Structure of 34334-96-8
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CAS No. : | 34334-96-8 |
Formula : | C4H5N3O2 |
M.W : | 127.10 |
SMILES Code : | O=[N+](C1=CC(C)=NN1)[O-] |
MDL No. : | MFCD00463977 |
InChI Key : | ASURMMBYYOJOTQ-UHFFFAOYSA-N |
Pubchem ID : | 135463736 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 32.38 |
TPSA ? Topological Polar Surface Area: Calculated from |
74.5 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.5 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.78 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.63 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.46 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.63 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.35 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.46 |
Solubility | 4.36 mg/ml ; 0.0343 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.93 |
Solubility | 1.51 mg/ml ; 0.0119 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.96 |
Solubility | 13.8 mg/ml ; 0.109 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 |
-6.52 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 |
2.0 |
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) |
2.09 |
* 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 potassium carbonate; In acetonitrile; for 18h;Reflux; | A solution of 5-methyl-3-nitro-lH-pyrazole (500 mg, 3.93 mmol) and potassium carbonate (1.08 g, 7.81 mmol) in acetonitrile (20 mL) was treated dropwise with 2- iodoethanol (2.00 g, 1 1.6 mmol) and the reaction stirred at reflux for 18 h. After this time, the reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the resulting residue purified by chromatography (silica, gradient, heptane to 1 : 1 ethyl acetate/heptane) to afford 2-(5-methyl-3-nitro-lH-pyrazol-l-yl)ethanol as a white solid: NMR (400 MHz, DMSO-i¾d 6.82 (s, 1H), 4.97 (t, J = 5.2 Hz, 1H), 4.19 (t, J = 5.2 Hz, 2H), 3.75 (q, J= 5.2 Hz, 2H), 2.35 (s, 3H). | |
With potassium carbonate; In acetonitrile; for 18h;Reflux; | Example 7 Preparation of 2-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethanol A solution of <strong>[34334-96-8]5-methyl-3-nitro-1H-pyrazole</strong> (500 mg, 3.93 mmol) and potassium carbonate (1.08 g, 7.81 mmol) in acetonitrile (20 mL) was treated dropwise with 2-iodoethanol (2.00 g, 11.6 mmol) and the reaction stirred at reflux for 18 h. After this time, the reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the resulting residue purified by chromatography (silica, gradient, heptane to 1:1 ethyl acetate/heptane) to afford 2-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethanol as a white solid: 1H NMR (400 MHz, DMSO-d6.) d 6.82 (s, 1H), 4.97 (t, J=5.2 Hz, 1H), 4.19 (t, J=5.2 Hz, 2H), 3.75 (q, J=5.2 Hz, 2H), 2.35 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
539 mg | With potassium carbonate; In acetonitrile; at 90℃; for 12h; | 5-methyl-3-nitro -1H- pyrazole (450 mg of) in 30mLacetonitrile and carbonatePotassium (733 mg) and 2-chloropyrimidine (608 mg of the),and the mixture was stirred at 90 12 smallTime. The mixture was concentrated under reduced pressure,the residue was mixed with water and extracted with ethyl acetate, withThe organic phase was dried over sodium sulfate, filteredand concentrated under reduced pressure. The crude product was stirred inn-hexane,Suction filtered and dried under reducedpressure. To give 539mg of the title compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | A solution of 5-methyl-3-nitro-1 H-pyrazole (2 g, 15.7 mmol) in THF (20 mL) was cooled to 0 C. NaH (0.7 g, 17.32 mmol) was added portion-wise over 10 min under nitrogen atmosphere. The resulting suspension was stirred for 10 min then treated with Mel (2.2 g, 15.7 mmol), warmed to ambient temperature and stirred for 4h. The reaction mixture was diluted with saturated NH4CI solution (20 mL) and extracted with EtOAc (2 x 30 mL). The organics were washed with water (30 mL), brine (30 mL), dried (Na2S04) and concentrated in vacuo to give 1 ,5-dimethyl-3-nitro-1 H-pyrazole as a white solid (2 g, 91 %). 1 H NMR (300 MHz, CDCIs): delta = 6.71 (s, 1 H), 3.87 (s, 3H), 2.34 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
