Structure of 101166-65-8
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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. : | 101166-65-8 |
Formula : | C8H19IOSi |
M.W : | 286.23 |
SMILES Code : | C[Si](OCCI)(C(C)(C)C)C |
MDL No. : | MFCD09909940 |
InChI Key : | CAAUZMMMFDVBFD-UHFFFAOYSA-N |
Pubchem ID : | 11129873 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H319 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 62.49 |
TPSA ? Topological Polar Surface Area: Calculated from |
9.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.09 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.96 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.44 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.84 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.51 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.97 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.85 |
Solubility | 0.0409 mg/ml ; 0.000143 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.85 |
Solubility | 0.04 mg/ml ; 0.00014 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.46 |
Solubility | 0.0983 mg/ml ; 0.000344 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) |
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 |
-5.23 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 |
3.0 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) |
4.2 |
* 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% | With sodium iodide; In acetone; at 120℃; for 4h;Inert atmosphere; Sealed tube; Microwave irradiation; | A solution of TBSCl (30.1 g, 200 mmol) in DCM (50 mL) was added dropwise over 15 min to a stirred solution of 2-chloroethanol (16.0 g, 200 mmol), imidazole (20.4 g, 300 mmol) and DMAP (0.244 g, 2.0 mmol) in DCM (200 mL) at 0 °C under an argon atmosphere, and the resulting mixture was warmed to room temperature where it was stirred for 12 h. The mixture was quenched with saturated aqueous NH4Cl (200 mL) and the separated aqueous layer was then washed with DCM (2*100 mL). The combined organic extracts were washed with saturated aqueous NH4Cl (100 mL) and brine (100 mL), then dried over MgSO4 and concentrated to leave 2-chloroethoxy tert-butyl dimethylsilane (37.1 g, 95percent) as a colourless oil. A solution of the silyl ether (3.88g, 20.0mmol) and sodium iodide (8.94g, 60 mmol) in acetone (10mL) was sealed in a microwave vial and heated at 120°C for 4h in a microwave reactor. The vial was cooled to room temperature and the reaction mixture was then diluted with diethyl ether (80mL) and filtered through silica. The filtrate was concentrated to leave 2-iodoethoxy tert-butyl dimethylsilane (5.72g, quant.) as a pale yellow oil, which was used without further purification. A solution of methyl acetoacetate (2.55g, 22.0mmol) in 79 THF (10mL) was added over 10 min to a stirred suspension of sodium hydride (0.88g, 22.0 mmol, 60percent) in THF (50mL) at 0°C under argon. The mixture was stirred for 15 min, and then a solution of n-butyl lithium (11.0 mL, 22.0 mmol, 2.0M in hexane) was added dropwise over 10 min and the mixture was stirred at 0°C for 15 min. A solution of the above, crude iodide (ca. 20 mmol) in THF (10 mL) was added dropwise over 10 min, and the resulting yellow mixture was then warmed to room temperature where it was stirred for 12 h. The mixture was quenched with saturated aqueous NH4Cl (100 mL) and diethyl ether (100mL), and the separated aqueous layer was then washed with diethyl ether (2×100mL). The combined organic extracts were washed with brine (100 mL), then dried over MgSO4 and concentrated