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CAS No. : | 2230820-11-6 | MDL No. : | MFCD32062688 |
Formula : | C18H20N8O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XISVSTPEXYIKJL-UHFFFAOYSA-N |
M.W : | 380.40 | Pubchem ID : | 135151360 |
Synonyms : |
|
Num. heavy atoms : | 28 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.39 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 103.57 |
TPSA : | 104.16 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.9 cm/s |
Log Po/w (iLOGP) : | 3.21 |
Log Po/w (XLOGP3) : | 1.01 |
Log Po/w (WLOGP) : | 1.58 |
Log Po/w (MLOGP) : | 1.79 |
Log Po/w (SILICOS-IT) : | -0.01 |
Consensus Log Po/w : | 1.51 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.11 |
Solubility : | 0.294 mg/ml ; 0.000772 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.79 |
Solubility : | 0.622 mg/ml ; 0.00163 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.92 |
Solubility : | 0.0459 mg/ml ; 0.000121 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.2 |
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 4 steps 1: lithium hydroxide; water / tetrahydrofuran / 3 h / 17 - 25 °C / Inert atmosphere 2: triethylamine; diphenyl phosphoryl azide / N,N-dimethyl acetamide / 17 h / 17 - 120 °C / Inert atmosphere 3: sodium hydroxide / tetrahydrofuran; water / 16 h / 17 - 25 °C / Inert atmosphere 4: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: lithium hydroxide / tetrahydrofuran; water / 3 h / 20 °C 2: diphenyl phosphoryl azide; triethylamine / N,N-dimethyl acetamide / 17 h / 20 - 120 °C 3: sodium hydroxide / tetrahydrofuran; water / 16 h / 20 °C 4: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C | ||
Multi-step reaction with 4 steps 1.1: lithium hydroxide / water; tetrahydrofuran / 12 h / 25 °C 2.1: triethylamine / acetonitrile / 30 min / 25 °C 2.2: 7 h / 100 °C 3.1: sodium hydroxide / water; tetrahydrofuran / 12 h / 25 °C 4.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Xantphos; caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 - 130 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine; diphenyl phosphoryl azide / N,N-dimethyl acetamide / 17 h / 17 - 120 °C / Inert atmosphere 2: sodium hydroxide / tetrahydrofuran; water / 16 h / 17 - 25 °C / Inert atmosphere 3: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: diphenyl phosphoryl azide; triethylamine / N,N-dimethyl acetamide / 17 h / 20 - 120 °C 2: sodium hydroxide / tetrahydrofuran; water / 16 h / 20 °C 3: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C | ||
Multi-step reaction with 3 steps 1.1: triethylamine / acetonitrile / 30 min / 25 °C 1.2: 7 h / 100 °C 2.1: sodium hydroxide / water; tetrahydrofuran / 12 h / 25 °C 3.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Xantphos; caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 - 130 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium hydroxide / tetrahydrofuran; water / 16 h / 17 - 25 °C / Inert atmosphere 2: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / tetrahydrofuran; water / 16 h / 20 °C 2: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / water; tetrahydrofuran / 12 h / 25 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Xantphos; caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 - 130 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With BrettPhos Pd G3; caesium carbonate In 1,4-dioxane at 100℃; for 1.5h; Inert atmosphere; | 3 Example 3: 7-methyl-2-((7-methyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl)amino)-9- (tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one Cesium carbonate (24.3 g, 74.4 mmol) was added to 2-chloro-7-methyl-9-(tetrahydro-2H- pyran-4-yl)-7,9-dihydro-8H-purin-8-one (10.0 g, 37.2 mmol) and 7-methyl- [l,2,4]triazolo[l,5-a]pyridin-6-amine (5.51 g, 37.2 mmol) in 1,4-dioxane (200 mL).Brettphos precat G3 (1.69 g, 1.86 mmol) was added and the resulting suspension was stirred vigorously at 100°C for 1 h. Added a further 1% of catalyst and stirred for a further 30 minutes. The reaction mixture was cooled to rt, filtered and the solid was washed with 10% MeOH in DCM (100 mL). The filtrate was taken and the solvent was removed in vacuo. The resulting crude product was purified by fee, eluting with 0-10% MeOH in DCM, then by recrystallization from MeOH and DCM to afford the title compound (7.59 g, 54%) as a cream solid;lH NMR (400 MHz, DMSO) 1.63 - 1.72 (2H, m), 2.40 (3H, s), 2.52 - 2.58 (2H, m), 3.31 (3H, s), 3.42 (2H, t), 3.97 (2H, dd), 4.42 (1H, tt), 7.70 (1H, s), 8.08 (1H, s), 8.37 (1H, s), 8.65 (1H, s), 9.11 (1H, s); m/z MH+381. Form AThe final product, 7-methyl-2-((7-methyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl)amino)-9- (tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one, was analysed by XRPD and DSC and found to be crystalline. XRPD of a sample of the material gave rise to a diffraction pattern as shown in Figure 1. 7-methyl-2-((7-methyl-[l,2,4]triazolo[l,5-a]pyridin-6- yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one Form A is characterised by at least one peak at a 2Θ value of 7.6° and 18.7°, measured using CuKa radiation. The ten most prominent peaks of the XRPD are shown in Table A. |
