Structure of 1177269-07-6
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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. : | 1177269-07-6 |
Formula : | C9H10BrNO |
M.W : | 228.09 |
SMILES Code : | BrC1=NC=C(OC2CCC2)C=C1 |
MDL No. : | MFCD20486710 |
InChI Key : | HMBZGGINIPDMQO-UHFFFAOYSA-N |
Pubchem ID : | 57821730 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.44 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 50.74 |
TPSA ? Topological Polar Surface Area: Calculated from |
22.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.53 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.76 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.78 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.85 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.83 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.55 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.23 |
Solubility | 0.134 mg/ml ; 0.000588 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.88 |
Solubility | 0.301 mg/ml ; 0.00132 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.5 |
Solubility | 0.0716 mg/ml ; 0.000314 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 |
-5.73 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) |
2.21 |
* 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 |
---|---|---|
70% | With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 80℃; for 19.0h; | 2-Bromo-5-hydroxypyridine (1.0 g, 5.75 mmol), bromocyclobutane (0.783 mL, 8.33 mmol), and potassium carbonate (1.59 g, 11.5 mmol) were mixed in DMF (11 mL) and stirred at 60 C. for 5 h, then at 80 C. for 14 h. The reaction mixture was diluted with EtOAc and washed with water, saturated NaHCO3, and brine. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by ISCO (40 g), eluting with a gradient of EtOAc/hexane 0-10% to provide to give 2-bromo-5-cyclobutoxypyridine (0.92 g, 4.0 mmol, 70% yield) as white solid. ESI (M+1) 229.9. |
69.9% | With potassium carbonate; In hexane; N,N-dimethyl-formamide; | Step 1: Synthesis of 2-bromo-5-cyclobutoxypyridine The mixture of 2-bromo-5-hydroxypyridine (1 g, 5.75 mmol), bromocyclobutane (0.783 mL, 8.33 mmol) and potassium carbonate (1.589 g, 11.49 mmol) in DMF (11.5 mL) was stirred at 60 C. for 5 h, then at 80 C. for 14 h. The reaction mixture was diluted with EtOAc and washed with water, saturated NaHCO3, and brine. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by ISCO (40 g), eluting with a gradient of EtOAc/hexane 0-10% to provide to give 2-bromo-5-cyclobutoxypyridine (0.916 g, 4.02 mmol, 69.9% yield) as white solid. MS: M+ 228, 230. C9H10BrNO, MW=228.09 |
With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 80℃; for 14.0h; | 2-bromo-5-(cyclobutyloxy)pyridine 6-Bromo-3-pyridinol (1 g, 5.75 mmol), bromocyclobutane (0.812 ml, 8.32 mmol) and potassium carbonate (1.589 g, 11.49 mmol) were mixed in N,N-dimethylformamide (11.5 ml) and were stirred at 60 C. for 5 hours then at 80 C. for 9 hours. The reaction was diluted with ethyl acetate (120 ml) and washed with water (40 ml), saturated aqueous sodium hydrogencarbonate (30 ml) and brine (30 ml). The organic phase was passed through a hydrophobic PTFE frit and evaporated. The crude was purified on silica eluding with cyclohexane/ethyl acetate: 99/1 to 9/1 to afford the title compound (820 mg), which eluted at cyclohexane/ethyl acetate: 95/5. 1H NMR (400 MHz, CDCl3): δ 7.91 (1H, d), 7.35 (1H, d), 7.02 (1H, dd), 4.64 (2H, qui), 2.39-2.53 (2H, m), 2.11-2.25 (2H, m), 1.84-1.97 (1H, m), 1.64-1.80 (1H, m); UPLC-MS: 0.78 min, 228, 230 [M+H]+; TLC: Rf=0.74 (cyclohexane/ethyl acetate: 3/1, silica). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With cesium acetate; copper; In dimethyl sulfoxide; at 100℃; for 20.0h;Inert atmosphere; | 5-(trans-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (Intermediate 30, 100 mg, 0.43 mmol), cesium acetate (512 mg, 2.67 mmol), <strong>[1177269-07-6]2-bromo-5-cyclobutoxypyridine</strong> (147 mg, 0.646 mmol), and copper (2.19 mg, 0.034 mmol) were weighed into a microwave vial. The vial was evacuated and flushed with nitrogen. DMSO (0.5 ml) was then added and the reaction mixture was heated to 100 C. for 20 h. The Reaction mixture was diluted with ethyl acetate and washed with aqueous ammonium hydroxide. The aqueous layer was back extracted with EtOAc (2*) and the combined organics was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by ISCO (12 g), eluting with a gradient of EtOAc/hexane 0-40%, followed by Gilson reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150*30 mm, 0.1% TFA in CH3CNiH2O, gradient 30% to 95% over 10 min, then neutralized with NaHCO3, to provide the title compound (34 mg, 0.09 mmol, 21% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.45 (s, 6H) 1.62-1.77 (m, 1H) 1.83-1.96 (m, 1H) 2.06-2.22 (m, 2H) 2.35-2.49 (m, 2H) 2.52-2.64 (m, 2H) 3.23-3.38 (m, 2H) 4.39-4.54 (m, 2H) 5.21-5.35 (m, 1H) 6.57 (d, J=9.39 Hz, 1H) 7.45 (dd, J=9.49, 2.64 Hz, 1H) 8.09 (dd, J=18.98, 3.13 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile;Reflux; | General procedure: 10.0 g (57.5 mmol) 2-bromo-5-hydroxypyridine, 28.3 g (230 mmol) 1-bromopropane and 19.9 g (143.7 mmol) K2CO3 are added to 1 L ACN and stirred at reflux over night. Afterwards the reaction is quenched by the addition of water and extracted with TBME. The org. layers are combined, dried over MgS04, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc). C8H10BrNO (M= 216.1 g/mol) ESI-MS: 216/218 [M+H]+ Rt (HPLC):1.88 min (method C) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2: Synthesis of (4S,6S)-4-(5-((5-cyclobutoxypyridin-2-yl)ethynyl)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine The title compound was synthesized by procedures and steps analogous to those described in Method Q for Example 125 above, but using <strong>[1177269-07-6]2-bromo-5-cyclobutoxypyridine</strong>. Light yellow solid. MS m/z=466.0 [M+H]+. Calculated for C23H20F5N3O2: 465.2 1H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J=2.74 Hz, 1H), 7.71 (dd, J=2.15, 7.63 Hz, 1H), 7.53 (ddd, J=2.15, 4.69, 8.41 Hz, 1H), 7.43 (d, J=8.61 Hz, 1H), 7.02-7.10 (m, 2H), 4.59-4.77 (m, 2H), 4.33-4.57 (m, 2H), 4.04-4.15 (m, 1H), 2.64 (dd, J=2.64, 13.60 Hz, 1H), 2.42-2.55 (m, 2H), 2.12-2.27 (m, 3H), 1.84-1.98 (m, 1H), 1.68-1.79 (m, 1H) |
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