Structure of 20430-18-6
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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. : | 20430-18-6 |
Formula : | C11H14O2 |
M.W : | 178.23 |
SMILES Code : | CC(C1=CC=C(C)C=C1)(C)C(O)=O |
MDL No. : | MFCD11036959 |
InChI Key : | SHDBWXXRCCHGQD-UHFFFAOYSA-N |
Pubchem ID : | 12369085 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H303-H315-H319-H335 |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P332+P313-P337+P313-P362-P403+P233-P405-P501 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.36 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 52.45 |
TPSA ? Topological Polar Surface Area: Calculated from |
37.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.69 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.68 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.36 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.58 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.4 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.34 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.84 |
Solubility | 0.256 mg/ml ; 0.00144 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.12 |
Solubility | 0.137 mg/ml ; 0.000766 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.98 |
Solubility | 0.187 mg/ml ; 0.00105 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 |
-5.48 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) |
1.21 |
* 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 sodium hydroxide; In water; diethylene glycol; | (2) Synthesis of 2-(4-Methylphenyl)-2-methylpropionic Acid A solution of 2-(4-methylphenyl)-2-methylpropionitrile (53.61 g), sodium hydroxide (40.4 g), diethylene glycol (160.8 ml) and water (60.6 ml) was refluxed for 18 hr. The reaction mixture was poured into water (3000 ml) and conc. hydrochloric acid (90 ml) was added. The generated crystals were collected by filtration to give the title compound (60.0 g) as pale-brown crystals, m.p.=78-81 C. 1H-NMR(CDCl3)δ: 1.57(6H, s), 2.32(3H, s), 7.14(2H, d, J=8.6 Hz), 7.28(2H, d, J=8.6 Hz). MS(EI): 178(M+). | |
With sulfuric acid; water; at 180℃; for 2h; | Step B: Preparation of 2-Methyl-2-p-tolylpropanoic acid; [0742] 9M H2SO4 (65.0 mL) was added to 2-methyl-2-p- tolylpropanenitrile (6.21 g, 39.0 mmol). The reaction mixture was then heated at 1800C in a sealed tube for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with 100 mL of diethyl ether, added to a separation funnel, washed with 5N HCl, partitioned with 5N NaOH (aqueous), washed 2 times with 20 mL of 5N NaOH (aqueous), and separated before the aqueous layer was acidified to pH = 3 with 3N HCl and extracted 3 times with 75 mL of diethyl ether, dried over Na2SO4, and concentrated in vacuo to give the title <n="170"/>compound (5.27 g) as brownish yellow amorphous solid. MS (m/z) = 180 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; at 65℃; for 1h; | Step C: Preparation of Diethyl 2-(2-methyl-2-p- tolylpropanoyl)malonate; [0744] To a mixture of magnesium (1.08 g, 44.3 mmol) and diethyl malonate (6.70 mL, 44.3 mmol) were added EtOH (15.5 mL, 266 mmol) and CCl4 (0.21 mL) at ambient temperature. The reaction was controlled by slowly adding THF (44 mL). The reaction mixture was stirred at 700C for 1 hour and then allowed to cool. The acid chloride formed from 2-methyl-2-p- tolylpropanoic acid (5.27 g, 29.6 mmol; converted to the acid chloride by reaction with thionyl chloride at 65C for 1 hour, and then concentrating) was added dropwise as an ether solution via addition funnel. The resulting mixture was stirred for 30 minutes at ambient temperature and then quenched with 5N HCl. The mixture was diluted with 200 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed 2 times with 75 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (9.24 g) as a brown oil which was used without further purification. MS (m/z) = 321 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B) 2-(para-Tolyl)-2-methylpropionic acid. 24.4 g of the compound prepared in the preceding stage in 1.44 1 of diethyl ethylene glycol and 1.88 1 of 40% aqueous potassium hydroxide are brought to reflux for 16 hours. The reaction mixture is diluted with water and then extracted with ether. The aqueous phase is acidified with concentrated hydrochloric acid, extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated. The product obtained is chromatographed on silica by eluding with an AcOEt/hexane/acetic acid (20/80/1; v/v/v) mixture. 22 g of the expected product are collected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In methanol; water; | (3) Synthesis of Methyl 2-(4-Methylphenyl)-2-methylpropionate A solution of 2-(4-methylphenyl)-2-methylpropionic acid (60.0 g), sulfuric acid (0.6 ml) and methanol (300 ml) was refluxed for 19 hr. The solvent was evaporated, and water (200 ml) was added and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (61.52 g) as a pale-brown oil. 1H-NMR(CDCl3)δ:1.56(6H, s), 2.32(3H, s), 3.64(3H, s), 7.13(2H, d, J=8.6 Hz), 7.22(2H, d, J=8.6 Hz). MS(EI): 192(M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 20 - 50℃; for 3h; | To a stirred mixture of Intermediate 28 (4.86 g, 26.5 mmol) and K2C03 (14.6 g, 106 mmol) in acetone (150 mL), methyl iodine (ALDRICH, 16 mL, 265 mmol) was added at room temperature, and, then, the reaction mixture was stirred at 50C for 3 hours. The mixture was filtered, the filtrate was evaporated to dryness, and the residue was chromatographed (silica gel, 1:1 hexane/ethyl acetate) to obtain 4.37 g of the desired product. 1H NMR (300 MHz, DMSO-d6) S ppm: 7.15 (m, 4H), 3.56 (s, 3H), 2.25 (s, 3H), 1.46 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of diisopropylamine (ALDRICH, 15.2 mL, 109 mmol) in 108 mL of anhydrous THF at -20C under N2 was added n-BuLi (55.7 mL, 106 mmol, 1.9M solution in hexane) droDwise via cannula. After stirrina for 2 hours. D-tolvlacetic acid (ALDRICH. 3.99 a. 26.5mmol) was added in 26 mL of THF. The mixture was stirred at -5C for 2 hours and, then, treated with iodomethane (9.9 mL, 159 mmol). The reaction mixture was allowed to gradually warm up to room temperature, stirred at that temperature for 15 hours, and then, quenched by pouring it into 20 mL of HCI (1N). The aqueous layer was extracted with Et20 (3x100 mL). The organic layer was treated with brine and dried over MgS04 and concentrated in vacuo to give 4.86 g of the title compound as a brown oil. 1H NMR (300 MHz, DMSO-d6) 8 ppm: 12.22 (br.s, 1H), 7.21 (m, 2H), 7.12 (m, 2H), 2.25 (s, 3H), 1.43 (s, 6H). No molecular peak is detected by MS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With isopropylmagnesium bromide; triphenylphosphine; cobalt(II) chloride; In tetrahydrofuran; at 20℃; for 18h;Green chemistry; | General procedure: The iPrMgBr (excess in THF) was added to a mixture of α,α-dimethyl phenylacetic acids (1 mmol), cobalt salt (10 mol%), ligand (20 mol%) in dried THF (3 mL), the reaction mixture was stirred at room temperature for 18 h. After that, the mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and dichloromethane to give the corresponding products. |