Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 1627856-64-7 | MDL No. : | MFCD30747847 |
Formula : | C22H21F4N3O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IDXKJSSOUXWLDB-UHFFFAOYSA-N |
M.W : | 467.41 | Pubchem ID : | 78427026 |
Synonyms : |
RET KInase inhibitor 1;RET Kinase Inhibitor 1
|
Num. heavy atoms : | 33 |
Num. arom. heavy atoms : | 17 |
Fraction Csp3 : | 0.32 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 9.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 112.08 |
TPSA : | 97.22 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.75 cm/s |
Log Po/w (iLOGP) : | 3.36 |
Log Po/w (XLOGP3) : | 3.38 |
Log Po/w (WLOGP) : | 6.08 |
Log Po/w (MLOGP) : | 3.06 |
Log Po/w (SILICOS-IT) : | 5.79 |
Consensus Log Po/w : | 4.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.65 |
Solubility : | 0.0104 mg/ml ; 0.0000222 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.1 |
Solubility : | 0.00371 mg/ml ; 0.00000794 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -8.59 |
Solubility : | 0.0000012 mg/ml ; 0.0000000026 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.65 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-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 |
---|---|---|
77% | With trifluoroacetic acid In dichloromethane at 25℃; for 2h; | 30.4 2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide To a suspension of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5- (l, l, l-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (100 g, 170 mmol) in DCM (1 L) was added TFA (80 mL, 1077 mmol) dropwise. The mixture was stirred at 25 °C for 2 h. The mixture was then concentrated. To the residue was added H20 (500 mL) dropwise and then neutralized with saturated Na2CC>3 solution to adjust pH = 7.5. The precipitate was filtered, washed with H20 (350 mL x 3) and dried in vacuo. To the solid was added PE/EA (3: 1, v/v, 300 mL) and stirred for 0.5 h. The solid was filtered and washed with PE/EA (3: 1, v/v, 100 mL x 2). The solid was redissolved in DCM/MeOH (20: 1, v/v, 1.5 L) and then concentrated in vacuo to a minimal amount of solvent (about 150 mL). The solid was filtered, washed with CH3CN (50 mL x 2) and dried in vacuo. The residual solid was added to EtOH (2.5 L) and heated to 80 °C. After the solid was dissolved completely, the mixture was concentrated in vacuo to give a white solid of 2-(4-(4-ethoxy-6-oxo- 1 ,6-dihydropyridin-3 -yl)-2-fluorophenyl)-N-(5 -( 1,1, 1 -trifluoro-2- methylpropan-2-yl)isoxazol-3-yl)acetamide (61.4 g, 131 mmol, 77% yield): l NMR (400 MHz, CD3OD) δ 7.40-7.30 (m, 2H), 7.25-7.18 (m, 2H), 6.88 (s, 1H), 5.98 (s, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.37 (t, J= 7.2 Hz, 3H); ES-LCMS m/z: 468 (M+H). |
77% | With trifluoroacetic acid In dichloromethane at 25℃; for 2h; | 1.13 Preparation of:2-(4-(4-Ethoxy-6-oxo- 1 ,6-dihydropyridin-3 -yl)-2-fluorophenyl)-N-(5-(1, 1,1 -trifluoro-2-methylpropan-2-yl)i soxazol-3 -yl)acetamide (Compound A)Step 13: 2-(4-(4-Ethoxy-6-oxo- 1, 6-dihydropyridin-3 -yl)-2-fluorophenyl)-N-(5 - (1,1,1 -trifluoro-2-methylpropan-2-yl)i soxazol-3 -yl)acetamide To a suspension of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3 -yl)-2-fluorophenyl)-N-(5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)i soxazol-3 -yl)acetamide (100 g,170 mmol) in DCM (1 L) was added TFA (80 mL, 1077 mmol) dropwise. The mixturewas stirred at 25 °C for 2 h. The mixture was then concentrated. To the residue was addedH20 (500 mL) dropwise and then neutralized with saturated Na2CO3 solution to adjust pH= 7.5. The precipitate was filtered, washed with H20 (350 mL x 3) and dried in vacuo. Tothe solid was added PE/EA (3:1, v/v, 300 mL) and stirred for 0.5 h. The solid was filteredand washed with PE/EA (3:1, v/v, 100 mL x 2). The solid was redissolved in DCM/MeOH (20:1, v/v, 1.5 L) and then concentrated in vacuo to a minimal amount of solvent (about 150 mL). The solid was filtered, washed with MeCN (50 mL x 2) and dried in vacuo. The residual solid was added to EtOH (2.5 L) and heated to 80 °C. After the solid wasdissolved completely, the mixture was concentrated in vacuo to give a white solid of 2-(4- (4-ethoxy-6-oxo- 1, 6-dihydropyridin-3 -yl)-2-fluorophenyl)-N-(5 -(1,1,1 -trifluoro-2- methylpropan-2-yl)isoxazol-3-yl)acetamide (61.4 g, 131 mmol, 77%): ‘H NMR (400 MFIz, CD3OD) ö 7.40-7.30 (m, 2H), 7.25-7.18 (m, 2H), 6.88 (s, 1H), 5.98 (s, 1H), 4.11 (q, J= 7.2 Hz, 2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.37 (t, J= 7.2 Hz, 3H); ES-LCMS m/z: 468 (M+H). |
77% | With trifluoroacetic acid In dichloromethane at 25℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: ethanol / 12 h / 60 °C / Inert atmosphere 2: sodium hydroxide; methanol / 12 h / 100 °C 3: sulfuric acid / Reflux 4: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 4 h / Inert atmosphere; Reflux 5: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / Inert atmosphere; Reflux 6: lithium hydroxide monohydrate; water / tetrahydrofuran / 10 h / 60 °C 7: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 8: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 8 steps 1: ethanol / 12 h / 60 °C / Inert atmosphere 2: sodium hydroxide; methanol / 20 - 80 °C / Inert atmosphere 3: sulfuric acid / Reflux 4: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 4 h / Reflux; Inert atmosphere 