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CAS No. : | 1627091-47-7 | MDL No. : | MFCD30536362 |
Formula : | C21H25N5O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ATUUNJCZCOMUKD-OKILXGFUSA-N |
M.W : | 379.46 | Pubchem ID : | 78319901 |
Synonyms : |
|
Num. heavy atoms : | 28 |
Num. arom. heavy atoms : | 15 |
Fraction Csp3 : | 0.48 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 111.3 |
TPSA : | 76.16 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.35 cm/s |
Log Po/w (iLOGP) : | 3.29 |
Log Po/w (XLOGP3) : | 3.19 |
Log Po/w (WLOGP) : | 3.12 |
Log Po/w (MLOGP) : | 1.79 |
Log Po/w (SILICOS-IT) : | 3.42 |
Consensus Log Po/w : | 2.96 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.33 |
Solubility : | 0.0176 mg/ml ; 0.0000463 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.46 |
Solubility : | 0.0131 mg/ml ; 0.0000346 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -6.07 |
Solubility : | 0.000324 mg/ml ; 0.000000855 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.88 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P332+P313-P337+P313-P362-P403+P233-P405-P501 | 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 |
---|---|---|
Stage #1: With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 110℃; for 3h; Stage #2: With hydrogenchloride In tetrahydrofuran; 1,4-dioxane; methanol at 70℃; for 0.5h; | B Scheme B General procedure: Parallel preparation of Examples 43-70: To a set of vials containing the chloropyridine from Scheme A (30mg, 0.070 mmol) in DMSO (0.3 mL) was individually added the requisite amine (0.084 mmol) and diisopropylethylamine (0.049 mL, 0.280 mmol). The vials were capped and the mixtures were heated to 110°C with stirring for 3 hours. The mixtures were cooled to RT. Water (2 mL) was added to each vial. The aqueous phase in each vial was extracted with DCM (2 x 1 mL). The organic layers from each vial were transferred to a clean vial and the solvent was removed in vacuo. To each vial was then added THF:MeOH (1 :3, 1 niL) followed by HC1 (4 N in dioxane, 0.20 mL, 0.80 mmol). The vials were capped and the solutions were heated to 70°C for 0.5 h. The solutions were allowed to cool to RT and the solvent was then removed from the vials in vacuo. Each crude product was redissolved in 1 mL of DMSO and filtered. The crude products were purified by mass triggered HPLC. Example 43 was purified using the following conditions: [Waters Sunfire CI 8 column, 5μηι, 19x100 mm, gradient 10% to 24% MeCN (0.1% formic acid) in water (0.1 % formic acid) 50 mL/min, 8 min run time] to provide the Example 43. Examples 44-70 were purified using the following conditions: [Waters XBridge CI 8 column, 5μηι, 19x100 mm, gradient ranges from 10-35% initial to 49-75% MeCN (0.1% NH4OH) in water (0.1% NH4OH) 50 mL/min, 8 min run time] to provide the Examples 44-70. | |
With hydrogenchloride In tetrahydrofuran; 1,4-dioxane; methanol at 70℃; for 0.5h; | 51 General procedure: To a set of vials containing the chloropyridine from Scheme A (30mg, 0.070 mmol) in DMSO (0.3 mL) was individually added the requisite amine (0.084 mmol) and diisopropylethylamine (0.049 mL, 0.280 mmol). The vials were capped and the mixtures were heated to 110°C with stirring for 3 hours. The mixtures were cooled to RT. Water (2 mL) was added to each vial. The aqueous phase in each vial was extracted with DCM (2 x 1 mL). The organic layers from each vial were transferred to a clean vial and the solvent was removed in vacuo. To each vial was then added THFMeOH (1 :3, 1 mL) followed by HC1 (4 N in dioxane, 0.20 mL, 0.80 mmol). The vials were capped and the solutions were heated to 70°C for 0.5 h. The solutions were allowed to cool to RT and the solvent was then removed from the vials in vacuo. Each crude product was redissolved in 1 mL of DMSO and filtered. The crude products were purified by mass triggered HPLC. Example 43 was purified using the following conditions: [Waters Sunfire C18 column, 5μιτι, 19x100 mm, gradient 10% to 24% MeCN (0.1% formic acid) in water (0.1 % formic acid) 50 mL/min, 8 min run time] to provide the Example 43. Examples 44-70 were purified using the following conditions: [Waters XB ridge CI 8 column, 5μιτι, 19x100 mm, gradient ranges from 10-35% initial to 49-75% MeCN (0.1% NH4OH) in water (0.1% NH4OH) 50 mL/min, 8 min run time] to provide the Examples 44-70. