Structure of 457889-46-2
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CAS No. : | 457889-46-2 |
Formula : | C14H11F3O |
M.W : | 252.23 |
SMILES Code : | OCC1=CC=C(C2=CC=C(C(F)(F)F)C=C2)C=C1 |
MDL No. : | MFCD01862515 |
InChI Key : | YCVFDTRUBSFXSA-UHFFFAOYSA-N |
Pubchem ID : | 22015014 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 63.01 |
TPSA ? Topological Polar Surface Area: Calculated from | 20.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 2.59 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 3.55 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 4.87 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 3.99 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 4.37 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 3.87 |
Log S (ESOL):? ESOL: Topological method implemented from | -3.94 |
Solubility | 0.0293 mg/ml ; 0.000116 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -3.66 |
Solubility | 0.0552 mg/ml ; 0.000219 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -5.63 |
Solubility | 0.000585 mg/ml ; 0.00000232 mol/l |
Class? Solubility class: Log S scale | Moderately 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) | No |
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) | Yes |
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 | -5.32 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 | 1.0 |
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<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 1.77 |
* 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 |
---|---|---|
With caesium carbonate;PdCl2[dppf]; In tetrahydrofuran; N,N-dimethyl-formamide; | Step 4. Preparation of (4'-Trifluoromethyl-biphenyl-4-yl)-methanol (compound 36D) 1-Bromo-4-trifluoromethyl-benzene (814 mg, 3.62 mmol), 4-hydroxymethylphenylboronic acid (600 mg, 3.98 mmol), cesium carbonate (2.36 g, 7.24 mmol), and PdCl2(dppf) (132 mg, 0.181 mmol) were added to 10 ml of a 1:1 solution of DMF/THF. The reaction was flushed with nitrogen and heated to 90 C. for 1 h. The reaction was cooled, poured into diethyl ether and washed with water (2*50 ml), brine (1*50 ml) and dried over anhydrous sodium sulfate. The crude product was filtered through silica gel, eluted with diethyl ether, and concentrated to provide the title compound. MS m/z 251 (M-1). | |
With caesium carbonate;palladium dichloride; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 90℃; for 1h;Heating / reflux; | Step 1.Preparation of (4'-Trifluoromethyl-biphenyl-4-yl)-methanol (Compound 3A) 1-Bromo-4-trifluoromethyl-benzene (814 mg, 3.62 mmol), 4-hydroxymethylphenylboronic acid (600 mg, 3.98 mmol), cesium carbonate (2.36 g, 7.24 mmol), and PdCl2(dppf) (132 mg, 0.181 mmol) were added to 10 ml of a 1:1 solution of DMF/THF. The reaction was flushed with nitrogen and heated to 90 C. for 1 h.The reaction was cooled, poured into diethyl ether and washed with water (2*50 ml), brine (1*50 ml) and dried over anhydrous sodium sulfate.The crude product was filtered through silica gel, eluted with diethyl ether, and concentrated to provide the title compound. MS m/z 251 (M-1). | |
With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 90℃; for 1h;Inert atmosphere; | A mixture of Compound 33A (450 mg, 2.0 mmol), 4- (hydroxymethyl)phenylboronic acid (334 mg, 2.2 mmol), CS2CO3 (1.30 g, 4.0 mmol), and Pd(PPh3)Cl2 (140 mg, 0.2 mmol) in DMF/THF (10 mL, 1 : 1 in volume) was heated at 90 C under nitrogen for 1 hour. The mixture was cooled down to room temperature, diluted with diethyl ether (50 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified with column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 33B: LC-MS (ESI) m/z: 235 [M-OH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With thionyl chloride; In chloroform; at 20℃; for 12h; | Example 23A 4-Chloromethyl-4'-trifluoromethylbiphenyl A solution of 5.0 g (19.82 mmol) of (4'-trifluoromethylbiphenyl-4-yl)methanol from Example 22A in 40 ml of chloroform is mixed with 2.89 ml (39.65 mmol) of thionyl chloride dissolved in 10 ml of chloroform, and the mixture is stirred at room temperature for 12 hours. After reaction is complete, the reaction mixture is concentrated to dryness, and the residue is taken up ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is subsequently separated off, dried over sodium sulfate and concentrated after filtration. