Structure of 2-(Benzyloxy)-5-bromopyridine
CAS No.: 83664-33-9
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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. : | 83664-33-9 |
Formula : | C12H10BrNO |
M.W : | 264.12 |
SMILES Code : | BrC1=CN=C(OCC2=CC=CC=C2)C=C1 |
MDL No. : | MFCD09037462 |
InChI Key : | LXKTVNFZAFTUNZ-UHFFFAOYSA-N |
Pubchem ID : | 11108191 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.08 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 62.92 |
TPSA ? Topological Polar Surface Area: Calculated from |
22.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.49 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.34 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.27 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.83 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.52 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.09 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.98 |
Solubility | 0.0279 mg/ml ; 0.000106 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.48 |
Solubility | 0.0871 mg/ml ; 0.00033 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.54 |
Solubility | 0.00076 mg/ml ; 0.00000288 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) |
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) |
Yes |
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) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.54 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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.09 |
* 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 n-butyllithium; In tetrahydrofuran; N-methyl-acetamide; hexane; | 6-Benzyloxy-pyridine-3-carbaldehyde To a solution of 2-benzyloxy-5-bromo-pyridine (1.64 g, 6.2 mmol) in tetrahydrofuran (25 mL, -78 C.) was added n-butyllithium (2.5 M in hexane, 2.61 mL, 1.05 equiv). After 1 h at -78 C., dimethylformamide (0.97 mL, 2 equiv) was added and the mixture stirred for 30 min. The reaction was quickly poured into a stirred solution of 5% aqueous sodium bicarbonate (50 mL) and extracted with diethyl ether (3*). The ethereal was washed with brine, dried over magnesium sulfate, and concentrated to give 1.16 g (quant.) which was used without purification. Mass spec.: 186.34 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a solution of [2-BENZYLOXY-5-BROMO-PYRIDINE] (1.64 g, 6.2 mmol) in tetrahydrofuran (25 [ML,-78C)] was added n-butyllithium (2.5 M in hexane, 2.61 mL, 1.05 equiv). After 1 h [AT-78C,] dimethylformamide (0.97 mL, 2 equiv) was added and the mixture stirred for 30 min. The reaction was quickly poured into a stirred solution of 5% aqueous sodium bicarbonate (50 [ML)] and extracted with diethyl ether [(-3X).-THE ETHEREAL-WAS WASHED-WITH BRINE, DNeD-OVER MaGNESIUM~SULFATE, AND] concentrated to give 1.16 g (quant. ) which was used without purification. Mass spec.: 186.34 [(MH)] [+.] | |
73% | n-Butyl lithium (2. 5M, 95. 9 mmol, 38. 4 mL, 1. 05 eq.) was added dropwise via syringe to a stirred solution OF 2- (BENZYLOXY)-5-BROMOPYRIDINE (91. 3 mmol, 24. 1 G, 1. 0 eq.) in THF (260 mL, c = 0. 35) cooled to-78 C. Upon completion of addition, the solution was allowed to continue stirring at the same low temperature for 1 hour. At this point, NN-dimethylformamide (183 mmol, 13. 4 G, 2. 0 eq.) was added dropwise as a solution in 5 mL THF. Stirring was continued at the same low temperature for a further 30 minutes at which point the reaction was quenched by addition of 5% sodium bicarbonate. The mixture was transferred to a separatory funnel and extracted with ether (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant yellow oil was purified on a Biotage Sp4 65i over a gradient OF 0-50% hexanes in ethyl acetate to afford the title compound (14. 1 g, 73%). LRMS : 214 (M+H) +. 'H NMR (DMSO-D6, 400 MHz) ; 10. 02 (1 H, s) 8. 86 (1 H, s) 8. 03 (1 H, d, J=9. 3 Hz) 7. 31-7. 43 (5 H, m) 6. 50 (1 H, d, J=9. 3 HZ) 5. 33 (2 H, s) | |
40% | Manufacturing Example 12-1-2 6-Benzyloxy-pyridin-3-carbaldehyde; To a solution of 2-benzyloxy-5-bromopyridine (15.1 g, 57.0 mmol) described in Manufacturing Example 12-1-1 in anhydrous tetrahydrofuran (250 mL) were added dropwise n-butyl lithium (2.67 M n-hexane solution, 25.6 mL, 68.4 mmol) under nitrogen atmosphere on a dry ice-ethanol bath (-78 C.), which was stirred for 30 minutes at -78 C. N,N-Dimethylformamide (6.60 mL, 85.5 mmol) was then added thereto at -78 C, and stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated after stirring for 10 minutes at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:7 then 1:5) to obtain the title compound (4.87 g, 40%).1H-NMR Spectrum (CDCl3) delta (ppm): 5.49 (2H, s), 6.89-6.92 (1H, m), 7.34-7.48 (5H, m), 8.07-8.10 (1H, m), 8.64-8.65 (1H, m), 9.97 (1H, s). |
40% | To a solution of 2-benzyloxy-5-bromopyridine (15.1 g, 57.0 mmol) described in Manufacturing Example 12-1-1 in anhydrous tetrahydrofuran (250 mL) were added dropwise n-butyl lithium (2.67 M n-hexane solution, 25.6 mL, 68.4 mmol) under nitrogen atmosphere on a dry ice-ethanol bath (-78 C.), which was stirred for 30 minutes at -78 C. N,N-Dimethylformamide (6.60 mL, 85.5 mmol) was then added thereto at -78 C., and stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated after stirring for 10 minutes at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:7 then 1:5) to obtain the title compound (4.87 g, 40%). 1H-NMR Spectrum (CDCl3) delta (ppm): 5.49 (2H, s), 6.89-6.92 (1H, m), 7.34-7.48 (5H, m), 8.07-8.10 (1H, m), 8.64-8.65 (1H, m), 9.97 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | A mixture of tert-butyl 3 -(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5 ,6-dihydropyridine-1(2H)-carboxylate (5 g, 16.1 mmol), 2-(benzyloxy)-5-bromopyridine (6.36 g,24.1 mmol), Pd(dppf)C12 (818 mg, 1.12 mmol) and K2C03 (4.44 g, 32.2 mmol) in dioxane/water(40 mL/5 mL) was purged with N2 for three times and stirred at 100 °C for 16 hrs. The mixturewas concentrated and purified by flash column chromatography (PE/EtOAc = 10:1) to afford thetitle compound (5.0 g, yield 84percent) as a yellow oil. MS (ES+) C22H26N203 requires: 366, found:367 [M+H1. |
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