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CAS No. : | 1644545-52-7 | MDL No. : | MFCD31630835 |
Formula : | C14H13ClF6N6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QCZAWDGAVJMPTA-RNFRBKRXSA-N |
M.W : | 414.74 | Pubchem ID : | 117817422 |
Synonyms : |
AG-881
|
Num. heavy atoms : | 27 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.43 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 10.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 86.29 |
TPSA : | 75.62 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.07 cm/s |
Log Po/w (iLOGP) : | 3.2 |
Log Po/w (XLOGP3) : | 5.29 |
Log Po/w (WLOGP) : | 6.45 |
Log Po/w (MLOGP) : | 2.33 |
Log Po/w (SILICOS-IT) : | 3.7 |
Consensus Log Po/w : | 4.19 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.61 |
Solubility : | 0.00102 mg/ml ; 0.00000245 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -6.63 |
Solubility : | 0.0000975 mg/ml ; 0.000000235 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -6.7 |
Solubility : | 0.0000831 mg/ml ; 0.0000002 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.48 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
90% | In methanol at 15℃; for 4h; Reflux; | 7 Example 7 (0728) [00300] Preparation of 6-(4,6-bis(((R)-1 , 1 , 1 -trifluoropropan-2-yl)amino)-1 ,3,5-triazin-2- yl)pyridin-2-ol (Compound 7) To a solution of sodium methoxide (ChhONa) (150 ml_, 30wt% in methanol) was added 6-(6-chloropyridin-2-yl)-/V2,/V4-bis((R)-1 , 1 , 1 -trifluoropropan-2-yl)-1 ,3,5- triazine-2,4-diamine (Compound 1 , 30 g, 72.3 mmol) in portions at 15 - 20°C. The reaction mixture was heated to reflux and stirred for 4 h. The reaction mixture was then cooled to room temperature and poured into ice-water (300 ml_) below 10°C. To the reaction mixture was added dichloromethane (DCM) (500 ml_). The layers were separated, and the organic layer was washed with water (200 ml_x2), dried over anhydrous sodium sulfate and concentrated in vacuum to afford 6-(6-methoxypyridin-2- yl)-/V2,/V4-bis((R)-1 , 1 ,1 -trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine (27 g) as a white solid in 90% yield. 1 H NMR (DMSO-de) δ 8.31 -8.12 (m, 2H), 7.92-7.83 (m, 2H), 6.99- 6.97 (m, 1 H), 5.10-4.93 (m, 2H), 3.94 (s, 3H), 1 .35 (m, 6H) ppm. (0732) [00302] A solution of 6-(6-methoxypyridin-2-yl)-/V2,/V4-bis((R)-1 , 1 , 1 -trifluoropropan-2- yl)-1 ,3,5-triazine-2,4-diamine (20 g, 48.7 mmol) in hydrogen bromide (HBr) (200 ml_, 40wt% aqueous solution) was stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature, water (1 L) was added, and sodium hydroxide (1 N aqueous solution) was added to adjust pH to 7. The resulting slurry was filtered, and the solids were dissolved in ethyl acetate (200 ml_). The organic layer was washed with water (200 ml_x2), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 6-(4,6-bis(((R)-1 ,1,1 -trifluoropropan-2-yl)amino)-1 ,3,5-triazin-2-yl)pyridin-2-ol (Compound 7, 18 g) as a white solid in 93% yield. LC-MS (Chromolith SpeedROD, RP- 18e, 50*4.6mm column eluting water/CH3CN over 5 minutes) found (M+1) =397.1H NMR (DMSO-de) δ 11.32 (br. s, 1H), 8.48-8.00 (m, 2H), 7.63-7.56 (m, 1H), 7.33-7.18 (m, 1H), 6.62-6.58 (m, 1H), 5.66-5.45 (m, 1H), 5.00-4.87 (m, 1H), 1.30 (m, 6H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With