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Chemical Structure| 1904-31-0
Chemical Structure| 1904-31-0
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Product Details of [ 1904-31-0 ]

CAS No. :1904-31-0 MDL No. :MFCD00466340
Formula : C4H7N3 Boiling Point : -
Linear Structure Formula :- InChI Key :MOGQNVSKBCVIPW-UHFFFAOYSA-N
M.W : 97.12 Pubchem ID :137254
Synonyms :

Calculated chemistry of [ 1904-31-0 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.25
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 27.89
TPSA : 43.84 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.97 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.88
Log Po/w (XLOGP3) : -0.11
Log Po/w (WLOGP) : 0.01
Log Po/w (MLOGP) : -0.27
Log Po/w (SILICOS-IT) : -0.26
Consensus Log Po/w : 0.05

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.9
Solubility : 12.2 mg/ml ; 0.125 mol/l
Class : Very soluble
Log S (Ali) : -0.36
Solubility : 42.6 mg/ml ; 0.439 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.35
Solubility : 43.0 mg/ml ; 0.443 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.29

Safety of [ 1904-31-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1904-31-0 ]

* 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 [ 1904-31-0 ]
  • Downstream synthetic route of [ 1904-31-0 ]

[ 1904-31-0 ] Synthesis Path-Upstream   1~12

  • 1
  • [ 110-13-4 ]
  • [ 1904-31-0 ]
  • [ 34605-66-8 ]
YieldReaction ConditionsOperation in experiment
98% for 4 h; Reflux Accordingly, as shown in step 3-i of Scheme 3, 1-methyl-1H-pyrazol-3-amine (compound 1007, 2.8 g, 28.8 mmol) and 2,5-hexanedione (3.38 mL, 28.8 mmol) were dissolved into 50 mL of toluene. p-Toluenesulfonic acid (1.4 mmol) was added, the reaction mixture refluxed, and water generated from the reaction collected in a Dean-Stark trap.
When no more water was generated (about 4 hours), the reaction mixture was cooled and the volatiles removed under reduced pressure.
The residue was passed through a plug of silica gel using dichloromethane as eluent to yield an oil, which solidified upon standing.
The solid was broken up, suspended in hexane, vigorously stirred for one hour, and collected by filtration to provide 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole (compound 1008, 5.0 g, 98percent yield) as a white powder: ESMS (M+1)=175; 1H-NMR (CDCl3) δ 7.38 (d, J=4 Hz, 1H), 6.14 (d, J=4 Hz, 1H), 5.84 (s, 2H), 3.95 (s, 3H), 2.09 (s, 6H).
98.1% With acetic acid In toluene at 155℃; Step 1)
3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole
To a solution of 1-methyl-1H-pyrazol-3-amine (3.90 g, 40.16 mmol) and hexane-2,5-dione (4.58 g, 40.13 mmol) in toluene (80 mL) was added acetic acid (0.73 g, 12.16 mmol).
The reaction mixture was heated to 155° C. and stirred overnight, then cooled down to rt and concentrated in vacuo.
The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the title compound as a yellow solid (6.90 g, yield 98.1percent).
LC-MS (ESI, pos. ion) m/z: 176.3 [M+H]+;
1H NMR (400 MHz, CDCl3): δ (ppm) 7.41 (d, J=2.1 Hz, 1H), 6.17 (d, J=2.2 Hz, 1H), 5.87 (s, 2H), 3.94 (s, 3H), 2.13 (s, 6H).
94% With toluene-4-sulfonic acid In benzene at 115℃; for 4 h; A solution of 1-methyl-1H-pyrazol-3-ylamine (0.92 g, 9.5 mmol) in benzene (4.8 mL) was treated with hexane-2,5-dione (1.34 mL, 11.4 mmol) and para-toluenesulfonic acid (182 mg, 0.95 mmol) and was heated to 115° C. under Dean-Stark conditions for 4 h. After this time, the reaction was cooled to 25° C., concentrated in vacuo and dried under high vacuum overnight. The resulting residue was dissolved in methylene chloride (100 mL) and was washed with water (1.x.150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 80 g, 1:4 ethyl acetate/hexanes) afforded 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (1.57 g, 94percent) as a green oil; ES+-HRMS m/e calcd for C10H13N3 [M+H+] 176.1182, found 176.1182.
