[ CAS No. 3034-41-1 ]

Name: 3034-41-1|1-Methyl-4-nitroimidazole|95%
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Quality Control of [ 3034-41-1 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 3034-41-1 ]

CAS No. :	3034-41-1	MDL No. :	MFCD00159683
Formula :	C₄H₅N₃O₂	Boiling Point :	328.9°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	-
M.W :	127.10 g/mol	Pubchem ID :	18209
Synonyms :

Calculated chemistry of of [ 3034-41-1 ]

Physicochemical Properties

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 :	0.0
Molar Refractivity :	32.31
TPSA :	63.64 Å²

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) :	-7.39 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.81
Log Po/w (XLOGP3) :	-0.44
Log Po/w (WLOGP) :	0.33
Log Po/w (MLOGP) :	0.06
Log Po/w (SILICOS-IT) :	-1.67
Consensus Log Po/w :	-0.18

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.7
Solubility :	25.6 mg/ml ; 0.201 mol/l
Class :	Very soluble
Log S (Ali) :	-0.43
Solubility :	47.1 mg/ml ; 0.371 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.14
Solubility :	92.5 mg/ml ; 0.728 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.08

Safety of [ 3034-41-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 3034-41-1 ]

* 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 [ 3034-41-1 ]
Downstream synthetic route of [ 3034-41-1 ]

[ 3034-41-1 ] Synthesis Path-Upstream 1~9

1
[ 553-90-2 ]
[ 3034-38-6 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1] Tetrahedron Letters, 1984, vol. 25, # 18, p. 1957 - 1960

2
[ 616-47-7 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1] Journal of the Chemical Society, 1924, vol. 125, p. 1434
[2] Synthesis, 2011, # 17, p. 2859 - 2864

3
[ 3034-38-6 ]
[ 77-78-1 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1] Liebigs Annalen der Chemie, 1987, p. 77 - 80
[2] Journal of the Chemical Society, 1925, vol. 127, p. 576
[3] Tetrahedron Letters, 1984, vol. 25, # 18, p. 1957 - 1960

4
[ 616-47-7 ]
[ 3034-41-1 ]
[ 3034-42-2 ]
[ 19183-15-4 ]

Reference： [1] Synthesis, 2011, # 17, p. 2859 - 2864

5
[ 212248-40-3 ]
[ 74-88-4 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1] Russian Journal of Organic Chemistry, 1997, vol. 33, # 12, p. 1764 - 1766

6
[ 186581-53-3 ]
[ 60-29-7 ]
[ 3034-38-6 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1] Journal of the Chemical Society, 1925, vol. 127, p. 576

7
[ 3034-38-6 ]
[ 77-78-1 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1] Journal of the Chemical Society, 1925, vol. 127, p. 576

8
[ 616-47-7 ]
[ 3034-41-1 ]
[ 5213-50-3 ]
[ 19183-20-1 ]
[ 1671-82-5 ]

Yield	Reaction Conditions	Operation in experiment
1%	at 110 - 120℃; for 2 h;	Nitration of 1-methylimidazole with Nitric Acid and Sulfuric Acid Fuming nitric acid (1.5 ml, excess, d.1.544 g/ml) was added to 1-methylimidazole (100 mg, 1.22 mmol) at room temperature with stirring. Then sulfuric acid (1.5 ml, excess, fuming 30percent SO₃) was added slowly from the top of condenser. After addition, the reaction mixture was heated to 110° C. and then the reaction temperature was maintained between 110-120° C. for 2.0 hrs. The reaction mixture was cooled to room temperature and the resulting mixture of products was extracted with methylene chloride and the organic phase was dried with Na₂SO₄/NaHCO₃. Evaporation of the solvent gave 61 mg of oil. Proton NMR showed that the ratio of the products was 7:25:45:2:1 (corresponding to 1-methyl-4-nitroimidazole, 1-methyl-2-nitroimidazole, 1-methyl-4,5-dinitroimidazole, 1-methyl-2,4-dinitroimidazole, and 1-methyl-2,4,5-trinitroimidazole). The yield of 1-methyl-2,4,5-trinitroimidazole is less then 1percent based on the integration of the NMR.

