Structure of 1000339-94-5
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CAS No. : | 1000339-94-5 |
Formula : | C7H4ClF3O2 |
M.W : | 212.55 |
SMILES Code : | ClC1=C(C=CC(=C1)O)OC(F)(F)F |
MDL No. : | MFCD04972754 |
Boiling Point : | No data available |
InChI Key : | ZDKAPCMMTRJKTR-UHFFFAOYSA-N |
Pubchem ID : | 40427108 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 40.16 |
TPSA ? Topological Polar Surface Area: Calculated from |
29.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.87 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.57 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.2 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.22 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.58 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.89 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.62 |
Solubility | 0.0514 mg/ml ; 0.000242 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.87 |
Solubility | 0.0284 mg/ml ; 0.000134 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.07 |
Solubility | 0.18 mg/ml ; 0.000847 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.06 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.75 |
* 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 |
---|---|---|
73% | With sodium hydroxide; tetrabutylammonium sulfate; In dichloromethane; water; at 20℃; for 18.0h; | Example 30; 2-Chloro-4-methoxy-l-(trifluoromethoxy)benzene; A mixture of <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (1.00 g, 4.71 mmol), dimethylsulfate (490 muL, 5.18 mmol), tetrabutylammonium sulfate, 2 M aqueous sodium hydroxide (2.59 mL, 5.18 mmol) and dichloromethane (25 mL) was vigorously stirred at room temperature for 18 h. The mixture was diluted with dichloromethane, washed with water, dried over sodium sulfate and concentrated in vacuo to give 780 mg (73% yield) of the title compound: 1H NMR (CDCl3) delta 7.22 - 7.26 (m, 1 H), 6.99 (d, J= 2.8 Hz, 1 H), 6.81 (dd, J = 9.1, 3.0 Hz, 1 H), 3.82 (s, 3 H). |
73% | With sodium hydroxide; tetrabutylammonium sulfate; In dichloromethane; water; at 20℃; for 18.0h; | A mixture of 3-chloro-4~(trifluoromethoxy)phenol (1.00 g, 4.71 mmol), dimethylsulfate (490 muL, 5.18 mmol), tetrabutylammonium sulfate, 2 M aqueous sodium hydroxide (2.59 mL, 5.18 mmol) and dichloromethane (25 mL) was vigorously stirred at room temperature for 18 h. The mixture was diluted with dichloromethane, washed with water, dried over sodium sulfate and concentrated in vacuo to give 780 mg (73% yield) of the title compound: 1HNMR (CDCl3) 5 7.22 - 7.26 (m, 1 H), 6.99 (d, J= 2.8 Hz, 1 H), 6.81 (dd, J = 9.1, 3.0 Hz, 1 H), 3.82 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 3.0h; | 4-Methylphenyl-5-chloro-2,4-difluorobenzoate (Preparation 10, 133 mg, 0.47 mmol) was added to a mixture of potassium carbonate (84 mg, 0.61 mmol), <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (100 mg, 0.47 mmol) in dimethylsulfoxide (1.0 mL) and the reaction stirred at room temperature for 3 hours. The reaction was diluted by addition of water (2.0 mL) and ethyl acetate (3.0 mL) and the mixture partitioned. The aqueous was further extracted with ethyl acetate (3.0 mL), the organics combined, dried with magnesium sulfate, filtered and evaporated to give a white solid. Purification was accomplished by column chromatography on silica, eluting with ethyl acetate:heptanes (3:97) to provide the title compound as a white solid (106 mg, 47%).LCMS Rt=6.15 minutes, no mass ion.1H-NMR (400 MHz, CDCl3): delta 2.37 (s, 3H), 6.75 (d, 1H), 7.01 (dd, 1H), 7.00 (d, 2H), 7.23-7.21 (m, 3H), 7.38 (d, 1H), 8.42 (d, 1H)19F-NMR (400 MHz, CDCl3): 6-58.1, -104.