69% at 20 - 100℃; for 6 h; Inert atmosphere A solution of 1 -methyl-1 -/-pyrazol-3-amine (2 g, 20.6 mmol,) in AcOH (50 mL) was treated with 2,5-hexane dione (4.9 g, 43.29 mmol) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was heated to 100 °C for 1 h then stirred at ambient temperature for 5 h. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The crude product was purified by column chromatography on silica gel using 10percent EtOAc- hexanes eluent to give 3-(2,5-dimethyl-1 H-pyrrol-1 -yl)-1 -methyl-1 H-pyrazole as a liquid (2.5 g, 69percent). 1 H NMR (300 MHz, CDCI3): δ = 7.39 (d, J = 2.1 Hz, 1 H), 6.15 (d, J = 2.4 Hz, 1 H), 5.84 (s, 2H), 3.92 (s, 3H), 2.10 (s, 6H).
63% With acetic acid In toluene for 3 h; Reflux To a solution of 1-methyl-3-aminopyrazole (50 g, 0.52 mol) in toluene (2 L), hexane-2,5-dione (58.5 g) and acetic acid (12.5 mL) were added. The solution was then refluxed for 3 hours. After the reaction mixture was cooled, water (0.6 L) was added thereto. The mixture was neutralized with sodium carbonate, and then separated. The organic layer was then concentrated. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether 1:10) to yield 62 as a brown solid (57 g, y. 63percent). 1H-NMR (500 Mz) (CDCl3): 2.10 (s, 6H), 3.92 (s, 3H), 5.84 (s, 1H), 6.14 (d, J = 3.5 Hz, 1H), 7.38 (d, J = 3.5 Hz, 1H).
55% With toluene-4-sulfonic acid In toluene at 115℃; for 6 h; Dean-Stark To a stirred suspension of 1-methyl-1H-pyrazol-3-amine 76a (0.5 g, 5.1 mmol) in toluene (20 mL) in an round bottom flask fitted with Dean-Stark apparatus was charged with hexane-2,5-dione (0.70 g, 6.1 mmol) followed by p-toluene sulfonic acid (0.097 g, 0.51 mmol) and the reaction mixture was heated at 115°C for about 6 h. The reaction mixture was cooled to room temperature. Reaction mass was concentrated fully under reduced pressure, residue obtained was dissolved in DCM, given water wash followed by brine wash, dried over Na2504 and concentrated under redcued pressure to obtain 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole 76b (0.55 g, 55percent yield) as green oil. 1HNMR (400 MHz, CDC13): 6 7.39 (d, 111), 6.15 (s, 1H), 5.85 (s, 2H), 3.92 (s, 3H), 2.10 (s, 6H), MS: 176.11 (M+H).
52% With toluene-4-sulfonic acid In toluene for 20 h; Reflux To a solution of 1-Methyl-1H-pyrazol-3-ylamine (2 g, 20.59 mmol), hexane-2,5-dione (2.82 g, 24.71 mmol) in toluene (35 ml) was added PTSA.H2O (392 mg, 2.059 mmol).
The mixture was refluxed for 20 h, after which the toluene was removed and water was added water.
The aqueous layer was then extracted with EtOAc, separated, and the organic phase was washed with brine, dried over Na2SO4, concentrated, and the crude material purified by column chromatography to give 3-(2,5-Dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (1.9 g, 52percent).