880 mg; 493 mg | General procedure: Mcthancsulfonyl chloride (6.683 mL, 1.48 g/mL, 86.338 mmol) was added to a solution of 3-methoxy-3-methylbutanol (5 g, 42.31 mmol ) and Et-,N (17.661 mL, 0.728 g/mL, 127.059 mmol ) in DCM (477.33 mL, 1 .326 g/mL, 7452.28 mmol) at rt and the reaction mixture was stirred for 18h. Water was added. The organic layer was separated, washed with I N HCI(aq) then with brine before drying over MgSC>4. The organic layer was filtered and evaporated to afford a mixture on intermediate 778 and 778' (10.3 g, quantitative yield ) that was used directly in the next step. Bromo-3-methoxypropane (1.20 mL, 10.51 mmol) was added at rt to a mixture of 5-nitro-lH-pyrazole (1.00 g, 8.84 mmol), 2 (2.35 g, 17.00 mmol) in DMF (10 mL).This reaction was stirred in a sealed tube at 120 C using one single mode microwave(Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min.Then, water was added and this mixture was extracted twice with EtOAc. The organic10 layers were mixed, dried over MgS04, filtered and the solvent was evaporated untildryness. The residue was purified by column chromatography on silica gel (IrregularSiOH, 40 |im, 80 g, mobile phase: gradient from 70% heptane, 29% EtOAc, 1% MeOH(+10% NH4OH) to 40% heptane, 52% EtOAc, 8% MeOH (+10% NH4OH)). The purefractions were collected and the solvent was evaporated until dryness to give 1.39 g of15 intermediate 56 (85% yield) and 267 mg of intermediate 56? (16% yield). Theseintermediates were used as it in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.5h;Sealed tube; | General procedure: Bromo-3-methoxypropane (1.20 mL, 10.51 mmol) was added at rt to a mixture of 5 - nitro-lH-pyrazole (1.00 g, 8.84 mmol), K2C03 (2.35 g, 17.00 mmol) in DMF (10 mL). This reaction was stirred in a sealed tube at 120 C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. Then, water was added and this mixture was extracted twice with EtOAc. The organic layers were mixed, dried over MgS04, filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography on silica gel (Irregular SiOH, 40 muiotaeta, 80 g, mobile phase: gradient from 70% heptane, 29% EtOAc, 1% MeOH (+10% NH4OH) to 40% heptane, 52% EtOAc, 8% MeOH (+10% NH4OH)). The pure fractions were collected and the solvent was evaporated until dryness to give 1.39 g of intermediate 56 (85% yield) and 267 mg of intermediate 56' (16% yield). These intermediates were used as it in the next step |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: Bromo-3-methoxypropane (1.20 mL, 10.51 mmol) was added at rt to a mixture of 5 - nitro-lH-pyrazole (1.00 g, 8.84 mmol), K2C03 (2.35 g, 17.00 mmol) in DMF (10 mL). This reaction was stirred in a sealed tube at 120 C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. Then, water was added and this mixture was extracted twice with EtOAc. The organic layers were mixed, dried over MgS04, filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography on silica gel (Irregular SiOH, 40 muiotaeta, 80 g, mobile phase: gradient from 70% heptane, 29% EtOAc, 1% MeOH (+10% NH4OH) to 40% heptane, 52% EtOAc, 8% MeOH (+10% NH4OH)). The pure fractions were collected and the solvent was evaporated until dryness to give 1.39 g of intermediate 56 (85% yield) and 267 mg of intermediate 56' (16% yield). These intermediates were used as it in the next step |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74%; 25% | In ethanol; at 140℃; for 4h;Sealed tube; | A mixture of 5-methyl-3-nitro-lH-pyrazole (7.00 g, 55.07 mmol) (+/-) -propylene oxide (7.71 mL, 110.15 mmol) in EtOH (64.31 mL) in a sealed tube was stirred at 140 C for 4 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 muiotaeta, 120 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 50:50). The fractions containing the product were combined to give 2.5 g of intermediate 182 (25% yield) and 7.5 g of intermediate 182' (74% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11%; 68% | With cyanomethylenetributyl-phosphorane; In toluene; at 60℃; for 19h;Sealed tube; | In a sealed tube, 2-(tributylphosphoranylidene)-acetonitrile (7.30 g, 30.25 mmol) was added to a solution of 5-Methyl-3-nitro-lH-pyrazole (2.00 g, 15.74 mmol) and 2- cyclopropylethanol (2.04 g, 23.68 mmol) in toluene (70 mL). The mixture was heated at 60 C for 19 h. After cooling down to rt, the mixture was diluted with EtOAc and water. The organic layer was decanted and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (Irregular SiOH, 20-45 muiotaeta, 40 g, mobile phase: heptane/EtOAc, gradient from 60:40 EtOAc to 50:50). The pure fractions were combined and the solvent was evaporated until dryness to give 2.10 g of intermediate 232' (68% yield) and 330 mg of intermediate 232 (11% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63%; 31% | With cyanomethylenetributyl-phosphorane; In