to leave a pale yellow gum. Purification by column chromatography (25:1, petrol/Et2O) gave the keto ester (5.05 g, 77percent) as a pale yellow oil (10percent enol form): deltaH (400 MHz, CDCl3) 3.73 (3H, s, CO2CH3), 3.61 (2H, t, J=6.0, CH2O), 3.46 (2H, s, CH2), 2.62 (2H, t, J=7.1, CH2C(O)), 1.80 (2H, tt, J=6.0, 7.1, CH2), 0.87 (9H, s, SiC(CH3)3), 0.03 (6H, s, SiCH3); deltaC (100 MHz, CDCl3) 202.6 (C=O), 167.6 (CO2CH3), 61.8 (CH2O), 52.2 (CO2CH3), 49.0 (CH2), 39.4 (CH2), 26.5 (CH2), 25.9 (SiC(CH3)3), 18.2 (SiC(CH3)3), ?5.4 (2×SiCH3); HRMS m/z C13H26O4SiNa+ (MNa+) requires 297.1498, found 297.1498. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | A solution of TBSCl (30.1 g, 200 mmol) in DCM (50 mL) was added dropwise over 15 min to a stirred solution of 2-chloroethanol (16.0 g, 200 mmol), imidazole (20.4 g, 300 mmol) and DMAP (0.244 g, 2.0 mmol) in DCM (200 mL) at 0 °C under an argon atmosphere, and the resulting mixture was warmed to room temperature where it was stirred for 12 h. The mixture was quenched with saturated aqueous NH4Cl (200 mL) and the separated aqueous layer was then washed with DCM (2*100 mL). The combined organic extracts were washed with saturated aqueous NH4Cl (100 mL) and brine (100 mL), then dried over MgSO4 and concentrated to leave 2-chloroethoxy tert-butyl dimethylsilane (37.1 g, 95percent) as a colourless oil. A solution of the silyl ether (3.88g, 20.0mmol) and sodium iodide (8.94g, 60 mmol) in acetone (10mL) was sealed in a microwave vial and heated at 120°C for 4h in a microwave reactor. The vial was cooled to room temperature and the reaction mixture was then diluted with diethyl ether (80mL) and filtered through silica. The filtrate was concentrated to leave 2-iodoethoxy tert-butyl dimethylsilane (5.72g, quant.) as a pale yellow oil, which was used without further purification. A solution of methyl acetoacetate (2.55g, 22.0mmol) in 79 THF (10mL) was added over 10 min to a stirred suspension of sodium hydride (0.88g, 22.0 mmol, 60percent) in THF (50mL) at 0°C under argon. The mixture was stirred for 15 min, and then a solution of n-butyl lithium (11.0 mL, 22.0 mmol, 2.0M in hexane) was added dropwise over 10 min and the mixture was stirred at 0°C for 15 min. A solution of the above, crude iodide (ca. 20 mmol) in THF (10 mL) was added dropwise over 10 min, and the resulting yellow mixture was then warmed to room temperature where it was stirred for 12 h. The mixture was quenched with saturated aqueous NH4Cl (100 mL) and diethyl ether (100mL), and the separated aqueous layer was then washed with diethyl ether (2×100mL). The combined organic extracts were washed with brine (100 mL), then dried over MgSO4 and concentrated to leave a pale yellow gum. Purification by column chromatography (25:1, petrol/Et2O) gave the keto ester (5.05 g, 77percent) as a pale yellow oil (10percent enol form): deltaH (400 MHz, CDCl3) 3.73 (3H, s, CO2CH3), 3.61 (2H, t, J=6.0, CH2O), 3.46 (2H, s, CH2), 2.62 (2H, t, J=7.1, CH2C(O)), 1.80 (2H, tt, J=6.0, 7.1, CH2), 0.87 (9H, s, SiC(CH3)3), 0.03 (6H, s, SiCH3); deltaC (100 MHz, CDCl3) 202.6 (C=O), 167.6 (CO2CH3), 61.8 (CH2O), 52.2 (CO2CH3), 49.0 (CH2), 39.4 (CH2), 26.5 (CH2), 25.9 (SiC(CH3)3), 18.2 (SiC(CH3)3), ?5.4 (2×SiCH3); HRMS m/z C13H26O4SiNa+ (MNa+) requires 297.1498, found 297.1498. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 1H-imidazole; In dichloromethane; at 30℃; for 17h; | (i) Preparation of (2-iodoethoxy)-tert-butyldimethylsilane To a stirred solution of 2-iodoethanol (17.2 g; 100 mmol) and imidazole (8.17 g; 120 mmol) in dichloromethane (100 mL) was added tert-butyldimethylsilyl chloride (15.83 g; 105 mmol) at such a rate that the reaction temperature did not rise above 30° C. Upon complete addition the solution was left stirring for 17 h, then washed with water (2*50 mL) and brine (50 mL) and dried over MgSO4. Evaporation of the solvent afforded the target compound (28.0 g; 97.8 mmol; 98percent) as a colourless liquid. 1H-NMR (400 MHz) (CDCl3): delta=3.83 (t, 2H, J=7.0 Hz), 3.83 (t, 2H, J=7.0 Hz), 3.20 (t, 2H, J=7 Hz), 0.90 (s, 9H), 0.08 (s, 6H) ppm. |
