Structure of 148366-28-3
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CAS No. : | 148366-28-3 |
Formula : | C10H10BrNO |
M.W : | 240.10 |
SMILES Code : | OCCN1C=CC2=C1C=CC(Br)=C2 |
MDL No. : | MFCD20486677 |
InChI Key : | VQBGZOPEJRCONC-UHFFFAOYSA-N |
Pubchem ID : | 10657650 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 56.87 |
TPSA ? Topological Polar Surface Area: Calculated from |
25.16 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.32 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.94 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.4 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.96 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.3 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.18 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.93 |
Solubility | 0.281 mg/ml ; 0.00117 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.09 |
Solubility | 1.94 mg/ml ; 0.00808 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.55 |
Solubility | 0.0675 mg/ml ; 0.000281 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.39 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.5 |
* 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 |
---|---|---|
51.66% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere; | To a stirred solution of LAH (0.67 g, 3.0 eq) dissolved in THE (10 mL) at 0CC, intermediate 28a (1.7 g, 6.0 mmol) in THE (10 mL) was added under argonatmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuo to yield title compound (0.75 g, 51 .66%) as a yellow gummy material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaH; phosphoric acid; In tetrahydrofuran; N,N-dimethyl-formamide; | 1-(2-Hydroxyethyl)-5-bromoindole: Under a N2 atmosphere, 2-bromoethanol (17.6 g, 141 mmol) and 2-methoxypropene (10.1 g, 141 mmol) were stirred in 71 mL of THF at 0 C. for 30 minutes The resulting solution was added to a stirring mixture of 5-bromoindole (22.83 g, 116 mmol) and 60% NaH (4.62 g, 193 mmol) in 40 mL of DMF and 60 mL of THF. The solution was stirred at ambient temperature for 4 hours. The reaction mixture was worked up by quenching the excess of NaH with water and removing the aqueous layer. The organic layer was vigorously stirred with 200 mL of 2% aqueous phosphoric acid for 5 hours when the layers were separated. The organic layer was washed with water (2*200 mL) and the solvent removed. The residue was purified by column chromatography (30:70 EtOAc-Hex) to give 17 g of 1-(2-hydroxylethyl)-5-bromoindole. Tris[1-(2-t-Butyldimethylsilyloxyethyl)indol-5-yl]bismuthane: | |
With NaH; phosphoric acid; In tetrahydrofuran; N,N-dimethyl-formamide; | 1-(2-Hydroxyethyl)-5-bromoindole: Under a N2 atmosphere, 2-bromoethanol (17.6 g, 141 mmol) and 2-methoxypropene (10.1 g, 141 mmol) were stirred in 71 mL of THF at 0 C. for 30 minutes The resulting solution was added to a stirring mixture of 5-bromoindole (22.83 g, 116 mmol) and 60% NaH (4.62 g, 193 mmol) in 40 mL of DMF and 60 mL of THF. The solution was stirred at ambient temperature for 4 hours. The reaction mixture was worked up by quenching the excess of NaH with water and removing the aqueous layer. The organic layer was vigorously stirred with 200 mL of 2% aqueous phosphoric acid for 5 hours when the layers were separated. The organic layer was washed with water (2*200 mL) and the solvent removed. The residue was purified by column chromatography (30:70 EtOAc-Hex) to give 17 g of 1-(2-hydroxylethyl)-5-bromoindole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | STEP 7B 1-(2-t-Butyldimethylsilyloxyethyl)-5-bromoindole A solution of 1(2-hydroxyethyl)-5-bromoindole (6 gm, 0.025 mol), t-butyldimethylsilyl chloride (4.5 gm, 0.03 mol) and triethylamine (4.2 ml, 0.03 mol) in CH2 Cl2 (60 ml) was stirred for 12 hours at room temperature. The reaction mixture was then washed twice with H2 O, dried over Na2 SO4, filtered and concentrated in vacuo to provide the title compound as a yellow oil. 1 H NMR was consistent with the desired structure. | |
With triethylamine; In dichloromethane; | STEP 1B 1-(2-t-Butyldimethylsilyloxyethyl)-5-bromoindole A solution of 1(2-hydroxyethyl)-5-bromoindole (6 gm, 0.025 mol), t-butyldimethylsilyl chloride (4.5 gm, 0.03 mol) and triethylamine (4.2 ml, 0.03 mol) in CH2 Cl2 (60 ml) was stirred for 12 hours at room temperature. The reaction mixture was then washed twice with H2 O, dried over Na2 SO4, filtered and concentrated in vacuo to provide the title compound as a yellow oil. 1 H NMR was consistent with the desired structure. | |
With triethylamine; In dichloromethane; | STEP 25B 1-(2-t-Butyldimethylsilyloxyethyl)-5-bromoindole A solution of 1(2-hydroxyethyl)-5-bromoindole (6 gm, 0.025 mol), t-butyldimethylsilyl chloride (4.5 gm, 0.03 mol) and triethylamine (4.2 ml, 0.03 mol) in CH2 Cl2 (60 ml) was stirred for 12 hours at room temperature. The reaction mixture was then washed twice with H2 O, dried over Na2 SO4, filtered and concentrated in vacuo to provide the title compound as a yellow oil. 1 H NMR was consistent with the desired structure. |
