Structure of 91192-32-4
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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. : | 91192-32-4 |
Formula : | C9H8N2O2 |
M.W : | 176.17 |
SMILES Code : | O=C1NC2=C(C=C(OC)C=C2)N=C1 |
MDL No. : | MFCD17215509 |
InChI Key : | SYEUUDPGKMMKRU-UHFFFAOYSA-N |
Pubchem ID : | 13437707 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.11 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 48.86 |
TPSA ? Topological Polar Surface Area: Calculated from |
54.98 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.52 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.77 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.93 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.45 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.05 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.14 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.92 |
Solubility | 2.12 mg/ml ; 0.012 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.5 |
Solubility | 5.51 mg/ml ; 0.0313 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.36 |
Solubility | 0.0769 mg/ml ; 0.000437 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 |
-6.83 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) |
1.8 |
* 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 |
---|---|---|
In ethanol; toluene; at 20℃;Reflux; | Step A: 7-Methoxyquinoxalin-2(1H)-one and 6-methoxyquinoxalin-2(1H)-one A 50% solution of ethyl 2-oxoacetate (18.47 mL, 93 mmol) in toluene was added to a solution of 4-methoxybenzene-1,2-diamine (10.73 g, 78 mmol) in ethanol (100 mL) at ambient temperature and the reaction was refluxed for 2 h. The reaction was concentrated in vacuo and crystallized from ethanol to afford a mixture of 6-methoxyquinoxalin-2(1H)-one and 7-methoxyquinoxalin-2(1H)-one (5.73 g, 32.50 mmol, 42% yield). MS (LC/MS) R.T.=0.68; [M+H]+=177.10. | |
In ethanol;Reflux; | To a solution of 4-methoxybenzene-1,2-diamine (5 g, 36.2 mmol) in ethanol (50 ml) was added ethyl 2-oxoacetate (4.06 g, 39.8 mmol)). The reaction mass was heated at reflux for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate and then evaporated to dryness to get the crude compound. The crude compound was washed with pet ether to get crude compound (5.1 g, 80% yield) as a mixture of regioisomers (black solid). This crude compound was taken to the next step without separation of isomers.1H NMR (400 MHz, DMSO-d6): δ ppm 8.17 (s, 1H), 7.98 (s, 1H), 7.70-7.68 (d, J=8 Hz, 1H), 7.31-7.30 (d, J=4 Hz, 1H), 7.27-7.20 (m, 2H), 6.93-6.90 (m, 1H), 6.77-6.76 (d, J=4 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H); MS: MS m/z 177.0 (M++1). | |
In toluene; at 20℃; for 2h;Reflux; | 50% solution of ethyl2-oxoacetate (18.47 ml., 93mmol) in toluene was added to a solution of 4-methoxybenzene-I,2-diamine (10.73 g, 78 mmol) in ethanol (100 mL) at ambient temperature and the reaction was ref/uxed for 2 h.The reaction was concentrated in vacuo and crystallized fromethanol to afford a mixture of 6-methoxyquinoxalin-2(1H)oneand 7-methoxyquinoxalin-2(1H)-one (5.73 g, 32.50mmol, 42% yield). |
