Structure of 3846-73-9
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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. : | 3846-73-9 |
Formula : | C10H9NO |
M.W : | 159.19 |
SMILES Code : | OC1=C2N=CC=C(C)C2=CC=C1 |
MDL No. : | MFCD02170459 |
InChI Key : | OYUKRQOCPFZNHR-UHFFFAOYSA-N |
Pubchem ID : | 345169 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.1 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 48.73 |
TPSA ? Topological Polar Surface Area: Calculated from |
33.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.89 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.41 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.25 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.49 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.44 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.1 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.96 |
Solubility | 0.174 mg/ml ; 0.00109 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.75 |
Solubility | 0.285 mg/ml ; 0.00179 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.5 |
Solubility | 0.0503 mg/ml ; 0.000316 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) |
Yes |
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 |
-5.56 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 |
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) |
1.08 |
* 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 |
---|---|---|
50.1% | With sodium hydroxide; In ethanol; at 80℃; for 20.0h; | <strong>[3846-73-9]4-methyl-8-hydroxyquinoline</strong> (3.18 g, 0.02 mol) and sodium hydroxide (1.60 g, 0.04 mol) were dissolved in ethanol (80 ml), mixed thoroughly and heated to 80 C. The mixture was added benzyl bromide (2.85 ml, 0.024 mol) dropwise and reflux for 20 h. After cooled to room temperature, the mixture was neutralized with dilute hydrochloric acid and then extracted with CH2Cl2. The solution was dried with anhydrous MgSO4 and then the solvent was removed on a rotary evaporator. The crude product was further purified by a column chromatography (silica gel) with CH2Cl2 as the eluent, giving a colorless solid (2.50 g, yield 50.1%). deltaH (400 MHz; CDCl3; Me4Si): 8.94 (d, 1H, J=4.5 Hz), 7.54-7.59 (m, 3H), 7.45 (t, 1H, J=8.0 Hz), 7.29-7.39 (m, 4H), 7.10 (d, 1H, J=8.0 Hz), 5.49 (s, 2H), 2.74 (s, 3H). |
With potassium hydroxide; In ethanol;Reflux; | The intermediate INT 1 was synthesized through ring closure from 2-aminophenol reacted with methyl vinyl ketone. INT 1 was reacted with various alkyl halides to afford 8-alkoxy-4methylquinoline derivatives as intermediates. Corresponding Rr(CH2)_,OH was reacted with intermediates to synthesize series of compounds J and I. The protective group J was removed by hydrogenation (method illustrated in example 1) to obtain compound K. | |
With potassium hydroxide; In ethanol;Reflux; | Example 7 - Preparation of 8-hydroxyquino -yi) or (S-alkovyquino -yl) aikyl alcohols SWT 1 11 = 11-12 n = 11-12 K1 - K2 J1 - J2 Reagents and conditions: (a) methyl vinyl ketone, HCL reflux, (b) Mel. sCCh, acetone, rt 8h; Elf or 2~bromopropane or methylenecyclopropyl bromide, K2CO3, DMF, 60 6C, (c) I) LH.MDS, THF, 0 C, 1 h.: 2) Br(CH2)..i H, rt. (d) BnBr. KOM, EtOH, reflux, (e) H Pd/C, MeOH, rt 24 h. Method: Te intermediate INT was synthesized through ring closure from 2-arninophenol reacted with methyl vin l ketone. INT I was reacled with various aJkyl halides to afford 8-alkoxy- 4methylquino.)me derivatives as intermediates. Corresponding Brt'CHs iOH was reacted with intermediates to synthesize series of compounds 3 and I. The protective group J was removed by hydrogenaiiori (method iliustraied in example I) to obtain compound K. 1 1 -(S-nietlioxyquinoIin-4-yl)imde?aii-i-oI ( I) YD: 34%. lH NMR (400 MHz, CDt) 88.80 (ckt J - 4.4, 0.6 Hz. IH), 7.59 (dd, J ~ 8.4, 0.8 Hz, I H), 7.44-7.49 (m, 1H 7.03 (d. J - 7.6 Hz, Hh 4.08 (3, 3H); 3.63 ( J ::: 6.8 Hz, 2H), 3.03 (t J - 7.6 Hz, 2H), 1.74 (quia - 7.6 Hz, 2H), S .55 (quin, J - 7.2 Hz, 2H), 1.23-1.45 (br, 1SH); MS. m/z 329.9, JM+Hf . |