Reference: [1] Patent: US2011/81316, 2011, A1, . Location in patent: Page/Page column 15; 16
[2] Patent: US2016/229837, 2016, A1, . Location in patent: Paragraph 0589; 0590; 0591
[3] Patent: US2009/264434, 2009, A1, . Location in patent: Page/Page column 27; 43
[4] Patent: WO2016/131098, 2016, A1, . Location in patent: Page/Page column 141
[5] Patent: EP2426135, 2012, A1, . Location in patent: Page/Page column 116
[6] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 000151
[7] Patent: US2011/71150, 2011, A1, . Location in patent: Page/Page column 32
  • 2
  • [ 1904-31-0 ]
  • [ 34605-66-8 ]
YieldReaction ConditionsOperation in experiment
98.1% With acetic acid In toluene at 155℃; 1-methyl-1-methyl -1H- pyrazol-3-amine (3.90g, 40.16mmol) and hexane-2,5-dione (4.58g, 40.13mmol) in toluene (80mL) was added acetic acid (0.73g, 12.16mmol). The reaction mixture was warmed to 155 deg.] C, stirred overnight, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc / PE (v / v) = 1/10) to give the title compound as a yellow solid (6.90 g of the, yield 98.1percent).
Reference: [1] Patent: CN105461694, 2016, A, . Location in patent: Paragraph 0762; 0764; 0765
  • 3
  • [ 54210-32-1 ]
  • [ 132038-69-8 ]
  • [ 1904-31-0 ]
Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1990, vol. 26, # 8, p. 955
  • 4
  • [ 75092-34-1 ]
  • [ 1904-31-0 ]
Reference: [1] Russian Chemical Bulletin, 1996, vol. 45, # 11, p. 2585 - 2587
  • 5
  • [ 91027-92-8 ]
  • [ 73810-75-0 ]
  • [ 1904-31-0 ]
Reference: [1] Polish Journal of Chemistry, 1982, vol. 56, # 10-12, p. 1273 - 1278
  • 6
  • [ 54210-32-1 ]
  • [ 1904-31-0 ]
Reference: [1] Russian Chemical Bulletin, 1996, vol. 45, # 11, p. 2585 - 2587
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 23, p. 10013 - 10030
  • 7
  • [ 1904-31-0 ]
  • [ 92525-10-5 ]
YieldReaction ConditionsOperation in experiment
81% With hydrogenchloride; potassium iodide; sodium nitrite In water at 0 - 20℃; for 4 h; Large scale The compound N-methyl-3-aminopyrazole (2000 g, 20.6 mol, 1.0 eq) was dissolved in 6000 ml of concentrated hydrochloric acidAnd 2000 ml of water,Cooled to 0-5 ° C in an ice-salt bath,Then, 3.5 L of a saturated aqueous sodium nitrite solution (NaNO2, 2842.8 g, 41.2 mol, 2.0 eq) was added dropwise,After mechanical stirring reaction for 20 min,The reaction solution was added dropwise to an aqueous solution of 8000 ml of potassium iodide (8549.0 g, 51.5 mol, 2.5 eq) at 0 ° C,After completion of the dropwise addition,The reaction was allowed to spontaneously rise to room temperature for 4 h,After TLC detection reaction was complete,Add ethyl acetate extraction 2 times,The organic phase was dried with saturated brine and concentrated,The crude product was purified via flash column to give compound 3-iodo-l-methyl-lH-pyrazole (3473.8 g, 16.7 mol)Yield 81.0percent.
54.4% With copper(l) iodide; diiodomethane; isopentyl nitrite In tetrahydrofuran for 5 h; Inert atmosphere; Reflux To a suspension of l-methyH/f-pyrazol-3-amine (200 mg, 2.06 mmol) in THF (5 mL) under 2 atmosphere were added Cul (431 mg, 2.27 mmol) and CH2I2 (0.5 mL, 6.18 mmol), followed by addition of isopentyi nitrite (8.30 mL, 61.78 mmol). The mixture was heated at reflux for 5 hours, then cooled to rt, and diluted with EtOAc (15 mL). The resulted mixture was washed with saturated Na2S203 aqueous solution (15 mL), then filtered through a pad of ('Η . ΠΤ. \ and the filtrate was washed with saturated brine (10 ml,). The organic phase was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtQAc (v/v) = 10/1) to get the title compound as yellow liquid (233 mg, yield 54.4percent). MS (ESI, pos. ion) m/z: 209.0 [M+H]+.
