Structure of 1818-27-5
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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. : | 1818-27-5 |
Formula : | C8H8O4 |
M.W : | 168.15 |
SMILES Code : | CC(C1=CC(O)=C(O)C=C1O)=O |
MDL No. : | MFCD00601422 |
InChI Key : | WCJLAYDOJJYRHF-UHFFFAOYSA-N |
Pubchem ID : | 74559 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 3.0 |
Molar Refractivity | 42.71 |
TPSA ? Topological Polar Surface Area: Calculated from |
77.76 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.22 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.09 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.01 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.07 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.72 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.79 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.87 |
Solubility | 2.25 mg/ml ; 0.0134 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.32 |
Solubility | 0.814 mg/ml ; 0.00484 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.0 |
Solubility | 16.7 mg/ml ; 0.0995 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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.55 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 |
1.0 alert |
Brenk? Structural Alert: implemented from |
2.0 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) |
1.35 |
* 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 |
---|---|---|
(F) (2,4,5-Trihydroxyphenyl)ethanone A mixture of triacetoxybenzene (25.2 g, 0.10 mol) and p-toluenesulfonic acid (19.0 g, 0.10 mol) was heated at 140 C. with stirring under nitrogen for 15 minutes. Then water (150 ml) was added, and the reaction was refluxed for 10 minutes. The solution was cooled to 5 C. for 16 hours. The solid was filtered, washed with water (2*40 ml), and dissolved in ethyl acetate (200 ml). The organic solution was dried over sodium sulfate and filtered through silica gel (60-200 mesh, 200 ml). The desired material was eluted with ethyl acetate (4*200 ml). The fractions were combined and the solvent removed in vacuo to give 11.0 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; In pyridine; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; hexane; chloroform; ethyl acetate; | (G) [4,5-Bis(acetyloxy)-2-hydroxyphenyl]ethanone To a solution of <strong>[1818-27-5](2,4,5-trihydroxyphenyl)ethanone</strong> (4.0 g, 0.0238 mol) in pyridine (12 ml) at 0 C. was added acetic anhydride (4.5 ml, 0.0476 mol) in pyridine (1 ml) over 2 minutes. After 10 minutes of stirring, ice water (100 ml) was added and the product oiled out. The water layer was decanted and the product was washed with water and the water decanted (3*30 ml). The residue was dissolved in chloroform (100 ml) and the organic layer was washed with water (20 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed twice on silica gel 60-200 mesh (100 ml) in ethyl acetate:hexane (4:1 to 1:1) to give 2.25 g of the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; sodium chloride; In ethyl acetate; | (a) 4,5-Bis(ethoxycarbonyloxy)-2-hydroxyacetophenone <strong>[1818-27-5]2,4,5-Trihydroxyacetophenone</strong> (3.36 g) was dissolved in 150 ml of ethyl acetate, and 3.24 ml of pyridine was added at about -5 C. with stirring. Then, 50 ml of a solution of 3.8 ml of ethyl chloroformate in ethyl acetate was added dropwise over 30 minutes. The mixture was stirred for 10 minutes at the same temperature. The resulting precipitate was collected by filtration and washed three times with 10 ml of ethyl acetate. The washings and the filtrate were combined, and the mixture was washed with water (once) and a saturated aqueous solution of sodium chloride (three times) and dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl ether-ethanol. The crystals were collected by filtration, and washed with ethanol and n-hexane and dried to afford 4.60 g of the desired product. Melting point: 58-60 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; sodium chloride; In ethyl acetate; | (a) 2-Hydroxy-4,5-bis(2,2,2-trichloroethoxycarbonyloxy)-acetophenone <strong>[1818-27-5]2,4,5-Trihydroxyacetophenone</strong> (16.8 g) was dissolved in 500 ml of ethyl acetate, and 15.98 ml of pyridine was added at about -5 C. with stirring. Then, a solution of 26.82 ml of 2,2,2-trichloroethyl chloroformate in 70 ml of ethyl acetate was added dropwise over the course of 2.5 hours. The mixture was stirred at the same temperature for 15 minutes. The precipitate formed was collected by filtration and washed with ethyl acetate. The washing and