Structure of 4835-90-9
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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. : | 4835-90-9 |
Formula : | C5H10O3 |
M.W : | 118.13 |
SMILES Code : | O=C(O)C(C)(C)CO |
MDL No. : | MFCD00059953 |
Boiling Point : | No data available |
InChI Key : | RDFQSFOGKVZWKF-UHFFFAOYSA-N |
Pubchem ID : | 78548 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H302-H318 |
Precautionary Statements: | P280-P301+P312+P330-P305+P351+P338+P310 |
Class: | 9 |
UN#: | 3077 |
Packing Group: | Ⅲ |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.8 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 28.82 |
TPSA ? Topological Polar Surface Area: Calculated from |
57.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.8 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.03 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.09 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.01 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.29 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.12 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.42 |
Solubility | 44.8 mg/ml ; 0.379 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.73 |
Solubility | 22.1 mg/ml ; 0.187 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
0.14 |
Solubility | 165.0 mg/ml ; 1.4 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 |
-7.04 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 |
0.56 |
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) |
1.23 |
* 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 |
---|---|---|
68% | With caesium carbonate In N,N-dimethyl-formamide at 50 - 70℃; | A dry 500 mL round-bottomed flask equipped with a magnetic stirring bar, a reflux condenser, and a rubber septum was charged under an atmosphere of nitrogen with 7.09 g (60.0 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid (hydroxypivalic acid, HPA) or 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (bis-hydroxypivalic acid, BHPA) and 19.55 g (60.0 mmol) of dried and freshly powdered cesium carbonate (Cs2CO3). 150 mL of anhydrous dimethylformamide (DMF) was added followed by 0.7-1.0 equivalents (40.0 to 60.0 mmol) of an appropriately substituted alkyl halide. The reaction mixture was heated under an atmosphere of nitrogen for overnight to ca. 50-70° C. (oil bath) (depending on the boiling point of the halide). The reaction mixture was diluted with ethyl acetate, precipitates were filtered off, and the filtrate was carefully diluted with a one molar (1.0 M) of hydrochloric acid (HCl). The aqueous phase was extracted several times with ethyl acetate and the combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3). The organic solvents were removed under reduced pressure using a rotary evaporator and the residue was diluted in methyl tert-butyl ether (MTBE). The organic solution was washed five times with water (to remove residual DMF), then brine, dried over anhydrous magnesium sulfate (MgSO4), filtered and the residual solvents removed under reduced pressure using a rotary evaporator. Generally, the products were of sufficient purity to be used directly in the next step without further purification or, optionally, were purified by fractional distillation under reduced pressure or silica gel column chromatography using ethyl acetate/hexane mixtures as eluent. Following the general procedure for the synthesis of hydroxypivalic ester derivatives of Description 2, 4.73 g (40.0 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid (hydroxypivalic acid, HPA) was reacted with 3.23 mL (6.24 g, 40.0 mmol) of iodoethane in 80 mL of DMF in the presence of 13.03 g (40.0 mmol) of Cs2CO3. After work-up, 3.40 g (68percent yield) of the title compound (2) was obtained as a yellow liquid. The material was of sufficient purity to be used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.20 (s, 6H), 1.28 (t, J=7.2 Hz, 3H), 2.50-2.55 (br. m, 1H), 3.52-3.57 (br. m, 2H), 4.16 (q, J=7.2 Hz, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 16 h; | Reference Example 1 Benzyl 3-hydroxy-2,2-dimethylpropanoate [0391] [0392] 2,2-Dimethyl-3-hydroxypropanoic acid (10.0 g) was dissolved in N,N-dimethylformamide (150 mL). To this solution, potassium hydrogen carbonate (10.2 g) was added, and then, benzyl bromide (10.7 mL) was added thereto. The resulting solution was stirred at room temperature for 16 hours. To the reaction mixture, water (300 mL) was added, and extraction was performed with a mixed solution of n-hexane and ethyl acetate (1:4) (200 mL×2). The organic layers were combined and washed with a saturated aqueous solution of sodium chloride (200 mL), and then dried over magnesium sulfate. After magnesium sulfate was removed by filtration, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (a medium-pressure preparative liquid chromatograph, W-prep 2XY manufactured by Yamazen Corporation (column: main column 4L, inject column 3L, n-hexane:ethyl acetate=1:0-1:1 (gradient time: 15 minutes), fractionation mode GR), whereby the title compound (17.6 g, 100percent) having the following physical properties was obtained. [0393] TLC (Rf value): 0.39 (n-hexane:ethyl acetate=3:1) [0394] NMR (CDCl3): δ 7.29-7.41 (m, 5H), 5.15 (s, 2H), 3.57 (d, J=6.3 Hz, 2H), 1.22 (s, 6H) |
3.04 g | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5 h; | LiOH (15.9 g, 37.9 mmol) in THF/MeOH/H2O (1:1:0.5, 62.5 mL) was added to a solution of 3-hydroxy-2,2-dimethylpropionate 14 (5 g, 37.9 mmol) in THF/MeOH (1:1, 25 mL) at 0 °C. The solution was warmed to rt and stirred for 1.5 h, the reaction mixture was adjusted to pH 2 by addition of H2SO4. The solution was concentrated under reduced pressure to remove THF and the residue washed with H2O (10 mL), extracted with EtOAc (3 12 mL), dried over Na2SO4 and concentrated under reduced pressure to give the acid (3.3 g, 27.9 mmol, 73percent) as a white solid. Benzyl bromide (1.9 mL, 16.1 mmol) was added to a solution of crude acid (2.0 g, 16.9 mmol) and K2CO3 (2.57 g, 18.6 mmol) in DMF (20 mL). The reaction mixture was stirred for 5 h then quenched by the addition of H2O (5 mL). The reaction mixture was extracted with Et2O (3 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography using 9:1 to 3:2 hexanes/EtOAc as eluent gave the title compound 20 (3.04 g, 86percent) as a yellow oil. Rf: 0.48 (60percent hexanes/EtOAc); δH (400 MHz, CDCl3): 7.39-7.29 (5H, m, Ph), 5.14 (2H, s, CH2Ph), 3.57 (2H, d, J = 6.4 Hz, H-3), 2.54 (1H, br s, OH), 1.21 (6H, s, 2 CH3); δC (100 MHz, CDCl3): 176.9 (C=O, C-1), 135.8 (C, Ph), 128.3 (2 CH, Ph), 127.9 (CH, Ph), 127.5 (2 CH, Ph), 69.3 (CH2, C-3), 66.1 (CH2, CH2Ph), 44.2 (C, C-2), 21.8 (2 CH3). The spectroscopic data were in agreement with those reported in the literature.7 |
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