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CAS No. : | 90729-43-4 | MDL No. : | MFCD00865661 |
Formula : | C32H39NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MJJALKDDGIKVBE-UHFFFAOYSA-N |
M.W : | 469.66 | Pubchem ID : | 3191 |
Synonyms : |
LAS-W 090;RP64305;Kestin;Evastel;Busidril;Bactil;Ebatrol;Aleva;Ebastel;Kestine;Brand name: Evastin
|
Num. heavy atoms : | 35 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.41 |
Num. rotatable bonds : | 10 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 149.12 |
TPSA : | 29.54 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -4.05 cm/s |
Log Po/w (iLOGP) : | 5.01 |
Log Po/w (XLOGP3) : | 7.2 |
Log Po/w (WLOGP) : | 6.51 |
Log Po/w (MLOGP) : | 4.73 |
Log Po/w (SILICOS-IT) : | 7.33 |
Consensus Log Po/w : | 6.16 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -7.01 |
Solubility : | 0.0000461 mg/ml ; 0.0000000981 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -7.64 |
Solubility : | 0.0000107 mg/ml ; 0.0000000228 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -9.94 |
Solubility : | 0.0000000537 mg/ml ; 0.0000000001 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 4.16 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P270-P273-P301+P312-P330 | UN#: | N/A |
Hazard Statements: | H302-H413 | 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 |
---|---|---|
55.27% | With potassium carbonate In 4-methyl-2-pentanone at 105 - 116℃; for 2.25 h; Inert atmosphere | 2.2 Synthesis of I" from Benzyhydryloxypiperidine toluenesulfonate Benzhydryloxypiperidine toluenesulfonate (1 1.44 g, 0.025 mol), 4'-tert-butyl-4- chlorobutyrophenone (10.15 g, 170 mol percent), potassium carbonate (8.47 g, 245 mol percent) and methyl isobutyl ketone (18.3 g) were placed in a round bottom flask and a further 20 mL of methyl isobutyl ketone were added and the reaction mixture was placed under a nitrogen atmosphere. The mixture was heated to between 1 15-116°C and vigorous evolution of gas was noted. The reaction mixture was heated at reflux temperature (105-1 15 °C) for 2 h and 15 minutes and then cooled to 30 °C internal temperature. Water (50 mL) was added and the phases were separated. The organic phase was washed with water (3x 50 mL) and then concentrated under reduced pressure (45 °C, 8 mbar) to give the crude product. The crude material was suspended in ethanol (30 mL, 96percent denatured with toluene) and the mixture was heated to reflux (82°C). The resulting solution was stirred at reflux temperature for 15 minutes and then cooled to 30 °C (the solution was seeded with a small quantity of I") and stirred at 30 °C for 30 minutes. The resulting suspension was then cooled to 2-3 °C and stirred at this temperature for 1 h. The product was isolated by filtration and washed with ethanol (3 x 5 niL). The moist product was dried in a vacuum oven (45°C) to give pure I" (6.49 g, 55.27percent). HPLC purity (areapercent): 99.27percent RRT 0.62 0.38percent. |
55.27% | With potassium carbonate In 4-methyl-2-pentanone at 105 - 116℃; Inert atmosphere | 2.2 Synthesis of I' from Benzyhydryloxypiperidine toluenesulfonate Benzhydryloxypiperidine toluenesulfonate (11.44 g, 0.025 mol), 4'-tert-butyl-4-chlorobutyrophenone (10.15 g, 170 mol percent), potassium carbonate (8.47 g, 245 mol percent) and methyl isobutyl ketone (18.3 g) were placed in a round bottom flask and a further 20 mL of methyl isobutyl ketone were added and the reaction mixture was placed under a nitrogen atmosphere. The mixture was heated to between 115-116°C and vigorous evolution of gas was noted. The reaction mixture was heated at reflux temperature (105-115 °C) for 2 h and 15 minutes and then cooled to 30 °C internal temperature. Water (50 mL) was added and the phases were separated. The organic phase was washed with water (3x 50 mL) and then concentrated under reduced pressure (45 °C, 8 mbar) to give the crude product. The crude material was suspended in ethanol (30 mL, 96percent denatured with toluene) and the mixture was heated to reflux (82°C). The resulting solution was stirred at reflux temperature for 15 minutes and then cooled to 30 °C (the solution was seeded with a small quantity of I') and stirred at 30 °C for 30 minutes. The resulting suspension was then cooled to 2-3°C and stirred at this temperature for 1 h. The product was isolated by filtration and washed with ethanol (3 x 5 mL). The moist product was dried in a vacuum oven (45°C) to give pure I' (6.49 g, 55.27percent). HPLC purity (areapercent): 99.27percent RRT 0.62 0.38percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.43% | With sodium hydrogencarbonate In toluene for 12 h; Reflux | Example 3. Preparation of discoloured l-[4-(l,l-dimethyIethyl)phenyI]-4-[4- (diphenylmethoxy)-l-piperidinyl]-l-butanone I"A toluene solution of 4-benzhydryloxypiperidine (73.27 g of the toluene solution contained 26.74 g of 4-benzhydryloxypiperidine), sodium hydrogen carbonate (14.28 g), DMF (5.3 mL) and 4'-tert-butyl-4-chloro-butyrophenone (28.65 g) were heated to reflux temperature. The reaction mixture was heated at reflux temperature for 12 h, to produce a solution of I" of 84.3percent) purity on the basis of HPLC area-percent and then cooled to room temperature. The orange reaction mixture was washed with water (3 x 100 mL) and the organic phase wasconcentrated under reduced pressure. Ethanol (110 mL) was added to the residue and the mixture was heated to reflux. The hot solution was filtered and the filtrate was cooled to 2 °C. The product was isolated by filtration and washed with ethanol (5 x 20 mL). The product was dried in a vacuum oven for several hours to afford the title compound (31.2 g, 66.43 percent) as a beige solid (commercial I" is white and specifications (such as those found in the European Pharmacopoeia) require a white to almost white crystalline substance). HPLC purity 99.77 percent, significant impurities at relative retention times 0.05 and 0.19 were observed and had HPLC area-percent of 0.04 and 0.06percent>. Discolouration was also sometimes observed when other solvents, including methyl isobutyl ketone were used, but was able to be efficiently suppressed when air was excluded from the reaction mixture, or was able to be efficiently suppressed when an adequate purification procedure by salt formation/neutralization, alternatively or optionally in combination with recrystallization, was used. |