Reference： [1] Patent: US7304164, 2007, B1, . Location in patent: Page/Page column 7

9
[ 3034-41-1 ]
[ 89088-69-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 1, p. 144 - 158
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 265 - 285

[ 3034-41-1 ] Synthesis Path-Downstream 1~31

1
[ 616-47-7 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1]Journal of the Chemical Society,1924,vol. 125,p. 1434
[2]Synthesis,2011,p. 2859 - 2864

2
[ 3034-41-1 ]
[ 74-88-4 ]
[ 3034-43-3 ]

Reference： [1]Journal of the Chemical Society,1924,vol. 125,p. 1434
[2]Journal of the Chemical Society,1924,vol. 125,p. 1434
[3]Chemical Communications,2005,p. 2750 - 2752

3
[ 186581-53-3 ]
[ 60-29-7 ]
[ 3034-38-6 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1]Journal of the Chemical Society,1925,vol. 127,p. 576

4
[ 3034-38-6 ]
furan-2,3,5(4H)-trione pyridine (1:1) [ No CAS ]
[ 77-78-1 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1]Journal of the Chemical Society,1925,vol. 127,p. 576

5
[ 3034-38-6 ]
[ 77-78-1 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1]Liebigs Annalen der Chemie,1987,p. 77 - 80
[2]Journal of the Chemical Society,1925,vol. 127,p. 576
[3]Tetrahedron Letters,1984,vol. 25,p. 1957 - 1960

6
[ 3034-41-1 ]
[ 7205-98-3 ]
[ 116271-00-2 ]

Reference： [1]Bulletin of the Polish Academy of Sciences: Chemistry,1987,vol. 35,p. 287 - 292
[2]Chemistry - A European Journal,2008,vol. 14,p. 6108 - 6118

7
[ 3034-41-1 ]
[ 79578-98-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃;	Example 268b 1-Methyl-1H-imidazol-4-amine 268b A 100-mL round-bottomed flask was charged with 268a (1.6 g, 12.6 mmol), 10% palladium on carbon (50% wet, 160 mg), and ethanol (15 mL). The flask was evacuated, charged with hydrogen gas, and stirred at room temperature overnight. The catalyst was removed by filtration through a pad of CELITE and the filtrate was concentrated under reduced pressure to afford 268b (1.2 g, 98%) as a yellow solid. MS-ESI: [M+H]+ 98.2
92%	With hydrogen;palladium 10% on activated carbon; In ethanol; for 1.5h;	Step B: To l-methyl-4-nitro-lH-imidazole (354 mg, 2.8 mmol) inEtOH (20 mL) was added 10%> Pd-C (90 mg) and the mixture was stirred under a hydrogen atmosphere for 1.5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 1 -methyl- lH-imidazol-4-amine (250 mg, 92%) as a yellow oil that darkened upon standing. 1H NMR (300 MHz, DMSO- d6) delta 7.05 (s, 1H), 6.08 (d, J= 1.3 Hz, 1H), 4.06 (br s, 2H), 3.47 (s, 3H).
92%	With palladium 10% on activated carbon; hydrogen; In ethanol;	Step B: To <strong>[3034-41-1]1-methyl-4-nitro-1H-imidazole</strong> (354 mg, 2.8 mmol) in EtOH (20 mL) was added 10% Pd-C (90 mg) and the mixture was stirred under a hydrogen atmosphere for 1.5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 1-methyl-1H-imidazol-4-amine (250 mg, 92%) as a yellow oil that darkened upon standing. 1H NMR (300 MHz, DMSO-d6) delta 7.05 (s, 1H), 6.08 (d, J=1.3 Hz, 1H), 4.06 (br s, 2H), 3.47 (s, 3H).