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.43 mmol, 98% yield) of a colorless solid are obtained. 1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.91 (2H, d), 7.82 (2H, d), 7.78 (2H, d), 7.58 (2H, d), 4.83 (2H, s). MS (EI): 270 (M+). |
98% | With thionyl chloride; In chloroform; at 20℃; for 12h; | Example 11A 4-Chloromethyl-4'-trifluoromethylbiphenyl A solution of 5.00 g (19.8 mmol) of (4'-trifluoromethylbiphenyl-4-yl)methanol in 40 ml of chloroform is mixed with 2.89 ml (39.7 mmol) of thionyl chloride dissolved in 10 ml of chloroform, and the mixture is stirred at room temperature over 12 hours. After reaction is complete, the reaction mixture is concentrated to dryness, and the residue is taken up ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is subsequently separated off, dried over sodium sulfate and concentrated after filtration. The resulting crude product is purified by flash chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.4 mmol, 98% of theory) of the title compound are obtained. 1H-NMR (300 MHz, DMSO-d6, delta/ppm): 4.83 (s, 2H), 7.58 (d, 2H), 7.78 (d, 2H), 7.91 (d, 2H), 7.82 (d, 2H). MS (E1): 270 (M+). |
98% | With thionyl chloride; In chloroform; at 20℃; for 12h; | Example 16A; 4-Chloromethyl-4'-trifluoromethylbiphenyl 2.89 ml (39.65 mmol) of thionyl chloride dissolved in 10 ml of chloroform are added to a solution of 5.0 g (19.82 mmol) of (4'-trifluoromethylbiphenyl-4-yl)methanol in 40 ml of chloroform, and the mixture is stirred at room temperature for 12 hours. After reaction is complete, the reaction mixture is evaporated to dryness, and the residue is taken up in ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is separated off, dried over sodium sulphate and evaporated after filtration. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.43 mmol, 98% yield) of a colourless solid are obtained.1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.91 (2H, d), 7.82 (2H, d), 7.78 (2H, d), 7.58 (2H, d), 4.83 (2H, s).MS (EI): m/z=270 (M+). |
98% | With thionyl chloride; In chloroform; at 20℃; | A solution of 5.0 g (19.82 mmol) of (4'-trifluoromethylbiphenyl-4-yl)methanol in 40 ml of chloroform is mixed with 2.89 ml (39.65 mmol) of thionyl chloride dissolved in 10 ml of chloroform, and the mixture is stirred at room temperature for 12 hours. After reaction is complete, the reaction mixture is concentrated to dryness, and the residue is taken up ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is subsequently separated off, dried over sodium sulfate and concentrated after filtration. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.43 mmol, 98% of theory) of a colorless solid are obtained.1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.91 (2H, d), 7.82 (2H, d), 7.78 (2H, d), 7.58 (2H, d), 4.83 (2H, s).MS (EI): 270 (M+). |
93% | With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 12h;Inert atmosphere; | To a solution of [(4?-(trifluoromethyl)-[1,1?-biphenyl]-4-yl)methanol (4a, 553 mg, 2.19 mmol) in anhydrous CH2Cl2 (20 mL) were added SOCl2 (391 mg, 3.29 mmol) and DMF (32.1 mg, 0.44 mmol) at 0 C. The reaction mixture was then allowed to warm to room tempreature. After stirring the reaction mixture at room temperature for 12 h, the reaction mixture was diluted with water and extracted with ethyl acetate for 3 times. The combined organic layer was dired over MgSO4, filtered, and concentrated. The obtained residue was purified by MPLC using hexane/ethyl acetate as the eluant to give the desired product 5 as a white solid (553 mg, 93%). 1H NMR (400 MHz, CDCl3) delta7.71-7.66 (m, 4H), 7.58 (d, 2H, J=8.2 Hz), 7.50 (d, 2H, J=8.2 Hz),4.55 (s, 2H). |