With potassium hydroxide; In ethanol;Reflux; | . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.5% | With hydrogenchloride; In water; at 120℃; for 6.0h; | Hydrochloric acid (37%, 45.5 ml) and 2-aminophenol (10.91 g, 0.1 mol) were put into a 250 ml two-necked round flask, mixed thoroughly and heated to 120 C. The mixture was added methyl vinyl ketone (14.32 ml, 0.175 mol) dropwise and reflux for 6 h. After being cooled to room temperature, the mixture was neutralized with aqueous sodium hydroxide solution and then extracted with dichloromethane (CH2Cl2) (50 ml × 3). The solution was dried with anhydrous MgSO4 and then the solvent was removed on a rotary evaporator. The crude product was further purified by column chromatography (silica gel) with CH2Cl2 as the eluent, followed by a recrystallization in the mixture of CH2Cl2 and n-hexane (1:1, v/v) to give a colorless solid (4.38 g, yield 27.5%). deltaH (400 MHz; (CD3)2CO; Me4Si): 8.68 (d, 1H, J=4.4 Hz), 7.55 (dd, 1H, J1=8.4 Hz, J2=1.5 Hz), 7.51 (dd, 1H, J1=8.4 Hz, J2=7.2 Hz), 7.41 (dd, 1H, J1=4.4 Hz, J2=0.8 Hz), 7.12 (dd, 1H, J1=7.2 Hz, J2=1.5 Hz), 2.71 (d, 3H, J=0.8 Hz). |
With hydrogenchloride; sodium hydroxide; | (A) 4-Methyl-8-quinolinol A solution of 100 ml of concentrated hydrochloric acid, 27.3 g (250 mmol) of 2-aminophenol and 41 ml (500 mmol, 2 eq.) of methyl vinyl ketone was heated to 110-120 C. for 18 hours. The reaction was cooled, poured onto crushed ice, brought to pH 7 using 10N sodium hydroxide and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography (silica gel, 1:2 ethyl acetate/petroleum ether) and crystallization (ethyl acetate) gave 5.3 g of the title compound as a light yellow solid: melting point 135-136 C. | |
With hydrogenchloride;Reflux; | The intermediate INT 1 was synthesized through ring closure from 2-aminophenol reacted with methyl vinyl ketone. INT 1 was reacted with various alkyl halides to afford 8-alkoxy-4methylquinoline derivatives as intermediates. Corresponding Rr(CH2)_,OH was reacted with intermediates to synthesize series of compounds J and I. The protective group J was removed by hydrogenation (method illustrated in example 1) to obtain compound K. |
With hydrogenchloride; In water;Reflux; | Example 7 - Preparation of 8-hydroxyquino -yi) or (S-alkovyquino -yl) aikyl alcohols SWT 1 11 = 11-12 n = 11-12 K1 - K2 J1 - J2 Reagents and conditions: (a) methyl vinyl ketone, HCL reflux, (b) Mel. sCCh, acetone, rt 8h; Elf or 2~bromopropane or methylenecyclopropyl bromide, K2CO3, DMF, 60 6C, (c) I) LH.MDS, THF, 0 C, 1 h.: 2) Br(CH2)..i H, rt. (d) BnBr. KOM, EtOH, reflux, (e) H FontWeight="Bold" FontSize="10" Pd/C, MeOH, rt 24 h. Method: Te intermediate INT was synthesized through ring closure from 2-arninophenol reacted with methyl vin l ketone. INT I was reacled with various aJkyl halides to afford 8-alkoxy- 4methylquino.)me derivatives as intermediates. Corresponding Brt'CHs iOH was reacted with intermediates to synthesize series of compounds 3 and I. The protective group J was removed by hydrogenaiiori (method iliustraied in example I) to obtain compound K. 1 1 -(S-nietlioxyquinoIin-4-yl)imde?aii-i-oI ( I) YD: 34%. lH NMR (400 MHz, CDt) 88.80 (ckt J - 4.4, 0.6 Hz. IH), 7.59 (dd, J ~ 8.4, 0.8 Hz, I H), 7.44-7.49 (m, 1H 7.03 (d. J - 7.6 Hz, Hh 4.08 (3, 3H); 3.63 ( J ::: 6.8 Hz, 2H), 3.03 (t J - 7.6 Hz, 2H), 1.74 (quia - 7.6 Hz, 2H), S .55 (quin, J - 7.2 Hz, 2H), 1.23-1.45 (br, 1SH); MS. m/z 329.9, JM+Hf . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Examples of hydroxyl compounds which were used according to the invention are: ... 2-hydroxy-pyridine, 3-hydroxy-pyridine, 4-hydroxy-pyridine, 5-hydroxy-4-methyl-quinoline, 8-hydroxy-4-methyl-quinoline. | ||
The reaction was warmed to 0 C., stirred for 15 minutes and 0.30 g (1.9 mmol) of 4-methyl-8-quinolinol in 10 ml of dry tetrahydrofuran was added. The temperature was maintained at 0 C. for 24 hours, then the solution was warmed to room temperature and 3.0 ml (15 mmol, 8 eq.) of 1-bromononane was added. After stirring for one hour at room temperature, water was added and the reaction mixture was extracted with ether. The organic layers were washed with saturated ammonium chloride, brine, dried (magnesium sulfate) and concentrated in vacuo. Flash chromatography (silica gel, 1:9 ethyl acetate:petroleum ether) and subsequent recrystallization (methanol) gave 0.23 g of the title compound as pale green crystals: melting point 67-68 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[1805] Into a 100 mL round bottom flask containing a stirring bar and fitted with a reflux condenser and a septum was placed 10 mL 70% sulfuric acid, sodium iodide (0.23 g, 0.24 mmol) and anisidine (2.96 g, 24 mmol). This mixture was heated to 110 C., and to it was added methyl vinyl ketone (3.2 mL, 38.45 mmol) slowly