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Structure of 299930-70-4

Chemical Structure| 299930-70-4

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Product Details of [ 299930-70-4 ]

CAS No. :299930-70-4
Formula : C4H4ClN3O2
M.W : 161.55
SMILES Code : O=[N+](C1=CN(C)N=C1Cl)[O-]
MDL No. :MFCD00463968
InChI Key :UEDIAFCRVLLBSS-UHFFFAOYSA-N
Pubchem ID :59620018

Safety of [ 299930-70-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 299930-70-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 5
Fraction Csp3 0.25
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 37.32
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

63.64 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.11
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.02
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.98
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.33
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-0.97
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.49

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.79
Solubility 2.63 mg/ml ; 0.0163 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.95
Solubility 1.83 mg/ml ; 0.0113 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-0.78
Solubility 26.6 mg/ml ; 0.164 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.56 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

2.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

2.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.87

Application In Synthesis of [ 299930-70-4 ]

* 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.

  • Downstream synthetic route of [ 299930-70-4 ]

[ 299930-70-4 ] Synthesis Path-Downstream   1~6

  • 1
  • [ 63425-54-7 ]
  • [ 299930-70-4 ]
YieldReaction ConditionsOperation in experiment
73% With sulfuric acid; nitric acid; at 27℃; for 6.0h;Cooling with ice; To an ice-cold solution of 3-chloro-1-methyl-1H-pyrazole (42) (30 g, 0.26 mol) in concentrated sulfuric acid (50 mL) was slowly added fuming nitric acid (40 mL, 0.91 mol) drop wise. The resulting mixture was stirred at room temperature for 6 hours. After completion of reaction (TLC monitoring), the reaction mixture was poured into ice-cold water, the resulting solid was filtered and washed with pentane afforded the desired product (43) as yellow solid (30 g; Yield: 73%).1H-NMR (400 MHz, CDCl3): δ 8.16 (s, 1H), 3.94 (s, 3H).
With sulfuric acid; nitric acid; at 20℃; for 2.5h;Cooling with ice; To a solution of 3-chloro-1-methylpyrazole (Maybridge, Basel, Switzerland, 953 mg, 8.18 mmol) in concentrated sulfuric acid (1.4 ml), cooled with an ice-bath, was added over 30 min fuming nitric acid (1 19 mL, 28.6 mmol). The reaction mixture was stirred at rt for 2 h before being poured on ice/water and extracted with EtOAc (2 x) The organic layers were washed with saturated aqueous NaHCO3 (2 x) and brine, dried over Na2SO4, filtered, evaporated and dried over vacuum to give the title compound as a white solid (HPLC tR 2 24 mm (Method A), M+H = 162 MS-ES)
3 g With sulfuric acid; nitric acid; at 0 - 27℃; for 6.0h; To a stirred solution of 3-chloro-1-methyl-1H-pyrazole 59 (4.0 g, 34 mmol) in Conc. H2S04 (4.0 mL) was added Fuming HNO3 (3.6 g, 120.0 mmol) dropwise at 0C and the mixture was stirred at RT for 6h. The mixture was then quenched slowly with ice, white solid precipitated out was filtered & dried over vacuum to obtain 3- chloro-1-methyl-4-nitro-1H-pyrazole (3.0 g, 54 % yield) as white solid. ‘HNMR (400 MHz, CDCl3): ö 8.16 (s, 1H), 3.94 (s, 3H).
  • 2
  • [ 20055-00-9 ]
  • [ 299930-70-4 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sodium nitrite; In water; acetonitrile; at 0 - 25℃; for 16.0h; Step 1: Into a 250 mL round bottom flask containing a solution of 1-methyl-4-nitro-1H-pyrazol-3-amine (4.0 g, 28 mmol) in acetonitrile (100 mL) was added concentrated hydrochloric acid (8mL) dropwise at 0 C. To this reaction mixture was added sodium nitrite (8.0 g, 116 mmol) inportions and the reaction mixture was gradually brought to room temperature and stirred for 16h. The reaction mixture was cooled to 0 C, treated with water (30 mL) and extracted with ethyl acetate (2x50 mL). The combined organics were washed with saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethylacetate in petroleum ether (20-30%) to furnish 3-chloro-1-methyl-4-nitro-1H-pyrazole as a solid.‘H NMR (CDC13, 300 MHz): 5 8.25 (s, 1H), 3.98 (s, 3H).
With hydrogenchloride; sodium nitrite; In water; acetonitrile; at 0 - 25℃; for 16.0h; Step 1: Into a 250 mL round bottom flask containing a solution of 1-methyl-4-nitro-1H-pyrazol- 3-amine (4.0 g, 28 mmol) in acetonitrile (100 mL) was added concentrated hydrochloric acid (8 mL) dropwise at 0 C. To this reaction mixture was added sodium nitrite (8.0 g, 116 mmol) in portions and the reaction mixture was gradually brought to room temperature and stirred for 16h. The reaction mixture was cooled to 0 C, treated with water (30 mL) and extracted with ethyl acetate (2x50 mL). The combined organics were washed with saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate in petroleum ether (20-30%) to furnish 3-chloro-1-methyl-4-nitro-1H-pyrazole as a solid.‘H NMR (CDC13, 300 MHz): 5 8.25 (s, 1H), 3.98 (s, 3H).
With hydrogenchloride; sodium nitrite; In water; acetonitrile; at 0 - 20℃; for 16.0h; Step 1: Into a 250 mL round bottom flask containing a solution of l-methyl-4-nitro-lH-pyrazol- 3-amine (4.0 g, 28 mmol) in acetonitrile (100 mL) was added concentrated hydrochloric acid (8 mL) dropwise at 0 C. To this reaction mixture was added sodium nitrite (8.0 g, 116 mmol) in portions and the reaction mixture was gradually brought to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 C, treated with water (30 mL) and extracted with ethyl acetate (2x50 mL). The combined organics were washed with saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate in petroleum ether (20-30%) to fumish 3-chloro-l-methyl-4-nitro-lH-pyrazole as a solid. 1H NMR (CDC13, 300 MHz): δ 8.25 (s, 1H), 3.98 (s, 3H).
With hydrogenchloride; sodium nitrite; In acetonitrile; at 0 - 20℃; for 16.0h; Step 1: Into a 250 mL round bottom flask containing a solution of 1-methyl-4-nitro-1H-pyrazol- 3-amine (4.0 g, 28 mmol) in acetonitrile (100 mL) was added concentrated hydrochloric acid (8 mL) dropwise at 0 oC. To this reaction mixture was added sodium nitrite (8.0 g, 116 mmol) in portions and the reaction mixture was gradually brought to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 oC, treated with water (30 mL) and extracted with ethyl acetate (2x50 mL). The combined organics were washed with saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate in petroleum ether (20-30%) to furnish 3-chloro-1-methyl-4-nitro-1H-pyrazole as a solid. 1H NMR (CDCl3, 300 MHz): δ 8.25 (s, 1H), 3.98 (s, 3H).