91% | With thionyl chloride; In chloroform; at 20℃; for 12h; | Compound 20' (1 eq, 9.51 mmol) was dissolved in 20 mL of CHC13. SOCl2 (2 eq, 19.0 mmol) was then added and the reaction was stirred at rt during 12h.The reaction mixture was evaporated to dryness and diluted with water (30 mL) and EtOAc (40 mL). The mixture was then extracted three times (3 x 20 mL). The combined organic phases were washed with saturated Na2C03, dried and filtered. After removal of the solvent under reduced pressure, the remaining oil was purified using column chromatography (silica gel, 98/2 Hex/EtOAc) to obtain the desired compound (Rf = 0.2) as an off white solid (2.35 g, 91%) 1H-NMR (CDC13, 600 MHz) delta 7.69 (s, 4H), 7.59 (d, J = 8.1Hz, 2H), 7.49 (d, J = 8.1Hz, 2H), 4.64 (s, 2H); 13C-NMR (CDCI3, 150 MHz) delta: 144.2, 140.0, 137.6, 129.8, 129.4, 127.8, 127.6, 125.9, 120.3, 45.9; ESI-MS m/z for Ci4HnF30 [M + H]+, [M + Na]+; |
With methanesulfonyl chloride; triethylamine; In dichloromethane; for 18h; | The product from Example 3A was dissolved in 10 ml methylene chloride. Triethylamine (468 mg, 4.62 mol) and methanesulfonyl chloride (422 mg, 3.68 mmol) were then added and stirred for 18 h. The reaction was poured into water and extracted with methylene chloride. The organic solution was dried over anhydrous sodium sulfate, decanted and concentrated to provide the title compound that was used without further purification. MS m/z 235 (M-Cl+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With phosphorus tribromide; In diethyl ether; dichloromethane; at 0℃; for 2h; | Step B. 4'-Bromomethyl-4-trifluoromethyl-biphenyl; Phosphorous tribromide (8.67mmol, 1.OM in dichloromethane) is added to a stirred solution of 4'-trifluoromethyl-biphenyl-4-yl)-methanol (2.08g, 8.25mmol) in ethyl ether (40mL) at 0 C under inert atmosphere of nitrogen. The reaction is stirred at 0 C for two hours, quenched at 0 C with water, diluted mixture with ethyl acetate, washed with water, then brine. Organics are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column (silica gel) in 0-40% ethyl acetate/hexane gradient to give 1.68g (5.33mmol, 65%) of title compound. |
With phosphorus tribromide; | The title compound was prepared in the manner analogous to Example 1F using 100F and 1-(bromomethyl)-4-[4-(trifluoromethyl)phenyl]benzene prepared from and phosphorous tribromide and <strong>[457889-46-2](4'-trifluoromethyl-biphenyl-4-yl)-methanol</strong> in a manner analagous to Example 3B. 400 MHz 1H NMR (CDCl3) delta 7.68 (m, 4H), 7.51 (d, 2H), 7.29 (d, 2H), 7.15 (m, 2H), 6.60 (d, 1H), 4.62 (s, 2H), 4.04 (s, 2H), 3.79 (s, 3H), 2.60 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 0.88 (t, 3H). | |
1.77 g | With phosphorus tribromide; In diethyl ether; at 20℃; for 1.5h;Cooling with ice; | To an ice cold solution of intermediate M10 (2.02g, lequiv) in anhydrous diethyl ether (20ml) protected with a CaCl2 drying tube to insulate moisture was added phosphorus tribromide (0.38ml, 0.5equiv). The mixture was stirred at room temperature for 1.5h to obtain a clear solution. TLC detection showed that the reaction was complete and then the mixture was quenched with saturated sodium bicarbonate solution. The resulting precipitate was filtered off and the filtrate was extracted with dichloromethane twice (40ml), dried over MgSO4, filtered and then evaporated in vacuo to give intermediate M11 (1.77g) as a white solid which could be used in next step without further purification. |