over 5 hours via a syringe pump. After heating an additional hour, the reaction was cooled and poured into 50 mL 1M aqueous Na2CO3 and extracted with CH2Cl2. The combined organic extracts were extracted with 12M HCl. The acidic extracts were neutralized with 6M NaOH and extracted with CH2Cl2. The combined organic extracts were washed with water, brine dried over Na2SO4, filtered and the solvent removed. The residue was dissolved in EtOAc and passed through a silica pad to get the methyl ether, which was dissolved in 50 mL HBr and heated to reflux for 30 hours, after which the reaction was cooled and neutralized with 1ON NaOH and extracted with CH2Cl2. The combined organic extracts were combined, washed with water, brine, dried over Na2SO4, filtered and the solvent removed in vacuo to give 4-methylquinolin-8-ol. [1806] 1H NMR (CDCl3) delta: 2.70(3H, s); 7.18(1H, t, j=4Hz); 7.27(1H, d, j=4.2 Hz); 7.47(1H, d, j=4Hz); 8.63(1H, d,j=4.2 Hz) ES MS M+1=160 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; | 8-(4-Chlorobenzyloxy)-4-methylquinoline (Step A): 4-methyl-8-hydroxy quinoline (2.65 g, 16.6 mmol) [prep. acc. P. Belser, S. Bernhard, U. Guerig, Tetrahedron 52, 1996, 2937-2944] was dissolved in a warm solution of KOH (930 mg, 16.6 mmol) in ethanol (50 mL). The mixture was heated to reflux and a solution of 4-chlorobenzyl chloride (3.5 g, 21.7 mmol) in ethanol (20 ml) was added dropwise to the refluxing solution during a period of 30 min. Refluxing was continued for 16 h. The solution was filtered by suction, and the filtrate was concentrated. The residue was diluted with ethyl acetate (100 ml), extracted with water (100 mL), dried (MgSO4) and concentrated. Flash chromatography (silicagel, hexane:ethyl acetate, 3:1) provided 1.69 (34%) beige solid. 1H NMR (CDCl3): delta 2.69 (s, 3H), 5.41 (s, 2H), 7.00 (d, J=7.7 Hz, 1H), 7.30 (d, J=4.3 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.40 (dd, J=7.7, 8.3 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 1H), 8.85 (d, J=4.3 Hz, 1H); GC-MS (pos.): 283. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; water; | (A) 4-(2-Phenylethyl)-8-quinolinol A solution of 0.60 ml (4.2 mmol, 2.2 eq.) of diisopropylamine in 10 ml of dry tetrahydrofuran was cooled to -78 C. and 1.6 ml (3.8 mmol, 2 eq.) of 2.4M n-butyl lithium in hexane was added dropwise. The reaction was warmed to 0 C., stirred for 15 minutes and 0.30 g (1.9 mmol) of <strong>[3846-73-9]4-methyl-8-quinolinol</strong> (see Example 1A) in 10 ml of dry tetrahydrofuran was added. The temperature was maintained at 0 C. for 24 hours, then was cooled to -78 C. and 0.23 ml (1.9 mmol, 1 eq.) of benzyl bromide was added. The reaction was stirred at -78 C. for one hour then stirred at room temperature for one hour. Water was added and this was extracted with ether. The organic layers were washed with saturated ammonium chloride, brine, dried (magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography (silica gel, 1:4 ethyl acetate:petroleum ether) and recrystallization (petroleum ether) gave 240 mg of the title compound as pale green crystals: melting point 102-103 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; diisopropylamine; lithium diisopropyl amide; In tetrahydrofuran; hexane; | (A) 4-Heptyl-8-quinolinol To a solution of 1.10 ml (7.88 mmol) of diisopropylamine in 20 ml of tetrahydrofuran at 0 C. under argon was added 4.1 ml (6.23 mmol) of 1.52M n-butyl lithium in hexanes dropwise. To the lithium diisopropylamide solution was added 502.0 mg (3.15 mmol) of <strong>[3846-73-9]4-methyl-8-quinolinol</strong> (see example 1A) in 10 ml of tetrahydrofuran over 15 minutes at 0 C. The dark solution, which contained some insoluble material, was allowed to stir for five hours at 0 C., cooled to -78 C. and 0.46 ml (3.31 mmol) of 1-bromohexane was added. After 30 minutes at -78 C., the reaction was allowed to warm gradually from -30 C. to room temperature over 1.5 hours. The solution was allowed to stir for 45 minutes at room temperature, quenched with pH 6.5 phosphate buffer and extracted with ether. The ether extract was washed with water and brine, dried (magnesium sulfate) and evaporated to afford 757 mg of a yellow-brown solid. This material was dissolved in hot hexane, filtered to remove an insoluble residue and the filtrate was evaporated. Recrystallization from heptane provided 511.7 mg of the title compound as yellow plates: melting point 92-93.5 C. |