5: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / water; 1,4-dioxane / 2 h / Inert atmosphere; Reflux 6: lithium hydroxide monohydrate; water / 60 °C 7: pyridine; propylphosphonic anhydride / 1 h / 25 °C 8: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 8 steps 1: ethanol / 12 h / 60 °C / Inert atmosphere 2: sodium hydroxide; methanol / 5 h / 80 °C / Inert atmosphere 3: sulfuric acid / water / Reflux 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 4 h / Inert atmosphere; Reflux 5: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / Inert atmosphere; Reflux 6: water; lithium hydroxide monohydrate / tetrahydrofuran / 10 h / 60 °C 7: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 8: trifluoroacetic acid / dichloromethane / 2 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol; water / 15 h / 0 - 65 °C / pH 7.5 1.2: 2 h / pH 1 / Reflux 2.1: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 3.1: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / water; methanol / 15 h / 0 - 65 °C / pH 7.5 2: pyridine; propylphosphonic anhydride / 1 h / 25 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / water; methanol / 15 h / 65 °C / pH 7.5 2: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 2 steps 1: pyridine; propylphosphonic anhydride / 1 h / 25 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 2 steps 1: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: tetrahydrofuran / 10 h / 25 °C 2: sulfuric acid; N-Bromosuccinimide / 10 h / 60 °C 3: potassium hydroxide; 18-crown-6 ether / toluene / 2 h / 120 °C 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / Inert atmosphere; Reflux 5: lithium hydroxide monohydrate; water / tetrahydrofuran / 10 h / 60 °C 6: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 7: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 7 steps 1: tetrahydrofuran / 12 h / 0 - 25 °C / Large scale 2: sulfuric acid; N-Bromosuccinimide / 3 h / 80 °C 3: potassium hydroxide; 18-crown-6 ether / toluene / 2 h / 120 °C 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / water; 1,4-dioxane / 2 h / Inert atmosphere; Reflux 5: lithium hydroxide monohydrate; water / 60 °C 6: pyridine; propylphosphonic anhydride / 1 h / 25 °C 7: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 7 steps 1: tetrahydrofuran / 12 h / 0 - 25 °C 2: sulfuric acid; N-Bromosuccinimide / 3 h / 80 °C 3: 18-crown-6 ether; potassium hydroxide / toluene / 2 h / 120 °C 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / Inert atmosphere; Reflux 5: water; lithium hydroxide monohydrate / tetrahydrofuran / 10 h / 60 °C 6: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 7: trifluoroacetic acid / dichloromethane / 2 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium hydroxide; 18-crown-6 ether / toluene / 2 h / 120 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / Inert atmosphere; Reflux 3: lithium hydroxide monohydrate; water / tetrahydrofuran / 10 h / 60 °C 4: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 5: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 5 steps 1: potassium hydroxide; 18-crown-6 ether / toluene / 2 h / 120 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / water; 1,4-dioxane / 2 h / Inert atmosphere; Reflux 3: lithium hydroxide monohydrate; water / 60 °C 4: pyridine; propylphosphonic anhydride / 1 h / 25 °C 5: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 5 steps 1: 18-crown-6 ether; potassium hydroxide / toluene / 2 h / 120 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / Inert atmosphere; Reflux 3: water; lithium hydroxide monohydrate / tetrahydrofuran / 10 h / 60 °C 4: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 5: trifluoroacetic acid / dichloromethane / 2 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / Inert atmosphere; Reflux 2: lithium hydroxide monohydrate; water / tetrahydrofuran / 10 h / 60 °C 3: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / water; 1,4-dioxane / 2 h / Inert atmosphere; Reflux 2: lithium hydroxide monohydrate; water / 60 °C 3: pyridine; propylphosphonic anhydride / 1 h / 25 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / Inert atmosphere; Reflux 2: water; lithium hydroxide monohydrate / tetrahydrofuran / 10 h / 60 °C 3: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / Inert atmosphere; Reflux 2: lithium hydroxide monohydrate; water / tetrahydrofuran / 10 h / 60 °C 3: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / water; 1,4-dioxane / 2 h / Inert atmosphere; Reflux 2: lithium hydroxide monohydrate; water / 60 °C 3: pyridine; propylphosphonic anhydride / 1 h / 25 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 2 h / Inert atmosphere; Reflux 2: water; lithium hydroxide monohydrate / tetrahydrofuran / 10 h / 60 °C 3: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: lithium hydroxide monohydrate; water / tetrahydrofuran / 10 h / 60 °C 2: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 3 steps 1: lithium hydroxide monohydrate; water / 60 °C 2: pyridine; propylphosphonic anhydride / 1 h / 25 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 25 °C | ||
Multi-step reaction with 3 steps 1: water; lithium hydroxide monohydrate / tetrahydrofuran / 10 h / 60 °C 2: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1 h / 25 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 25 °C |