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 19.0h; | To a mixture of tert-butyl 5-chloro-2,4-difluorobenzoate (WO2012007883A1, 1.17 g, 4.72 mmol) and <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (1.02 g, 4.80 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added potassium carbonate (1.31 g, 9.45 mmol). The mixture was stirred at ambient temperature for 19 h. The reaction mixture was then diluted with diethyl ether (200 mL), washed with saturated aqueous sodium bicarbonate (2 chi 200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound as a white solid (2.02 g, 97%): FontWeight="Bold" FontSize="10" H NMR (300 MHz, CDC13) delta 7.98 (d, J= 13 Hz, 1H), 7.34-7.31 (m, 1H), 7.12 (d, J= 2.9 Hz, 1H), 6.93 (dd, J= 2.9, 9.0 Hz, 1H), 6.68 (d, J= 10.8 Hz, 1H), 1.57 (s, 9H); MS (ES+) m/z 440.9, 441.9 (M + 1). |
75% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 18.0h; | <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (22.6 g, 0.106 mol) and tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 26.4 g, 0.106 mol) were dissolved in dimethlysulfoxide (105 mL). Then potassium carbonate (29.4 g, 0.213 mol) was added portionwise to the mixture, which was stirred at room temperature for 18 hours. The reaction mixture was dropped into iced water (500 mL) and stirred vigorously for 4 hours. The resulting solid was collected by filtration then taken up in isopropanol (75 mL) and water (15 mL). The reaction was heated to 55 C., then cooled down to room temperature. The resulting solid was collected by filtration to yield the title compound as an off-white white solid (35.3 g, 75%).1H NMR (400 MHz; CDCl3): delta 1.62 (s, 9H), 6.72 (d, 1H), 6.97 (dd, 1H), 7.16 (d, 1H), 7.35-7.38 (m, 1H), 8.02 (d, 1H)LC Rt=8.637 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; at 90℃; for 18.0h; | A suspension of 3-(2-ethoxypyridin-3-yl)-4-fluorobenzaldehyde (Preparation 8, 346 mg, 1 .41 mmol), <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (300 mg, 1 .41 mmol), and potassium carbonate (585 mg, 4.23 mmol) was stirred for 18 hours at 90 C. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with water (4 x 50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a brown oil (604 mg, 98%). 1H NMR (400MHz, Acetone-D6): delta ppm 1 .22 (m, 3H), 4.32 (m, 2H), 6.92 (m, 2H), 7.10 (m, 2H), 7.25 (m, 1 H), 7.54 (m, 1 H), 7.89 (m, 1 H), 7.92 (m, 1 H), 8.16 (m, 1 H), 10.00 (s, 1 H). 19F NMR (400MHz, Acetone-D6): delta ppm -58.3 LCMS Rt = 3.92 minutes MS m/z 438 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 48.0h; | To a solution of terf-butyl 2,4-difluoro-5-iodobenzoate (Preparation 16, 579 mg, 1 .70 mmol) and <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (362 mg, 1 .70 mmol) in DMSO (15 mL) was added potassium carbonate (706 mg, 5.1 1 mmol) and the mixture stirred at room temperature for two days. The mixture was poured onto water (20 mL) and extracted with EtOAc (2 x 30 mL), washed with water (3 x 30 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (870 mg, 96%). LCMS Rt = 4.1 1 minutes, no mass ion observed |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 16.0h; | A solution of tert-butyl N-[6-(bromomethyl)-5-chloro-l,2-benzoxazol-3-yl]-N-[(tert-butoxy)carbonyl]carbamate (100 mg, 0.22 mmol) in DMF (2 mL) was added <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (55 mg, 0.26 mmol) and potassiumm carbonate (61 mg, 0.44 mmol). After stirring at 25C for 16 h, the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford tert-butyl N-[(tert-butoxy)carbonyl]-N-{5-chloro-6-[3-chloro-4-(trifluoromethoxy)phenoxymethyl]-1,2-benzoxazol-3-yl} carbamate (100 mg, crude) as an oil which was used in the next step without further purification. LCMS (ESI) m/z: 437.0 [M-156+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.647 g | With potassium carbonate; In acetonitrile; at 80℃; | Compound 3-Chloro-4- (trifluoromethyl) phenol (200 mg, 1.017 mmol)Compound 1-a-4 (395 mg, 1.017 mmol),Potassium carbonate (218 mg, 