disodium sulphide In (methylsulfinyl)methane at 5 - 25℃; for 16.25h; Inert atmosphere; | 3 Preparation of 6-(4, 6-bis (((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl) pyridine-2-thiol (Compound 3). DMSO (100 mL) and 6-(6-chloropyridin-2-yl)-N2, N4-bis((R)-1,1,1-trifluoropropan-2- yl) -1,3,5-triazine-2,4-diamine (AG-881 free base, 10 g, 24.1 mmol) were charged into a 250 mL flask under N2 at 15~20 °C. The resulting solution was stirred for 10 min at 15~20 °C to get a clear brown solution. The reaction mixture was cooled to 5 °C, and was added Na2S (4.2 g, 90% purity, 24.4 mmol) in portions over 5 min at 5~10 °C. The reaction mixture was stirred for 16 h at 20~25 °C, poured into ice water (500 mL) and acetic acid (50 mL) was added at 5~10 °C with stirring. After stirring for 15-30 min at 10-15 °C, the solid was filtered. The wet cake was dissolved in DCM (100 mL), phase separated, and the aqueous layer was discarded. The organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica gel chromatography (Elutant: DCM/MeOH - 30:1 to 10:1). The pure fractions containing product were combined and concentrated under reduced pressure to afford the purified product as yellow solid which was further dried in vacuum oven at ambient temperature to obtain 6-(4, 6-bis (((R)- 1,1,1-trifluoropropan-2-yl)amino)-1,3,5 -triazin-2-yl)pyridine -2-thiol as a yellow solid (8.0 g, 80% yield). 1H-NMR (400 MHz, DMSO-d6) 12.68-11.90 (m, 1H), 8.68-7.66 (m, 2H), 7.61-7.48 (m, 3H), 5.36-4.86 (m, 2H), 1.37-1.34 (m, 6H). 13C-NMR (101 MHz, DMSO-d6) 179.09, 178.77, 166.12, 165.71, 165.62, 163.46, 142.85, 142.66, 137.97, 137.62, 136.76, 136.35, 127.83, 125.02, 113.60, 112.82, 47.60-47.17, 14.0 (d, J = 16.2 Hz). LC-MS (ESI): m/z 413 [M+H]+. |
80% | With disodium sulphide In (methylsulfinyl)methane at 5 - 25℃; for 16.25h; Inert atmosphere; | 3 Preparation of 6-(4, 6-bis (((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl) pyridine-2-thiol (Compound 3). DMSO (100 mL) and 6-(6-chloropyridin-2-yl)-N2, N4-bis((R)-1,1,1-trifluoropropan-2- yl) -1,3,5-triazine-2,4-diamine (AG-881 free base, 10 g, 24.1 mmol) were charged into a 250 mL flask under N2 at 15~20 °C. The resulting solution was stirred for 10 min at 15~20 °C to get a clear brown solution. The reaction mixture was cooled to 5 °C, and was added Na2S (4.2 g, 90% purity, 24.4 mmol) in portions over 5 min at 5~10 °C. The reaction mixture was stirred for 16 h at 20~25 °C, poured into ice water (500 mL) and acetic acid (50 mL) was added at 5~10 °C with stirring. After stirring for 15-30 min at 10-15 °C, the solid was filtered. The wet cake was dissolved in DCM (100 mL), phase separated, and the aqueous layer was discarded. The organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica gel chromatography (Elutant: DCM/MeOH - 30:1 to 10:1). The pure fractions containing product were combined and concentrated under reduced pressure to afford the purified product as yellow solid which was further dried in vacuum oven at ambient temperature to obtain 6-(4, 6-bis (((R)- 1,1,1-trifluoropropan-2-yl)amino)-1,3,5 -triazin-2-yl)pyridine -2-thiol as a yellow solid (8.0 g, 80% yield). 1H-NMR (400 MHz, DMSO-d6) 12.68-11.90 (m, 1H), 8.68-7.66 (m, 2H), 7.61-7.48 (m, 3H), 5.36-4.86 (m, 2H), 1.37-1.34 (m, 6H). 