89%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 16h;	[0280j To a solution of i-methyl-4-nitro-1H-imidazole (500 mg, 3.94 mmol) in MeOH (10 mL) was added Pd/C (50 mg). The mixture was stirred at rt for 16 h under hydrogen atmosphere. Then the mixture was filtered and the filtrate was concentrated in vacuo. The crude product (340 mg. yield: 89%) was used in the next step without further purification. ESI-MS (M+H): 98.1.
82%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 25℃; for 12h;	Under hydrogen (1 atm), to a solution of compound <strong>[3034-41-1]1-methyl-4-nitro-1H-imidazole</strong> (500 mg, 3.94 mmol) in ethanol (20 mL) was added 10% Pd-C (0.1 g). The mixture was stirred at 25 C. for 12 hours, and then filtrated, the filtrate was concentrated under reduced pressure to give compound 48-a (310 mg, yield: 82%), which was used directly for the next step without purification.
	With hydrogen;5% Pd(II)/C(eggshell); at 18 - 25℃; under 760.051 Torr; for 3h;Product distribution / selectivity;	Intermediate 10; 2-Chloro-N-(l-methyl-lH-imidazol-4-v?-7-r(4-methylphenyl)sulfonyl1-7H-pyrrolor2.3- J1pyrimidin-4-aminel-Methyl-4-nitro-lH-imidazole (Intermediate 1, 50 mg, 0.39 mmol) was dissolved in ethanol (5 mL) and Pd/C (5 wt%, Degussa, 20.93 mg, 9.83 mumol) was added. The reaction mixture stirred under 1 atm of hydrogen at r.t. for 3 hours and was then filtered through diatomaceous earth (Celite brand) to give 1 -methyl- lH-imidazol-4-amine. 2,4-Dichloro-7-[(4- methylphenyl)sulfonyl]-7H-pyrrolo[2,3-<i]pyrimidine (Intermediate 9, 108 mg, 0.31 mmol) and TEA (0.110 mL, 0.79 mmol) was added to the reaction mixture. The reaction mixture was stirred at 1000C in a microwave reactor for 2hr. After completion of the reaction as indicated by TLC, the reaction mixture was evaporated in vacuo to obtain a light yellow solid, which was purified by column chromatography (3% MeOH, 0.3% NH4OH in DCM) to provide the title product (90 mg, 57%) as a white solid. LCMS: 403 [M+H]+.1U NMR (400 MHz, CHLOROFORM-D) delta ppm 8.92 (s, 1 H) 8.03 (d, J=8.34 Hz, 2 H) 7.41 (s, 1 H) 7.39 (d, J=3.79 Hz, 1 H) 7.25 (d, J=8.08 Hz, 2H) 6.48 (s, 1 H) 3.67 (s, 3 H) 2.33 (s, 3 H).
	With hydrogen;palladium on activated charcoal; In methanol;	Building block 6, a prime side amine (BB6)1 -Methyl-1 H-imidazol-4-amine (BB6)The title compound was achieved by catalytic hydrogenation in MeOH of 1 -methyl-4-nitro-1 H- imidazole using Pd/C as catalyst. Removal of the catalyst by filtration of the reaction mixture through Celite followed by evaporation of the solvent gave the title compound, which was used in the next step without further purification.
	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 6h;Inert atmosphere;	Synthesis of LXXI:To a stirred solution of compound LXX (4g, 31 mmol) in ethanol (20 mL) was added 1 0%Pd-C (catalytic) under nitrogen atmosphere. The reaction mixture was evacuated using high vacuum and stirred in presence of hydrogen gas at balloon pressure at room temperature for 6 h. The reaction mixture was filtered through a celite bed. The organic solvent was evaporated under reduced pressure to afford 1-methyl-1H-imidazol-4-amine (LXXI, 2.5g) MS (M+1) 98. The crude material was carried forward to next step without purification.
	With hydrogen;palladium on activated carbon; In ethanol; at 18 - 25℃; under 760.051 Torr; for 3h;	1 -Methyl-4-nitro- lH-imidazole (Intermediate 1, 500 mg, 3.93 mmol) was dissolved in ethanol (7.868 mL) and Pd/C (10 wt.%, Degussa, 105 mg, 0.10 mmol) was added. The reaction mixture was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered and the filtrate was cooled to 00C. 2,4,6-trichloro-l,3,5-triazine (580 mg, 3.15 mmol) and TEA (1.097 mL, 7.87 mmol) were then added. The reaction mixture was allowed to warm to 25C overnight. The reaction mixture was then filtered providing the title product as a tan solid (572 mg). LCMS: 246 [M+eta]+.
0.75 g	With palladium on activated charcoal; hydrogen; In ethanol; at 20℃; for 24h;	1-Methyl-4-nitroimidazole (1 g), Pd/C (0.1 g) and 20 ml of ethanol were exchanged in a balloon of hydrogen at room temperature for about 24 h.Vacuum filtration through celite, the filtrate was dried under reduced pressure to give the title product (0.75g).
	With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃; under 775.743 Torr; for 1h;	To a solution of 1 -methyl-4-nitro-imidazole (2 g, 15.7 mmol, 1 eq.) in MeOH (100 ml) was added 10 % Pd/C (1 g, 15.7 mmol) under H2 . The mixture was stirred under H2 (15 psi) at 25 C for 1 h. The mixture was diluted with MeOH (50 ml) and filtered under reduced pressure. The filtrate was evaporated to give the title compound as a yellow oil. NMR (400 MHz, CDCl3) d = 7.03 (s, 1H), 6.17 (s, 1H), 3.60 - 3.10 (m, 5H).
0.75 g	With palladium on activated charcoal; hydrogen; In ethanol; at 10 - 35℃; for 24h;	Mix <strong>[3034-41-1]<strong>[3034-41-1]1-methyl-4-nitroimidazol</strong>e</strong> (1g), Pd / C (0.1g) and 20ml ethanol,Replace the air with a hydrogen balloon,The reaction was carried out at room temperature for about 24 h.The celite was suction-filtered under reduced pressure, and the filtrate was dried under reduced pressure to obtain the title product (0.75 g).