  • 3
  • [ 3994-50-1 ]
  • [ 299930-70-4 ]
YieldReaction ConditionsOperation in experiment
50% With N-chloro-succinimide; lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃;Inert atmosphere; The solution of compound 12 (11 g, 86.55mmol) and NCS(1.2 eq,13.87g, 103.85mmol) in dry THF (100 ml) was cooled to -78 C under N2. LiHMDS (1.5 eq, 26% in THF, 21.72g, 129.82mmol, 93.77mL) was added dropwise into the solution while the inner temperature was maintained at -78C. The reaction was stirred at same temperature for 2 h, and then warmed to room temperature and quenched with water (200 mL), extracted with EA, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified with column chromatography (PE:EA=20:1) to obtain the target compound 13 (7.0 g, 50 % yield).
  • 4
  • [ 299930-70-4 ]
  • [ 75-33-2 ]
  • 3-(isopropylthio)-1-methyl-4-nitro-1H-pyrazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
80.3% With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 14.0h;Inert atmosphere; The solution of compound 13 (7.0 g, 43.39mmol), propane-2-thiol (SM8, 3.97g, 52.07mmol) and K2CO3 (14.99g, 108.48mmol) in dry DMF (30mL) under N2 was stirred at 100C for 14 h. Then the solution was cooled to room temperature and quenched with water (100 mL), extracted with EA, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified with column chromatography (PE:EA=10:1) to obtain the target compound 14 (7.00 g, 80.3 % yield).
  • 5
  • [ 110-82-7 ]
  • [ 299930-70-4 ]
  • C10H16ClN3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
27% With hydrogenchloride; tetrakis(tetrabutylammonium)decatungstate(VI); In water; acetonitrile; at 20℃; for 24.0h;Glovebox; Sealed tube; Irradiation; Inert atmosphere; General procedure: In a glovebox, the 1,3,5-trichloro-2-nitrobenzene(0.1 mmol, 1.0 equiv., 22.5 mg), TBADT (1 mol%, 3.3 mg), and cyclohexane (1 mmol, 5 equiv., 0.05 mL) were mixed in a sealed culture tube. Then degassed MeCN(1 mL) was added. HCl (0.3 mmol, 3.0 equiv., 0.03 mL) wasadded followed with a pipettor (avoid using metal material).The tube was set between two 50 W, 395 nm light-emitting diodes (LED, 3 cm away from the lamp) and stirred at roomtemperature (with a fan to cool down the reaction) for 24 h.After the reaction was completed, 5 mL of saturated aqueoussodium bicarbonate solution and 10 mL × 3 of ethyl acetatewere added and the combined organic layers were dried overNa2SO4. The solvent was removed under vacuum. The crudeproduct was purified by preparative thin layer chromatography(PTLC) to afford the corresponding product (hexane:ethyl acetate = 50:1).
  • 6
  • [ 74-98-6 ]
  • [ 299930-70-4 ]
  • C7H12ClN3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% With hydrogenchloride; tetrakis(tetrabutylammonium)decatungstate(VI); In water; acetonitrile; at 20℃; for 24.0h;Glovebox; Irradiation; Inert atmosphere; General procedure: In a glovebox, the 1,3,5-trichloro-2-nitrobenzene(0.4 mmol, 1.0 equiv., 90 mg), TBADT (1 mol%,13.2 mg) were mixed in a Shrek tube. Then degassed MeCN(4 mL) was added. HCl (1.2 mmol, 3.0 equiv., 0.12 mL) wasadded with a pipettor (avoid using metal material). The reactiontube is placed and frozen with liquid nitrogen, andthen ventilated to make it full of propane gas (Figure S4, Supporting Information online). The tube was set betweentwo 50 W, 395 nm LED (3 cm away from the lamp) andstirred at room temperature (with a fan to cool down thereaction) for 24 h. After the reaction was completed (FigureS5), Zn (130 mg, 2 mmol, 20 equiv.) and 2N HCl (1 mL)were added to the reaction mixture. After stirring at 60 C foranother 1 h, the reaction mixture was cooled to room temperatureand filtered through Celite. After the filter cakewas washed with EtOAc, the filtrate was neutralized withsaturated NaHCO3 (aq.) and extracted with EtOAc threetimes. The combined organic layers were washed with brine,dried over Na2SO4, filtered, and concentrated under reducedpressure. The solvent was removed under vacuum. The crudeproduct was purified by PTLC to afford the correspondingproduct (hexane:ethyl acetate = 50:1).
 

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Technical Information

Categories

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