Reference: [1] Patent: CN105669733, 2016, A, . Location in patent: Paragraph 0031; 0032; 0033; 0034
[2] Patent: WO2015/175579, 2015, A1, . Location in patent: Paragraph 351
  • 8
  • [ 1904-31-0 ]
  • [ 151049-87-5 ]
YieldReaction ConditionsOperation in experiment
818 mg
Stage #1: With hydrogen bromide; sodium nitrite In water for 0.5 h; Cooling with ice
Stage #2: for 30 h; Cooling with ice
A)
3-bromo-1-methyl-1H-pyrazole
To a solution of 1-methyl-1H-pyrazol-3-amine (2.00 g) in hydrobromic acid (14.0 mL) was slowly added an aqueous solution (2.06 mL) of sodium nitrite (1.56 g) under ice-cooling.
The reaction mixture was stirred under ice-cooling for 30 min, and a solution of copper(I) bromide (7.39 g) in hydrobromic acid (14.0 mL) was slowly added thereto.
The reaction mixture was stirred under ice-cooling for 30 hr, neutralized with saturated aqueous sodium hydrogen carbonate solution, and diluted with dichloromethane.
The insoluble substance was removed by filtration, the filtrate was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (818 mg).
1H NMR (400 MHz, CDCl3) δ 3.88 (3H, s), 6.25 (1H, d, J = 2.4 Hz), 7.25 (1H, d, J = 2.0 Hz).
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 22, p. 6313 - 6320
[2] Patent: EP2818473, 2014, A1, . Location in patent: Paragraph 0577
[3] Synthesis (Germany), 2015, vol. 47, # 5, p. 679 - 691
  • 9
  • [ 1904-31-0 ]
  • [ 89501-90-6 ]
Reference: [1] Patent: US4931081, 1990, A,
  • 10
  • [ 1904-31-0 ]
  • [ 146941-72-2 ]
YieldReaction ConditionsOperation in experiment
59% With hydrogen bromide; sodium hydrogencarbonate; sodium bromide In water at 25℃; Electrochemical reaction General procedure: Amino-pyr azole 1 (0.291 g, 0.003 mol) and an aqueous solution of NaBr (100 mL) (concentrations were as follows: 1 in entries 1 and 2, 2 Min entries 3 and 5-9, and 3 in entry 4) were placed in a cell. In experiment 2, NaHCO3 (0.504 g, 0.006 mol) was added to the solution. The electrolysis was carried out at the following currents: 426 mA for entries 1—4, 213 mA for entry 5, 710 mA for entries 6, 8, and 9, and 852 mA for entry 7. In experiment 9, 48percent aqueous solution of HBr was periodically added to the reaction mixture to maintain 7. After passing 2 F of electricity per 1 mole of the starting aminopyrazole 1(Q= 579 C) for entries 1—7or 8 F (Q= 2316 C) for entries 8and 9, the electrolysis was stopped, the reaction mixture was stirred for 1 h and analyzed by TLC (eluent light petroleum ether—ethyl acetate (1 : 1)). Then, the mixture obtained was diluted with concentrated HCl (to 3) and the products were extracted with CHCl3 (3×30 mL). The extracts were combined, dried with anhydrous MgSO4, and concentrated in vacuo. The products were isolated using column chromatography on SiO2 (eluent light petroleum ether-ethyl acetate). The following compounds were isolated: 1,2-bis(1-methyl-1H-pyrazol-3-yl)-diazene (7) (entries 1-7; the product was identified by m.p. 201—202 °C (cf. Refs 2 and 4: m.p. 201 °C) and the reported 2,41 NMR spectra) and 1,2-bis(4-bromo-1-methyl-1H-pyrazol-3-yl)diazene (8) (entries 8 and 9, the product was identified by NMR spectroscopy and high resolution mass spectrometry). The aqueous layer obtained after extraction was concentrated in vacuo, diluted with NaOH with stirring (to 10), and treated as described above. This resulted in the isolation of 3-amino-4-bromo-1-methyl-1H-pyrazole (6) (entries 1-9; the product was identifi ed by m.p. 97 °C (cf. Ref. 10: m.p. 97-98 °C) and the reported 51 NMR spectra) and unreacted aminopyr-azole 1(entries 1-8; the starting compound was identified by TLC and NMR spectroscopy). 