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CAS No. : | 841290-80-0 | MDL No. : | MFCD09970820 |
Formula : | C22H23FN6O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NHHQJBCNYHBUSI-UHFFFAOYSA-N |
M.W : | 470.45 | Pubchem ID : | 11213558 |
Synonyms : |
R406;free base
|
Num. heavy atoms : | 34 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.27 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 9.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 124.82 |
TPSA : | 128.75 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.96 cm/s |
Log Po/w (iLOGP) : | 3.3 |
Log Po/w (XLOGP3) : | 3.11 |
Log Po/w (WLOGP) : | 3.48 |
Log Po/w (MLOGP) : | 1.56 |
Log Po/w (SILICOS-IT) : | 2.46 |
Consensus Log Po/w : | 2.78 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.65 |
Solubility : | 0.0106 mg/ml ; 0.0000226 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.48 |
Solubility : | 0.00155 mg/ml ; 0.00000329 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -7.93 |
Solubility : | 0.00000553 mg/ml ; 0.0000000117 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.86 |
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 |
---|---|---|
91% | at 120℃; for 10 h; Inert atmosphere; Large scale | Step B: Preparation of 6-[[5-Fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one 6-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (Step A) (568 kg, 1.00 mol eq) is mixed with 3,4,5-trimethoxyaniline (402 kg, 1.25 mol eq) in N-methylpyrrolidin-2-one (2835 kg) with stirring under a nitrogen atmosphere. To this is added water (11 kg) and the mixture heated to about 120° C. and stirred for about 10 hours. This is then cooled to about 65° C. and the pH adjusted to pH 8.5 with 4percent w/w aqueous sodium hydroxide solution. The resulting slurry is further cooled to about 20° C., stirred for at least 6 hours and then filtered. The filtered solid is washed twice with water (2*1440 kg) then twice with acetone (2*1140 kg) and finally dried under vacuum at about 40° C. to give the title compound (754 kg, 91percent) as a colored solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 6H) 3.59 (s, 3H) 3.66 (s, 6H) 7.04 (s, 2H) 7.32 (d, J=8.5 Hz, 1H) 7.68 (d, J=8.5 Hz, 1H) 8.13 (d, J=3.4 Hz, 1H) 9.10 (br. s, 1H) 9.14 (br. s, 1H) 11.06 (br. s, 1H). m/z 471 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With trifluoroacetic acid In dichloromethane at 0℃; for 1.58 h; | 7.1.2 N4-(2,2-dimethy1-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5- pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4- pyrimidinediamine (Compound 4); [0210] Trifluoroacetic acid (1.5 mL) was added dropwise as a neat for 5 min to N4-(2,2- dimethy1-4-[(di-tert-butyl phosphonoxy)methyl] -3 -oxo-5-pyrido [ 1 ,4] oxazin-6-yl)-5-fluoro- N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 3, 120 mg, 0.173 mmol ) dissolved in CH2Cl2 (10 mL) at O0C under nitrogen atmosphere. The contents were allowed to stir for 1.5 h. Progress of the reaction mixture was monitored by LC/MS. After complete consumption of the starting material, reaction mixture was concentrated, dried and triturated with ether. The ethereal layer was decanted and dried to provide the crude solid. LC/MS analysis of the crude displayed three peaks with M++H 581, 471 and 501. The peak corresponding to M++H 581 was collected by preparative HPLC chromatographic purification. The fractions were lyophilised and dried to provide 53 mg (52percent) of off white fluffy solid and characterized as N4-(2,2-dimethy1-4-[(dihydrogen phosphonoxy)methyl]-3- oxo-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 4). 1H NMR (DMSO-d6): δ 9.21 (br s, 2H), 8.16 (d, 1H, J = 2.6 Hz), 7.93 (d, 1H, J = 8.5 Hz), 7.39 (d, 1H, J = 8.5 Hz), 7.05 (s, 2H), 5.79 (d, 1H, J3PH = 6.6 Hz), 3.67 (s, 6H), 3.59 (s, 3H), 1.44 (s, 6H). LCMS: ret. time: 8.52 min.; purity: 95percent; MS (m/e): 581 (MH+). 31P NMR (DMSO-d6): -2.17. |