Structure of 877399-47-8
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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. : | 877399-47-8 |
Formula : | C23H26BrCl2FN2O5 |
M.W : | 580.27 |
SMILES Code : | C[C@H](C1=C(Cl)C=CC(F)=C1Cl)OC2=CC(Br)=CN=C2N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O |
MDL No. : | MFCD28134573 |
InChI Key : | ODVAQMSMMKGMLV-GFCCVEGCSA-N |
Pubchem ID : | 59599413 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 34 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.43 |
Num. rotatable bonds | 10 |
Num. H-bond acceptors | 7.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 133.79 |
TPSA ? Topological Polar Surface Area: Calculated from |
77.96 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
4.75 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
7.02 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
8.2 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.66 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
5.85 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
6.1 |
Log S (ESOL):? ESOL: Topological method implemented from |
-7.46 |
Solubility | 0.0000201 mg/ml ; 0.0000000346 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
Log S (Ali)? Ali: Topological method implemented from |
-8.47 |
Solubility | 0.00000195 mg/ml ; 0.0000000034 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-7.94 |
Solubility | 0.00000665 mg/ml ; 0.0000000115 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
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) |
No |
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) |
Yes |
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 |
-4.86 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
2.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
1.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.17 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<3.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
4.33 |
* 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 |
---|---|---|
100% | at 20℃; for 18 h; | To a solution of 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (12.83 g, 33.76 mmol) in anhydrous DMF (100 mL) was added di-tert-butyl dicarbonate (21.25 g, 97.35 mmol) and 4-dimethylaminopyridine (0.793 g, 6.49 mmol). The reaction was stirred at ambient temperature for 18 hours under nitrogen. To the mixture was added saturated NaHCO3 solution (300 mL), and extracted with EtOAc (3x250 mL). The combined extracts were washed with water (5x100 mL), sat. NaHCO3, and brine, then dried over Na2SO4. After filtration, evaporation, and high vacuum drying, di-boc protected 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine was obtained as an off-white foam solid (19.59 g, 100percent yield). 1H NMR (DMSO-d6, 400 MHz) ? 8.18 (d, 1H), 7.83 (d, 1H), 7.59 (dd, 1H), 7.48 (t, 1H), 6.25 (q, 1H), 1.75 (d, 3H), 1.39 (s, 9H), 1.19 (s, 9H). |
100% | With dmap In N,N-dimethyl-formamide at 20℃; for 18 h; | To a solution of 5-bromo-3-[(fl)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (12.83 g, 33.76 mmol) in anhydrous DMF (100 ml_) was added di-tert-butyl dicarbonate (21.25 g, 97.35 mmol) and 4-dimethylaminopyridine (0.793 g, 6.49 mmol). The reaction was stirred at ambient temperature for 18 hours under nitrogen. To the mixture was added saturated NaHCO3 solution (300 ml_), and extracted with EtOAc (3x250 ml_). The combined extracts were washed with water (5x100 mL), sat. NaHCO3, and brine, then dried over Na2SO4. After filtration, evaporation, and high vacuum drying, di-boc protected 5-bromo-3-[(fl)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine was obtained as an off-white foam solid (19.59 g, 100percent yield). 1H NMR (DMSO-d6, 400 MHz) 6 8.18 (d, 1H), 7.83 (d, 1H), 7.59 (dd, 1H), 7.48 (t, 1H), 6.25 (q, 1H), 1.75 (d, 3H), 1.39 (s, 9H), 1.19 (s, 9H). |
