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CAS No. : | 1446712-19-1 | MDL No. : | MFCD28975329 |
Formula : | C21H17F3O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OXHMDMVBLQNMGP-UHFFFAOYSA-N |
M.W : | 406.35 | Pubchem ID : | 71621167 |
Synonyms : |
|
Num. heavy atoms : | 29 |
Num. arom. heavy atoms : | 16 |
Fraction Csp3 : | 0.19 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 102.71 |
TPSA : | 90.9 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.74 cm/s |
Log Po/w (iLOGP) : | 3.26 |
Log Po/w (XLOGP3) : | 5.69 |
Log Po/w (WLOGP) : | 6.26 |
Log Po/w (MLOGP) : | 2.45 |
Log Po/w (SILICOS-IT) : | 5.3 |
Consensus Log Po/w : | 4.59 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -6.09 |
Solubility : | 0.000332 mg/ml ; 0.000000816 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -7.36 |
Solubility : | 0.0000176 mg/ml ; 0.0000000432 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -6.48 |
Solubility : | 0.000136 mg/ml ; 0.000000334 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.81 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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: zinc(II) chloride; hydrogenchloride / diethyl ether / 5 h / Cooling with ice 2: pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene / 75 °C 3: boron tribromide / dichloromethane / 4 h / 0 - 25 °C 4: caesium carbonate / water / 25 °C / Cooling with ice | ||
Multi-step reaction with 4 steps 1.1: zinc(II) chloride; hydrogenchloride / diethyl ether / 5 h / Cooling with ice 1.2: 3 h / Reflux 2.1: pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene / 75 °C 3.1: boron tribromide / dichloromethane / 4 h / 0 - 20 °C 4.1: caesium carbonate / water / 20 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene / 75 °C 2: boron tribromide / dichloromethane / 4 h / 0 - 25 °C 3: caesium carbonate / water / 25 °C / Cooling with ice | ||
Multi-step reaction with 3 steps 1: pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene / 75 °C 2: boron tribromide / dichloromethane / 4 h / 0 - 20 °C 3: caesium carbonate / water / 20 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.5% | With caesium carbonate In water at 25℃; Cooling with ice; | 1.4 Step 4: preparation of 2-(4-trifluoromethylphenyl)-3,5,7-trihydroxy-8-(3-methyl-2-buten-1-yl)-4H-chromen-4-one (compound 1) Step 4: preparation of 2-(4-trifluoromethylphenyl)-3,5,7-trihydroxy-8-(3-methyl-2-buten-1-yl)-4H-chromen-4-one (compound 1) Compound 2-(4-trifluomethylphenyl)-3,5,7-trihydroxy-4H-chrom-4-one (3.38g, 10mmol) and cesium carbonate (33g, 100mmol) were dissolved into 100mL water, and prenyl bromide (1.9g, 10mmol) was dripped into the solution under icewater bath condition. After that, the solution was kept overnight under room temperature, and pH was adjusted about 6 with 2N hydrochloride. The solution was extracted with ethyl acetate for 2 times. Organic phases were combined, washed with saturated sodium chloride aqueous solution once and dried with anhydrous sodium sulfate. After filteration, crude product was eluted with ethyl actate/petroleum (1:25) through silica gel column. Yellow target compound (508mg, yield 12.5%) was obtained. 1H NMR(300 MHz, DMSO-d6): δ=12.20 (s, 1H), 10.87 (brs, 1H), 10.07 (brs, 1H), 8.35 (d, 2H, J=8.1Hz), 7.94 (d, 2H, J=7.7Hz), 6.33 (s, 1H), 5.19 (t, 1H, J=5.4Hz), 3.45 (d, 2H, J=6.0Hz), 1.75 (s, 3H), 1.64 (s, 3H); LC-MS (ESI, m/z): 407.0[M+H]-. |
12.5% | With caesium carbonate In water at 20℃; Cooling with ice; | 1.4 Step 4: preparation of 2-(4-trifluoromethylphenyl)-3,5,7-trihydroxy-8-(3-methyl-2-buten-1-yl)-4H-chromen-4-one (compound 1) Compound 2-(4-trifluomethylphenyl)-3,5,7-trihydroxy-4H-chrom-4-one (3.38 g, 10 mmol) and cesium carbonate (33 g, 100 mmol) were dissolved into 100 mL water, and prenyl bromide (1.9 g, 10 mmol) was dripped into the solution under ice water bath condition. After that, the solution was kept overnight under room temperature, and pH was adjusted about 6 with 2N hydrochloride. The solution was extracted with ethyl acetate for 2 times. Organic phases were combined, washed with saturated sodium chloride aqueous solution once and dried with anhydrous sodium sulfate. After filtration, crude product was eluted with ethyl acetate/petroleum (1:25) through silica gel column. Yellow target compound (508 mg, yield 12.5%) was obtained. 1H NMR (300 MHz, DMSO-d6): 8=12.20 (s, 1H), 10.87 (brs, 1H), 10.07 (brs, 1H), 8.35 (d, 2H, J=8.1 Hz), 7.94 (d, 2H, J=7.7 Hz), 6.33 (s, 1H), 5.19 (t, 1H, J=5.4 Hz), 3.45 (d, 2H, J=6.0 Hz), 1.75 (s, 3H), 1.64 (s, 3H); LC-MS (ESI, m/z): 407.0 [M+H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: boron tribromide / dichloromethane / 4 h / 0 - 20 °C 2: caesium carbonate / water / 20 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sulfuric acid In tetrahydrofuran; isopropyl alcohol at 50℃; for 12h; Inert atmosphere; | 1.4 Reaction Under nitrogen protection,The reactor was charged with the compound of formula Va (50 g)Tetrahydrofuran (250 mL) and sulfuric acid in isopropanol (0.4 M, 250 mL).The reaction mixture was heated to 50 ° C,The reaction for 12 