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Chemical Structure| 138786-86-4 Chemical Structure| 138786-86-4
Chemical Structure| 138786-86-4

Methyl 4-nitro-1H-pyrazole-3-carboxylate

CAS No.: 138786-86-4

4.5 *For Research Use Only !

Cat. No.: A193303 Purity: 97%

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Product Details of [ 138786-86-4 ]

CAS No. :138786-86-4
Formula : C5H5N3O4
M.W : 171.11
SMILES Code : COC(=O)C1=NNC=C1[N+]([O-])=O
MDL No. :MFCD00505604
InChI Key :ARAFBUCGMOKZMI-UHFFFAOYSA-N
Pubchem ID :1276704

Safety of [ 138786-86-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Calculated chemistry of [ 138786-86-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 5
Fraction Csp3 0.2
Num. rotatable bonds 3
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 38.69
TPSA ?

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

100.8 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.37
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

0.23
Log Po/w (WLOGP)?

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

0.1
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.

-1.37
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

-1.23
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.38

Water Solubility

Log S (ESOL):?

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

-1.16
Solubility 11.9 mg/ml ; 0.0698 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.

-1.91
Solubility 2.12 mg/ml ; 0.0124 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

-0.69
Solubility 35.1 mg/ml ; 0.205 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

No
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.

-7.18 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

1.0
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)

2.17

Application In Synthesis of [ 138786-86-4 ]

* 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.

  • Upstream synthesis route of [ 138786-86-4 ]
  • Downstream synthetic route of [ 138786-86-4 ]

[ 138786-86-4 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 138786-86-4 ]
  • [ 74-88-4 ]
  • [ 400877-57-8 ]
  • [ 309740-49-6 ]
YieldReaction ConditionsOperation 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).
References: [1] Patent: US2007/27166, 2007, A1, . Location in patent: Page/Page column 79.
[2] Patent: EP1956009, 2008, A1, . Location in patent: Page/Page column 40.
[3] Patent: EP1970373, 2008, A1, . Location in patent: Page/Page column 91.
  • 2
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YieldReaction ConditionsOperation in experiment
61% With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In toluene at 20℃; To a solution of 14 (5 g, 29.2 mmol), methanol (5.93 mL, 146mmol) and tributylphosphine (14.6 mL, 58.4 mmol) in toluene(500 mL) was added 1,10-(azodicarbonyl)dipiperidine (14.8 g,58.4 mmol) at room temperature. The mixture was stirred at roomtemperature overnight. The insoluble material was removed by filtration,and the filtrate was partitioned between EtOAc and water.The organic layer was separated, washed with aqueous saturatedNaHCO3 and brine, dried over Na2SO4, filtered, and concentratedin vacuo. The residue was purified by column chromatography (silicagel, 30 g, eluted with 0–70percent EtOAc in hexane) to give 15b (3.28g, 61percent yield) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) d 4.03(3H, s), 4.03 (3H, s), 8.02 (1H, s).
References: [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2452 - 2465.
  • 3
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  • [ 74-88-4 ]
  • [ 309740-49-6 ]
YieldReaction ConditionsOperation in experiment
34.5% With potassium carbonate In acetone at 50℃; for 4 h; 4-Nitro-lH-pyrazole-3-carboxylic acid methyl ester (3.4 g, 19.9 mmol) was dissolved in acetone (50 mL)Methyl iodide (5.7 g, 40.22 mmol) and potassium carbonate (5.5 g, 39.9 mmol)Heated to 50 ° C,Reaction for 4 hours.Cooled to room temperature,filter,The filtrate was concentrated in vacuo,The residue was purified by silica gel column chromatography (petroleum ether: 1: ethyl acetate = 2) to give the product(1.27 g, yield: 34.5percent).
References: [1] Patent: CN107226807, 2017, A, . Location in patent: Paragraph 0274-0276.
  • 4
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  • [ 309740-49-6 ]
YieldReaction ConditionsOperation 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).

References: [1] Patent: WO2011/154327, 2011, A1, . Location in patent: Page/Page column 136; 137.
[2] Patent: US2010/63106, 2010, A1, . Location in patent: Page/Page column 11;13.
[3] Patent: WO2008/51047, 2008, A1, . Location in patent: Page/Page column 25; 28-29.
[4] Patent: US2009/156582, 2009, A1, . Location in patent: Page/Page column 30.
[5] Patent: EP1847531, 2007, A1, . Location in patent: Page/Page column 43.
  • 5
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  • [ 400877-57-8 ]
  • [ 309740-49-6 ]
YieldReaction ConditionsOperation 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.
References: [1] Patent: WO2018/2217, 2018, A1, . Location in patent: Page/Page column 299; 306.
 

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