the filtrate were combined, and the mixture was washed with water (once) and a saturated aqueous solution of sodium chloride (twice), and dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl ether-ethanol. The crystals were collected by filtration, washed with ethanol and n-hexane and dried to afford 43.6 g of the desired product. Melting point: 107.5-108 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.9% | With trichlorosilane; In chlorobenzene; at 20℃; for 24h;Inert atmosphere; | Compound 2 (4 g, 19.03 mmol) was dissolved in chlorobenzene (20 mL) at room temperature, protected with nitrogen, and trichlorosilane (6.6 g 49.47 mmol) was slowly added dropwise; the mixture was heated at reflux for one day and the chlorobenzene was separated by rotary evaporation. The mixture was dissolved in ImoL/L hydrochloric acid (50 mL), extracted with ethyl acetate, and after-treated, and was purified by silica gel column chromatography to give a pale yellow solid 3 (2.1 g, 12.7 mmol). The yield was 66.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.6% | With boron tribromide; In dichloromethane; at 20℃;Inert atmosphere; | Step C: Compound 128 was dissolved in dichloromethane (20mL), N2 protection, was added dropwise under ice-cooling BBr3,After the addition was completed, the mixture was stirred at room temperature overnight. Pour the reaction solution into crushed ice and adjust the pH to 4-5 with 2N NaOH solution.Add ethyl acetate (50 mL × 2) for extraction.The combined organic phases were washed with saturated brine.Dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure.The product is purified by column chromatography (200-300 mesh silica gel,Ethyl acetate: dichloromethane = 1:5 to 1:1 elution),1-(2,4,5-Trihydroxyphenyl)ethanone (129) (1.41 g),The yield was 76.6%. |
75.87% | With aluminum (III) chloride; In chlorobenzene; at 20℃; for 12h; | A solution of 2,4,5-trimethoxyacetophenone (4.00 g,19.03 mmol) in chlorobenzene (20 mL) was treated with AlCl3(6.60 g, 49.47 mmol) at room temperature and then refluxed for12 h. The solvent was evaporated and the residue was hydrolyzedwith cooled 1 M HCl (50 mL) and extracted with ethyl acetate(3 50 mL). The organic layer was washed with water (2 50 mL), dried over sodium sulfate anhydrous and then filtered.After evaporation, the crude product was purified by column chromatography(methanol/dichloromethane [0.5:9.5]) to provide2,4,5-trihydroxyacetophenone as the pale yellow solid (2.42 g,75.87%); m.p. 206-207 C; FTIR (KBr) (cm1): 3405, 3238 (OAHst.), 1634 (CO st.) 1589, 1536 (CC st.), 1300, 1211, 1135 (CAOst.); 1H NMR 300 MHz (CD3OD): d 2.46 (s, 3H, CH3), 6.27 (s, 1H,H3), 7.14 (s, 1H, H6); HRMS (ESI) m/z calculated for C8H8O4,168.0428 [M]+, 167.0350 [MH]+; found 167.0356 [MH]+. |
With aluminum (III) chloride; In toluene; for 24h;Reflux; | A mixture of l-(2,4,5-trimethoxyphenyl)ethanone (10 g, 47.6 mmol, 1 eq) and AICI3 (16.5 g, 124 mmol, 2.6 eq) in toluene (48 mL) is stirred at reflux for 24 h. The mixture is concentrated to dryness and quenched with cooled 1 N HC1. The mixture is extracted with ethyl acetate. The organic layer is dried (Na2S04) and concentrated. The residue is purified by flash column chromatography (S1O2, dichloromethane/methanol 100:0 to 95:5) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.19% | To a solution of 2,4,5-trihydroxyacetophenone (1.50 g,8.93 mmol) in acetone (24 mL) was added anhydrous potassiumcarbonate (2.22 g, 16.07 mmol). The mixture was stirred at roomtemperature for 10 min. Then benzyl bromide (2.75 g, 16.08 mmol)was added and the reaction mixture was refluxed for 5 h. Aftercooling to room temperature, the solvent was evaporated andwater was added to the residue. The aqueous mixture wasextracted with ethyl acetate (3 40 mL). The combined organiclayer was washed with water (2 40 mL) and dried over sodiumsulfate anhydrous, then filtered. After removing the solvent, thecrude product was purified by column chromatography (ethyl acetate/hexane [1:4]) to provide 4,5-bis(benzyloxy)-2-hydroxyacetophenoneas the white solid (2.18 g, 70.19%); m.p. 99-100 C; FTIR(KBr) (cm1): 3065, 3037 (aromatic CAH st.), 2867 (aliphaticCAH st.), 1633 (CO st.), 1510, 1455 (CC st.), 1370 (CAH bending),1263, 1210, 1166 (CAO st.); 1H NMR 300 MHz (CDCl3): d 2.48 (s, 3H, CH3), 5.10 (s, 2H, CH2-Ph), 5.21 (s, 2H, CH2-Ph), 6.54 (s,1H, H3), 7.19 (s, 1H, H6), 7.34-7.48 (m, 10H, H20, H30, H40, H50, H60 ,H200, H300, H400, H500, H600); LRMS (ESI) m/z [M+Na]+ 371.29 (46.0),280.20 (100.0), 189.29 (10.0). |
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