Structure of 126120-87-4
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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. : | 126120-87-4 |
Formula : | C7H5BF2O4 |
M.W : | 201.92 |
SMILES Code : | OB(O)C1=CC=CC2=C1OC(F)(F)O2 |
MDL No. : | MFCD08062343 |
InChI Key : | GCIIKWAIWSFGLA-UHFFFAOYSA-N |
Pubchem ID : | 16427145 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 6.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 42.47 |
TPSA ? Topological Polar Surface Area: Calculated from |
58.92 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 |
1.41 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.53 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.24 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.28 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.28 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.23 |
Solubility | 1.19 mg/ml ; 0.00587 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.25 |
Solubility | 1.13 mg/ml ; 0.0056 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.59 |
Solubility | 5.14 mg/ml ; 0.0255 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) |
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) |
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 |
-6.53 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) |
2.83 |
* 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 |
---|---|---|
With hydrogenchloride; n-butyllithium; sodium chloride; In tetrahydrofuran; Petroleum ether; | Step F Preparation of (2,2-difluoro-1,3-benzodioxol-4-yl)boronic acid A solution of n-butyllithium (5.57 mL of a 2.5M solution in hexanes, 13.9 mmol) was added to dry tetrahydrofuran (75 mL) at room temperature under a nitrogen atmosphere. The resulting solution was cooled to -15 C. and N,N,N',N'-tetramethylenediamine (2.10 mL, 13.9 mmol) was added dropwise. The reaction was stirred at -15 C. for 0.5 h and then <strong>[1583-59-1]2,2-difluoro-1,3-benzodioxole</strong> was added dropwise while maintaining the reaction temperature below -10 C. After the addition was complete, the reaction was stirred at -15 C. for 1 h before a solution of trimethylborate (1.58 mL, 13.9 mmol) in dry tetrahydrofuran (5 mL) was added dropwise while maintaining the reaction temperature below -10 C. The reaction mixture was stirred at -10 C. for 1 h and then allowed to come to room temperature while stirring overnight. To the reaction mixture was added a 1N solution of hydrochloric acid and then concentrated hydrochloric acid until the solution was strongly acidic. The acidic solution was poured into water. The resulting mixture was saturated with sodium chloride and extracted with diethyl ether three times. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to give a dark-brown oil. The oil was suspended in boiling petroleum ether and the hot solution filtered to remove a small amount of brown solid. The filtrate was then cooled and filtered to obtain a light-gray solid. The filtrate was concentrated under reduced pressure to give a light-brown solid which was combined with the gray solid obtained from recrystallization to afford the title compound of Step F (1.28 g, 50%). 1 H NMR (CDCl3): delta4.92 (s,2H), 7.15 (m,2H), 7.5 (d, 1H). 19 F NMR (CDCl3): delta-50.33 (s,2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 195(2,2-difluoro-l,3-benzodioxol-4-yl)boronic acid2,2-Difluoro-l,3-benzodioxole (960 mg, 6.1 mmol) was dissolved in THF (8 mL) and cyclohexane (4 mL) and the resulting solution cooled to -78 C. sec-BuLi 1.4M solution in cyclohexane (4.3 mL, 6.1 mmol) was added dropwise and the reaction mixture stirred for 1.5 hours at -78C. Trimethylborate (694 mg, 6.75 mmol) was added and the mixture was allowed to warm slowly to -30 C. The reaction mixture was quenched with a 2N solution of HCI and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2S04 and evaporated to dryness affording the title compound as yellow oil which was used in the next step without further purification. 1H-NMR (400 MHz, DMSO-d6 + D20): delta ppm 7.39 (1H, dd), 7.34 (1H, dd), 7.14 (t, 1H, 7=7.90 Hz). 19F-NMR (376 MHz, DMSO-d6 + D20): delta ppm -48.92. 13C-NMR (200 MHz, DMSO-d6 + D20): delta ppm 147.3, 142.8, 131.6 (t, 7=250.7 Hz), 130.1, 124.3, 112.0 | ||