1.77 g | With phosphorus tribromide; In diethyl ether; at 20℃; for 1.5h; | To an ice cold solution of intermediate Mi0 (2.02 g, 1 equiv) in anhydrous diethyl ether (20 ml) protected with a CaC12 drying tube to insulate moisture was added phosphorus tribromide (0.38 ml, 0.5 equiv). The mixture was stirred at room temperature for 1 .5 h to obtain a clear solution. TLC detection showed that the reaction was complete and then themixture was quenched with saturated sodium bicarbonate solution. The resulting precipitate was filtered off and the filtrate was extracted with dichloromethane twice (40 ml), dried over MgSO4, filtered and then evaporated in vacuo to give intermediate Ml 1 (1.77 g) as a white solid which could be used in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.5 g | With sodium tetrahydroborate; ethanol; at 20℃; for 1h;Cooling with ice; | General procedure: To an ice cold solution of intermediate M1 (2.5g, lequiv) in absolute ethanol (20ml) was added NaBH4 (190mg) in batches, and then the mixture was stirred at room temperature for 1h. After the reaction was complete, solvent was evaporated and the residue was diluted with water. Concentrated hydrochloric acid was added dropwise to the solution in an ice bath until no more bubbles were generated. Then, sodium bicarbonate solution was added and the mixture was extracted with dichloromethane three times. The combined organic phase was washed with brine twice, dried over MgSO4, and then filtered. The filtrate was evaporated in vacuo to give intermediate M10 as a white solid (2.5g). 1H-NMR (CDCl3, 300MHz) delta 4.77(s, 2H), 7.48 (d, 2H, J=8.4), 7.61 (d, 2H, J=8.1), 7.70 (s, 4H). |
2.5 g | With sodium tetrahydroborate; In ethanol; at 20℃; for 1h; | To an ice cold solution of intermediate Mi (2.5 g, 1 equiv) in absolute ethanol (20 ml) was added NaI3H4 (190 mg) in batches, and then the mixture was stirred at room temperature for 1 h. After the reaction was complete, solvent was evaporated and the residue was diluted with water. Concentrated hydrochloric acid was added dropwise to the solution in an ice bath until no more bubbles were generated. Then, sodium bicarbonate solution was added and the mixture was extracted with dichloromethane three times. The combined organic phase was washed with brine twice, dried over MgSO4, and then filtered. The filtrate was evaporated in vacuo to give intermediate M10 as a white solid (2.5 g). ?H-NMR (CDC13, 300 MHz) oe 4.77 (s, 2H), 7.48 (d, 2H, J8.4), 7.61 (d, 2H, J8.i), 7.70 (s, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Example 107; 3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-ylmethyl)-propoxy]-benzoylamino}- propionic acid; Step A. (4'-Trifluoromethyl-biphenyl-4-yl)-methanol; To a solution of 4'-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (3.71g, 13.3mmol) in tetrahydro-furan (30mL) is added lithium aluminum hydride (14.6 mmol, 1.0 M in tetrahydro-furan) at 0 C under inert atmosphere of nitrogen. After the reaction is stirred at 0 C for 10 minutes following completion of hydride addition, it is quenched with ethyl acetate (lOmL) followed by potassium hydrogen sulfate (1.0 M, 15mmol) slowly at 0 C, diluted mixture with ethyl ether and filtered. Organic layers are washed with brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. Column chromatography (silica gel) with 20-80% ethyl acetate/hexane gradient gives 3.1g (12.3mmol, 93%) of title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h;Inert atmosphere; | Under nitrogen atmosphere, at 0 C, to a stirring mixture of LiAlH4 (2.0 M THF solution, 3.0 mL, 6.00 mmol) in dry THF (10 mL), commercially available 4-[4- (trifluoromethyl)-phenyl]-benzoic acid (0.4 g, 1.5 mmol) in dry THF (10 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0 C H20 (0.23 mL), 3.0 M KOH solution (0.23 mL) and H20 (0.77 mL) were very slowly added. The mixture was stirred for 1 h at 0 C, filtered to remove the solid residue, and the organic phase dried over Na2S04. The organic solution was again filtered, concentrated to dryness and the resulting crude product purified by column chromatography using a Teledyne ISCO apparatus, eluting with CyrEtOAc (from 100:0 to 70:30) to afford the title compound (0.3 g, 79%), as white solid. 1H NMR (DMSO-d6): delta 4.56 (d, J= 5.7 Hz, 2H), 5.25 (t, J= 5.7 Hz, 1H), 7.45 (d, J= 8.1 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.81 (d, J= 8.1 Hz, 2H), 7.89 (d, J= 8.1 Hz, 2H). |
79% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h;Inert atmosphere; | Step 1. Preparation of [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methanol Under nitrogen atmosphere, at 0 C., to a stirring mixture of LiAlH4 (2.0 M THF solution, 3.0 mL, 6.00 mmol) in dry THF (10 mL), commercially available 4-[4-(trifluoromethyl)-phenyl]-benzoic acid (0.4 g, 1.5 mmol) in dry THF (10 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0 C. H2O (0.23 mL), 3.0 M KOH solution (0.23 mL) and H2O (0.77 mL) were very slowly added. The mixture was stirred for 1 h at 0 C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered, concentrated to dryness and the resulting crude product purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:EtOAc (from 100:0 to 70:30) to afford the title compound (0.3 g, 79%), as white solid. 1H NMR (DMSO-d6): delta 4.56 (d, J=5.7 Hz, 2H), 5.25 (t, J=5.7 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.89 (d, J=8.1 Hz, 2H). |
66.8% | Description 8a: 4-(4-trifluoromethylphenyl)-benzyl alcohol (D8a); To a solution of 4-(4-trifluoromethylphenyl)-benzoic acid (Apollo, 3g, 11.27mmol) in THF (100ml) was added dropwise a solution of LiAIH4 1 M in THF (1 1.3ml, 11.27mmol) and the mixture was stirred at room temperature for 30 minutes. Water (50ml) was then added dropwise. The insoluble material was filtered on a Celite pad and washed with CH2CI2.The filtrate was washed with CH2CI2 and the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a white solid (1.9g, yield= 66.8%); 1H NMR (300MHz, DMSO d6, ppm): 7.9 (d, 2H), 7.85 (d, 2H), 7.7 (d,2H), 7.45 (d, 2H), 5.3 (t, 1 H), 4.55 (d, 2H). |
66.8% | Description 5a: 4-(4-trifluoromethylphenyl)-benzyl alcohol (D5a); To a solution of 4-(4-trifluoromethylphenyl)-benzoic acid (Apollo, 3g, 11.27mmol) in THF (100ml) was added dropwise a solution of LiAIH4 1 M in THF (11.3ml, 11.27mmol) and the mixture was stirred at room temperature for 30 minutes. Water (50ml) was then added dropwise. The insoluble material was filtered on a Celite pad and washed with CH2CI2. The filtrate was washed with CH2CI2 and the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a white solid (1.9g, yield= 66.8%). H1 NMR (300MHz, DMSO d6, ppm): 7.9 (d, 2H), 7.85 (d, 2H), 7.7 (d, 2H), 7.45 (d, 2H), 5.3 (t, 1 H), 4.55 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Example 22A (4'-Trifluoromethylbiphenyl-4-yl)methanol 12.73 ml (12.73 mmol) of a 1 M solution of lithium aluminum hydride in THF are added dropwise to a solution of 6.24 g (21.21 mmol) of ethyl 4'-trifluoromethylbiphenyl-4-carboxylate from Example 21A in 60 ml of dry THF at 0 C. After the reaction is complete, the mixture is mixed with saturated ammonium chloride solution and taken up in ethyl acetate, and the organic phase is separated off and dried over sodium sulfate. After filtration, the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). 5.1 g (20.21 mmol, 95% yield) of a colorless solid are obtained. 1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.88 (2H, d), 7.82 (2H, d), 7.71 (2H, d), 7.46 (2H, d), 5.23 (1H, t), 4.58 (2H, d). MS (EI): 252 (M+). | |
95% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; | Example 10A (4'-Trifluoromethylbiphenyl-4-yl)methanol 12.7 ml (12.7 mmol) of a 1 M lithium aluminum hydride solution in THF are slowly added to a solution of 6.24 g (21.2 mmol) of ethyl 4'-trifluoromethylbiphenyl-4-carboxylate in 60 ml of dry THF at 0 C. After the reaction is complete, the mixture is hydrolyzed with saturated ammonium chloride solution and taken up in ethyl acetate, and the organic phase is separated off and dried over sodium sulfate. After filtration, the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 5:1). 5.10 g (20.2 mmol, 95% of theory) of the title compound are obtained. 1H-NMR (300 MHz, DMSO-d6, delta/ppm): 4.58 (d, 2H), 5.23 (t, 2H), 7.46 (d, 2H), 7.71 (d, 2H), 7.82 (d, 2H), 7.88 (d, 2H). MS (EI): 252 (M+). |
95% | Example 15A; (4'-Trifluoromethylbiphenyl-4-yl)methanol 12.73 ml (12.73 mmol) of a 1 M solution of lithium aluminium hydride in THF are added dropwise to a solution of 6.24 g (21.21 mmol) of ethyl 4'-trifluoromethylbiphenyl-4-carboxylate in 60 ml of dry THF at 0 C. After reaction is complete, saturated ammonium chloride solution is added to the mixture, which is taken up in ethyl acetate, and the organic phase is separated off and dried over sodium sulphate. After filtration, the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). 5.1 g (20.21 mmol, 95% yield) of a colourless solid are obtained.1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.88 (2H, d), 7.82 (2H, d), 7.71 (2H, d), 7.46 (2H, d), 5.23 (1H, t), 4.58 (2H, d).MS (EI): m/z=252 (M+). |
95% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; | 12.73 ml (12.73 mmol) of a 1 M solution of lithium aluminum hydride in THF are added dropwise to a solution of 6.24 g (21.21 mmol) of ethyl 4'-trifluoromethylbiphenyl-4-carboxylate in 60 ml of dry THF at 0 C. After the reaction is complete, the mixture is mixed with saturated ammonium chloride solution and taken up in ethyl acetate, and the organic phase is separated off and dried over sodium sulfate. After filtration, the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). 5.1 g (20.21 mmol, 95% of theory) of a colorless solid are obtained.1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.88 (2H, d), 7.82 (2H, d), 7.71 (2H, d), 7.46 (2H, d), 5.23 (1H, t), 4.58 (2H, d).MS (EI): 252 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step B. 5-(Trifluoromethyl)-1-(2'-[4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-2,3'-bipyridin-6-yl)-1H-pyrazole-4-carboxylic acid; To a vial were added successively KOtBu (15.0 mg, 0.13 mmol), <strong>[457889-46-2][4'-(trifluoromethyl)biphenyl-4-yl]methanol</strong> (US Patent 2004209936) (36.0 mg, 0.14 mmol) and DMF (0.3 mL). After 5 min, the title compound from Example 237 Step A (20.0 mg, 0.05 mmol) was added. After 30 min, the reaction mixture was treated with NaOH (0.1 mL, 3 N aqueous, 0.3 mmol), MeOH (0.1 mL) and 1,4-dioxane (0.1 mL) at 50 C. for 20 min. Reverse phase HPLC using a YMC C-18 column (65 to 100% acetonitrile in water, each with 0.1% v/v TFA) gave the title compound: LCMS m/z 584.9 [M+H]+; 1H NMR (400 MHz, CDCl3) delta 8.44 (dd, J=7.6, 1.9 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 8.27 (dd, J=4.9, 2.0 Hz, 1H), 8.20 (s, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.69 (s, 4H), 7.62-7.53 (m, 5H), 7.10 (dd, J=7.5, 4.9 Hz, 1H), 5.63 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Under nitrogen atmosphere, to a stirred mixture of <strong>[457889-46-2][4-[4-(trifluoromethyl)-phenyl]-phenyl]-methanol</strong> (0.3 g, 1.19 mmol) in dry CH2Cl2 (2.0 mL), DMAP (0.015 g, 0.12 mmol) and di-2-pyridyl-carbonate (0.309 g, 1.43 mmol) were added. The reaction mixture was left to react at rt for 15 h, then diluted with CH2Cl2 and washed first with a saturated NH4Cl solution (3.0 mL) and subsequently with a saturated NaHCO3 solution (3×3 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford a colorless oil (0.3 g, 68%), as a mixture (ratio 1.8:1) of 2-pyridyl-[4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2-oxopyridine-1-carboxylate. The