Structure of 193014-01-6
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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. : | 193014-01-6 |
Formula : | C9H10N2O4 |
M.W : | 210.19 |
SMILES Code : | O=C(OCC)C1=CC=CC(N)=C1[N+]([O-])=O |
MDL No. : | MFCD12911920 |
InChI Key : | IJNYIIHVEXLJGI-UHFFFAOYSA-N |
Pubchem ID : | 18315537 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 55.75 |
TPSA ? Topological Polar Surface Area: Calculated from |
98.14 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.51 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.84 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.36 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.61 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.79 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.91 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.33 |
Solubility | 0.973 mg/ml ; 0.00463 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.52 |
Solubility | 0.0633 mg/ml ; 0.000301 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.91 |
Solubility | 2.6 mg/ml ; 0.0124 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 |
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 |
-6.28 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 |
3.0 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) |
2.32 |
* 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 sulfuric acid; sodium hydrogencarbonate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol; hexane; ethyl acetate; | PRODUCTION EXAMPLE 35 Production of ethyl 3-amino-2-nitrobenzoate A mixture of 20.2 g of 3-acetylamino-2-nitrobenzoic acid, 11.4 g of 97% sulfuric acid and 300 ml of ethanol was stirred for 23 hours while being heat-refluxed. One-hundred milliliters of ethanol were distilled off under reduced pressure, and the residue was cooled to room temperature. Subsequently, the reaction solution was poured into 200 ml of ice water containing 19.5 g of sodium hydrogencarbonate. The crystals precipitated were separated through filtration, and were washed with water. Further, these crystals were dispersed in 30 ml of a mixed solution of ethyl acetate and hexane at a ratio of 1:2. The crystals were separated through filtration, washed with hexane, and then dried to give 18.0 g of ethyl 3-amino-2-nitrobenzoate. Properties of the compound: 1 H-NMR(CDCl3, delta): 1.39(3H, t, J=7.1 Hz), 4.37(2H, q, J=7.1 Hz), 6.41(2H, br s), 6.83(1H, d, J=8.7 Hz), 8.00(1H, dd, J=1.8 and 8.7 Hz), 8.85(1H, d, J=1.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-aniline; | PRODUCTION EXAMPLE 36 Production of ethyl 3-acetylamino-2-nitrobenzoate Acetyl chloride (13 ml) was added dropwise to a solution of 2.98 g of <strong>[193014-01-6]ethyl 3-amino-2-nitrobenzoate</strong> and 20 ml of N,N-dimethylaniline in an ice bath. The mixture was stirred at room temperature for 48 hours. The reaction solution was acidified with 10% hydrochloric acid, and was extracted twice with ethyl acetate. The organic layer was washed three times with water. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized with hexane. The crystals were separated through filtration, washed with hexane, and dried to give 3.30 g of ethyl 3-acetylamino-2-nitrobenzoate. Properties of the compound: 1 H-NMR(CDCl3, delta): 1.42(3H, t), 2.33(3H, s), 4.42(2H, q), 8.27(1H, dd, J=1.9 and 8.9 Hz), 8.89(1H, d, J=1.9 Hz), 8.91(1H, d, J=8.9 Hz), 10.54(1H, br s). | |
In N,N-dimethylaniline; at 0 - 20℃; for 48.0h; | Acetyl chloride (13 ml) was added dropwise to a solution of 2.98 g of <strong>[193014-01-6]ethyl 3-amino-2-nitrobenzoate</strong> and 20 ml of N,N-dimethylaniline in an ice bath.. The mixture was stirred at room temperature for 48 hours.. The reaction solution was acidified with 10% hydrochloric acid, and was extracted twice with ethyl acetate.. The organic layer was washed three times with water.. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized with hexane.. The crystals were separated through filtration, washed with hexane, and dried to give 3.30 g of ethyl 3-acetylamino-2-nitrobenzoate. Properties of the compound: 1H-NMR(CDCl3, delta): 1.42(3H, t), 2.33(3H, s), 4.42(2H, q), 8.27(1H, dd, J=1.9 and 8.9 Hz), 8.89(1H, d, J=1.9 Hz), 8.91(1H, d, J=8.9 Hz), 10.54(1H, br s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; for 23.0h;Heating / reflux; | A mixture of 20.2 of 3-acetylamino-2-nitrobenzoic acid, 11.4 g of 97% sulfuric acid and 300 ml of ethanol was stirred for 23 hours while being heat-refluxed. One-hundred milliliters of ethanol were distilled off under reduced pressure, and the residue was cooled to room temperature.. Subsequently, the reaction solution was poured into 200 ml of ice water containing 19.5 g of sodium hydrogencarbonate.. The crystals precipitated were separated through filtration, and were washed with water.. Further, these crystals were dispersed in 30 ml of a mixed solution of ethyl acetate and hexane at a ratio of 1:2.. The crystals were separated through filtration, washed with hexane, and then dried to give 18.0 g of ethyl 3-amino-2-nitrobenzoate. Properties of the compound: 1H-NMR(CDCl3, delta): 1.39(3H, t, J=7.1 Hz), 4.37(2H, q, J=7.1 Hz), 6.41(2H, br s), 6.83(1H, d, J=8.7 Hz), 8.00(1H, dd, J=1.8 and 8.7 Hz), 8.85(1H, d, J=1.8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | The following process was adapted from a similar process according to Chen et al., International Publication WO 2004/078714. Ethyl 3-amino-2-nitrobenzoate (1.0 eq, 2.5 g, 11.9 mmol) was dissolved in methanol (48 mL). Ethyl glyoxylate (4 eq, 9.71 g, 47.6 mmol, 50% wt in toluene) was added in one portion and the reaction was heated to reflux. After 15 h, a Dean-Stark trap was attached and half of the solvent was removed. Methanol (24 mL) was added, then half the solvent was removed again. Additional ethyl glyoxylate (2 mL) and methanol (24 mL) were added and the reaction was returned to reflux for 1 h. The solvent was removed in vacuo and used without further purification. The residue was dissolved in ethanol (150 mL). Tosylmethyl isocyanide (TosMIC, 1.3 eq, 6.27 g, 32.1 mmol) and K2CO3 (1.5 eq, 3.69 g, 26.7 mmol) were added. The solution was heated to 50 ºC for 3.5 h. The solution was concentrated in vacuo, then diluted with water (75 mL) and extracted with EtOAc (3 x 75 mL). The organics were washed with brine (200 mL), dried over MgSO4, filtered and concentrated in vacuo to an orange oil. Purification via flash column chromatography (40-60% EtOAc/hexanes) provided ethyl l-[3-(ethoxycarbonyl)-2- nitrophenyl]-1H-imidazole-5-carboxylate (589 mg, 15% over two steps). LCMS (ES): >;95% pure, m/z 334 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Ethyl 3-amino-2-nitrobenzoate [prepared according to the U.S. Patent 6,166,219] (1.0 eq, 5 g, 23.8 mmol) and 2, 5-dimethoxytetrahydrofuran (1.1 eq, 3.4 mL, 26.2 mmol) were mixed in glacial acetic acid (16 mL). The mixture was fitted with a condenser and placed in a 120 ºC oil bath. After 1 h, the reaction was concentrated in vacuo to give a reddish brown oil which was partitioned between ethyl acetate (250 mL) and saturated NaHCO3 (250 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (10-15% EtOAc/hexanes) to afford ethyl 2-nitro-3- (1H-pyrrol-1-yl)benzoate (5.45 g, 88%) as a bright yellow solid. 1H NMR (CDC13, 400 MHz) delta: 8.04 (dd, 1H, J = 7.2, 1.8 Hz), 7.60-7.67 (m, 2H), 6.82 (dd, 2H, J = 2.4, 2.4 Hz), 6.34 (dd, 2H, J = 2.4, 2.4 Hz), 4.40 (q, 2H, J = 7.2 Hz), 1.38 (t, 3H, J = 7.2 Hz). 13C NMR (CDC13, 100 MHz) delta: 162.6, 133.6, 131.8, 130.6, 129.7 (two carbons), 124.4, 122.0, 111.0, 62.6, 13.7. LCMS (ES): >;95% pure, m/z 261 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 18.0h; | To a cooled solution of 4-chloro-5,8-difluoroquinoline (171 g, 859.3 mmol) in DMF (1.7 L) were added <strong>[193014-01-6]ethyl 3-amino-2-nitrobenzoate</strong> (181.5 g, 859.3 mmol) and Cs2CO3 (614.4 g, 1890 mmol). The reaction mixture was stirred at 90 C. for 18 hours. The reaction mixture was cooled down and filtered through a pad of Celite. The filtrate was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to afford ethyl 3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate. ES/MS m/z=374.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; palladium diacetate; XPhos; In toluene; at 90℃; for 16.0h; | Palladium (II) acetate (103 mg, 0.46 mmol) was added to a mixture of <strong>[193014-01-6]ethyl 3-amino-2-nitrobenzoate</strong> (1.2 g, 5.7 mmol), 4,8-dichloroquinoline (1.24 g, 6.3 mmol), dicyclohexyl(2?,4?,6?-triisopropyl-[1,1?-biphenyl]-2-yl)phosphine (653 mg, 1.37 mmol), and potassium phosphate (2.42 g, 11.4 mmol) in toluene (23 mL). The resultant was degassed and stirred at 90 C. for 16 hours. The reaction mixture was cooled to room temperature and dry loaded onto silica gel and purified eluting with 0 to 100% ethyl acetate in hexanes to afford the title compound as a brown solid. ES/MS m/z=372.1 (M+H). |
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