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CAS No. : | 1557268-88-8 | MDL No. : | |
Formula : | C30H30FN7O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VRHPZWLHPIENFW-BTJKTKAUSA-N |
M.W : | 603.60 | Pubchem ID : | 121596128 |
Synonyms : |
Abivertinib maleate;AC0010 maleate
|
Chemical Name : | N-(3-((2-((3-Fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide maleate |
Num. heavy atoms : | 44 |
Num. arom. heavy atoms : | 21 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 10 |
Num. H-bond acceptors : | 10.0 |
Num. H-bond donors : | 5.0 |
Molar Refractivity : | 169.22 |
TPSA : | 173.01 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -8.93 cm/s |
Log Po/w (iLOGP) : | 4.06 |
Log Po/w (XLOGP3) : | 1.48 |
Log Po/w (WLOGP) : | 3.69 |
Log Po/w (MLOGP) : | 2.2 |
Log Po/w (SILICOS-IT) : | 3.19 |
Consensus Log Po/w : | 2.92 |
Lipinski : | 2.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 1.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.11 |
Log S (ESOL) : | -4.21 |
Solubility : | 0.0374 mg/ml ; 0.000062 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.72 |
Solubility : | 0.0115 mg/ml ; 0.000019 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -8.1 |
Solubility : | 0.00000485 mg/ml ; 0.000000008 mol/l |
Class : | Poorly soluble |
PAINS : | 1.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.33 |
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 |
---|---|---|
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 5 h / 90 - 100 °C / 7500.75 Torr / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.5 h / -5 - 0 °C 3: ethanol; water / 6 h / 25 - 40 °C / Large scale | ||
Multi-step reaction with 3 steps 1.1: palladium on activated charcoal / tetrahydrofuran / 0.5 h / 1500.15 - 6000.6 Torr / Inert atmosphere; Large scale 1.2: 11 h / 85 °C / 1500.15 - 6000.6 Torr / Large scale 2.1: potassium carbonate / tetrahydrofuran; water / 1 h / 10 °C 2.2: 1 h / 10 °C 3.1: water; ethanol / 1 h / 40 °C / Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.5 h / -5 - 0 °C 2: ethanol; water / 6 h / 25 - 40 °C / Large scale | ||
Multi-step reaction with 2 steps 1.1: potassium carbonate / tetrahydrofuran; water / 1 h / 10 °C 1.2: 1 h / 10 °C 2.1: water; ethanol / 1 h / 40 °C / Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | In ethanol; water; at 25 - 40℃; for 6h;Large scale; | N- (3- (2- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenylamino) -7H-pyrrolo [2, 3-d] pyrimidin-4-yloxy) phenyl) acrylamide (12.20 kg) was added to a reactor containing purified water (180 kg) and ethanol (7.54 kg) . The mixture was heated to 40 ± 5 . A solution of maleic acid (3.14 kg) in purified H2O (53.1 kg) and EtOH (2.26 kg) was added to the reactor. The resulting mixture was agitated for 1 h at 40 ± 5 , then was cooled to 25 ± 5 at a rate of 20 /h and was stirred for another 5 h. The resulting precipitate was centrifuged and the cake was washed with the rest of the H2O/EtOH solution. The wet cake (16.92 kg) was dried for 48 h at 30 ± 5 under vacuum to afford the title compound (14.30 kg, 89.3) . LC-MS: m/z 488.6 [M+H] +. 1H NMR (500 MHz, DMSO-d6) delta 11.39 (s, 1H) , 10.44 (s, 1H) , 9.02 (s, 1H) , 7.62 (s, 1H) , 7.53 (d, J 8.3 Hz, 1H) , 7.50 (d, J 15.4 Hz, 1H) , 7.42 (t, J 8.2 Hz, 1H) , 7.11-7.05 (m, 2H) , 6.97 (ddd, J 8.1, 2.3, 0.7 Hz, 1H) , 6.82 (t, J 9.4 Hz, 1H) , 6.38 (dd, J 16.9, 10.2 Hz, 1H) , 6.26 (ddd, J 18.5, 10.2, 1.7 Hz, 2H) , 6.14 (s, 2H) , 5.76 (dd, J 10.2, 1.5 Hz, 1H) , 3.30 (br, 4H) , 3.11 (br, 4H) , 2.80 (s, 3H) . 13C NMR (125 MHz, DMSO-d6) delta168.68 (*2) , 164.50, 162, 36, 156.18, 155.36, 154.97, 154.25, 153.34, 140.30, 137.90 (d, J 11.1 Hz) , 136.25 (*2) , 131.50, 131.42 (d, J 9.8 Hz) , 130.53, 128.52, 122.80, 120.03, 117.70, 116.92, 114.43, 113.47, 106.65 (d, J 26.5 Hz) , 98.93 (d, J 23.6 Hz) , 53.38 (*2) , 48.15 (*2) , 42.88. |
