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CAS No. : | 1260907-17-2 | MDL No. : | MFCD22417091 |
Formula : | C22H22ClN5O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AAAQFGUYHFJNHI-SFHVURJKSA-N |
M.W : | 423.90 | Pubchem ID : | 46943432 |
Synonyms : |
I-BET-762;GSK525762;GSK525762A
|
Num. heavy atoms : | 30 |
Num. arom. heavy atoms : | 17 |
Fraction Csp3 : | 0.27 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 119.37 |
TPSA : | 81.4 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.86 cm/s |
Log Po/w (iLOGP) : | 3.18 |
Log Po/w (XLOGP3) : | 2.85 |
Log Po/w (WLOGP) : | 2.95 |
Log Po/w (MLOGP) : | 2.44 |
Log Po/w (SILICOS-IT) : | 4.2 |
Consensus Log Po/w : | 3.12 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.29 |
Solubility : | 0.0219 mg/ml ; 0.0000516 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.22 |
Solubility : | 0.0257 mg/ml ; 0.0000605 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -7.65 |
Solubility : | 0.0000094 mg/ml ; 0.0000000222 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.29 |
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 |
---|---|---|
47% | Stage #1: With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 20℃; for 3 h; Stage #2: for 48 h; |
Example 1 : 2-[(4S)-6-(4-Chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3- To a solution of [(4S)-6-(4-Chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1 .2.4]triazolo[4,3- a][1 ,4]benzodiazepin-4-yl]acetic acid (for a preparation see Intermediate 1 )(16.0 g, 40 mmol) in THF at RT was added DIEA (14 mL, 80 mmol) followed by HATU (30.4 g, 80 mmol). The reaction mixture was stirred for 3h at this temperature and ethylamine (40 mL, 2M in THF, 80 mmol) was added. The mixture was stirred for 48h before being concentrated under reduced pressure. The crude material was suspended in water and extracted with DCM. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude solid was purified by chromatography on Si02 (DCM/MeOH 95/5) and the resulting solid recrystallised in MeCN. The solid was then dissolved in DCM and precipited with /'-Pr20 to give the title compound (8 g, 47percent yield) as a white solid. Rf = 0.48 (DCM/MeOH : 90/10). Mp >140 °C (becomes gummy). 1H NMR (300 MHz, CDCI3) 7.53-7.47 (m, 2H), 7.39 (d, J = 8.9 Hz, 1 H), 7.37-7.31 (m, 2H), 7.20 (dd, J = 2.9 and 8.9 Hz, 1 H), 6.86 (d, J = 2.9 Hz, 1 H), 6.40 (m, 1 H), 4.62 (m, 1 H), 3.80 (s, 3H), 3.51 (dd, J = 7.3 and 14.1 Hz, 1 H), 3.46-3.21 (m, 3H), 2.62 (s, 3H), 1.19 (t, J = 7.3 Hz, 3H). LC/MS : m/z 424 [M(35CI)+H]+, Rt 2.33 min. |
47% | Stage #1: With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 20℃; for 3 h; Stage #2: for 48 h; |
Example 1 : 2-r(4S)-6-(4-Chlorophenyl)-1 -methyl-8-(methyloxy)-4H-ri ,2,41triazolor4,3- alH ,41benzodiazepin-4-yll-/V-ethylacetamide To a solution of Intermediate 2 (16.0 g, 40 mmol) in THF at RT was added DIEA (14 mL, 80 mmol) followed by HATU (30.4 g, 80 mmol). The reaction mixture was stirred for 3h at this temperature and ethylamine (40 mL, 2M in THF, 80 mmol) was added. The mixture was stirred for 48h before being concentrated under reduced pressure. The crude material was suspended in water and extracted with DCM. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude solid was purified by chromatography on Si02 (DCM/MeOH 95/5) and the resulting solid recrystallised in MeCN. The solid was then dissolved in DCM and precipited with /'-Pr20 to give the title compound (8 g, 47percent yield) as a white solid. Rf = 0.48 (DCM/MeOH : 90/10). Mp >140 °C (becomes gummy). 1H RMN (300 MHz, CDCIs) 57.53-7.47 (m, 2H), 7.39 (d, J = 8.9 Hz, 1 H), 7.37-7.31 (m, 2H), 7.20 (dd, J = 2.9 and 8.9 Hz, 1 H), 6.86 (d, J = 2.9 Hz, 1 H), 6.40 (m, 1 H), 4.62 (m, 1 H), 3.80 (s, 3H), 3.51 (dd, J = 7.3 and 14.1 Hz, 1 H), 3.46-3.21 (m, 3H), 2.62 (s, 3H), 1 .19 (t, J = 7.3 Hz, 3H). LC/MS : m/z 424 [M(35CI)+H]+, Rt 2.33 min. |
47% | Stage #1: With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 20℃; for 3 h; Stage #2: for 48 h; |
EXAMPLE 1 2-[(4S)-6-(4-Chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide To a solution of [(4S)-6-(4-Chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid (for a preparation see Intermediate 1) (16.0 g, 40 mmol) in THF at RT was added DIEA (14 mL, 80 mmol) followed by HATU (30.4 g, 80 mmol). The reaction mixture was stirred for 3 h at this temperature and ethylamine (40 mL, 2M in THF, 80 mmol) was added. The mixture was stirred for 48 h before being concentrated under reduced pressure. The crude material was suspended in water and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude solid was purified by chromatography on SiO2 (DCM/MeOH 95/5) and the resulting solid recrystallised in MeCN. The solid was then dissolved in DCM and precipited with i-Pr2O to give the title compound (8 g, 47percent yield) as a white solid.Rf=0.48 (DCM/MeOH:90/10). Mp>140° C. (becomes gummy). 1H NMR (300 MHz, CDCl3) δ7.53-7.47 (m, 2H), 7.39 (d, J=8.9 Hz, 1H), 7.37-7.31 (m, 2H), 7.20 (dd, J=2.9 and 8.9 Hz, 1H), 6.86 (d, J=2.9 Hz, 1H), 6.40 (m, 1H), 4.62 (m, 1H), 3.80 (s, 3H), 3.51 (dd, J=7.3 and 14.1 Hz, 1H), 3.46-3.21 (m, 3H), 2.62 (s, 3H), 1.19 (t, J=7.3 Hz, 3H). LC/MS: m/z 424 [M(35Cl)+H]+, Rt 2.33 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With DIEA; HBTU In tetrahydrofuran; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; acetonitrile | Example 2 2-[(4S)-6-(4-Chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide To a solution of Intermediate 1 (4.5 g, 11.4 mmol) in THF at r.t. was added DIEA (4 mL, 22.7 mmol) followed by HBTU (8.6 g, 22.7 mmol). The reaction mixture was stirred for 3 h at this temperature and ethylamine (11.3 mL, 2M in THF, 22.7 mmol) was added dropwise. The mixture was stirred overnight before being concentrated under reduced pressure. The crude material was dissolved in DCM and washed successively with water, 1N NaOH and 1N HCl. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude solid was recrystallised in MeCN to give the title compound (4.1 g, 85percent yield) as a white solid. Rf=0.48 (DCM/MeOH:90/10). Mp 140-145° C. (becomes gummy). HRMS (M+H)+ calculated for C22H23ClN5O2 424.1540. found 424.1525. Chiral HPLC: column: chiralpak AD 250*4.6 mm 10 μm; mobile phase: 60/40, EtOH/Hexane; Flow rate: 1.0 mL/min; UV wavelength: 210 and 254 nm. |