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: potassium carbonate; caesium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 16 h / 100 °C / Inert atmosphere 2.1: ammonium formate; palladium 10% on activated carbon / ethanol / 5 h / 20 °C 3.1: triethylamine / dichloromethane / 16 h / 0 - 20 °C 4.1: acetic anhydride; isopentyl nitrite; potassium acetate / toluene / 16 h / 80 °C 5.1: ammonia / methanol / 2 h / 20 °C 6.1: N-Methyldicyclohexylamine / tetrahydrofuran / 16 h / 20 °C 7.1: n-butyllithium / tetrahydrofuran / 0.33 h / -78 - -20 °C 7.2: 5 h / -78 - 20 °C 8.1: triethylamine / dimethyl sulfoxide / 2 h / 100 °C / Sealed tube 9.1: hydrogenchloride / methanol; 1,4-dioxane / 0.5 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: ammonium formate; palladium 10% on activated carbon / ethanol / 5 h / 20 °C 2.1: triethylamine / dichloromethane / 16 h / 0 - 20 °C 3.1: acetic anhydride; isopentyl nitrite; potassium acetate / toluene / 16 h / 80 °C 4.1: ammonia / methanol / 2 h / 20 °C 5.1: N-Methyldicyclohexylamine / tetrahydrofuran / 16 h / 20 °C 6.1: n-butyllithium / tetrahydrofuran / 0.33 h / -78 - -20 °C 6.2: 5 h / -78 - 20 °C 7.1: triethylamine / dimethyl sulfoxide / 2 h / 100 °C / Sealed tube 8.1: hydrogenchloride / methanol; 1,4-dioxane / 0.5 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: triethylamine / dichloromethane / 16 h / 0 - 20 °C 2.1: acetic anhydride; isopentyl nitrite; potassium acetate / toluene / 16 h / 80 °C 3.1: ammonia / methanol / 2 h / 20 °C 4.1: N-Methyldicyclohexylamine / tetrahydrofuran / 16 h / 20 °C 5.1: n-butyllithium / tetrahydrofuran / 0.33 h / -78 - -20 °C 5.2: 5 h / -78 - 20 °C 6.1: triethylamine / dimethyl sulfoxide / 2 h / 100 °C / Sealed tube 7.1: hydrogenchloride / methanol; 1,4-dioxane / 0.5 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: acetic anhydride; isopentyl nitrite; potassium acetate / toluene / 16 h / 80 °C 2.1: ammonia / methanol / 2 h / 20 °C 3.1: N-Methyldicyclohexylamine / tetrahydrofuran / 16 h / 20 °C 4.1: n-butyllithium / tetrahydrofuran / 0.33 h / -78 - -20 °C 4.2: 5 h / -78 - 20 °C 5.1: triethylamine / dimethyl sulfoxide / 2 h / 100 °C / Sealed tube 6.1: hydrogenchloride / methanol; 1,4-dioxane / 0.5 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: ammonia / methanol / 2 h / 20 °C 2.1: N-Methyldicyclohexylamine / tetrahydrofuran / 16 h / 20 °C 3.1: n-butyllithium / tetrahydrofuran / 0.33 h / -78 - -20 °C 3.2: 5 h / -78 - 20 °C 4.1: triethylamine / dimethyl sulfoxide / 2 h / 100 °C / Sealed tube 5.1: hydrogenchloride / methanol; 1,4-dioxane / 0.5 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: N-Methyldicyclohexylamine / tetrahydrofuran / 16 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran / 0.33 h / -78 - -20 °C 2.2: 5 h / -78 - 20 °C 3.1: triethylamine / dimethyl sulfoxide / 2 h / 100 °C / Sealed tube 4.1: hydrogenchloride / methanol; 1,4-dioxane / 0.5 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 0.33 h / -78 - -20 °C 1.2: 5 h / -78 - 20 °C 2.1: triethylamine / dimethyl sulfoxide / 2 h / 100 °C / Sealed tube 3.1: hydrogenchloride / methanol; 1,4-dioxane / 0.5 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With hydrogenchloride In 1,4-dioxane; methanol at 65℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 5 h / 0 - 20 °C 2.1: potassium carbonate; caesium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 16 h / 100 °C / Inert atmosphere 3.1: ammonium formate; palladium 10% on activated carbon / ethanol / 5 h / 20 °C 4.1: triethylamine / dichloromethane / 16 h / 0 - 20 °C 5.1: acetic anhydride; isopentyl nitrite; potassium acetate / toluene / 16 h / 80 °C 6.1: ammonia / methanol / 2 h / 20 °C 7.1: N-Methyldicyclohexylamine / tetrahydrofuran / 16 h / 20 °C 8.1: n-butyllithium / tetrahydrofuran / 0.33 h / -78 - -20 °C 8.2: 5 h / -78 - 20 °C 9.1: triethylamine / dimethyl sulfoxide / 2 h / 100 °C / Sealed tube 10.1: hydrogenchloride / methanol; 1,4-dioxane / 0.5 h / 65 °C |