Structure of 176251-49-3
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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. : | 176251-49-3 |
Formula : | C8H12F2O2 |
M.W : | 178.18 |
SMILES Code : | FC(CC1)(F)CCC21OCCO2 |
MDL No. : | MFCD11847478 |
InChI Key : | FLSBLABUGHZWBS-UHFFFAOYSA-N |
Pubchem ID : | 22225014 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 38.69 |
TPSA ? Topological Polar Surface Area: Calculated from |
18.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.18 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.56 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.78 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.62 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.62 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.15 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.93 |
Solubility | 2.11 mg/ml ; 0.0118 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.56 |
Solubility | 4.93 mg/ml ; 0.0277 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.11 |
Solubility | 1.37 mg/ml ; 0.00771 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) |
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 |
-6.28 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 |
1.0 |
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 |
0.0 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) |
2.93 |
* 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 |
---|---|---|
91% | Stage #1: With diethylamino-sulfur trifluoride In dichloromethane at 10 - 25℃; for 12 h; Stage #2: With boron trifluoride diethyl etherate; hydrogen fluoride In triethylamine at 5 - 30℃; for 12 h; |
In turn will 8, 8 - difluoro - 1, 4 - dioxo-spiro [4.5] decane and 8 - fluoro - 1, 4 - dioxo-spiro [4.5] decyl -7 - ene mixture (146 g, 1.0 µM, 1.0 eq) and catalyst boron trifluoride ether (142 g, 1.0 µM, 1.0 eq) in 1000 ml three-neck bottle in, keeping the temperature at 5 ± 5 °C dropping hydrogen fluoride under the conditions of the triethylamine solution (459.4 g, 3.0 µM, 3.0 eq), after the completion of the dropping, the reaction temperature is raised to 30 ± 5 °C reaction 12 hours; after the reaction, the reaction solution is poured into the water in the, layered water phase after dichloromethane is used for extraction three times (dichloromethane total consumption is 438 g × 3), combining all the organic phase, dried with anhydrous sodium sulfate and filtered, the resulting organic phase and the filtrate is concentrated under reduced pressure to obtain crude, the crude distillation, in 30 mm Hg pressure, receiving 70 - 72 °C fraction, to obtain 162 g, yield 91percent.The resulting product is subjected to gas chromatography (GC) detecting, in the GC map only 8,8-difluoro-1,4-dioxaspiro[4.5]decane peak, its purity is 99.3percent. By nuclear magnetic resonance spectroscopy (HNMR) detection for determining the structural formula thereof is 8,8-difluoro-1,4-dioxaspiro[4.5]decane . |
73% | Stage #1: With morpholinosulfur trifluoride In dichloromethane at 0 - 20℃; for 72 h; Inert atmosphere Stage #2: With potassium permanganate In dichloromethane; water for 24 h; |
Method B A solution of ketone 6 (4.40 g, 28.2 mmol) in dry CH2Cl2 (100 mL) was cooled to 0 °C under argon atmosphere. Morph-DAST (11.85 g, 67.7 mmol, 2.4 equiv) was added dropwise upon stirring. The reaction mixture was allowed to warm to a room temperature and was stirred for 72 h. A saturated solution of NaHCO3 in water (50 mL) was added and the reaction mixture was stirred for 10 min to quench the unreacted fluorinating agent. The organic layer was separated and the water phase was extracted with CH2Cl2 (2*50 mL). Solution of KMnO4 (5.7 g, 36 mmol, 10 equiv) in water (100 mL) was added to the combined organic phase and the formed suspension was vigorously stirred for 24 h. The organic layer was separated and the water phase was extracted with CH2Cl2 (2*100 mL). The combined organic phases were dried over Na2SO4, and evaporated under vacuum at 30 °C to provide pure compound 7 (3.65 g, 20.5 mmol, 73percent yield) as a colourless oil, which crystallized upon storage. |
60% | With (diethylamino)sulfur trifluoride In dichloromethane; water | EXAMPLE 46 8,8-Difluoro-1,4-dioxa-spiro[4.5]decane 1,4-Dioxa-spiro[4.5]decan-8-one (9.0 g, 56 mmol) and (diethylamino)sulfur trifluoride (19 g, 112 mmol) are reacted in dichloromethane (180 ml) for 2 h at room temperature. The mixture is poured in water (300 ml), the layers are separated and the aqueous phase back-extracted twice with dichloromethane (50 ml). The combined organic phases are dried with magnesium sulfate and evaporated. Distillation under reduced pressure over a vigreux-column afforded the title compound as colorless liquid (6.0 g, 60percent), bp 65-72° C. at 13-14 mbar, MS: m/e=186 (M+), contaminated with ~30percent 8-Fluoro-1,4-dioxa-spiro[4.5]dec-7-ene, MS: m/e=158 (M+). |
45% | With N-methyl-N-phenylaminodifluorosulfiniumtetrafluoroborate; triethylamine tris(hydrogen fluoride) In dichloromethane at 20℃; for 3 h; Inert atmosphere | General procedure: To a solution of triethylamine trihydrofluoride (1equiv.) in dichloromethane (2mL) at room temperature was added the N,N-disubstituted aminodifluorosulfinium tetrafluoroborate (1.5equiv.) followed by 1,4-dioxaspiro[4.5]decan-8-one (1.0mmol, 1equiv.). After 3h of stirring under nitrogen, the reaction mixture was quenched at room temperature with a 5percent aqueous sodium bicarbonate solution, stirred for 15min, and the resulting mixture was extracted twice using dichloromethane. The organic phases were combined, dried over sodium sulfate and solvents were evaporated under low-vacuum at 40°C. NMR yield was calculated by integration of 19F NMR and/or 1H NMR signals of the resulting crude material+internal standard (2-fluoro-4-nitrotoluene). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With pyrrolidinodifluorosulfiniumtetrafluoroborate; triethylamine tris(hydrogen fluoride) In dichloromethane at 20℃; for 3 h; Inert atmosphere | General procedure: To a solution of triethylamine trihydrofluoride (1equiv.) in dichloromethane (2mL) at room temperature was added the N,N-disubstituted aminodifluorosulfinium tetrafluoroborate (1.5equiv.) followed by 1,4-dioxaspiro[4.5]decan-8-one (1.0mmol, 1equiv.). After 3h of stirring under nitrogen, the reaction mixture was quenched at room temperature with a 5percent aqueous sodium bicarbonate solution, stirred for 15min, and the resulting mixture was extracted twice using dichloromethane. The organic phases were combined, dried over sodium sulfate and solvents were evaporated under low-vacuum at 40°C. NMR yield was calculated by integration of 19F NMR and/or 1H NMR signals of the resulting crude material+internal standard (2-fluoro-4-nitrotoluene). |
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