Reference： [1]Patent: EP2773638,2015,B1 .Location in patent: Paragraph 1084; 1086
[2]Patent: WO2012/30944,2012,A2 .Location in patent: Page/Page column 103
[3]Patent: US2012/53174,2012,A1 .Location in patent: Page/Page column 57
[4]Patent: WO2015/89337,2015,A1 .Location in patent: Paragraph 0280
[5]Patent: US2015/336982,2015,A1 .Location in patent: Paragraph 0329; 0330
[6]Acta Chemica Scandinavica,1990,vol. 44,p. 67 - 74
[7]Heterocycles,1996,vol. 42,p. 213 - 218
[8]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5703 - 5707
[9]Patent: WO2010/38060,2010,A1 .Location in patent: Page/Page column 69
[10]Patent: WO2012/172473,2012,A1 .Location in patent: Page/Page column 28
[11]Patent: WO2015/97121,2015,A1 .Location in patent: Page/Page column 136; 137
[12]Patent: WO2009/150462,2009,A1 .Location in patent: Page/Page column 68
[13]Patent: CN109678803,2019,A .Location in patent: Paragraph 0202-0207
[14]Patent: WO2019/121691,2019,A1 .Location in patent: Paragraph 0857
[15]Patent: CN110330484,2019,A .Location in patent: Paragraph 0076; 0086; 0087; 0089; 0090

8
[ 553-90-2 ]
[ 3034-38-6 ]
[ 3034-41-1 ]

Reference： [1]Tetrahedron,1990,vol. 46,p. 6113 - 6124
[2]Tetrahedron,1990,vol. 46,p. 6113 - 6124

9
[ 553-90-2 ]
[ 3034-38-6 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1]Tetrahedron Letters,1984,vol. 25,p. 1957 - 1960

10
[ 3034-38-6 ]
[ 616-38-6 ]
[ 3034-41-1 ]

Reference： [1]Liebigs Annalen der Chemie,1987,p. 77 - 80

11
[ 212248-40-3 ]
[ 74-88-4 ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1]Russian Journal of Organic Chemistry,1997,vol. 33,p. 1764 - 1766

