Structure of 1,2,3,4-Tetramethylbenzene
CAS No.: 488-23-3
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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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Amarawan Intasiri ; Siena E. Illa ; Supadach Prertprawnon ; Shenghong Wang ; Li Li ; Thomas W. Bell , et al.
Abstract: The parallel artificial membrane permeability assay (PAMPA) is widely used for estimating biomembrane permeabilities of experimental drugs in pharmaceutical research. However, there are few reports of studies using PAMPA to measure membrane permeabilities of chemicals of environmental concern (CECs) outside the pharmaceutical domain, many of which differ substantially from drugs in their physicochemical properties. We applied PAMPA methods simulating gastrointestinal (PAMPA-GIT) and blood-brain barrier (PAMPA-BBB) membranes under consistent conditions to 51 CECs, including some pharmaceuticals. A backward stepwise multivariate linear regression was implemented to explore the correlation between the differences of measured permeabilities from PAMPA-GIT and PAMPA-BBB and Abraham solute descriptors. In addition, a previously reported in silico model was evaluated by comparing predicted and measured permeability results. PAMPA-GIT and PAMPA-BBB experimental permeability results agreed relatively well. The backward stepwise multivariate linear regression identified excess molar refraction and polarizability to be significant at the 0.10 level in predicting the differences between PAMPA-GIT and PAMPA-BBB. The in silico model performed well – with predicted permeability of most compounds within two-fold of experimentally measured values. We found that CECs pose experimental challenges to the PAMPA method in terms of having lower solubility and lower stability compared to most drugs.
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Keywords: PAMPA ; Blood-brain barrier ; Gastrointestinal tract ; Permeability ; Chemicals of environmental concern
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CAS No. : | 488-23-3 |
Formula : | C10H14 |
M.W : | 134.22 |
SMILES Code : | CC1=CC=C(C)C(C)=C1C |
MDL No. : | MFCD00008521 |
InChI Key : | UOHMMEJUHBCKEE-UHFFFAOYSA-N |
Pubchem ID : | 10263 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.4 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 46.31 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.42 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.0 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.92 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.47 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.72 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.51 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.64 |
Solubility | 0.031 mg/ml ; 0.000231 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.7 |
Solubility | 0.0267 mg/ml ; 0.000199 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.91 |
Solubility | 0.0164 mg/ml ; 0.000122 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
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) |
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) |
Yes |
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 |
-4.28 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
1.0 |
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 |
2.0 |
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<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.0 |
* 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 |
---|---|---|
100% | One equivalent of oxalyl chloride (26.5 g, 208 mmol) was addedto a 2 L reaction vessel containing one equivalent of (E)-<strong>[16957-70-3]2-methylpent-2-enoic acid</strong> (23.9 g, 208 mmol) in DCM (500 mL) under aflow of N2. While stirring, five drops of dry DMF were added intothe mixture resulting in effervescence. The reaction mixture wasleft stirring for 2 h. Then, the reaction was cooled to 8 C andallowed to equilibrate. 1.1 equivalents of aluminium trichloride(30.6 g, 230 mmol) was added, under a flow of N2, to the reactor.The reaction mixture changed in colour from a pale yellow to adeep orange almost instantly. 0.9 equivalents of 1,2,3,4-tetramethylbenzene(25.0 g, 176 mmol) was diluted in DCM (100 mL)and transferred to an addition funnel. This mixture was added tothe reaction vessel dropwise over 15 min where a colour changefrom deep orange to blood red was observed. The solution wasthen left to stir for 4 h, after which a 1:1 mixture of conc. HCland ice (200 mL) was added slowly to quench the reaction. Thereaction mixture changed colour from blood red to a light orangeduring this work-up. The product was extracted with DCM(3 100 mL) and the combined organic layers were washed withdeionised water (3 100 mL) before being dried using anhydrousMgSO4. This was filtered and the DCM solvent was removed in vacuo to afford (3-EtInd)O as a beige solid in 100percent yield (41.8 g,214 mmol). Colourless crystals suitable for a single crystal X-raydiffraction study were grown from a hexanes solution at 5 C. 1HNMR (400 MHz, CDCl3, 25C): d (ppm) 0.56 (t, 3H, 3JHH = 7.5 Hz,Me), 1.27 (d, 3H, 3JHH = 7.2 Hz, Me), 1.763 (m, 2H, CH2), 2.23 (s,3H, Ar-Me), 2.28 (s, 3H, Ar-Me), 2.28 (s, 3H, Ar-Me), 2.62 (s, 3H,Ar-Me), 2.74 (dq, 1H, 3JHH = 7.2 Hz, CH), 3.45 (m, 1H, CH). 13C{1H}NMR (101 MHz, CDCl3, 25 C): d (ppm) 9.9 (Me), 11.0 (Me), 13.8(Ar-Me), 15.2 (Ar?Me), 15.4 (Ar-Me), 16.8 (Ar-Me), 23.9 (CH2),41.4 (CH), 48.1 (CH), 130.1 (Ar), 131.1 (Ar), 133.4 (Ar), 134.9 (Ar),141.4 (Ar), 152.7 (Ar), 209.7 (CO). MS (ESI): Calculated231.17434; Found: 231.17446. CHN Anal. (percent): Expected: C 83.43,H 9.63; Found: C 83.53, H 9.75. IR (cm1): 1691.52 (COstretching). X-ray parameters: C16H22O, M = 230.33 g/mol,Triclinic, P1, a = 5.2601(2) A, b = 8.7982(3) A, c = 15.0482(6) A,a = 74.690(1), b = 85.558(2), c = 78.454(2), V = 657.89(4) A3,Z = 2, l = 0.07 mm1, R = 0.056 and CCDC number: 1472636. |