mixture of isomers was not separated and used in the next step without any further purification. To a stirred mixture of D-threonine (0.063 g, 0.53 mmol) and NaHCO3 (0.067 g, 0.8 mmol) in H2O (3.0 mL), the crude mixture containing 2-pyridyl-[4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2-oxopyridine-1-carboxylate (0.3 g, 0.8 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound as transparent oil (0.21 g, quant.), which was used in the next step without further purification. MS (ESI) m/z: 415 [M-NH4]+; (ESI) m/z: 396 [M-H]-. 1H NMR (DMSO-d6): delta 1.11 (d, J=6.4 Hz, 3H), 3.97 (dd, J=3.5, 8.9 Hz, 1H), 4.05-4.12 (dq, J=3.5, 6.4 Hz, 1H), 5.13 (s, 2H), 7.00 (d, J=8.9 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.1 Hz, 2H), 7.91 (d, J=8.1 Hz, 2H), 12.59 (s, 1H). | |
0.21 g | To a stirred mixture of D-threonine (0.063 g, 0.53 mmol) and NaHC03 (0.067 g, 0.8 mmol) in H20 (3.0 mL), the crude mixture containing 2-pyridyl-[4-[4-(trifluoromethyl)- phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2- oxopyridine-l-carboxylate (0.3 g, 0.8 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et20 (3x5 mL). The aqueous phase was acidified with 2.0 M HC1 solution to pH 2-3 and subsequently extracted with EtOAc (3x10 mL). The organic fraction was dried over Na2S04, filtered and concentrated to dryness to afford the title compound as transparent oil (0.21 g, quant.), which was used in the next step without further purification. MS (ESI) m/z: 415 [M- NH4]+; (ESI) m/z: 396 [M-H]-. 1H NMR (DMSO-d6): delta 1.1 1 (d, J= 6.4 Hz, 3H), 3.97 (dd, J= 3.5, 8.9 Hz, 1H), 4.05 - 4.12 (dq, J= 3.5, 6.4 Hz, 1H), 5.13 (s, 2H), 7.00 (d, J= 8.9 Hz, 1H), 7.51 (d, J= 8.1 Hz, 2H), 7.75 (d, J= 8.1 Hz, 2H), 7.82 (d, J= 8.1 Hz, 2H), 7.91 (d, J= 8.1 Hz, 2H), 12.59 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In dichloromethane; at 20℃; for 15h;Inert atmosphere; | Under nitrogen atmosphere, to a stirred mixture of [4-[4-(trifluoromethyl)-phenyl]- phenylj-methanol (0.3 g, 1.19 mmol) in dry CH2C12 (2.0 mL), DMAP (0.015 g, 0.12 mmol) and di-2-pyridyl-carbonate (0.309 g, 1.43 mmol) were added. The reaction mixture was left to react at rt for 15 h, then diluted with CH2C1 and washed first with a saturated NH4CI solution (3.0 mL) and subsequently with a saturated NaHC03 solution (3X3 mL). The organic fraction was dried over Na2S0 , filtered and concentrated to dryness to afford a colorless oil (0.3 g, 68%), as a mixture (ratio 1.8: 1) of 2-pyridyl-[4-[4-(trifluoromethyl)- phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2- oxopyridine-l-carboxylate. The mixture of isomers was not separated and used in the next step without any further purification. MS (ESI) m/z : 396 [M-Na]+, 412 [M-K]+. | |
With dmap; In dichloromethane; at 20℃; for 15h;Inert atmosphere; | Under nitrogen atmosphere, to a stirred mixture of <strong>[457889-46-2][4-[4-(trifluoromethyl)-phenyl]-phenyl]-methanol</strong> (0.3 g, 1.19 mmol) in dry CH2Cl2 (2.0 mL), DMAP (0.015 g, 0.12 mmol) and di-2-pyridyl-carbonate (0.309 g, 1.43 mmol) were added. The reaction mixture was left to react at rt for 15 h, then diluted with CH2Cl2 and washed first with a saturated NH4Cl solution (3.0 mL) and subsequently with a saturated NaHCO3 solution (3×3 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford a colorless oil (0.3 g, 68%), as a mixture (ratio 1.8:1) of 2-pyridyl-[4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2-oxopyridine-1-carboxylate. The mixture of isomers was not separated and used in the next step without any further purification. MS (ESI) m/z: 396 [M-Na]+, 412 [M-K]+. |
Tags: 457889-46-2 synthesis path| 457889-46-2 SDS| 457889-46-2 COA| 457889-46-2 purity| 457889-46-2 application| 457889-46-2 NMR| 457889-46-2 COA| 457889-46-2 structure
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