Structure of 55453-89-9
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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. : | 55453-89-9 |
Formula : | C16H14O5 |
M.W : | 286.28 |
SMILES Code : | O=C(O)C1=CC=CC=C1COC2=CC=C(CC(O)=O)C=C2 |
MDL No. : | MFCD16619181 |
Boiling Point : | No data available |
InChI Key : | BCYWXPITXHFIQM-UHFFFAOYSA-N |
Pubchem ID : | 12292309 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 21 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 75.93 |
TPSA ? Topological Polar Surface Area: Calculated from |
83.83 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.62 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.5 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.44 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.36 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.6 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.1 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.59 |
Solubility | 0.741 mg/ml ; 0.00259 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.87 |
Solubility | 0.388 mg/ml ; 0.00135 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.21 |
Solubility | 0.0178 mg/ml ; 0.0000621 mol/l |
Class? Solubility class: Log S scale |
Moderately 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 |
-6.98 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 |
0.0 |
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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.14 |
* 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 |
---|---|---|
96.4% | The whole quantity of the 2-(4-carboxymethylphenoxymethyl)benzoic acid obtained in the above Step 4 and 200 ml of chlorobenzene were charged into a 500-ml four-necked flask, 75.0 g (0.3753 mol) of trifluoroacetic anhydride was added thereto, and the mixture was stirred at about 20°C for 4 hours. Subsequently, 2.3 g (0.0162 mol) of BF3-etherate complex was added dropwise thereto at -10 to 0°C over 10 minutes, then the mixture was stirred for 30 minutes. An aqueous phase was then separated, and the organic layer was washed with 200 ml of water. The washed organic layer was added to a solution of 7.2g of sodium hydroxide dissolved in 300 ml of water, and stirred for 30 minutes. An aqueous phase was then separated. To the separated aqueous layer, 2.0 g of activated carbon was added, stirred for 30 minutes, and filtered though a Buchner funnel to separate activated carbon. The activated carbon was washed on a Buchner funnel with 10 ml of water. A mixture of the filtrate and the cleaning solution was maintained at about 40°C, and a mixed solution of 11.3 g (0.1876 mol) of acetic acid and 50 ml of water was added dropwise thereto over 30 minutes. After the dropwise addition was completed, the mixture was cooled to 0 to 10°C, filtered through a Buchner funnel to collect crystals, and washed with 200 ml of water. The washed crystals were dried under reduced pressure to obtain 42.0 g of the title compound, (11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid). The yield (yield from 2-(4-carboxymethylphenoxymethyl)benzoic acid) was 96.4percent, and the purity as measured by HPLC was 99.9percent.(HPLC conditions) Column: Inertsil ODS-5 mum (4.6 mm ID x 15 cm)Mobile Phase: 0.02percent trifluoroacetic acid aqueous solution/acetonitrile = 5/5 --> 3/7 (30 minutes)Detection Wavelength: UV 254 nm(Physical Property Data) 1H NMR (400 MHz, DMSOd6) delta 3.63 (s, 2H), 5.30 (s, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 3.6 Hz, 1H), 7.55 (d-d, J = 7.9 Hz, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H) | |
71.3% | Example 2; Synthesis of the Intermediate 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) To a suspension of 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (300.09 g, 1.04 mol; assay: 99.0percent) and trifluoromethane sulfonic acid (4.77 g, 0.03 mol; assay: 98.0percent) in toluene (1122 g) was added slowly trifluoroacetic anhydride (255.18 g, 1.20 mol; assay: 99.0percent) at 20-35° C. The brown solution was stirred after complete addition of trifluoroacetic anhydride for 1 hour at 20-25° C. and the mixture was then hydrolyzed with water (99.0 g). Afterwards, the mixture was distilled under normal pressure until the steam temperature was 105-110° C. (1191 g two-phase distillate). The residue was diluted with toluene (261 g) and the suspension was heated to reflux. The dark solution was then cooled to 75° C. and seeded with crystals of 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2). The suspension was stirred after cooling to 20-25° C. for additional 1-2 hours at this temperature. The product was filtered off, washed with cyclohexane (600 g) and water (390 g) and dried under vacuum (20 h, 50° C.) to give 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (yield: 203.21 g, 0.76 mol, 73.0percent; HPLC assay >99.5percent, HPLC purity: 99.62percent). This product was then recrystallized from a mixture of cyclohexane (700 g) and toluene (1892 g). After filtration the wet product was washed with cyclohexane (466 g) and dried under vacuum (15 h, 70° C.) to give slightly gray colored 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (yield: 198.4 g, 0.74 mol, 97.6percent; HPLC assay >99.5percent, HPLC purity: 99.90percent; overall yield: 71.3percent). | |
69.9% | With acetic anhydride; at 80 - 90℃; for 2h;Large scale; | The 10 kg acetic anhydride heated to 70-80°C, batch by adding 2 kg intermediate II, after adding to 80-90 °C stirring 2h, cooling to room temperature, to the reaction solution slowly and 40L water, precipitating a large amount of the yellow solid, stirring for 30 min, filtration, recrystallization with isopropanol/water, shall be intermediate III1.31kg, yield: 69.9percent, purity of 99.1percent. |
With PPA; In water; acetic acid; | (e) As an alternative to step (d) above, 43.7 g. of polyphosphoric acid are added to 10.0 g. of 4-(2-carboxybenzyloxy)-phenylacetic acid in 35 ml. of glacial acetic acid. The mixture is vigorously stirred at 76° C. for 12/3 hours and then hydrolyzed with 250 ml of water, the temperature being kept at 40° C. The precipitate which separates is collected and, when recrystallized from 2-propanol-water, provides pale yellow crystals, m.p. 137°-138°, of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid. Analysis: Calculated for C16 H12 O4: 71.64percent C; 4.51percent H. Found: 71.58percent C; 4.58percent H. | |
With acetic acid; at 70 - 75℃; for 2.5h;Product distribution / selectivity; | Example 12: Preparation of ll-oxo-6,ll-dihydrobenz[b,e]oxepin-2-acetic acid formula-2.A mixture of polyphosphoric acid (385 g), 2-((4-(carboxymethyl)phenoxy) methyl)benzoic acid (110 g) and acetic acid (330 ml) was heated to 70-75°C and stirred for 2 1/2 hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C, further to 10-15°C. Quenched the reaction mixture with water at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at same temperature. Filtered the precipitated solid, washed with water and dried. Ethylacetate (300 ml) was added to the obtained solid and heated the reaction mixture to 70-75°C and then stirred for 15 minutes at same temperature. Carbon (6 g) was added to the reaction mixture and stirred for 15 minutes. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Cooled the obtained filtrate to 0-5 °C and stirred for 1 hour at same temperature. Filtered the precipitated solid, washed with cyclohexane and then dried to get the title compound.Yield: 55 gmsMR: 137-138°C. | |
0.8 kg | With acetic acid; In cyclohexane; at 70 - 85℃; | 15 mg of HAClL, cyclohexane 0. 5 L and 4- (2-hydroxybenzyloxy) phenylacetic acid were charged into a reaction vessel, stirred and the reaction was stirred at 70-85 ° C for 2-4 hours. Stir under the conditions of adding appropriate amount of drinking water, stirring, filtering, drinking water to wash the solid. |
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