Structure of 866100-14-3
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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. : | 866100-14-3 |
Formula : | C15H16B2O4 |
M.W : | 281.91 |
SMILES Code : | CC1(C)C2=C(C3=C1C=C(B(O)O)C=C3)C=CC(B(O)O)=C2 |
MDL No. : | MFCD08704228 |
InChI Key : | LUVUGOUOAXADNE-UHFFFAOYSA-N |
Pubchem ID : | 24820467 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 21 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 4.0 |
Molar Refractivity | 84.04 |
TPSA ? Topological Polar Surface Area: Calculated from |
80.92 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.23 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.65 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.55 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.74 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.28 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.28 |
Solubility | 0.147 mg/ml ; 0.00052 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.56 |
Solubility | 0.0768 mg/ml ; 0.000273 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.73 |
Solubility | 0.0527 mg/ml ; 0.000187 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 |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
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) |
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 |
-6.44 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) |
2.84 |
* 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 |
---|---|---|
50% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 8h;Heating / reflux; | In a stream of argon, 14 g (0.05 mol) of Intermediate 7, 25 g (0.11 mol) of 2-bromobenzoate ethylester, 2.8 g (5 mmol) of tetrakistriphenylphosphinepalladium(0), 200 mL of toluene, and the mixture of 16 g (0.15 mol) of sodium carbonate and 150 mL of water were added to a 1-L three-necked flask, and the whole was refluxed under heat for 8 hours. After the completion of the reaction, an organic layer was washed with water and dried with magnesium sulfate, and then the solvent was removed by distillation with a rotary evaporator. The resultant coarse crystal was recrystallized with ethanol, whereby 12 g of Intermediate 8 (white crystal, 50% yield) as a target were obtained. |
50% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 8h;Reflux; Inert atmosphere; | (4-3) Synthesis of Intermediate 9; Into a 1 liter three-necked flask, 14 g (0.05 moles) of Intermediate 8, 25 g (0.11 moles) of ethyl 2-bromobenzoate, 2.8 g (5 mmole) of tetrakistriphenylphosphinepalladium(0), 200 ml of toluene and a solution prepared by dissolving 16 g (0.15 moles) of sodium carbonate into 150 ml of water were placed under the stream of argon, and the resultant mixture was heated under the refluxing condition for 8 hours. After the reaction was completed, the organic layer was washed with water and dried with magnesium sulfate, and the solvent was removed by distillation using a rotary evaporator. The obtained crude crystals were recrystallized from ethanol, and 12 g of Intermediate 9 of the object compound was obtained (white crystals; the yield: 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In a stream of argon, 35 g (0.1 mol) of Intermediate 6 and 1 L of tetrahydrofuran (THF) were added to a 3-L three-necked flask, and the whole was cooled to - 65C. Subsequently, 220 mL (0.22 mol, 1 mol/L (hexane)) of n-butyllithiumwere slowlyaddedto the resultant. After the reaction liquid had been stirred at - 70C for 6 hours, 45 g (0.24 mol) of boronic triisopropoxide were slowly added to the reaction liquid at - 65C, and the whole was stirred at - 70C for 1 hour. After that, the resultant was stirred at room temperature overnight. After the completion of the reaction, dilute hydrochloric acid was added to the reaction liquid to adjust the pH of the liquid to 3, and an organic layer was separated and washed with a saturated salt solution. After the washed product had been dried with magnesium sulfate, the solvent was removed by distillation with a rotary evaporator, and ethyl acetate was added to the remainder. The resultant crystal was separated by filtration, and was washed with hexane three times, whereby 20 g of Intermediate 7 (white crystal, 70% yield) as a target were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 2,7-dibromo-9,9-dimethylfluorene (14.8 g, 42.4 mmol)Add to three bottles,100 mL of THF was added,Nitrogen protection,-78 deg.] C for 30 minutes,Then, 21 mL of n-butyllithium (2.5 M)Reaction for 1 hour, againAdd triisopropyl borate 14g,Low temperature reaction for 1 hour,Gradually restored room temperature.After the addition of 2M hydrochloric acid to the solution, the pH value of the solution was 4-5, and the aqueous layer was extracted with ethyl acetate. The organic layer was combined and dried to give intermediate A1 (9.5 g, yield 80% ). | |
70% | (4-2) Synthesis of Intermediate 8; Into a 3 liter three-necked flask, 35 g (0.1 mole) of Intermediate 7 and 1 liter of THF were placed under the stream of argon, and the obtained solution was cooled at -65 C. To the cooled solution, 220 ml of a solution of n-butyllithium (0.22 moles, a 1 mole/liter hexane solution) was slowly added. After the reaction fluid was stirred at -70 C. for 6 hours, 45 g (0.24 moles) of boronic acid triisopropoxide was slowly added at -65 C. The resultant fluid was stirred at -70 C. for 1 hour and then at the room temperature for one night. After the reaction was completed, dilute hydrochloric acid was added to the reaction fluid to adjust pH at 3, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was removed by distillation using a rotary evaporator, and ethyl acetate was added to the residue. The obtained crystals were separated by filtration and washed with hexane three times, and 20 g of Intermediate 8 of the object compound was obtained (white crystals; the yield: 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; for 10h;Reflux; | A solution of tetraphenylphenylphosphine palladium (2.1 g, 1.83 mmol)And potassium carbonate (75.7 g, 549 mmol)Was added to a solution of intermediate Al (51.6 g, 183 mmol)And intermediate C1 (111.4 g, 384 mmol)In a degassed tetrahydrofuran (500 mL)And the mixture was heated under reflux for 10 hours.The reaction mixture was cooled to room temperature, after which the solvent was removed.The target product TM1 was obtained by silica gel column chromatography(49.5 g, 65% theoretical). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Dibromo-9,9-dimethylfluorene (14.9 g, 42.4 mmol) was added to a three-necked flask and 100 mL of THF was added thereto and protected by nitrogen. The mixture was stirred at -78 C for 30 minutes and then n-butyllithium M) 21 mL, reacted for 1 hour, added triisopropyl borate 14 g, reacted at low temperature for 1 hour, and gradually returned to room temperature.In the post-treatment process, 2M hydrochloric acid was added to the system to make the solution have a pH of 4-5, and the mixture was allowed to stand for liquid separation. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined and spin-dry.2,7-Diboronic acid-9,9-dimethylhydrazine (8.9 g, 75% yield) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; for 4h;Reflux; | Tetrakistriphenylphosphine palladium (2.1 g, 1.83 mmol)And potassium carbonate (75.7g, 549mmol) was added to 9,9-dimethyl-fluorene-2,7-diboronic acid (51.4g, 183mmol)And a solution of compound c3 (174.7 g, 384 mmol) in degassed tetrahydrofuran (500 mL)And the mixture was heated under reflux for 4 hours.Hot and suction filtration,Get a lot of solids,Dissolve the solid with a solvent,After concentration,The compound 50 (120.6 g, yield 70%) was obtained by silica gel column chromatography. |