89.3% | In ethanol; water; at 40℃; for 1h;Large scale; | Containing purified water (180 kg) and ethanol(7.54 kg) of the reactor was added N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)anilinyl)-7H-pyrrolo[2,3-d] Pyrimidin-4-yloxy)phenyl)propenylamine (12.20 kg).The mixture was heated to 40 C ± 5 C. A solution of maleic acid (3.14 kg) in pure H2O (53.1 kg) and EtOH (2.26 kg) was added to the reactor. The resulting mixture was stirred at 40 C ± 5 C for 1 h, and then cooled to 25 C ± 5 C at a rate of 20 C / h and stirred for another 5 h. The resulting precipitate was centrifuged and the filter cake was washed with the remainder of the H2O / EtOH solution. The wet cake (16.92 kg) was dried under vacuum at 30 C ± 5 C for 48 h to give the title compound (Compounds of Example 7 (see Scheme 1) (14.30 kg, 89.3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: potassium carbonate / N,N-dimethyl-formamide / 48 h / 35 °C / Large scale 2: tris-(dibenzylideneacetone)dipalladium(0); XPhos; potassium carbonate / <i>tert</i>-butyl alcohol / 6 h / 40 - 85 °C / Inert atmosphere; Large scale 3: sodium hydroxide; water / water; methanol / 4.25 h / 10 - 15 °C / Large scale 4: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 5 h / 90 - 100 °C / 7500.75 Torr / Inert atmosphere 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.5 h / -5 - 0 °C 6: ethanol; water / 6 h / 25 - 40 °C / Large scale | ||
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 48 h / 35 °C / Large scale 2.1: potassium carbonate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / 6 h / 40 - 85 °C / Inert atmosphere; Large scale 3.1: sodium hydroxide; water / methanol / 4 h / 10 - 15 °C / Large scale 4.1: palladium on activated charcoal / tetrahydrofuran / 0.5 h / 1500.15 - 6000.6 Torr / Inert atmosphere; Large scale 4.2: 11 h / 85 °C / 1500.15 - 6000.6 Torr / Large scale 5.1: potassium carbonate / tetrahydrofuran; water / 1 h / 10 °C 5.2: 1 h / 10 °C 6.1: water; ethanol / 1 h / 40 °C / Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: potassium carbonate / tetrahydrofuran; water / 12 h / 35 °C / Large scale 2: potassium carbonate / N,N-dimethyl-formamide / 48 h / 35 °C / Large scale 3: tris-(dibenzylideneacetone)dipalladium(0); XPhos; potassium carbonate / <i>tert</i>-butyl alcohol / 6 h / 40 - 85 °C / Inert atmosphere; Large scale 4: sodium hydroxide; water / water; methanol / 4.25 h / 10 - 15 °C / Large scale 5: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 5 h / 90 - 100 °C / 7500.75 Torr / Inert atmosphere 6: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.5 h / -5 - 0 °C 7: ethanol; water / 6 h / 25 - 40 °C / Large scale | ||
Multi-step reaction with 7 steps 1.1: potassium carbonate / tetrahydrofuran; water / 12 h / 35 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 48 h / 35 °C / Large scale 3.1: potassium carbonate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / 6 h / 40 - 85 °C / Inert atmosphere; Large scale 4.1: sodium hydroxide; water / methanol / 4 h / 10 - 15 °C / Large scale 5.1: palladium on activated charcoal / tetrahydrofuran / 0.5 h / 1500.15 - 6000.6 Torr / Inert atmosphere; Large scale 5.2: 11 h / 85 °C / 1500.15 - 6000.6 Torr / Large scale 6.1: potassium carbonate / tetrahydrofuran; water / 1 h / 10 °C 6.2: 1 h / 10 °C 7.1: water; ethanol / 1 h / 40 °C / Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: tris-(dibenzylideneacetone)dipalladium(0); XPhos; potassium carbonate / <i>tert</i>-butyl alcohol / 6 h / 40 - 85 °C / Inert atmosphere; Large scale 2: sodium hydroxide; water / water; methanol / 4.25 h / 10 - 15 °C / Large scale 3: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 5 h / 90 - 100 °C / 7500.75 Torr / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.5 h / -5 - 0 °C 5: ethanol; water / 6 h / 25 - 40 °C / Large scale | ||
Multi-step reaction with 5 steps 1.1: potassium carbonate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / 6 h / 40 - 85 °C / Inert atmosphere; Large scale 2.1: sodium hydroxide; water / methanol / 4 h / 10 - 15 °C / Large scale 3.1: palladium on activated charcoal / tetrahydrofuran / 0.5 h / 1500.15 - 6000.6 Torr / Inert atmosphere; Large scale 3.2: 11 h / 85 °C / 1500.15 - 6000.6 Torr / Large scale 4.1: potassium carbonate / tetrahydrofuran; water / 1 h / 10 °C 4.2: 1 h / 10 °C 5.1: water; ethanol / 1 h / 40 °C / Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: sodium hydroxide; water / water; methanol / 4.25 h / 10 - 15 °C / Large scale 2: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 5 h / 90 - 100 °C / 7500.75 Torr / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.5 h / -5 - 0 °C 4: ethanol; water / 6 h / 25 - 40 °C / Large scale | ||
Multi-step reaction with 4 steps 1.1: sodium hydroxide; water / methanol / 4 h / 10 - 15 °C / Large scale 2.1: palladium on activated charcoal / tetrahydrofuran / 0.5 h / 1500.15 - 6000.6 Torr / Inert atmosphere; Large scale 2.2: 11 h / 85 °C / 1500.15 - 6000.6 Torr / Large scale 3.1: potassium carbonate / tetrahydrofuran; water / 1 h / 10 °C 3.2: 1 h / 10 °C 4.1: water; ethanol / 1 h / 40 °C / Large scale |
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