12
[ 616-47-7 ]
HNO₃+H₂SO₄ [ No CAS ]
[ 3034-41-1 ]
[ 3034-42-2 ]

Reference： [1]Journal of the Chemical Society,1924,vol. 125,p. 1434

13
[ 616-47-7 ]
[ 3034-41-1 ]
[ 5213-50-3 ]
[ 19183-20-1 ]
[ 1671-82-5 ]

Yield	Reaction Conditions	Operation in experiment
< 1%	With sulfuric acid; sulfur trioxide; nitric acid; at 110 - 120℃; for 2h;Product distribution / selectivity;	Nitration of 1-methylimidazole with Nitric Acid and Sulfuric Acid Fuming nitric acid (1.5 ml, excess, d.1.544 g/ml) was added to 1-methylimidazole (100 mg, 1.22 mmol) at room temperature with stirring. Then sulfuric acid (1.5 ml, excess, fuming 30% SO3) was added slowly from the top of condenser. After addition, the reaction mixture was heated to 110 C. and then the reaction temperature was maintained between 110-120 C. for 2.0 hrs. The reaction mixture was cooled to room temperature and the resulting mixture of products was extracted with methylene chloride and the organic phase was dried with Na2SO4/NaHCO3. Evaporation of the solvent gave 61 mg of oil. Proton NMR showed that the ratio of the products was 7:25:45:2:1 (corresponding to 1-methyl-4-nitroimidazole, 1-methyl-2-nitroimidazole, 1-methyl-4,5-dinitroimidazole, 1-methyl-2,4-dinitroimidazole, and 1-methyl-2,4,5-trinitroimidazole). The yield of 1-methyl-2,4,5-trinitroimidazole is less then 1% based on the integration of the NMR.

Reference： [1]Patent: US7304164,2007,B1 .Location in patent: Page/Page column 7

14
[ 3034-41-1 ]
[ 72904-46-2 ]
[ 120721-86-0 ]

Reference： [1]Canadian Journal of Chemistry,1989,vol. 67,p. 508 - 516

15
[ 3034-41-1 ]
[ 132882-85-0 ]
RuCl₂(tmso)2(NMe-4-NO₂Im)2 [ No CAS ]

Reference： [1]Canadian Journal of Chemistry,1989,vol. 67,p. 508 - 516

16
[ 3034-41-1 ]
[ 194497-67-1 ]
[ 114384-14-4 ]

Reference： [1]Canadian Journal of Chemistry,1988,vol. 66,p. 117 - 122

17
[ 60314-39-8 ]
[ 3034-41-1 ]
[ 136537-80-9 ]

Reference： [1]Inorganic Chemistry,1991,vol. 30,p. 4374 - 4380

18
[ 3034-41-1 ]
[ 7205-98-3 ]
[ 100-00-5 ]
[ 89303-10-6 ]
[ 116271-00-2 ]

Reference： [1]Chemistry - A European Journal,2008,vol. 14,p. 6108 - 6118

19
[ 3034-41-1 ]
[ 7205-98-3 ]
[ 350-46-9 ]
[ 89303-18-4 ]
[ 116271-00-2 ]

