Structure of 1219741-54-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 1219741-54-4 |
Formula : | C18H21BO3 |
M.W : | 296.17 |
SMILES Code : | OC1=CC=CC=C1C2=CC=C(B3OC(C)(C)C(C)(C)O3)C=C2 |
MDL No. : | MFCD18383811 |
InChI Key : | KHMILAPQGZSSST-UHFFFAOYSA-N |
Pubchem ID : | 59267813 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 22 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 90.38 |
TPSA ? Topological Polar Surface Area: Calculated from |
38.69 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.18 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.36 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.39 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.96 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.58 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.58 |
Solubility | 0.00777 mg/ml ; 0.0000262 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.7 |
Solubility | 0.00589 mg/ml ; 0.0000199 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.93 |
Solubility | 0.000349 mg/ml ; 0.00000118 mol/l |
Class? Solubility class: Log S scale |
Moderately 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) |
Yes |
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) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.14 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 |
1.0 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) |
3.11 |
* 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 |
---|---|---|
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 150.0℃; for 0.166667h;Microwave irradiation; | Step B 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-2-ol. Potassium acetate (366 mg, 3.73 mmol) and dichloro[1,1'-his (diphenylphosphino) ferrocene]palladium II DCM adduct (25.4 mg, 31 mumol) were added to a solution of 4'-bromobiphenyl-2-ol (310 mg, 1.24 mmol), and bis(pinacolato)diboron (348 mg, 1.37 mmol) in DME (3 mL). The reaction was heated at 150 C. under microwave irradiation for 10 min. Reaction mixture was filtered through a pad of celite and purified by chromatography over silica eluting with 0-50% EtOAc/hexane to furnish the title compound as a white solid. | |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 150.0℃; for 0.166667h;Microwave irradiation; | Potassium acetate (366 mg, 3.73 mmol) and dichloro [1,1 '-bis (diphenylphosphino) ferrocene] palladium II DCM adduct (25.4 mg, 31 mumol) were added to a solution of 4'-bromobiphenyl-2-ol (310mg, 1.24 mmol), and bis(pinacolato)diboron (348 mg, 1.37 mmol) in DME (3 mL). The reaction was heated at 1500C under microwave irradiation for 10 min. Reaction mixture was filtered through a pad of celite and purified by chromatography over silica eluting with 0-50% EtOAc/hexane to furnish the title compound as a white solid. | |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 150.0℃; for 0.166667h;Microwave irradiation; | Potassium acetate (366 mg, 3.73 mmol) and dichloro [l,l'-bis (diphenylphosphino) ferrocene] palladium II DCM adduct (25.4 mg, 31 mumol) were added to a solution of 4'-bromobiphenyl-2-ol (310mg, 1.24 mmol), and bis(pinacolato)diboron (348 tug, 1.37 mmol) in DME (3 mL). The reaction was heated at 15O0C under microwave irradiation for 10 min. Reaction mixture was filtered through a pad of Celite and purified by chromatography over silica eluting with 0-50% EtOAc/hexane to furnish the title compound as a white solid. |
With potassium phosphate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 150.0℃; for 0.166667h;Microwave irradiation; | Potassium acetate (366 mg, 3.73 mmol) and dichloro [1,1 '-bis (diphenylphosphino) ferrocene] palladium II DCM adduct (25.4 mg, 31 mumol) were added to a solution of 4'-bromobiphenyl-2-ol (3 lOmg, 1.24 mmol), and bis(pinacolato)diboron (348 mg, 1.37 mmol) in DME (3 mL). The reaction was heated at 1500C under microwave irradiation for 10 min. Reaction mixture was filtered through a pad of Celite and purified by chromatography over silica eluting with 0-50% EtOAc/hexane to furnish the title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140.0℃; for 0.333333h;Microwave irradiation; | Step A Methyl 5-[(6-fluoro-5-(2'-hydroxybiphenyl-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoate. Potassium phosphate (2 M in water) (270 ul, 0.54 mmol) and Pd(PPh3)4 (6.3 mg, 5.4 mumol) were added to a solution of Intermediate 11B (100 mg, 0.18 mmol), and Intermediate 38 (80 mg, 0.27 mmol) in dioxane (2 mL). The reaction was heated at 140 C. under microwave irradiation for 20 min, then filtered through a membrane syringe filter and concentrated. The residue was re-dissolved in 2 mL methanol, filtered and purified by HPLC eluting with 20-80% MeCN:water to afford the desired product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80.0℃; for 15.0h; | A solution of potassium carbonate (1 M solution in water, 0.15 mL, 0.15 mmol), Pd(PPh3^ (3 mg, 0.0002 mmol), 41-(4,4,5,5-tetramethyl-l,3^-dioxaborolan-2-yl)biphenyl-2-ol (15 mg, 0.05 mmol) and Intermediate 4 (21 mg, 0.05 mmol) in dioxane (0.25 mL) was heated at 80C for 15 h. The aqueous phase was removed and the organic phase was concentrated, diluted with EtOAc, filtered and concentrated to afford the desired product as a