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Structure of 78471-43-9
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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.
4.5
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CAS No. : | 78471-43-9 |
Formula : | C9H8Br2O2 |
M.W : | 307.97 |
SMILES Code : | BrC1=CC(=C(C(=O)OC)C=C1)CBr |
MDL No. : | MFCD04114319 |
InChI Key : | SGFACFBLUAWICV-UHFFFAOYSA-N |
Pubchem ID : | 22031079 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314-H290 |
Precautionary Statements: | P501-P260-P234-P264-P280-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P406-P405 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅲ |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 58.26 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.7 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.02 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.98 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.39 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.39 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.1 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.8 |
Solubility | 0.0493 mg/ml ; 0.00016 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.24 |
Solubility | 0.178 mg/ml ; 0.000579 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.57 |
Solubility | 0.00833 mg/ml ; 0.000027 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 |
-6.03 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<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 |
---|---|---|
In methanol; for 18h;Heating; Reflux; | A solution of methyl 4-bromo-2-(bromomethyl)benzoate (410 mmol) in MeNH2ZMeOH (1500 niL) was heated to reflux and stirred for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica eluting with petroleum ether / ethyl acetate (6:1 to 3:1) to afford the sub-titled compound (48.5 g).1H NMR (400 MHz, CDCl3): delta 7.63-7.61 (m, IH), 7.53-7.54 (m, 2H), 4.29 (s, 2H), 3.12 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 1.5h; | As shown in step 5-i of Scheme 5, methyl 4-bromo-2-(bromomethyl)benzoate (Compound 2018, 2.08 g, 6.75 mmol; prepared by reacting l-(4-bromo-2- methylphenyl)ethanone with NBS),lH-pyrazol-4-amine (561 mg, 6.75 mmol), and DIEA (873 mg, 1.18 mL, 6.75 mmol) were combined in DMF (7.78 mL) and heated at 110 C for 90 min. The reaction mixture was diluted with MeOH (60 mL) and the resulting white crystaline solid was collected by filtration and dried under vacuum to give 5-bromo-2-(lH- pyrazol-4-yl)isoindolin-l-one (Compound 2019, 1.21 g, 4.35 mmol, 64% yield): ESMS (Mu+Eta) 279.99 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In tetrahydrofuran; at 50℃;Sealed tube; | [00530] Intermediate 51 b: 5-bromo-2-methyl-isoindolin-1 -one[00531] To a reaction tube containing methyl 4-bromo-2-(bromomethyl)benzoate (1 .2g, 3.gmmol) was added methylamine (2.OM in THF, lOmL, 2Ommol). The tube was sealed and the mixture was stirred and heated at 50 C overnight. The mixture was then cooled to room temperature, filtered and the precipitate washed with THF. The filtrate was concentrated in vacuo and the residue waspurified by column chromatography using an eluent of 0-100% EtOAc in heptane to give 5-bromo-2- methyl-isoindolin-1-one (623mg, 2.7Smmol, 71% yield) as a white solid.1H NMR (CDCI3, 400MHz) O/ppm: 7.73-7.68 (1H, m), 7.64-7.56 (2H, m), 4.36 (2H, 5), 3.19 (3H, 5). MS Method 3: RT: 3.18 mi m/z226.0/228.0 [M+H] |
68% | With triethylamine; In tetrahydrofuran; at 100℃; for 12h;Sealed tube; | Synthesis of 5-bromo-2-methylisoindolin-1-one (2) A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (1, 1 g, 3.26 mmol), 2 M methylamine in tetrahydrofuran (1.95 mL, 3.9 mmol) and triethylamine (0.9 mL, 6.52 mmol) was heated at 100 C. for 12 h in a sealed tube. After completion of the reaction, the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with water. The organic was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hexane to afford 5-bromo-2-methylisoindolin-1-one (2). Yield: 0.5 g, 68%; MS (ESI) m/z 226, 228 [M+1]+. |
0.112 g | In methanol; at 90℃; for 24h; | Step A: 5-bromo-2-methylisoindolin-l-one [0234] Methyl 4-bromo-2-(bromomethyl)benzoate (0.153 g, 0.497 mmol) was suspended in methanamine (2M solution in MeOH, 2.484 mL, 4.97 mmol) and the mixture was heated to reflux (90C) for 24 hours. The reaction mixture was cooled, concentrated in vacuo, and dried under high vacuum to give the title compound (0.112 g). lU NMR (500 MHz, CDC13) delta ppm 3.19 (s, 3 H), 4.36 (s, 2 H), 7.57 - 7.62 (m, 2 H), 7.70 (d, J=8.30 Hz, 1 H); ESI-MS m/z [M+H]+ 226.3. |
In methanol; ethanol;Reflux; | To a solution of compound 1a (15 g, 50 mmol) in methanol (150 ml) was added methylamine (25 ml, 33% inethanol), and the reaction was refluxed overnight. After the organic solvent was drained off, the mixture was separatedby silica gel column chromatography (PE/EA= 3:1) to provide a yellow oily compound 1b.HNMR(CDCl3),7.5-7.7(m,3H),4.3(s,2H),3.1(s,3H).MS(ESI)m/z:225.9(M+H)+. | |
for 18h;Reflux; | Methyl 4-bromo-2- (bromomethyl) benzoate (Formula 5-1, 2.5 g, 8.12 mmol) was dissolved in 2M methanamine (122 ml, 244 mmol, 30 eq) and then stirred at reflux for 18 hours. After completion of the reaction, Extracted with dichloromethane. The organic layer was washed with H 2 O, dried over anhydrous MgSO 4, and the solvent was removed under reduced pressure.Thereafter, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain a target compound (Formula 5-2). |
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