Reference： [1]Chemistry - A European Journal,2008,vol. 14,p. 6108 - 6118

20
[ 3034-38-6 ]
[ 74-88-4 ]
[ 3034-41-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate; In acetonitrile; at 60℃;	Example 268a 1-Methyl-4-nitro-1H-imidazole 268a To a mixture of 4-nitro-1H-imidazole (2.0 g, 17.7 mmol) and K2CO3 (3.67 g, 26.5 mmol) in acetonitrile (20 mL) was added iodomethane (1.3 mL, 3.0 g, 21.2 mmol) dropwise while stirring at room temperature. The resulting mixture was stirred at 60C overnight. It was then evaporated under reduced pressure and the residue was diluted with water (20 mL). The mixture was extracted with dichloromethane (2 X 20 mL). The combined extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 268a as a yellow solid (1.8 g, 82%). MS-ESI: [M+H]+ 128.1. 1H NMR (500 MHz, DMSO-d6) delta 8.37 (s, 1H), 7.82 (s, 1H), 3.76 (s, 3H).
71%	With potassium carbonate; In acetonitrile; at 0 - 95℃; for 3h;	Synthesis of LXX:To stirred solution of 4-nitro-1H-imidazole (LXIX, 5g: 44 mmol) in acetonitrile (20 mL) was added K2C03 (18.2 g, 137 mmol) at 0C, followed by addition of methyl iodide (8.9 mL, 57mmol). The reaction mixture was heated at 95C for 3h. The reaction mixture was concentrated, filtered through a celite bed and diluted with water. The aqueous layer was extracted with chloroform and the separated organic layer was washed with brine solution and dried over anhydrous Na2SO4 before being filtered and evaporated under reduced pressure to afford 1-methyl-4-nitro-1H-imidazole (LXX, 4g, 71%). ?H NMR (400 MHz, DMSO-d6) oe 8.35 (s, 1H), 7.8 (s, 1H), 3.74 (s, 3H). MS (M+1): 128.
70%	With potassium carbonate; In acetonitrile; at 65℃; for 20h;	Intermediate P2: 1 -Methyl-4-nitro-1H-imidazole To the mixture of 4-nitro-1H-imidazole (3.00 g, 17.7 mmol), potassium carbonate (3.67 g, 26.5 mmol) and acetonitrile (20 mL) iodomethane (1 .32 mL, 21.2 mmol) was added during 10 minutes. The reaction mixture was stirred while heating at 65 C for 20 hours, cooled to room temperature and filtered through the sintered glass funnel. Filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: chloroform/methanol 98:2 to 90: 10, v/v) to obtain an amorphous, creamy solid. The solid was hot-crystallized from isopropanol to obtain after filtration and drying title product in the form of light-creamy crystals with the yield of 70% (1.58 g, 12.4 mmol). Melting point 134.7-135.3C. 1H NMR (500 MHz, CDCl3) delta 7.79 (d, J=1 ,4 Hz, 1 H), 7.44 (s, 1 H), 3.84 (s, 3H). 13C NMR (125 MHz, CDCI3) delta 148.1 , 136.7, 120.3, 34.60.