54% | With BrettPhos Pd G3; caesium carbonate In 1,4-dioxane at 100℃; for 1.5h; | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; Xantphos In N,N-dimethyl-formamide at 100 - 130℃; Inert atmosphere; | 2 Compound 1 : 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro- 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one A mixture of Intermediate 1h (1.3 g, 1.0 equiv.), Intermediate Id (1.0 equiv.), Pd(dppf)Cl2 (0.1 - 0.2 equiv.), XantPhos (0.1 - 0.2 equiv.) and CS2CO3 (2.0 equiv.) in DMF (0.05 - 0.3 M) was degassed and purged 3x with N2 and the mixture was stirred at 100-130 °C for at least 12 h under N2 atmosphere. The reaction mixture was then poured into water and extracted 3x with DCM. The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography to afford product as a pale yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 9.13 (s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.72 (s, 1H), 4.50 - 4.36 (m, 1H), 3.98 (dd, J = 11.6, 4.4 Hz, 2H), 3.44 (d, J = 11.9 Hz, 2H), 3.32 (s, 3H), 2.44-2.38 (m, 3H), 1.69 (d, J = 11.6 Hz, 2H). MS: 381.3 m/z [M+H]. |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; Xantphos In N,N-dimethyl-formamide at 100 - 130℃; Inert atmosphere; | 2 Compound 1 : 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro- 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one A mixture of Intermediate 1h (1.3 g, 1.0 equiv.), Intermediate Id (1.0 equiv.), Pd(dppf)Cl2 (0.1 - 0.2 equiv.), XantPhos (0.1 - 0.2 equiv.) and CS2CO3 (2.0 equiv.) in DMF (0.05 - 0.3 M) was degassed and purged 3x with N2 and the mixture was stirred at 100-130 °C for at least 12 h under N2 atmosphere. The reaction mixture was then poured into water and extracted 3x with DCM. The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography to afford product as a pale yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 9.13 (s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.72 (s, 1H), 4.50 - 4.36 (m, 1H), 3.98 (dd, J = 11.6, 4.4 Hz, 2H), 3.44 (d, J = 11.9 Hz, 2H), 3.32 (s, 3H), 2.44-2.38 (m, 3H), 1.69 (d, J = 11.6 Hz, 2H). MS: 381.3 m/z [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride / methanol / 1 h / Reflux; Inert atmosphere 2: trifluoroacetic anhydride / tetrahydrofuran / 18 h / 0 - 25 °C / Inert atmosphere 3: 10% Pd/C; ammonium formate / ethanol / 2 h / Reflux; Inert atmosphere 4: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride / methanol / 1 h / Reflux 2: trifluoroacetic anhydride / tetrahydrofuran / 18 h / 0 - 20 °C 3: ammonium formate; 10% Pd/C / ethanol / 2 h / Reflux 4: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C | ||
Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride / methanol / 1 h / 80 °C 2: trifluoroacetic anhydride / tetrahydrofuran / 18 h / 25 °C 3: 10% Pd/C; ammonium formate / ethanol / 2 h / 105 °C 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Xantphos; caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 - 130 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: trifluoroacetic anhydride / tetrahydrofuran / 18 h / 0 - 25 °C / Inert atmosphere 2: 10% Pd/C; ammonium formate / ethanol / 2 h / Reflux; Inert atmosphere 3: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: trifluoroacetic anhydride / tetrahydrofuran / 18 h / 0 - 20 °C 2: ammonium formate; 10% Pd/C / ethanol / 2 h / Reflux 3: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C | ||
Multi-step reaction with 3 steps 1: trifluoroacetic anhydride / tetrahydrofuran / 18 h / 25 °C 2: 10% Pd/C; ammonium formate / ethanol / 2 h / 105 °C 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Xantphos; caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 - 130 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 10% Pd/C; ammonium formate / ethanol / 2 h / Reflux; Inert atmosphere 2: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: ammonium formate; 10% Pd/C / ethanol / 2 h / Reflux 2: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C | ||
Multi-step reaction with 2 steps 1: 10% Pd/C; ammonium formate / ethanol / 2 h / 105 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Xantphos; caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 - 130 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: toluene / 2 h / Reflux; Inert atmosphere 2: hydroxylamine hydrochloride / methanol / 1 h / Reflux; Inert atmosphere 3: trifluoroacetic anhydride / tetrahydrofuran / 18 h / 0 - 25 °C / Inert atmosphere 4: 10% Pd/C; ammonium formate / ethanol / 2 h / Reflux; Inert atmosphere 5: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 5 steps 1: toluene / 2 h / Reflux 2: hydroxylamine hydrochloride / methanol / 1 h / Reflux 3: trifluoroacetic anhydride / tetrahydrofuran / 18 h / 0 - 20 °C 4: ammonium formate; 10% Pd/C / ethanol / 2 h / Reflux 5: caesium carbonate; BrettPhos Pd G3 / 1,4-dioxane / 1.5 h / 100 °C | ||
Multi-step reaction with 5 steps 1: toluene / 2 h / 110 °C 2: hydroxylamine hydrochloride / methanol / 1 h / 80 °C 3: trifluoroacetic anhydride / tetrahydrofuran / 18 h / 25 °C 4: 10% Pd/C; ammonium formate / ethanol / 2 h / 105 °C 5: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Xantphos; caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 - 130 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: potassium carbonate / acetonitrile / 12 h / 20 - 25 °C 2.1: lithium hydroxide / water; tetrahydrofuran / 12 h / 25 °C 3.1: triethylamine / acetonitrile / 30 min / 25 °C 3.2: 7 h / 100 °C 4.1: sodium hydroxide / water; tetrahydrofuran / 12 h / 25 °C 5.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Xantphos; caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 - 130 °C / Inert atmosphere |