toluene; at 90℃; for 18h;Sealed tube; | 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 muiotaeta, 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 (79% yield, orange oil) directly used as it in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With cyanomethylenetributyl-phosphorane; In toluene; at 90℃; for 5h;Sealed tube; | 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 muiotaeta, 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 (79% yield, orange oil) directly used as it in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22%; 23% | With cyanomethylenetributyl-phosphorane; In toluene; at 50℃; for 18h;Sealed tube; | 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 muiotaeta, 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In acetonitrile; at 65℃; | Add acetonitrile (56 mL) to a mixture of 5-methyi-3-nitro-1H-pyrazoie (3.0 g, 22 mniol), potassium carbonate (6.2 g, 2.0 eq), and I -bromo-3-methoxypropane (3.8 g, 1.1 eq). Stir at 65 C overnight. Cool to EtOAc (50 mE) and filter. Concentrate the filtrate in vacuo. Subject the residue to normal phase chromatography, eluting with 35% EtOAc in hexanes, to give the title compound (3.3 g, 70%). MS (ES) ,n/z 200 (M-fH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate; In acetonitrile; at 75℃; for 3h; | Add acetonitrile (35 mE) to a mixture of 5-methyi-3-nitro-1H-pyrazoie (095 g,7.1 minol), potassium carbonate (2.0 g, 2.0 eq), and I-brorno-2-methoxyethane (2.0 rnL,3.0 eq). Stir at 75 C for three hours. Cool to rt. Add diethyl ether (-35 mL) and filter. Rinse the solids with EtOAc (2 x 25 rnL). Concentrate the filtrate in vacuo to provide aresidue. Subject the residue to normal phase chromatography, eluting with a 0-100%EtOAc in hexanes gradient, to give the title compound as a yellow oil (1.1 g, 64%). MS(ES) m/z = 186 (M-i-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; In acetonitrile; at 85℃; | Add acetonitrile (75 rnL) to a mixture of (2.0 g, 15rnmoi). potassium carbonate (4.1 g, 2.0 eq), and 1-chioro-2-propanol (3.8 mL, 3.0 eq).Stir at 85 C overnight. Cool to rt. Filter and rinse the solids with EtOAc. Concentrate the filtrate in vacuo to provide a residue. Subject the residue to normal phase chromatography, eluting with 50% EtOAc in hexanes, to give the title compound (2.0 g, 65%). MS (ES) ,n/z 186 (M+1-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium carbonate; In acetonitrile; at 85℃; for 96h; | Add acetonitrile (45 mL) to a mixture of 5-rnethyi-3-nitro-IH-pyrazoie (1.2 g, 9.0 rnmoi). potassium carbonate (2.5 g, 2.0 eq). and (S)-1-chloro-2-propanol (().98 g, 1.2 eq). Stir at 85 C for four days. Cool to a Filter to collect the solid and rinse the solid with EtOAc, then discard the solid. Collect and concentrate the filtrate n vacuo to provide aresidue. Subject the residue to normal phase chromatography, eluting with 50% EtOAc in hexanes. to give the title compound as a white solid (1.1 g, 67%). MS (ES) m/z 186 (4+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium carbonate; In acetonitrile; at 85℃; | Add acetonitrile (41 mL) to a mixture of 5-methyi-3-nitro-IH-pyrazole (1.1 g, 8.2mmnoi), potassium carbonate (2.3 g, 2.0 eq). and (R)-I-chioro-2-propanoi (092 mL, 1.3eq). Stir at 85 ?C overnighi. Cool to ri. Filter and rinse the solids with EtOAc, Concentrate the filtrate in vacuo to provide a residue. Subject the residue to normal phase chromatography, eluting with 50% EtOAc in hexanes, to give the title compound as a white solid (0.74 g, 48%). MS (ES) in/i 186 (M+F1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | To a solution of 4- nitro-1H-imidazole (500 mg, 4.42 mmol) in DMF (6 mL) was added 1.0 M (2568) NaHMDS/THF (4.33 mL, 4.33 mmol) slowly at rt. After stirring at rt for 15 min, 1- (bromomethyl)-4-fluorobenzene (892 mg, 4.72 mmol) was added. The mixture was stirred at rt for 2 h. EtOAc (50 mL) was added, and the organics were washed with brine and water, then concentrated in vacuo. The residue was purified via silica gel chromatography (24g, hexanes-60%EtOAc) to give the first spot as 1-(4-fluorobenzyl)-3- methyl-5-nitro-1H-pyrazole (150 mg, 0.638 mmol, 16 % yield), and the second spot as 1- (4-fluorobenzyl)-<strong>[34334-96-8]5-methyl-3-nitro-1H-pyrazole</strong> (700 mg, 2.98 mmol, 76 % yield). (2569) 1H NMR (499 MHz, CDCl3) delta 7.20 (t, J=6.5 Hz, 2H), 7.07 (t, J=8.2 Hz, 2H), 6.72 (s, 1H), 5.34 (s, 2H), 2.28 (s, 3H). |
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