Structure of 400877-57-8
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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. : | 400877-57-8 |
Formula : | C6H7N3O4 |
M.W : | 185.14 |
SMILES Code : | O=C(C1=NN(C)C=C1[N+]([O-])=O)OC |
MDL No. : | MFCD19443825 |
InChI Key : | KRIOGKNOYPHJPC-UHFFFAOYSA-N |
Pubchem ID : | 54775322 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 43.59 |
TPSA ? Topological Polar Surface Area: Calculated from |
89.94 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.35 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.25 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.11 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.0 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-1.88 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.23 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.23 |
Solubility | 10.9 mg/ml ; 0.0586 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.7 |
Solubility | 3.7 mg/ml ; 0.02 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.26 |
Solubility | 103.0 mg/ml ; 0.555 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 |
-7.25 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 |
2.0 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) |
2.26 |
* 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 |
---|---|---|
33% | With potassium carbonate In acetone at 70℃; for 2 h; | Compound 6 and 6A: To a mixture containing 5 (3.1 g, 18.1 mmol) and potassium carbonate (5.0 g, 36.2 mmol) in 60 mL of acetone was added methyl iodide (2.2 mL, 36.2 mmol). The resulting solution was heated and stirred at 70° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate (.x.3). The combined organics were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 20percent ethyl acetate in hexanes as the eluent to afford 6 (1.1 g, 33percent) as white solid. 1H NMR (d6-DMSO) δ 3.96 (s, 3H) 3.98 (s, 3H) 8.36 (s, 1H); ES (+) MS m/e=186 (M+1) and using 30percent ethyl acetate in hexanes to afford 6A (2.2 g, 66percent) as white solid. 1H NMR (d-CDCl3) δ 3.98 (s, 3H) 4.00 (s, 3H) 8.13 (s, 1H); ES (+) MS m/e=186 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate In acetone at 0 - 70℃; Inert atmosphere | To a solution of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (3.1 g, 18.1 mmol) in dry acetone (2 ml) was added K2C03 (5 g, 36.2 mmol) at 25°C. The reaction mixture was cooled to 0°C, and methyl iodide (2.2 ml, 36.3 mmol) was added. The temperature was again raised to 25°C, and then heated to 70°C for 2 hrs. The solvent was removed in vacuo The residue was diluted with EtOA and washed with water and with brine, dried (Na2S04), filtered, and concentrated. The crude product was purified by column chromatography over silica gel. Elution with 20percent EtOAc/hexane) gave the undesired isomer 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1 g, 30percent), subsequent elution with 40percent EtOAc/hexane provided the desired isomer l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.8 g, 54percent). |
53% | With caesium carbonate In N,N-dimethyl-formamideInert atmosphere | Preparative Example 7 4-nitro-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester 340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 195 mg (53percent) of the title compound and 110 mg (30percent) of the compound of Preparative Example 13. 1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H), 4.02 (s, 3H), 8.15 (s, 1H). Mass: 185 (M+) ; 340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 110 mg (30percent) of the title compound and 195 mg (53percent) of the compound of Preparative Example 7.1H NMR (300 MHz, CDCl3) δ 4.03 (s, 3H), 4.04 (s, 3H), 8.03 (s, 1H). |
53% | With caesium carbonate In N,N-dimethyl-formamide for 0.5 h; | 340 mg (1.99 mM) of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane : ethyl acetate = 2 : 1), to obtain 195 mg (53percent) of the title compound and 110 mg (30percent) of the compound of Preparative Example 13. 1H νMR(300MHz, CDCl3) δ 4.00(s, 3H), 4.02(s, 3H), 8.15(s, IH).Mass : 185(M+); 340 mg (1.99 mM) of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced EPO <DP n="31"/>pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane : ethyl acetate = 2 : 1), to obtain 110 mg (30percent) of the title compound and 195 mg (53percent) of the compound of Preparative Example 7.1H NMR(SOOMHZ, CDCl3) δ 4.03(s, 3H), 4.04(s, 3H), 8.03(s, IH). |
28% | With potassium carbonate In acetone at 30℃; for 5 h; | Reference Example 20 Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate A mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate obtained in Reference Example 18 (2.0 g, 11.7 mmol), methyl iodide (2.0 g, 14.0 mmol), potassium carbonate (1.62 g, 11.7 mmol) and acetone (60 mL) was stirred at 30° C. for 5 hr. The mixture was diluted with water, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4:1-1:1) to give the title compound, methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (Rf value 0.43) (0.95 g, yield 44percent) and the title compound, methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (Rf value 0.71) (0.61 g, yield 28percent). |
44% | With potassium carbonate In acetone at 30℃; for 5 h; | A mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate obtained in Reference Example 18 (2.0 g, 11.7 mmol), methyl iodide (2.0 g, 14.0 mmol), potassium carbonate (1.62 g, 11.7 mmol) and acetone (60 mL) was stirred at 30°C for 5 hr. The mixture was diluted with water, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4:1 - 1:1) to give the title compound, methyl 1-methyl-4-nitro-1-pyrazole-3-carboxylate (Rf value 0.43) (0.95 g, yield 44percent) and the title compound, methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (Rf value 0.71) (0.61 g, yield 28percent). Methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate 1H-NMR (CDCl3):δ 3.99(3H, s), 4.01(3H, s), 8.13(1H, s). Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate 1H-NMR (CDCl3):δ 4.02(3H, s), 4.03(3H, s), 8.01 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With cyanomethylenetributyl-phosphorane In toluene at 110℃; for 0.5 h; Sealed tube; Microwave irradiation | General procedure: The reaction was performed in 2 batches. In a sealed tube, cyanomethylenetributyl phosphorane (9.28 mL, 35.40 mmol) was added to a solution of 3-methyl-5-nitro-lH- pyrazole (1.50 g, 1 1.80 mmol) and 3-hydroxymethyl-3-methyloxethane (3.53 mL, 35.40 mmol) in toluene (100 mL). The solution was heated at 60 °C for 18 h. The 2 batches were combined and the solvent was evaporated in vacuo. The residue (black oil) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μιη, 330 g, liquid loading on DCM, mobile phase: heptane/EtOAc, gradient from 90: 10 to 50:50). The fractions containing the product were combined and evaporated to dryness to give 3.95 g of intermediate 303 (79percent yield, orange oil) directly used as it in the next step. |
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