Structure of 52980-28-6
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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. : | 52980-28-6 |
Formula : | C12H11NO3 |
M.W : | 217.22 |
SMILES Code : | O=C(C1=CNC2=C(C=CC=C2)C1=O)OCC |
MDL No. : | MFCD01314279 |
InChI Key : | YBEOYBKKSWUSBR-UHFFFAOYSA-N |
Pubchem ID : | 220876 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H320-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 60.66 |
TPSA ? Topological Polar Surface Area: Calculated from |
59.16 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.83 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.99 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.7 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.98 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.78 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.86 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.7 |
Solubility | 0.428 mg/ml ; 0.00197 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.86 |
Solubility | 0.301 mg/ml ; 0.00138 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.1 |
Solubility | 0.0174 mg/ml ; 0.0000802 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 |
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 |
-6.21 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 |
0.55 |
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) |
1.88 |
* 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 |
---|---|---|
87% | With lithium hydroxide monohydrate; In tetrahydrofuran; water; at 20℃; | General procedure: The ethyl 4(1H)-oxo-quinolone-3-carboxylate (1?2 mmol) was dissolved in 5 mL MeOH. LiOH·H2O (3.0equiv), dissolved in 1?2 mL H2O, was added to the reaction mixture. The reaction mixture was stirredat ambient temperature overnight or monitored by TLC analysis. After the starting material was fullyconsumed (judged by TLC-analysis), the reaction volume was reduced to one third of its initialvolume. The solution was acidified to pH 2?3 (pH-paper) with 1 M HCl. The resulting white solutionwas centrifuged and the liquid carefully removed. The remaining solid was washed with water andcentrifuged twice, leaving a pure off-white solid. |
80% | With water; lithium hydroxide; at 0 - 80℃; for 16h; | Ex mple 2: Synthesis of 4-Oxo-l,4-dihydroquinoline-3-carboxylic acid (3): (0084) (0085) To a suspension of ethyl 4-oxo- l,4-dihydroquinoline-3-carboxylate (2) (0.5 g, 2.30 mmol) in THF (10 mL), a solution of aqueous 1 M LiOH (aq) (4.60 mL, 4.60 mmol) was added drop wise at 0 C, and then the reaction mixture was heated at 80 C for 16h. Reaction mass was evaporated to dryness, dissolved in H20 (5 mL), washed with diethyl ether (2x5 mL).The aqueous layer was acidified with 1 M HC1 (aq),compound thus precipitated was filtered, dried under vacuum to give desired compound as off-white solid. Yield: (0.35g; 80%) 1H NMR (400MHz ,DMSO-d6) delta = 15.36 (brs, 1H), 13.43 (brs, 1H), 8.91 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.98 - 7.75 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H). |
75% | With sodium hydroxide; In ethanol; for 5h;Reflux; | General procedure: A suspension of ester 3e-k (2 mmol) in 4% NaOHhydroalcoholic solution (5 ml) was refluxed until no startingmaterial could be detected by Thin Layer Chromatography(5 h). After cooling, the mixture was completely acidifiedby adding concentrated HCl and the solid obtained wascollected by filtration, washed with water, and crystallizedfrom ethanol to afford compound 4e-k. 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (4e) Starting from 3e (1 g); Yield (white powder): 600 mg(75 %); m.p. 280 C (decomposed); IR (KBr) numax1400-1600 (aromatic), 1717 (carbonyl), 2790-3260 (acidicOH) cm-1; 1H-NMR (DMSO-d6, 500 MHz) delta = 7.59-7.63 (1H, t, J = 7.2 Hz, H6), 7.83 (1H, d, J = 8.2 Hz, H8), 7.90(1H, t, J = 7.0 Hz, H7), 8.30 (1H, d, J = 7.3 Hz, H5), 8.90(1H, s, H2), 13.42 (1H, br s, enolic OH), 15.34 (1H, br s,carboxylic OH); 13C-NMR (DMSO-d6, 60 MHz) delta = 105.3(C, C-3), 119.7 (CH, C-9), 123.6 (CH, C-7), 125.6 (CH,C-6), 125.9 (C, C-5), 133.9 (CH, C-8), 138.5 (C,C-10), 158.9 (CH, C-2), 167.2 (C,COOH), 178.5 (C, C=O);LC-MS (ESI) m/z 212.1 (M+Na+); Anal. Calcd. forC10H7NO3: C, 63.49; H, 3.73; N, 7.40. Found: 63.62; H,3.96; N, 7.69. |
With hydrogenchloride; water; at 85 - 90℃; for 6.5h;Product distribution / selectivity; | Compound 25 (1.0 eq) was suspended in a solution of HCl (10.0 eq) and H2O (11.6 vol). The slurry was heated to 85 - 90 0C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 C. In some instances, the hydrolysis is performed at a temperature of from about 80 to about 95 0C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 C (e.g., from about 82.5 to about 92.5 C or from about 86 to about 89 0C). After stirring at 85 - 90 0C for approximately 6.5 hours, the reaction was sampled for reaction completion. Stirring may be performed under any of the temperatures suited for the hydrolysis. The solution was then cooled to 20 - 25 0C and filtered. The reactor/cake was rinsed with H2O (2 vol x 2). The cake was then washed with 2 vol H2O until the pH >; 3.0. The cake was then dried under vacuum at 60 0C to give compound 26. | |
Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 0C and then the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m). | ||
Procedure for the preparation of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (26) Method 2Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 C. and then the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m). | ||