With triethylamine; In dichloromethane; | STEP 25B 1-(2-t-Butyldimethylsilyloxyethyl)-5-bromoindole A solution of 1(2-hydroxyethyl)-5-bromoindole (6 gm, 0.025 mol), t-butyldimethylsilyl chloride (4.5 gm, 0.03 mol) and triethylamine (4.2 ml, 0.03 mol) in CH2 Cl2 (60 ml) was stirred for 12 hours at room temperature. The reaction mixture was then washed twice with H2 O, dried over Na2 SO4, filtered and concentrated in vacuo to provide the title compound as a yellow oil. 1 H NMR was consistent with the desired structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In dimethyl sulfoxide; | STEP 7A 1-(2-Hydroxyethyl)-5-bromoindole A mixture of NaOH (4.4 gm, 0.011 mol) in DMSO (175 ml) was stirred at 100 C. for 5 hours at which time it was cooled to 20 C. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo whereupon crystallization took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm). | |
With sodium hydroxide; In dimethyl sulfoxide; | STEP 1A 1-(2-Hydroxyethyl)-5-bromoindole A mixture of NaOH (4.4 gm, 0.011 tool) in DMSO (175 ml) was stirred at 100 C. for 5 hours at which time it was cooled to 20 C. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo whereupon crystallization took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm). | |
With sodium hydroxide; In dimethyl sulfoxide; | STEP 25A 1-(2-Hydroxyethyl)-5-bromoindole A mixture of NaOH (4.4 gm, 0.011 mol) in DMSO (175 ml) was stirred at 100 C. for 5 hours at which time it was cooled to 20 C. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo whereupon crystallization took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm). |
With sodium hydroxide; In dimethyl sulfoxide; | STEP 25A 1-(2-Hydroxyethyl)-5-bromoindole A mixture of NaOH (4.4 gm, 0.011 mol) in DMSO (175 ml) was stirred at 100 C. for 5 hours at which time it was cooled to 20 C. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo whereupon crystallization took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisobutylaluminium hydride; In tetrahydrofuran; hexane; at 0 - 20℃; | Step B 2-(5-bromo-1H-indol-1-yl)ethanol. DIBAL-H (1 M in hexanes) (6.1 mL, 6.1 mmol) was added to a 0 C. solution of methyl (5-bromo-1H-indol-1-yl)acetate (660 mg, 2.46 mmol) in anhydrous THF (12 mL). The reaction was warmed to ambient temperature and maintained for 1 h. The reaction mixture was poured into saturated aqueous Rochelle's salt (25 mL) and Et2O (25 mL). The mixture was stirred vigorously for 30 min. The layers were separated and the aqueous phase was extracted with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to afford the desired product as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; N,N-dimethyl-formamide;tetrakis(triphenylphosphine) palladium(0); In water; at 150℃; for 0.133333h;Microwave irradiation; | Step C Methyl 5-[(6-chloro-5-[1-(2-hydroxyethyl)-1H-indol-5-yl]-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoate. A microwave vial was charged with Intermediate 13 (170 mg, 0.297 mmol), <strong>[148366-28-3]2-(5-bromo-1H-indol-1-yl)ethanol</strong> (100 mg, 0.415 mmol), Pd(PPh3)4 (51 mg, 0.045 mmol), DMF (4.3 mL), and K2CO3 (1 M in water) (0.89 mL). The reaction was heated at 150 C. under microwave irradiation for 8 min. The reaction was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. Chromatography over silica eluting with 50% EtOAc/hexanes afforded the desired product as a viscous, yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.20% | With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; N,N-dimethyl-formamide; for 0.666667h;Inert atmosphere; Microwave irradiation; | Potassium phosphate (0.64 g, 3.0 eq) was added to a solution of intermediate 3 (0.25g, 1.0 mmol) and intermediate 28 (0.35 g, 1.2 mmol) in a mixture of 1,4-dioxane (4mL), DMF (4 mL) and water (1 mL). After degasified with nitrogen, Pd(PPh3)4 (0.058 g, 0.05 mmol) was added and irradiated under microwave for 40 mm. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous Na2SO4. The organic layer wasconcentrated under vacuo. The crude product was purified to yield the title compound(0.05 g, 15.20%) as a colourless oily. LCMS: (M+H) = 327.0 ; 1H NMR: (DMSO-d6,300MHz) 6 10.52 (5, 1H), 7.50-7.52 (d, 2H), 7.39-7.40 (d, 1H), 7.24 (5, 1H), 7.10-7.13 (d, 1H), 6.92 (5, 1H), 6.44-6.45 (d, 1H), 4.89-4.92 (t, 1H), 4.22-4.26 (t, 2H),3.71 -3.76 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | General procedure: A solution of 5-bromo-lH-indazole (10 g; commercial) in DMF (330 mL) was cooled to 0C and treated portion wise with NaH (in 60% mineral oil; 2.41 g). The reaction mixture was allowed to reach rt, further stirred at rt for 1 h, treated with ethylene carbonate (17.9 g) and heated for 3 h at 80C. The reaction mixture was concentrated under reduced pressure, diluted with 10% aq. NaHS04 solution (150 mL) and extracted with EA (2 x 50 mL). The combined org. layers were washed with brine, dried over Na2S04, concentrated under reduced pressure and purified by CC (Hept-EA) to afford the title compound, contaminated with ethylene carbonate, as a yellow oil (10.71 g). XH NMR (d6-DMSO) delta: 8.02 (s, 1H); 7.96 (d, J = 1.5 Hz, 1H); 7.63 (dd, J = 1.8, 8.9 Hz, 1H); 7.46 (dd, J = 1.8, 8.9 Hz, 1H); 4.82 (t, J = 5.4 Hz, 1H); 4.41 (t, J = 5.5 Hz, 2H); 3.77 (q, J = 5.4 Hz, 2H). MS (ESI, m/z): 243.0 [M+H+] for C9H9N2OBr; tR = 0.68 min. |
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