100% | With dmap In N,N-dimethyl-formamide at 20℃; for 18 h; Inert atmosphere | To a solution of 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (12.83 g, 33.76 mmol) in anhydrous DMF (100 mL) was added di-tert-butyl dicarbonate (21.25 g, 97.35 mmol) and 4-dimethylami[pi]opyridine (0.793 g, 6.49 mmol). The reaction was stirred at ambient temperature for 18 hours under nitrogen. To the mixture was added saturated NaHCd3 solution (300 mL), and extracted with EtOAc (3×250 mL). The combined extracts were washed with water (5×100 mL), sat. NaHCO3, and brine, then dried over Na2SO4. After filtration, evaporation, and high vacuum drying, di-boc protected 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine was obtained as an off-white foam solid (19.59 g, 100percent yield). 1H NMR (DMSO-d6, 400 MHz) δ 8.18 (d, 1H), 7.83 (d, 1H), 7.59 (dd, 1H), 7.48 (t, 1H), 6.25 (q, 1H), 1.75 (d, 3H), 1.39 (s, 9H), 1.19 (s, 9H). |
87.28% | With dmap; triethylamine In tetrahydrofuran at 70℃; | Step 4) (R)-5-bromo-N.N-bis(ter/-butoxycarbonyl)-3-(l-(2.6-dichloro-3-fluorophenyl)ethoxy) pyridin-2-amine [0171] To a solution of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2- amine (4.5 g, 1 1.8 mmol), DMAP (1.46 g, 1 1.8 mmol) and (Boc)20 (7.33 g, 35.4 mmol) in THF (100 mL) was added Et3N (3.65 g, 36 mmol). The reaction was stirred at 70 °C overnight, then concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as vicious liquid (6 g, 87.28percent). |
87.28% | With dmap; triethylamine In tetrahydrofuran at 70℃; | To a solution of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2- amine (4.5 g, 1 1.8 mmol), DMAP (1.46 g, 11.8 mmol) and (Boc)20 (7.33 g, 35.4 mmol) in THF (100 mL) was added Et3N (3.65 g, 36 mmol). The reaction was heated at 70 °C overnight, then concentrated in vacuo. The residue was purified by a silica column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as vicious liquid (6 g, 87.28percent). |
87.28% | With dmap; triethylamine In tetrahydrofuran at 70℃; | A solution of (R) -5-bromo-3- (1- (2,6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine (4.5 g, 11.8 mmol)4-dimethylaminopyridine (1.46 g, 11.8 mmol) andBoc anhydride (7.33 g, 35.4 mmol)Was dissolved in tetrahydrofuran (100 mL)To this was added triethylamine (3.65 g, 36 mmol).The reaction solution was stirred at 70 ° C overnight,Concentrated under reduced pressure. The residue was passed through a silica gel column(Petroleum ether / ethyl acetate (v / v) = 10/1) to give the title compound as a viscous liquid (6 g, 87.28percent). |
4.4 g | With dmap; triethylamine In tetrahydrofuran at 68℃; for 11 h; | To a mixture of (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2- amine (2.52 g, 6.63 mmol), DMAP (809 mg, 6.63 mmol) in THF(66 mL) was added (Boc)20 (4.7 mL, 19.89 mmol) and Et3N (2.8 mL, 19.89 mmol). The reaction was stirred at 68°C for 11 h, then quenched with saturated NaHCO3 aqueous solution (50 mL). The mixture was extracted with EtOAc (50 mL x 3) and the combined organic phases were washed with water (50 mL), saturated NaHCO3 aqueous solution (50 mL) and brine (50 mL). The solution was dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a yellow solid (4.4 g, 114percent).LC-MS (ESI, pos. ion) m/z: 603 [M + Na]. |
4.4 g | With dmap; triethylamine In tetrahydrofuran at 68℃; for 11 h; | The (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (2.52g, 6.63mmol), DMAP (809 mg, 6 . 63mmol) dissolved in tetrahydrofuran (66 ml) in, and adding Boc anhydride (4.7 ml, 19 . 89mmol) and triethylamine (2.8 ml, 19 . 89mmol). The reaction liquid 68 °C stirring 11 hours later, by adding saturated aqueous solution of sodium bicarbonate (50 ml) quenching, and using ethyl acetate (50mLx3) extraction. Combined organic phase with water (50 ml), saturated aqueous solution of sodium bicarbonate (50 ml) and saturated salt water (50 ml) to wash. The obtained solution is dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Residue column chromatography (PE/EtOAc = 4/1 (v/v)) purification, to obtain the title compound as yellow solid (4.4g, 114percent). |
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