2,2-Difluoro-l,3-benzodioxole (960 mg, 6.1 mmol) was dissolved in THF (8 mL) and cyclohexane (4 mL) and the resulting solution cooled to -78 C. sec-BuLi 1.4M solution in cyclohexane (4.3 mL, 6.1 mmol) was added dropwise and the reaction mixture stirred for 1.5 hours at -78C. Trimethylborate (694 mg, 6.75 mmol) was added and the mixture was allowed to warm slowly to -30 C. The reaction mixture was quenched with a 2N solution of HCI and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2S04 and evaporated to dryness affording the title compound as yellow oil which was used in the next step without further purification. 1H-NM (400 M Hz, DMSO-d6 + D20): delta ppm 7.39 (1H, dd), 7.34 (1H, dd), 7.14 (t, 1H,7=7.90 Hz). 19F-NMR (376 MHz, DMSO-d6 + D20): delta ppm -48.92. 13C-NMR (200 M Hz, DMSO-d6 + D20): delta ppm 147.3, 142.8, 131.6 (t, 7=250.7 Hz), 130.1, 124.3, 112.0 | ||
2,2-Difluoro-1,3-benzodioxole (960 mg, 6.1 mmol) was dissolved in THF (8 mL) and cyclohexane (4 mL) and the resulting solution cooled to -78 C. sec-BuLi 1.4M solution in cyclohexane (4.3 mL, 6.1 mmol) was added dropwise and the reaction mixture stirred for 1.5 hours at -78 C. Trimethylborate (694 mg, 6.75 mmol) was added and the mixture was allowed to warm slowly to -30 C. The reaction mixture was quenched with a 2N solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness affording the title compound as yellow oil which was used in the next step without further purification. 1H-NMR (400 MHz, DMSO-d6+D2O): delta ppm 7.39 (1H, dd), 7.34 (1H, dd), 7.14 (t, 1H, J=7.90 Hz). 19F-NMR (376 MHz, DMSO-d6+D2O): delta ppm -48.92. 13C-NMR (200 MHz, DMSO-d6+D2O): delta ppm 147.3, 142.8, 131.6 (t, J=250.7 Hz), 130.1, 124.3, 112.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 195 (2,2-difluoro-1,3-benzodioxol-4-yl)boronic acid [1074] [1075] 2,2-Difluoro-1,3-benzodioxole (960 mg, 6.1 mmol) was dissolved in THF (8 mL) and cyclohexane (4 mL) and the resulting solution cooled to -78 C. sec-BuLi 1.4M solution in cyclohexane (4.3 mL, 6.1 mmol) was added dropwise and the reaction mixture stirred for 1.5 hours at -78 C. Trimethylborate (694 mg, 6.75 mmol) was added and the mixture was allowed to warm slowly to -30 C. The reaction mixture was quenched with a 2N solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness affording the title compound as yellow oil which was used in the next step without further purification. [1076] 1H NMR (400 MHz, DMSO-d6+D2O): delta ppm 7.39 (1H, dd), 7.34 (1H, dd), 7.14 (t, 1H, J=7.90 Hz). 19F-NMR (376 MHz, DMSO-d6+D2O): delta ppm -48.92. 13C-NMR (200 MHz, DMSO-d6+D2O): delta ppm 147.3, 142.8, 131.6 (t, J=250.7 Hz), 130.1, 124.3, 112.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.82% | 2,2-Difluoro-1 ,3-benzodioxole (3 g, 18.98 mmol) was dissolved in TBF(60 mL) and the resulting solution cooled to -78 oc. Sec-butyllithium (1.3M, 15 mL) wasadded dropwise and the reaction mixture stirred for 1.5 h at -78 oc. Trimethyl borate (2.44mL, 21.63 mmol) was added and the mixture was allowed to warm slowly to -30 oc for lh.The reaction mixture was quenched with 2N solution of HCl, adjusted to pH .~ 2-3 anddiluted with H20 (30 mL). The reaction was extracted with EA (200 mL), two phases wereseparated and the organic layer was washed with brine (1 00 mL), dried over Na2S04, filteredand evaporated to dryness. Compound 107A (3.25 g, yield 84.82(%) was obtained as a whitesolid, which was used for next step without purification. 1H NMR (400 MHz, DMSO-d6) 88.44 (br s, 2B), 7.42 (del, J "' 7.8, 15.3 Hz, 2H), 7.23-7.12 (m, lEI). |