With water; sodium hydroxide; In ethanol; for 16h;Reflux; | Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 C and then the pH was adjusted to 2-3 with 8% HC1. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give Compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m). | |
With hydrogenchloride; water; at 85 - 90℃; | Compound 25 (1.0 eq) was suspended in a solution of HQ (10,0 eq) and H20 (1 1.6 vol). The slum'' was heated to 85 - 90 C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 C. in some instances, fee hydrolysis is performed at a temperature of from about 80 to about 95 C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 C (e.g., from about 82.5 to about 92.5 C or from about 86 to about 89 C). After stirring at 85 - 90 C for approximately 6.5 hours, fee reaction was sampled for reaction completion. Stirring may be performed under any of the temperatures suited for the hydrolysis. The solution was then cooled to 20 - 25 C and filtered. The reactor/cake was rinsed wife H2?> (2 vol x 2), The cake was then washed with 2 vol 0 until fee pH > 3.0, The cake was then dried under vacuum at 60 C to give Compound 26. | |
With water; sodium hydroxide; In ethanol; for 16h;Reflux; | Method 1[00326] Compound 25 (1.0 eq) was suspended in a solution ofHCl (10.0 eq) and H20 (11.6vol). The slurry was heated to 85 - 90 C, although alternative temperatures are also suitable forthis hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperatureof from about 75 to about 100 C. In some instances, the hydrolysis is performed at atemperature of from about 80 to about 95 C. In others, the hydrolysis step is performed at atemperature of from about 82 to about 93 oc (e.g., from about 82.5 to about 92.5 oc or fromabout 86 to about 89 C). After stirring at 85 - 90 oc for approximately 6.5 hours, the reactionwas sampled for reaction completion. Stirring may be performed under any of the temperaturessuited for the hydrolysis. The solution was then cooled to 20 - 25 oc and filtered. Thereactor/cake was rinsed with H20 (2 vol x 2). The cake was then washed with 2 vol H20 untilthe pH 2: 3.0. The cake was then dried under vacuum at 60 octo give compound 26.Method 2[00327] Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL)and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 oc andthen the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours andfiltered. The cake was washed with water (50 mL) and then dried in vacuo to give compound 26as a brown solid. 1H NMR (DMSO-d6; 400 MHz) 8 15.33 (s), 8 13.39 (s), 8 8.87 (s), 8 8.26 (m),8 7.87 (m), 8 7.80 (m), 8 7.56 (m). | |
7.5 g | With water; sodium hydroxide; at 80 - 85℃; for 3h; | In a clean round bottom flask, ethyl 4-oxo-l, 4-dihydroquinoline-3-carboxylate (10.0 gm) was charged to a solution of sodium hydroxide (3.7 gm) in 13.0 ml water. The reaction mass was heated for 3.0 hr at 80-85 C and then cooled to 25-30. To this was added 0.10 gm of activated charcoal and filtered. The pH was adjusted using con HCL and the product was filtered and washed with water. The wet cake slurried in methanol at 25 -30 C and filtered. The product was dried under vacuum at 50.0 C to get 7.50 gm of title productPurity by HPLC - 99.75 % |
Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 C. and then the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give Compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m). | ||
With hydrogenchloride; In water; at 85 - 90℃; | Method 1 [00341] Compound 25 (1.0 eq) was suspended in a solution of HC1 (10.0 eq) and H20 (1 1.6 vol). The slurry was heated to 85 - 90 C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 C. In some instances, the hydrolysis is performed at a temperature of from about 80 to about 95 C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 C (e.g., from about 82.5 to about 92.5 C or from about 86 to about 89 C). After stirring at 85 - 90 C for approximately 6.5 hours, the reaction was sampled for reaction completion. Stirring may be performed under any of the temperatures suited for the hydrolysis. The solution was then cooled to 20 - 25 C and filtered. The reactor/cake was rinsed with H20 (2 vol x 2). The cake was then washed with 2 vol H20 until the pH > 3.0. The cake was then dried under vacuum at 60 C to give compound 26. | |
With sodium hydroxide; at 90 - 100℃; | Step c : 4-Oxo 1,4-dihydroquinoline- 3-carboxylic acid 4-hydroxyquinoline 3- carboxylic acid ethyl ester (100 g) was suspended in 2N sodium hydroxide solution at room temperature and was heated to 90-100 C. and maintained for 2-4 hours. After completion, the reaction mass was cooled to room temperature and filtered to remove undissolved material. The obtained filtrate was acidified to pH 3-4 with 2N Hydrochloric acid at 25-30 C. The resultant solid was filtered, washed with water and dried at 50 C. until constant weight was observed to obtain the title compound (55-65 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.8% | With thionyl chloride; at 85℃; | <strong>[13721-01-2]4-oxo-1,4-dihydroquinoline-3-carboxylic acid</strong> (1.08 g, 5.7 mmol, 1.0 eq) was dissolved in ethanol (15 mL), and socl2 (6.8 g, 57 mmol) was added dropwise with stirring. , 10.0 eq.), And reacted at 85 C. overnight.The reaction was monitored for completeness by TLC, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 60: 1 to 40: 1) to obtain the product (901.3 mg, yield: 72.8%). |
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