Structure of 887268-22-6
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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. : | 887268-22-6 |
| Formula : | C8H8BrFO |
| M.W : | 219.05 |
| SMILES Code : | COCC1=CC=C(F)C(Br)=C1 |
| English Name : | 2-Bromo-1-fluoro-4-(methoxymethyl)benzene |
| MDL No. : | MFCD04116324 |
| InChI Key : | QBVRUQXKXJMOGC-UHFFFAOYSA-N |
| Pubchem ID : | 2769416 |
| Num. heavy atoms | 11 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.25 |
| Num. rotatable bonds | 2 |
| Num. H-bond acceptors | 2.0 |
| Num. H-bond donors | 0.0 |
| Molar Refractivity | 44.96 |
| TPSA ? Topological Polar Surface Area: Calculated from |
9.23 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.45 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.36 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.0 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.03 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.24 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.82 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.96 |
| Solubility | 0.242 mg/ml ; 0.00111 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.19 |
| Solubility | 1.4 mg/ml ; 0.0064 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.07 |
| Solubility | 0.0187 mg/ml ; 0.0000855 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) |
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 |
-5.96 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 |
1.0 |
| 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) |
1.65 |
* 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 |
|---|---|---|
| 84% | Stage #1: 3-bromo-4-fluoro-benzyl alcohol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h; | 228.1 Step 1. Preparation of 2-bromo-1-fluoro-4-(methoxymethyl)benzene To a solution of (3-bromo-4-fluorophenyl)methanol (5.00 g, 24.4 mmol) in N,N-anhydrous N,N-dimethylformamide (50 mL) was added a 60% suspension of sodium hydride in mineral oil (1.37 g, 34.2 mmol) in portions at 0° C., and the mixture was stirred at 0° C. for 30 minutes. To it was then added iodomethane (4.15 g, 29.3 mmol) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction was quenched by addition of water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with 2 to 5% of ethyl acetate in petroleum ether, afforded the title compound as a colorless oil (4.50 g, 84% yield): 1H NMR (400 MHz, CDCl3) δ7.57 (dd, J=6.4, 2.0 Hz, 1H), 7.28-7.23 (m, 1H), 7.11 (t, J=8.0 Hz, 1H), 4.42 (s, 2H), 3.41 (s, 3H). |
| With sodium hydride In tetrahydrofuran at 0℃; for 3h; | 33.2 Step 2: Cool a solution of the product of Step 1 (1.20 g, 5.9 mmol) in THF (50 ml) in ice and add NaH (60% in oil, 0.33 g, 8.2 mmol), then CH3I (1.00 ml, 7.1 mmol). Stir 3 h and partition between ether and water. Dry (MgSO4) and concentrate to obtain the crude methyl ether as a yellow oil. | |
| With sodium hydride In tetrahydrofuran for 3h; | 22.2 Cool a solution of the product of Step 1 (1.20 g, 5.9 mmol) in THF (50 ml) in ice and add NaH (60% in oil, 0.33 g, 8.2 mmol), then CH3l (1.00 ml, 7.1 mmol). Stir 3 h and partition between ether and water. Dry (MgSO4) and concentrate to obtain the crude methyl ether as a yellow oil. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 51% | With 2,6-dimethylpyridine at 20℃; for 88h; | |
| With 2,6-dimethylpyridine at 20℃; for 88h; | 15 A solution of 3-bromo-4-fluorobenzyl methanesulfonate (Intermediate 14, 330 mg; 1.17 mmol) and 2,6-lutidine (176 μl 1.52 mmol) in methanol (4 ml.) was stirred for 16 hours at RT. Additional aliquots of 2,6-lutidine (176 μl 1.52 mmol each) were added once a day for a total of three days, during which stirring was continued at RT. The mixture was taken up in Et2O, washed with water, HCI (0.1 N in water) and brine. The organic phase was dried over MgSO4, filtered and concentrated with moderate vacuum and without heating affording the title compound as a pale yellow liquid. 1H NMR (300MHz, DMSO-d6) δ [ppm] 7.66 (1 H, d, J= 7.3 Hz), 7.38 (2H, m), 4.41 (2H, s), 3.30 (3H, s). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / -20 - 20 °C 2: 2,6-dimethylpyridine / 88 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 6 steps 1.1: n-butyllithium / diethyl ether; tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: caesium carbonate / dichloromethane / 12 h / 20 °C 3.1: dichloromethane; diethyl ether / 1 h / -50 - 20 °C 4.1: hydrogenchloride / methanol / 2 h / 20 °C 5.1: caesium carbonate / dimethyl sulfoxide / 12 h / 20 °C 6.1: hydrogenchloride / ethyl acetate / 1 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1.1: n-butyllithium / diethyl ether; tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: caesium carbonate / dichloromethane / 12 h / 20 °C 3.1: dichloromethane; diethyl ether / 1 h / -50 - 20 °C 4.1: hydrogenchloride / methanol / 2 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: n-butyllithium / diethyl ether; tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: caesium carbonate / dichloromethane / 12 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1.1: n-butyllithium / diethyl ether; tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: caesium carbonate / dichloromethane / 12 h / 20 °C 3.1: dichloromethane; diethyl ether / 1 h / -50 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1.1: n-butyllithium / diethyl ether; tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: caesium carbonate / dichloromethane / 12 h / 20 °C 3.1: dichloromethane; diethyl ether / 1 h / -50 - 20 °C 4.1: hydrogenchloride / methanol / 2 h / 20 °C 5.1: caesium carbonate / dimethyl sulfoxide / 12 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 66% | Stage #1: 2-bromo-1-fluoro-4-(methoxymethyl)benzene With n-butyllithium In tetrahydrofuran; diethyl ether at -78℃; for 0.5h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; diethyl ether at -78 - 20℃; for 1h; | 228.2 Step 2. Preparation of 2-fluoro-5-(methoxymethyl)benzaldehyde To a solution of 2-bromo-1-fluoro-4-(methoxymethyl)benzene (4.50 g, 20.54 mmol) in anhydrous tetrahydrofuran (50 mL) was added a 2.5 M solution of n-butyllithium in diethyl ether (9.86 mL, 3.94 mmol) -78° C. The reaction mixture was stirred for 30 minutes -78° C., and then anhydrous N,N-dimethylformamide (3.00 g, 41.09 mmol) was added to it. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h, and then quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with 2 to 10% of ethyl acetate in petroleum ether, afforded the title compound as a colorless oil (2.30 g, 66% yield): 1H NMR (400 MHz, CDCl3) δ10.30 (s, 1H), 7.76 (dd, J=6.4, 2.0 Hz, 1H), 7.59-7.50 (m, 1H), 7.10 (dd, J=10.0, 8.4 Hz, 1H), 4.39 (s, 2H), 3.33 (s, 3H); MS (ES+) m/z 169.1 (M+1) |