46%	With potassium carbonate; In acetonitrile; at 60℃;Sealed vial;	Step B: To a mixture of 4-nitro-lH-imidazole (2.0 g, 17.7 mmol) and K2CO3 (3.67 g, 26.6 mmol) in acetonitrile (18 mL) was added iodomethane (1.32 mL, 21.2 mmol). The mixture was heated at 60 C in a sealed vial overnight. The mixture was filtered and the filter cake washed with acetone. The filtrate was concentrated under reduced pressure, the residue was diluted with hot propan-2-ol, cooled, and then filtered. The obtained solid was dissolved in chloroform, filtered, and the filtrate concentrated under reduced pressure. The residue was triturated with propan-2-ol and filtered to afford l-methyl-4-nitro-lH-imidazole (1.03 g, 46%) as a tan solid. 1H NMR (300 MHz, DMSO-t/6) delta 8.37 (d, J= 1.1 Hz, 1H), 7.82 (s, 1H), 3.76 (s, 3H).
46%	With potassium carbonate; In acetonitrile; at 60℃;Sealed vial;	Example 20Preparation of 3-(4-fluorophenylsulfonyl)-N-Q-methyl-lH-imidazol-4- vDisoq uinolin- 1-amine[00277] Step A: To a mixture of 4-nitro-lH-imidazole (2.0 g, 17.7 mmol) andK2CO3 (3.67 g, 26.6 mmol) in acetonitrile (18 mL) was added iodomethane (1.32 mL, 21.2 mmol) and the mixture was heated in a sealed vial at 60 C overnight. The mixture was filtered washing with acetone. The filtrate was concentrated under reduced pressure, and the residue was diluted with hot isopropanol and cooled, and the precipitated solid was collected by filtration. The solid was dissolved in chloroform and filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with propan-2-ol and collected by filtration to afford 1- methyl-4-nitro-lH-imidazole (1.03 g, 46%) as a tan solid. 1H NMR (300 MHz, DMSO-t/e) delta 8.37 (d, J= 1.1 Hz, 1H), 7.82 (s, 1H), 3.76 (s, 3H).
46%	With potassium carbonate; In acetonitrile; at 60℃;	Step A: To a mixture of 4-nitro-1H-imidazole (2.0 g, 17.7 mmol) and K2CO3 (3.67 g, 26.6 mmol) in acetonitrile (18 mL) was added iodomethane (1.32 mL, 21.2 mmol) and the mixture was heated in a sealed vial at 60 C. overnight. The mixture was filtered washing with acetone. The filtrate was concentrated under reduced pressure, and the residue was diluted with hot isopropanol and cooled, and the precipitated solid was collected by filtration. The solid was dissolved in chloroform and filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with propan-2-ol and collected by filtration to afford 1-methyl-4-nitro-1H-imidazole (1.03 g, 46%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) delta 8.37 (d, J=1.1 Hz, 1H), 7.82 (s, 1H), 3.76 (s, 3H).
	With potassium carbonate; In acetonitrile; at 65℃;	4-Nitro-lH-imidazole (2 g, 17.69 mmol) was dissolved in acetonitrile (20 mL) and potassium carbonate (3.67 g, 26.53 mmol) and iodomethane (1.327 mL, 21.22 mmol) were added. The reaction mixture was then heated at 650C overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo leaving a reddish orange solid (3.214 g). This material was purified utilizing ISCO (0-10% MeOEta/DCM). Concentration of the fractions in vacuo provided the title compound as a yellow solid (2.071 g). The title compound was re-crystalized out of isopropanol leaving an off-white solid (1.564 g). LCMS: 128 [M+H]+.
	With potassium carbonate; In acetonitrile; at 65℃;	Intermediate 1; 1 -Methyl-4-nitro- lH-imidazole4-Nitro-lH-imidazole (2 g, 17.69 mmol) was dissolved in acetonitrile (20 niL) and potassium carbonate (3.67 g, 26.53 mmol) and iodomethane (1.327 mL, 21.22 mmol) were added. The reaction mixture then heated at 650C overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo leaving a reddish orange solid (3.214 g). This material was purified by ISCO (0-10% MeOEta/DCM). Concentration of the fractions in vacuo provided the title product as a yellow solid (2.071 g). The title product was re-crystalized out of isopropanol leaving an off- white solid (1.564 g). LCMS: 128 [M+Eta]+.
	With potassium carbonate; In acetonitrile; at 65℃;	4-Nitro- IH- imidazole (2 g, 17.69 mmol) was dissolved in acetonitrile (20 niL), and potassium carbonate (3.67 g, 26.53 mmol) and iodomethane (1.327 mL, 21.22 mmol) were added. The reaction mixture was then heated at 65C overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo leaving a reddish orange solid (3.214 g). This material was purified by ISCO (0-10% MeOeta/DCM). Concentration of the fractions in vacuo provided the title product as a yellow solid (2.058 g)-LCMS: 128 [M+eta]+.
1.5 g	With potassium carbonate; In acetonitrile; for 12h;Reflux;	4-Nitroimidazole (1.41 g), potassium carbonate (2.5 g), iodomethane (1.9 g) and 20 mL of acetonitrile were refluxed for 12 h.Dry under reduced pressure, add 50 mL of water, and extract three times with 50 mL of ethyl acetate.The organic layers were combined, washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous Na2SO4 was added,Drying under reduced pressure gave 1-methyl-4-nitroimidazole (1.5 g).
	With potassium carbonate; In acetonitrile; at 60℃; for 14h;	To a solution of 4-nitro- 1 H-imidazole (5.0 g, 44 mmol, 1 eq.) in ACN (50 ml) was added K2C03 (9.17 g, 66 mmol). Methyl iodide (7.53 g, 53 mmol, 3.30 ml) was added slowly to the mixture at rt, then the mixture was warmed to 60 C for 14 h. The solvent was removed under reduced pressure, then the residue was diluted with water (30 ml), extracted with DCM (5 x 30 ml) and the combined organic layers dried over Na2S04. The organic phase was concentrated in vacuo to give the title compound as a yellow solid. 'H NMR (400 MHz, DMSO-de) d = 8.35 (s, 1H), 7.80 (s, 1H), 3.75 (s, 3H).
1.5 g	With potassium carbonate; In acetonitrile; for 12h;Reflux;	4-nitroimidazole(1.41 g), potassium carbonate (2.5 g), methyl iodide (1.9 g), and 20 mL of acetonitrile,The reaction was refluxed for 12 h. Spin dry under reduced pressure, add 50mL of water,It was extracted three times with 50 mL of ethyl acetate. The organic layers were combined and washed with saturated brine.The organic phase was dried by adding anhydrous Na2SO4, and dried under reduced pressure.1-methyl-4-nitroimidazole(1.5g).