In ethanol; toluene; at 0 - 20℃; for 2h; | Intermediate 149: 2-Chloro-7-methoxyquinoxalineA solution of 4-methoxybenzene-l,2-diamine (16.8 g, 0.12 mmol) in ethanol (250 mL) was treated with a solution of ethyl oxoacetate (50 wt % in toluene, 50 mL, 0.23 mmol) dropwise with cooling in an ice bath. The reaction was allowed to warm to room temperature and after 2 hours, a precipitate was collected by filtration giving 15 g of a brown solid as a 2:1 mixture of 6-methoxyquinoxalin-2(lH)-one to 7-methoxyquinoxalin-2(lH)-one. These EPO <DP n="135"/>isomers were inseparable by TLC. The mixture was suspended in phosphorus oxychloride (150 niL) and heated to reflux for 1 hour. The reaction was cooled to room temperature and was quenched on ice. The pH of the mixture was adjusted to pH 8 with solid sodium carbonate, it was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness to give 10.4 g of a crude mixture of 2-chloro-6- methoxyquinoxaline and the desired 2-chloro-7-methoxyquinoxaline. Chromatography on silica gel with 5% ethyl acetate in hexanes afforded 0.77 g of the product as a colorless solid. MS (ESt: 195 (MH+) for C9H7ClN2O1H NMR (CDCht δ 3.96 (s, 3H); 7.29 (d, IH); 7.41 (dd, IH); 7.97 (d, IH); 8.63 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.6% | In ethyl acetate; trichlorophosphate; | Step 2: Preparation of 2-chloro-6-methoxyquinoxaline and 3-chloro-6-methoxyquinoxaline A solution of 6-methoxyquinoxalin-2(1H)-one & <strong>[55687-30-4]7-methoxyquinoxalin-2(1H)-one</strong> (3 g, 18.28 mmol) in POCl3 (20 ml) was refluxed for 3 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to afford mixture of regioisomers (3.7 g). 2 g of the above mixture was separated by SFC purification to afford 2-chloro-7-methoxyquinoxaline (0.7 g, 34.7%) and 2-chloro-7-methoxyquinoxaline (0.9 g, 44.6%) as off white solid. 2-chloro-6-methoxyquinoxaline: 1H NMR (400 MHz, DMSO-d6): δ ppm 1H NMR (400 MHz, CDCl3): δ ppm 8.71 (s, 1H), 7.91-7.89 (d, J=8 Hz, 1H), 7.46-7.38 (m, 2H), 3.97 (s, 3H); MS: MS m/z 194.9(M++1). |
With trichlorophosphate; for 1h;Heating / reflux; | Intermediate 149: 2-Chloro-7-methoxyquinoxalineA solution of 4-methoxybenzene-l,2-diamine (16.8 g, 0.12 mmol) in ethanol (250 mL) was treated with a solution of ethyl oxoacetate (50 wt % in toluene, 50 mL, 0.23 mmol) dropwise with cooling in an ice bath. The reaction was allowed to warm to room temperature and after 2 hours, a precipitate was collected by filtration giving 15 g of a brown solid as a 2:1 mixture of 6-methoxyquinoxalin-2(lH)-one to 7-methoxyquinoxalin-2(lH)-one. These EPO <DP n="135"/>isomers were inseparable by TLC. The mixture was suspended in phosphorus oxychloride (150 niL) and heated to reflux for 1 hour. The reaction was cooled to room temperature and was quenched on ice. The pH of the mixture was adjusted to pH 8 with solid sodium carbonate, it was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness to give 10.4 g of a crude mixture of 2-chloro-6- methoxyquinoxaline and the desired 2-chloro-7-methoxyquinoxaline. Chromatography on silica gel with 5% ethyl acetate in hexanes afforded 0.77 g of the product as a colorless solid. MS (ESt: 195 (MH+) for C9H7ClN2O1H NMR (CDCht δ 3.96 (s, 3H); 7.29 (d, IH); 7.41 (dd, IH); 7.97 (d, IH); 8.63 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Step B: 2-Chloro-6-methoxyquinoxaline A mixture of 6-methoxyquinoxalin-2(1H)-one and <strong>[55687-30-4]7-methoxyquinoxalin-2(1H)-one</strong> (5.67 g, 32.20 mmol) was refluxed in phosphorus oxychloride (120 mL) for 1 h. The reaction was concentrated and quenched by addition of ice, then basified with sodium carbonate, and extracted with ethyl acetate (3×200 mL). The organic layers were combined and concentrated in vacuo. The crude product was absorbed onto sodium sulfate and purified by column chromatography (0 to 5% ethyl acetate/hexanes) to afford 2-chloro-6-methoxyquinoxaline (2.21 g, 11.36 mmol, 35% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (s, 1H), 7.88 (d, J=9.32 Hz, 1H), 7.43 (dd, J=9.32, 2.77 Hz, 1H), 7.37 (d, J=2.77 Hz, 1H), 3.95 (s, 3H). |
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