hours.Post-processingThe reaction solution was cooled to 30 ° C,Slowly add 8% aqueous potassium bicarbonate solution (250mL) concentrated to about 250mL,Then ethyl acetate (500 mL) and then tetrahydrofuran (100 mL)Liquid separation.The organic phase was washed with 15% aqueous sodium chloride solution (250 mL).The organic phase was concentrated to about 150 mL, ethyl acetate (300 mL) and tetrahydrofuran (60 mL) were added,Concentrated to about 150mL,Ethyl acetate (300 mL) and tetrahydrofuran (60 mL) were further added,Concentrate to about 150mL.Acetonitrile (550 mL) was added at 65-75 ° C,Then cooled to -5 to 5 ° C.Filtration yielded 25.5 g of compound of formula A,Based on the molar amount of compound of formula Va,Yield 62%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: triethylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 2: potassium hydroxide / tetrahydrofuran / 10 h / 30 - 50 °C / Inert atmosphere 3: florisil / toluene / 85 - 95 °C 4: sulfuric acid / tetrahydrofuran; isopropyl alcohol / 12 h / 50 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: triethylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 2: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 2 h / -4 - 0 °C / Inert atmosphere 3: florisil / toluene / 85 - 95 °C 4: sulfuric acid / tetrahydrofuran; isopropyl alcohol / 12 h / 50 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 2: potassium hydroxide / tetrahydrofuran / 10 h / 30 - 50 °C / Inert atmosphere 3: florisil / toluene / 85 - 95 °C 4: sulfuric acid / tetrahydrofuran; isopropyl alcohol / 12 h / 50 °C / Inert atmosphere |
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 2: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 2 h / -4 - 0 °C / Inert atmosphere 3: florisil / toluene / 85 - 95 °C 4: sulfuric acid / tetrahydrofuran; isopropyl alcohol / 12 h / 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 2 h / -4 - 0 °C / Inert atmosphere 2: florisil / toluene / 85 - 95 °C 3: sulfuric acid / tetrahydrofuran; isopropyl alcohol / 12 h / 50 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: potassium hydroxide / tetrahydrofuran / 10 h / 30 - 50 °C / Inert atmosphere 2: florisil / toluene / 85 - 95 °C 3: sulfuric acid / tetrahydrofuran; isopropyl alcohol / 12 h / 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: florisil / toluene / 85 - 95 °C 2: sulfuric acid / tetrahydrofuran; isopropyl alcohol / 12 h / 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76 mg | With triethylamine In dichloromethane at 45℃; for 8h; Inert atmosphere; | 7 Compound P (200 mg, 0.49 mmol) was dissolved in dichloromethane,Under nitrogen, the reagent T bis- (2,5-dioxopyrrol-1-yl) carbonate was added sequentially (126 mg, 0.49 mol), Triethylamine Et3N (50 mg, 0.49 mmol). After mixing, the mixture was stirred at 45 ° C for 8 hours. Reagent V (90 mg, 0.49 mmol)(4- (4-methylpiperazin-1-yl) -piperidine) and triethylamine (50 mg, 0.49 mmol, 1 equiv), Stirring was continued for 12 hours at 45 ° C,The residue obtained by concentration under reduced pressure was separated by a silica gel column,Recovery of raw materials P (50%),The resulting product, 3,5-dihydroxy-8- (3-methyl-2- butenyl) -2- (4- trifluoromethylphenyl) -7- (4H-chromen-4- Ketone) 4- (4-methylpiperazin-1-yl) -piperidine-1-carboxylate (76 mg) was dissolved in 1,4-dioxane, A solution of HCl (4N, 4.9 mmol) in 1,4-dioxane was added and the mixture was stirred for 30 minutes. The solution was then concentrated under reduced pressure to give 3,5-dihydroxy-8- (3-methyl-2- butenyl) - 2- (4-trifluoromethylphenyl) -7- (4H-chromen-4-one) 4- (4-methylpiperazin- 1 -yl) -piperidine- 1 -carboxylate dihydrochloride,Product W (84 mg, 25%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; dmap / tetrachloromethane; dichloromethane / 5 h / 0 °C / Inert atmosphere 2: trimethylsilyl bromide / dichloromethane / 6 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; dmap / tetrachloromethane; dichloromethane / 5 h / 0 °C / Inert atmosphere 2: trimethylsilyl bromide / dichloromethane / 6 h / 0 - 20 °C / Inert atmosphere 3: sodium hydroxide / methanol / 0.33 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 8 h / 45 °C / Inert atmosphere 2: triethylamine / dichloromethane / 12 h / 45 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 8 h / 45 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 12 h / 45 °C 2.2: 0.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; N-ethyl-N,N-diisopropylamine; In tetrachloromethane; dichloromethane; at 0℃; for 5h;Inert atmosphere; | Compound P (300 mg, 0.74 mmol) was dissolved in dichloromethane and cooled to 0 C,Under nitrogen, <strong>[13086-84-5]di-tert-butyl phosphite</strong> (143 mg, 0.74 mmol)CCl4 (1.14 g, 7.4 mmol), DIPEA (191 mg, 1.48 mmol), DMAP (19 mg, 0.15 mol). After mixing, the mixture was stirred at 0 C for 5 hours. The reaction mixture was poured into a saturated aqueous solution of KH2PO4 and extracted with CH 2 Cl 2. The organic phase was dried over MgSO 4 and concentrated under reduced pressure.The resulting residue was separated on a silica gel column to give the product Q (352 mg, 88%). |