2.035 mmol)Was added to 10 ml of acetonitrile solution,Stirring at 80 degrees Celsius overnight.The reaction ends,Cooled to room temperature,Poured into the water,Ethyl acetate extraction,Saturated salt water wash,Dried over anhydrous sodium sulfate,filter,The filtrate was concentrated to give the yellow solid compound 9-b (0.647 g).MS m / z (ESI): 503.9 [M-H] & lt; & quot; & gt ;. Directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.3 mg | With potassium carbonate; In acetonitrile; at 60℃; for 2.0h; | Compound 1-b (117 mg, 0.32 mmol),3-chloro-4- (trifluoromethyl) phenol (68 mg, 0.32 mmol)Potassium carbonate (89 mg, 0.64 mmol)Was added to 5 ml of acetonitrile solution,60 degrees Celsius for 2 hours.The reaction ends,Cooled to room temperature,The reaction solution was concentrated under reduced pressure,Add 10 ml of water,Adjust the pH to 7,Dichloromethane extraction (2 x 10 ml),The organic phase was washed with saturated brine,Dried over anhydrous sodium sulfate,filter,The filtrate was concentrated under reduced pressure to give crude product.Purification by preparative liquid phase gave the white solid compound Z-1 (60.3 mg) in a yield of 39.2% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With nitric acid; acetic acid; at 0 - 20℃; for 2.0h; | To a solution of <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (5.0 g, 28.3mmol) in acetic acid (2OmL) was added a solution of nitric acid (1.4mL, 33.96mmol) in acetic acid (4.OmL) at 0 00 slowly. The reaction mixture was stirred at rt for 2h. TLC showed the reaction to be complete. The reaction mixture was poured in to ice-water (200mL), extracted with EtOAC (3xlOOmL) and washed with brine (200mL). The organics were dried (Na2504), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel (100-200 mesh), eluting with 5% EtOAc in hexane to give 5-chloro-2-nitro-4-(trifluoromethoxy)phenol as a yellow solid . Yield: 3.2g (52 %). 1H NMR (400 MHz, DMSO-d6): 11.98 (bs, 1H), 8.15 (5, 1H), 7.36 (5, 1H). MS (ESI-) for CHNOS m/z256.07 [M-H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.0h; | To a flask charged with methyl 6-bromo-4-chloro-pyridine-3-carboxylate (2.80 g, 11.2 mmol) and CS2CO3 (9.5 g, 29 mmol) in DMF (28 inL) at 0 C was added <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (2.37 g, 11.2 mmol). The reaction mixture was gradually warmed to room temperature, stirred for 3 hours and quenched with water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over MgSO/i, filtered and concentrated in vacuo. Silica gel chromatography (0-10% ethyl acetate/hexanes) provided methyl 6-bromo-4-[3-chloro-4- (trifluoromethoxy)phenoxy]pyridine-3-carboxylate (2.52 g, 53%). ESI-MS m/z calc. 424.92, found 428.1 (M+2)+; retention time (Method B): 2.01 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 8.77 (s, 1H), 7.71 - 7.65 (m, 2H), 7.35 - 7.30 (m, 2H), 3.82 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper(l) iodide; caesium carbonate; In toluene; at 100℃; for 0.333333h; | A pressure bottle was charged with 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5 g, 17.42 mmol), cesium carbonate (11.35 g, 34.84 mmol), <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (3.70 g, 17.42 mmol) and toluene (150 mL). The mixture was degassed with nitrogen. After ca. 2 minutes, copper (I) iodide (663.5 mg, 3.484 mmol) was added and the reaction was stirred at 100 C for 20 minutes. The mixture was diluted with ethyl acetate and water, and the organic layer was washed with brine and dried over sodium sulfate. Trituration with hexane and filtration yielded 6-[3-chloro-4- (trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoic acid (6.27 g, 86%). ESI-MS m/z calc. 417.98, found 419.1 (M+l)+; retention time (Method B): 1.93 minutes (3 minute run). |
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