90% | With 1H-imidazole; In N,N-dimethyl-formamide; at 30 - 40℃; for 4h; | Preparation of tert-butyl(2-iodoethoxy)dimethylsilane After 2-iodoethanol (1.72 g, 10 mmol) was dissolved in dimethylformamide (8 mL), imidazole (0.817 g, 12 mmol) and tert-butyldimethylsilyl chloride (1.66 g, 11 mmol) were added thereto, and the mixture was stirred for 4 hours at 30° C. to 40° C. Water (50 mL) was added to the reaction solution, and the result was extracted with an ethyl acetate/normal-hexane=1/1 solution (100 mL). The organic layer was washed again with salt water (30 mL*3), dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 2.85 g (90percent) of a target compound. This compound was used as it was for the next reaction without purification. |
90% | With 1H-imidazole; In N,N-dimethyl-formamide; at 30 - 40℃; for 4h; | Preparation of tert-butyl(2-iodoethoxy)dimethylsilane After 2-iodoethanol (1.72 g, 10 mmol) was dissolved in dimethylformamide (8 mL), imidazole (0.817 g, 12 mmol) and tert-butyldimethylsilyl chloride (1.66 g, 11 mmol) were added thereto, and the mixture was stirred for 4 hours at 30°C to 40°C. Water (50 mL) was added to the reaction solution, and the result was extracted with an ethyl acetate/normal-hexane=1/1 solution (100 mL). The organic layer was washed again with salt water (30 mLx3), dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 2.85 g (90percent) of a target compound. This compound was used as it was for the next reaction without purification. |
With 2-(Dimethylamino)pyridine; N-ethyl-N,N-diisopropylamine; In dichloromethane; | Step 2 tert-Butyl-(2-iodo-ethoxy)-dimethyl-silane To 2-iodoethanol (20 gm, 116 mmol) suspended in methylene chloride (500 mL) was added dimethylaminopyridine (100 mg) followed by diisopropylethylamine (30 mL, 174 mmol) and tert-butyldimethylsilyl chloride (19 gm, 128 mmol). The reaction was stirred overnight and the solvent was removed in vacuo and the residue was passed through a short column of silica gel and eluted with 95:5 methylene chloride: methanol. The desired fractions were combined and the solvent was removed in vacuo to give the desired product. 1 H NMR (400 MHz, CDCl3) delta 3.84 (dd, 2H); 3.20 (dd, 2H); 0.9 (m, 9H); 0.1 (m, 6H). | |
With 1H-imidazole; In dichloromethane; at 20℃; for 20h;Cooling with ice; Large scale; | Step C (1,1 -dimethylethyl)(2-iodoethoxy)dimethylsilane .OTBDMS Iodoethanol (2.68 kg, 15.4 mol), CH2CI2 (12 L) and imidizaole (1.556 kg, 22.63 mol) were chilled in an ice bath. A solution of t-butyldimethylchlorosilane (2.536 kg, 16.32 mol) in CH2CI2 (2.5 L) was added to the reaction over a 2 h period. The resulting white suspension was allowed to warm to rt over an 18 h. The reaction was worked up by washing with water and brine). The organic layer was dried (MgSC^) and evaporated under reduced pressure to provide the product of Step C as a light yellow oil. FontWeight="Bold" FontSize="10" H NMR (400MHz, CDC13) delta = 3.75 (t, J = 7.0 Hz, 2 H), 3.11 (t, J = 7.0 Hz, 2 H), 0.77 - 0.89 (m, 10 H), 0.00 (s, 6 H). |