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CAS No. : | 908112-43-6 | MDL No. : | MFCD16038907 |
Formula : | C23H27F3N4O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZFVRYNYOPQZKDG-UHFFFAOYSA-N |
M.W : | 464.48 | Pubchem ID : | 24772860 |
Synonyms : |
PF-04928473
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
14.1 mg | A solution of 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro H-indazol-l-yl)-2-(((lr,4r)-4- hydroxycyclohexyl)amino)benzamide (46.4 mg, 0.10 mmol), disuccinimidyl carbonate (38.4 mg, 0.15 mmol) and triethylamine (0.10 mL) in DMF (2.0 mL) was stirred at room temperature for 4 hrs. After 3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-a mine (crizotinib) (90 mg, 0.20 mmol) was added, the reaction mixture was continually stirred at room temperature for overnight. Solvent was evaporated under reduced pressure to give a residue, which was purified by ISCO over silica gel to afford (lr,4r)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-lH-ind azol- 1 -yl)phenyl)amino)cyclohexyl 4-(4-(6-amino-5-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- lH-pyrazol-l-yl)piper idine-l-carboxylate (14.1 mg) as a white solid. 1H NMR (400 MHz, Methanol-^) delta 7.84 (d, / = 0.8 Hz, 1H), 7.66 (d, /= 8.4 Hz, 1H), 7.58 - 7.47 (m, 2H), 7.41 (dd, /= 9.0, 4.8 Hz, 1H), 7.24 - 7.15 (m, 1H), 7.06 (d, /= 1.7 Hz, 1H), 6.82 (d, /= 2.1 Hz, 1H), 6.65 (dd, /= 8.5, 2.1 Hz, 1H), 6.26 (q, / = 6.6 Hz, 1H), 4.63-4.59 (m, 2H), 4.33-4.28 (m, 1H), 4.16 (d, / = 13.6 Hz, 2H), 3.48 - 3.38 (m, 1H), 3.00-2.86 (m, 6H), 2.40 (s, 2H), 2.12 - 1.74 (m, 11H), 1.59- 1.34 (m, 4H), 1.01 (s, 6H). ESMS calculated for C45H47CI2F4N9O5: 939.3; found: 940.7 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | A solution of 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-lH-indazol-l-yl)-2-(((lr,4r)-4- hydroxycyclohexyl)amino)benzamide (557 mg, 1.2 mmol), disuccinimidyl carbonate (460 mg, 1.8 mmol) and triethylamine (0.40 mL) in DMF (10 mL) was stirred at room temperature for overnight. ie/t-Butyl piperazine- 1-carboxylate (452 mg, 2.40 mmol) was added and the reaction mixture was continually stirred at room temperature for 4 hrs. Solvent was evaporated under reduced pressure to give a residue, which was purified by ISCO over silica gel to afford 1-tert-butyl 4-((lr,4r)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-lH- indazol-l-yl)phenyl)amino)cyclohexyl) piperazine- 1,4-dicarboxylate (469 mg, 58%) as a white solid. 1H NMR (400 MHz, Chloroform-J) delta 8.19 (d, /= 7.3 Hz, 1H), 7.50 (d, /= 8.4 Hz, 1H), 6.77 (d, / = 2.0 Hz, 1H), 6.61 (dd, / = 8.4, 2.0 Hz, 1H), 5.68 (s, 2H), 4.74 (s, 1H), 3.44-3.40 (m, 9 H), 2.85 (s, 2H), 2.49 (s, 2H), 2.15-2.08 (m, 4H), 1.57-1.51 (m, 4H), 1.47 (s, 9H), 1.14 (s, 6H). ESMS calculated for C33H43F3N6O6: 676.3; found: 677.5 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.2 mg | With triethylamine; In N,N-dimethyl-formamide; at 20 - 45℃; for 5.5h; | A solution of 4-(6,6-dimethyl-4-oxo-3-(trifluoro hydroxycyclohexyl)amino)benzamide (46.4 mg, 0.10 mmol), 4-nitrophenyl (2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)carbamate (42.4 mg, 0.10 mmol) and triethylamine (0.05 mL) in DMF (1.5 mL) was stirred at room temperature for 1.5 hrs and at 45 C for 4 hrs. Solvent was evaporated under reduced pressure to give a residue, which was purified by ISCO over silica gel to afford (lr,4r)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-lH-ind azol- 1 -yl)phenyl)amino)cyclohexyl (2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)carbamate (19.2 mg) as an yellow solid. 1H NMR (400 MHz, DMSO-J6) delta 11.02 (s, 1H), 9.52 (s, 1H), 8.45 (d, / = 7.6 Hz, 1H), 7.82-7.76 (m, 3H), 7.53 - 7.43 (m, 3H), 6.92 (d, / = 2.0 Hz, 1H), 6.78 - 6.70 (m, 1H), 5.13 (dd, / = 13.3, 5.1 Hz, 1H), 4.72-4.68 (m, 1H), 4.44 (d, / = 17.6 Hz, 1H), 4.36 (d, / = 17.6 Hz, 1H), 3.52-3.47 (m, 1H), 2.99 (s, 2 H), 2.64-2.60 (m, 2H), 2.45(s, 2H), 2.11 - 1.99 (m, 6H), 1.60-1.34 (m, 4H), 1.04 (s, 6H). ESMS calculated for C37H38F3N7O7: 749.3; found: 750.6 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In dichloromethane; at 20℃; for 1.5h; | A solution of 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-lH-indazol-l-yl)-2-(((lr,4r)-4- hydroxycyclohexyl)amino)benzamide (464 mg, 1.0 mmol), 4-nitrophenylchloroformate (240 mg, 1.2 mmol) and DMAP (366 mg, 3.0 mmol) in DCM was stirred at room temperature for 1.5 hrs. The reaction mixture was diluted with DCM, washed with 0.1 N HCl and dried with Na2S04. Solvent was evaporated under reduced pressure to give (lr,4r)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-lH-ind azol-l-yl)phenyl)amino)cyclohexyl (4-nitrophenyl) carbonate (702 mg, 90% purity) as a yellow solid. ESMS calculated for C30H30F3N5O7: 629.2; found: 630.5 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24.0h; | A mixture of compound 5 (50 mg, 0.107 mmol), compound 1 (23 mg, 0.117 mmol), EDC (41 mg, 0.214 mmol), DMAP (2 mg, 0.017 mmol) in CH2C12 (6 mL) was stirred at room temperature for 24 h. Water was added to the reaction mixture and was extracted with CH2C12, organic layer was washed with saturated NaHC03 solution in water (50 mL x 3), brine (50 mL x 2), dried over MgS04, and concentrated. The residue was purified over silica gel column using 2-10% MeOH in DCM to afford a pure product 6 (20 mg, 29%). MR (500 MHz, DMSO-de) delta 1.03 (s, 6 H), 1.23 (s, 2 H), 1.42-1.49 (m, 2 H), 1.70-1.78 (m, 2 H), 2.04-2.12 (m, 4 H), 2.44 (s, 2 H), 2.99 (s, 2 H), 3.57-3.59 (m, 1 H), 3.88 (s, 3 H), 5.06-5.11 (m, 1 H), 6.74 (dd, J = 8.5 and 1.8 Hz, 1 H), 6.93 (d, J = 1.5 Hz, 1 H), 7.35 (br s, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 8.00 (br. S, 1 H), 8.54 (d, J = 7 Hz, 1 H), 8.83 (s, 1 H); MS m/z 664 (M+Na)+, 642 (M+H)+. |