13C-NMR (101 MHz, DMSO-d6) 179.09, 178.77, 166.12, 165.71, 165.62, 163.46, 142.85, 142.66, 137.97, 137.62, 136.76, 136.35, 127.83, 125.02, 113.60, 112.82, 47.60-47.17, 14.0 (d, J = 16.2 Hz). LC-MS (ESI): m/z 413 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In (methylsulfinyl)methane at 5 - 25℃; for 3.5h; Inert atmosphere; | 1; 7 Preparation of 6-(6-(methylthio)pyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl) -1,3,5-triazine-2,4-diamine (Compound 1) DMSO (500 mL) and 6-(6-chloropyridin-2-yl)-N2, N4-bis((R)-1,1,1-trifluoropropan-2- yl)- 1,3,5-triazine -2,4-diamine (AG-881 free base, 100 g, 0.241 mol) were charged into a 1 L flask under N2 at 15~20 °C. The resulting solution was stirred for 10 min at 15~20 °C to form a clear brown solution. The reaction solution was cooled to 5 °C and sodium thiomethoxide (NaSMe, 35.6 g, 0.508 mol) was added in portions over 20 min at 5~10 °C. The reaction mixture was stirred at 20~25 °C for 3 h. The mixture was poured into ice water (3 L) at 5~10 °C with stirring. After 30 min at 20~25 °C, the solid was filtered and the wet cake was triturated with water (1.5 L) over 30 min at 20~25 °C. The solid was filtered, washed with water (200 mL) and dried in vacuum oven at 50-55 °C to afford 6-(6-(methylthio) pyridin-2-yl)-N2,N4- bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine as an off-white solid (100.8 g, 98% yield). 1H NMR: (400 MHz, DMSO-d6) 8.41-7.81 (m, 4H), 7.45-7.42 (m, 1H), 5.12-4.91 (m, 2H), 2.59 (s, 3H), 1.34 (d, J = 6.1 Hz, 6H). 13C-NMR: (101 MHz, DMSO-d6) 170.65, 170.24, 166.65, 166.38, 160.58, 160.15, 154.20(d, J=14.4 Hz), 137.77, 127.99, 125.19, 122.87, 122.34, 119.89, 119.76 (d, J=21.9 Hz), 47.44, 47.13, 13.89 (d, J=9.6 Hz), 13.53, 13.23. LC-MS (ESI): m/z 427 [M+H]+ |
98% | In (methylsulfinyl)methane at 5 - 25℃; for 3.5h; Inert atmosphere; | 1; 7 Preparation of 6-(6-(methylthio)pyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl) -1,3,5-triazine-2,4-diamine (Compound 1) DMSO (500 mL) and 6-(6-chloropyridin-2-yl)-N2, N4-bis((R)-1,1,1-trifluoropropan-2- yl)- 1,3,5-triazine -2,4-diamine (AG-881 free base, 100 g, 0.241 mol) were charged into a 1 L flask under N2 at 15~20 °C. The resulting solution was stirred for 10 min at 15~20 °C to form a clear brown solution. The reaction solution was cooled to 5 °C and sodium thiomethoxide (NaSMe, 35.6 g, 0.508 mol) was added in portions over 20 min at 5~10 °C. The reaction mixture was stirred at 20~25 °C for 3 h. The mixture was poured into ice water (3 L) at 5~10 °C with stirring. After 30 min at 20~25 °C, the solid was filtered and the wet cake was triturated with water (1.5 L) over 30 min at 20~25 °C. The solid was filtered, washed with water (200 mL) and dried in vacuum oven at 50-55 °C to afford 6-(6-(methylthio) pyridin-2-yl)-N2,N4- bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine as an off-white solid (100.8 g, 98% yield). 1H NMR: (400 MHz, DMSO-d6) 8.41-7.81 (m, 4H), 7.45-7.42 (m, 1H), 5.12-4.91 (m, 2H), 2.59 (s, 3H), 1.34 (d, J = 6.1 Hz, 6H). 13C-NMR: (101 MHz, DMSO-d6) 170.65, 170.24, 166.65, 166.38, 160.58, 160.15, 154.20(d, J=14.4 Hz), 137.77, 127.99, 125.19, 122.87, 122.34, 119.89, 119.76 (d, J=21.9 Hz), 47.44, 47.13, 13.89 (d, J=9.6 Hz), 13.53, 13.23. LC-MS (ESI): m/z 427 [M+H]+ |