solid, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tetrahydrofuran; ethanol; toluene; at 115.0℃; for 2.0h;Inert atmosphere; | A glass tube was charged with <strong>[1219741-54-4]4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-ol</strong> (86.2 mg, 0.29 mmol), methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (84 mg, 0.29 mmol), toluene (1.2 mL), THF (0.6 mL), EtOH (0.6 mL), and 2.0 M potassium carbonate solution (0.6 mL, 1.2 mmol). Nitrogen was then bubbled through the mixture for 5 minutes then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28 mg, 0.032 mmol) was added. The tube was sealed and heated to 115 C. for 2 hours. The reaction was cooled to room temperature, opened, and neutralized with 1.0 M sodium hydrogensulfate then diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate (x2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash column chromatography (20% to 100% ethyl acetate/heptane) was then used to to provide the title compound as a white solid (80 mg, 73% yield). MS (ES-) 376.1 (M-H). 1H NMR (500 MHz, DMSO-d6) delta 12.09 (br. s., 1H), 9.60 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.68 (s, 1H), 7.65 (d, 2H), 7.47 (d, 2H), 7.34 (dd, 1H), 7.19 (dt, 1H), 6.98 (d, 1H), 6.91 (dt, 1H), 3.81 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In ethanol; water; toluene; at 110.0℃;Inert atmosphere; Sealed tube; | To a solution of methyl 6-bromo-5-iodo-1H-indole-3-carboxylate (100 mg, 0.26 mmol) in toluene (1 ml) and ethanol (1 ml) was added <strong>[1219741-54-4]4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-2-ol</strong> (70 mg, 0.24 mmol) followed by aqueous potassium carbonate (2 M, 1 ml, 2.0 mmol). The solvent was degassed by passing nitrogen through the system for 5 min. Pd(dppf)Cl2 (10 mg, 0.0053 mmol) was added then sealed and reaction heated to 110 C. The reaction was cooled then partitioned between water and ethyl acetate, then washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo to afford the title compound mixed with unidentified byproducts as a dark tan solid (120 mg). TLC (50% EtOAc/Heptane) indicates no separation between product and byproducts. Crude was taken on to the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In 1,4-dioxane; at 210.0℃; for 1.0h;Microwave irradiation; | A mixture of 2,2-dimethylpropane-1,3-diol (4.0 g, 38 mmol) and 4'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-ol (1.0 g, 3.4 mmol) in 1,4-dioxane (2 mL) was subjected to microwave irradiation at 210 C. for 1 hour. The cooled reaction mixture was partitioned between water (50 mL) and 1:1 EtOAc/heptane (25 mL:25 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (0.95 g, 99% yield). GC/MS, M=282 at 5.31 min. 1H NMR (500 MHz, CDCl3) delta 7.94 (d, J=7.81 Hz, 2H), 7.48 (d, J=7.81 Hz, 2H), 7.31-7.26 (m, 2H), 7.03-6.98 (m, 2H), 3.82 (s, 4H), 1.08-1.04 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; ethanol; water; toluene; at 85.0℃;Inert atmosphere; | 4?-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) biphenyl-2-ol (98 mg, 0.33 mmol), Pd(dppf)Cl2 (10 mg, 0.01 mmol) and, lastly, an aqueous solution (5 ml) of K2CO3 (150 mg, 1.08 mmol) are added to a solution of iodised derivative 2 (87 mg, 0.27 mmol) in a solvent mixture of 1,4-dioxane:toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85 C. all night in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated at reduce pressure. The residue is dissolved in water (10 ml) and extracted with AcOEt (3×10 ml). The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated under reduce pressure. The crude obtained is purified by column chromatography (CH2Cl2:MeOH 20:1). 56 mg (60%) are obtained as a beige solid. MS (ES, positive mode): m/z 357 (96%) (M+1)+. 1H NMR (DMSO-d6) delta 11.96 (s, 1H), 9.63 (s, 1H), 8.18-6.05 (m, 12H), 4.30 (d, J=7.1 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H). 13C NMR (DMSO-d6) delta 14.4, 60.7, 113.1, 116.5, 119.9, 120.9, 121.1, 122.8, 123.1, 125.5, 127.2, 127.9, 128.8, 130.4, 130.7, 132.1, 136.6, 137.5, 154.8, 161.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; ethanol; water; toluene; at 85.0℃; for 3.0h;Inert atmosphere; | 4?-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) biphenyl-2-ol (255 mg, 0.86 mmol), Pd(dppf)Cl2 (26 mg, 0.036 mmol) and, lastly, an aqueous solution (5 ml) of K2CO3 (398 mg, 2.88 mmol) are added to a solution of the iodised benzyl derivative 3 (290 mg, 0.72 mmol) in a solvent mixture of 1,4-dioxane: toluene:ethanol:water 10:1:3:6 (20 ml). The mixture is stirred at 85 C. for 3 hours in a nitrogen atmosphere. Once the reaction has concluded, the solvent is evaporated at reduced pressure. The residue is dissolved in water (10 ml) and extracted with AcOEt (3×10 ml). The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated. The crude is purified by column chromatography (CH2Cl2:MeOH 50:1). 305 mg (95%) are obtained as a beige solid. MS (ES, positive mode): m/z 447 (95%) (M+1)+. 1H NMR (DMSO-d6) delta 9.59 (s, 1H), 8.05-6.45 (m, 17H), 5.79 (s, 2H), 4.12 (q, J=6.5 Hz, 2H), 1.00 (t, J=7.1, 6.5 Hz, 3H). 13C NMR (DMSO-d6) delta 13.8, 47.8, 55.3, 61.0, 111.7, 116.5, 119.9, 121.3, 121.5, 123.8, 125.0, 125.7, 126.2, 126.7, 127.5, 127.8, 128.8, 128.9, 129.0, 130.0, 130.6, 132.3, 137.5, 138.1, 138.7, 154.8, 162.2. |