1,2-Bis(4-bromo-1-methyl-1H-pyrazol-3-yl)diazene (8).Yellow crystals. M.p. 211—213 °C. Rf 0.13 (eluent light petroleum ether—ethyl acetate (1:5)). 1H NMR, :4.02 (s, 6 H, Me); 7.50 (s, 2 H, CH). 13C NMR, :40.4 (2 Me), 90.1 (2 CBr), 132.9 (2 CH), 157.5 (2 CN). Found: m/z 348.9217 [M + H]+. C8H979Br2N6. Calculated: [M + H]+= 348.9230
Reference: [1] Russian Chemical Bulletin, 2018, vol. 67, # 3, p. 510 - 516[2] Izv. Akad. Nauk, Ser. Khim., 2018, # 3, p. 510 - 516,7
  • 11
  • [ 1904-31-0 ]
  • [ 146941-72-2 ]
YieldReaction ConditionsOperation in experiment
29% With sodium hydrogencarbonate; sodium bromide In water at 25℃; Electrochemical reaction General procedure: Amino-pyr azole 1 (0.291 g, 0.003 mol) and an aqueous solution of NaBr (100 mL) (concentrations were as follows: 1 in entries 1 and 2, 2 Min entries 3 and 5-9, and 3 in entry 4) were placed in a cell. In experiment 2, NaHCO3 (0.504 g, 0.006 mol) was added to the solution. The electrolysis was carried out at the following currents: 426 mA for entries 1—4, 213 mA for entry 5, 710 mA for entries 6, 8, and 9, and 852 mA for entry 7. In experiment 9, 48percent aqueous solution of HBr was periodically added to the reaction mixture to maintain 7. After passing 2 F of electricity per 1 mole of the starting aminopyrazole 1(Q= 579 C) for entries 1—7or 8 F (Q= 2316 C) for entries 8and 9, the electrolysis was stopped, the reaction mixture was stirred for 1 h and analyzed by TLC (eluent light petroleum ether—ethyl acetate (1 : 1)). Then, the mixture obtained was diluted with concentrated HCl (to 3) and the products were extracted with CHCl3 (3×30 mL). The extracts were combined, dried with anhydrous MgSO4, and concentrated in vacuo. The products were isolated using column chromatography on SiO2 (eluent light petroleum ether-ethyl acetate). The following compounds were isolated: 1,2-bis(1-methyl-1H-pyrazol-3-yl)-diazene (7) (entries 1-7; the product was identified by m.p. 201—202 °C (cf. Refs 2 and 4: m.p. 201 °C) and the reported 2,41 NMR spectra) and 1,2-bis(4-bromo-1-methyl-1H-pyrazol-3-yl)diazene (8) (entries 8 and 9, the product was identified by NMR spectroscopy and high resolution mass spectrometry). The aqueous layer obtained after extraction was concentrated in vacuo, diluted with NaOH with stirring (to 10), and treated as described above. This resulted in the isolation of 3-amino-4-bromo-1-methyl-1H-pyrazole (6) (entries 1-9; the product was identifi ed by m.p. 97 °C (cf. Ref. 10: m.p. 97-98 °C) and the reported 51 NMR spectra) and unreacted aminopyr-azole 1(entries 1-8; the starting compound was identified by TLC and NMR spectroscopy).
Reference: [1] Russian Chemical Bulletin, 2018, vol. 67, # 3, p. 510 - 516[2] Izv. Akad. Nauk, Ser. Khim., 2018, # 3, p. 510 - 516,7
  • 12
  • [ 1904-31-0 ]
  • [ 146941-72-2 ]
Reference: [1] Patent: US5201938, 1993, A,
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