Structure of 4488-40-8
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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. : | 4488-40-8 |
Formula : | C12H10O2 |
M.W : | 186.21 |
SMILES Code : | C1=CC=CC2=C(C=CC(=C12)C(O)=O)C |
MDL No. : | MFCD00671557 |
InChI Key : | SIVYRLBDAPKADZ-UHFFFAOYSA-N |
Pubchem ID : | 3014285 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.08 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 55.87 |
TPSA ? Topological Polar Surface Area: Calculated from |
37.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.32 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.46 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.85 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.92 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.82 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.67 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.64 |
Solubility | 0.043 mg/ml ; 0.000231 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.92 |
Solubility | 0.0221 mg/ml ; 0.000119 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.83 |
Solubility | 0.0272 mg/ml ; 0.000146 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 |
-4.98 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 |
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) |
1.0 |
* 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 thionyl chloride; for 0.25h;Heating / reflux; | To a stirred solution of 0.080 g (0.50 mmol) of 1-propylindole in 1.5 mL of dry CH2Cl2 at 0 C. under N2 was added dropwise 0.75 mL (0.75 mmol) of Me2AlCl (1 M in hexanes). The solution was stirred at 0 C. for 30 min and a solution of 0.122 g (0.6 mmol) of freshly prepared 4-methyl-1-naphthoyl chloride in 1.5 mL of CH2Cl2. The acid chloride was prepared form 0.122 g (0.60 mmol) of 4-methyl-1-naphthoic acid to which was added dropwise 1 mL of thionyl chloride at a rate sufficient to maintain a steady evolution of gas. This solution was heated at reflux for 15 min, cooled to ambient temperature and the excess thionyl chloride was removed in vacuo to give the acid chloride which was used without further purification. The deep red acylation reaction mixture was stirred at 0 C. until the reaction was complete as indicated by tlc (approximately 1 h). The reaction mixture was poured carefully into iced 1 M aqueous HCl and extracted with three portions of CH2Cl2. The combined extracts were washed wth three portions of aqueous NaHCO3, dried (MgSO4) and the solvent was removed in vacuo to give the crude product. After chromatography (petroleum ether:ethyl acetate, 9: 1) there was obtained 0.140 g (86%) of indole 41 as a white solid. Recrystallization from hexanes/ethyl acetate gave the analytical sample: m.p. 207-208 C.; 1H NMR (300 MHz, CDCl3) delta 0.90 (t, J=7.3 Hz, 3H), 1.81-1.88 (m, 2H), 2.78 (s, 3H), 4.03 (t, J=7.0 Hz, 2H), 7.37-7.38 (m, 5H), 7.48-7.59 (m, 3H), 8.09 (d, J=8.2 Hz, 1H), 8.27 (d, J=8.2 Hz, 1H), 8.52-8.54 (m, 1H); 13C NMR (75.5 MHz, CDCl3) delta 11.3, 19.7, 23.1, 48.7, 109.9, 117.6, 122.7, 122.9, 123.5, 124.2, 125.5, 125.8, 126.1, 126.3, 126.6, 127.0, 130.9, 132.8, 136.6, 137.0, 137.5, 137.9, 192.2; Anal. Calcd for C23H21NO: C, 84.37; H, 6.46; N, 4.28; Found: C, 84.25; H, 6.46; N, 4.30. | |
With thionyl chloride; In dichloromethane; for 4h;Reflux; Inert atmosphere; | 4-Methyl-l-napthoyl chloride[0151] To a solution of 0.35 g (1.89 mmol) of 4-methyl-l-napthoic acid in 3 mL of dry dichloromethane under argon, was added 2.5 ml (34.3 mmol) of thionyl chloride. The solution was refluxed for 4 hrs and the solvent and excess thionyl chloride were removed by vacuum distillation to give a red oil, which was used without further purification. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; | Step B: 4-Methylnaphthalenecarbonyl chloride.; Step B: 4-Methylnaphthalenecarbonyl chloride. Oxalyl chloride (0.53 niL, 6.1 mmol), followed by anhydrous DMF (2-3 drops) was added to a stirred solution of 4-methylnaphthalenecarboxylic acid (0.227 g, 1.22 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 2 h, evaporated and dried under vacuum for 0.5 h. to give the title acid chloride , which was used without further purification in step A. |
With thionyl chloride; | Step B. 2-(4-Methyl-l-naphthalenyl)-4H-pyrido [3,2-d] [1,3]oxazin-4-one; Following the procedure for Step B in Example 1, a suspension of 3-amino-2- pyridinecarboxylic acid (414 mg, 3.0 mmol) in CH2Cl2 (10 mL) and DIPEA (1.25 mL, 7.2 mmol) was treated with 4-methyl-l-naphthalenecarbonyl chloride, prepared from 4- methyl-1-naphthalenecarbonylic acid (590 mg, 3.17 mmol) with thionyl chloride (4.11 g, 35 mmol), and then with HATU (1.25 g, 3.3 mmol) in DMF (10 mL). The title compound was formed and directly used in Step A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane; ethyl acetate; | 4-Bromomethylnaphthoic Acid: A mixture of 4-methylnaphthoic acid (10 g, 54 mmol), N-bromosuccinimide (10 g, 56 mmol) and AIBN (100 mg) in CCl4 (250 mL) was refluxed for 3 hr. The reaction mixture was concentrated and dissolved in ethyl acetate. The organic layer was washed with water, brine and dried over MgSO4. Evaporation of the solvent gave the desired product (16 g, 80%). 1H NMR (DMSO-D6): delta 5.24 (s, 2H), 7.73 (m, 3H), 8.03 (d, 1H), 8.28 (d, 1H), 8.86 (d, 1H), 13.29 (brd s, 1H). |
71% | With N-Bromosuccinimide;1,1'-azobis(1-cyanocyclohexanenitrile); In 1,2-dichloro-ethane; at 80℃; for 4h; | Step A. The preparation of 4-(bromomethy I)-I -naphthoic acid; <n="45"/>4-MethyInaphthoic acid (1.05 g, 5.66 mmol), N-bromosuccinimide (1.01 g) and 1,1'- azobis(cyclohexane-carbonitrile) (50 mg, catalytic amount) were placed in a round- bottomed flask. 1,2-Dichloroethane (40 ml) was added and the mixture heated at 8O0C for 4 h. Volatiles were evaporated tinder vacuum. The residue was dissolved in a mixture of ethyl acetate and water, phases were separated and the organic phase dried over calcium chloride. After evaporation of solvent, the product was obtained as a white solid (1.07 g, 71%). 1H- NMR (400 MHz, CD3OD) delta: 5:08 (s, 2 H); 7.51 - 7.81 (m, 3 H); 8.10 (d, J=7.42 Hz, 1 H); 8.18 - 8.39 (m, 1 H); 8.85 - 9.09 (m, 1 H). |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 2h;Reflux; | 4-methylnaphthalen-l-carboxylic acid (5 g), N-bromosuccinimide (5.7 g) and 2,2'- azobisisobutyronitrile (0.2 g) were suspended in carbon tetrachloride (50 ml) and then heated to <n="65"/>reflux for 2 hours. The mixture was returned to room temperature and added a 15% aqueous solution of citric acid (20 ml), and stirred for some time. Resulting crystals were filtered and washed with the 15% aqueous solution of citric acid (20 ml), and then dried, to obtain 4- (bromomethyl)naphthalen-l-carboxylic acid (7 g).IH-NMR (acetone-d6) delta: 5.19 (2H, s), 7.69-7.76 (3H, m), 8.23-8.29 (2H, m), 9.04-9.06 (IH, m) |
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