To this was added 3-fluoro-2-nitropyridine (8.2 g, 57.41 mmol)In tetrahydrofuran (80 mL).The reaction solution was stirred at room temperature for 3 hours,Add ice water (10 mL) and concentrate under reduced pressure.The residue was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3).The combined organic phases were washed successively with saturated sodium bicarbonate solution (400 mL)Brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4/1)The title compound was obtained as a white solid (13.4 g, 84.6percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.3% | Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 1 h; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 12 h; |
3-Hydroxy-2-nitropyridine (175 mg, 1.21 mmol) and triphenylphosphine (440 mg, 1.65 mmol) were added sequentially to a stirred solution of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (229.8 mg, 1.1 mmol) in THF (10 mL) under a nitrogen atmosphere. The reaction mixture was maintained at room temperature for 1 h and then diisopropyl azo-dicarboxylate (0.34 mL, 1.65 mmol) was added at 0°C. The mixture was stirred for an additional 12 h. The reaction mixture was evaporated under vacuum to give an oil. The residue was purified by flash chromatography (eluting with 20->25percent EtOAc in hexanes) to give the title compound as a white solid (321.5 mg; 0.97 mmol; 88.3percent yield); MS (APCI) (M+H)+ 331; SFC-MS: 99.5percent ee. 1H NMR (400 MHz, chlorqform-D) 5 ppm 1.85 (d, ^6.6 Hz, 3 H) 6.10 (q, J=6.6 Hz, 1 H) 7.04 -7.13 (m, 1 H) 7.21 (dd, J=8.5, 1.14 Hz, 1 H) 7.30 (dd, J=9.0, 4.9 Hz, 1 H) 7.37 (dd, J=8.6, 4.6 Hz, 1 H) 8.04 (dd, J=4.6, 1.3Hz, 1 H). |
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