Reference： [1]Patent: EP2773638,2015,B1 .Location in patent: Paragraph 1084; 1085
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 144 - 158
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 265 - 285
[4]Patent: WO2015/97121,2015,A1 .Location in patent: Page/Page column 136; 137
[5]Patent: WO2014/20531,2014,A1 .Location in patent: Page/Page column 14-15
[6]Patent: WO2012/30914,2012,A1 .Location in patent: Page/Page column 77
[7]Patent: WO2012/30944,2012,A2 .Location in patent: Page/Page column 103
[8]Patent: US2012/53174,2012,A1 .Location in patent: Page/Page column 57
[9]Patent: WO2010/20810,2010,A1 .Location in patent: Page/Page column 57-58
[10]Patent: WO2010/38060,2010,A1 .Location in patent: Page/Page column 64
[11]Patent: WO2009/150462,2009,A1 .Location in patent: Page/Page column 68
[12]Patent: CN109678803,2019,A .Location in patent: Paragraph 0202; 0205
[13]Patent: WO2019/121691,2019,A1 .Location in patent: Paragraph 0856
[14]Patent: CN110330484,2019,A .Location in patent: Paragraph 0086; 0088

21
[ 3034-41-1 ]
[ 6693-08-9 ]
[ 1208893-82-6 ]

Yield	Reaction Conditions	Operation in experiment
		2,6-Dichloro-5-fluoro-Lambda/-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 500 mg, 3.93 mmol) was dissolved in ethanol (6.771 mL) and Pd/C (10 wt%, Degussa, 105 mg, 0.10 mmol) was added. The reaction was subjected to 1 atm of hydrogen for 3 hours. TLC indicated that the reaction was completed, and the reaction mixture was filtered through Celite. The filtrate was cooled to 00C and TEA (1.097 mL, 7.87 mmol) and <strong>[6693-08-9]2,4,6-trichloro-5-fluoropyrimidine</strong> (obtained via the procedure described in PCT Pub. No. WO2008/132502, 792 mg, 3.93 mmol) were added. The reaction was allowed to warm to room temperature slowly overnight. The reaction mixture was filtered providing the title compound as a yellow solid (820 mg) with 95% purity. LCMS: 263 [M+Eta]+.

Reference： [1]Patent: WO2010/20810,2010,A1 .Location in patent: Page/Page column 67

22
[ 3034-41-1 ]
[ 5750-76-5 ]
[ 1208893-78-0 ]

Yield	Reaction Conditions	Operation in experiment
		2, 5-Dichloro-Lambda/-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 500 mg, 3.93 mmol) was dissolved in ethanol (7.868 mL) and Pd/C (10 wt%, Degussa, 105 mg, 0.10 mmol) was added. The reaction mixture was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite and 2,4,5-trichloropyrimidine (0.361 mL, 3.15 mmol) and TEA (1.097 mL, 7.87 mmol) were added. The reaction mixture was stirred overnight at rt. The reaction mixture was filtered providing the title compound as a pale yellow solid (538 mg). LCMS: 245 [M+Eta]+.

Reference： [1]Patent: WO2010/20810,2010,A1 .Location in patent: Page/Page column 66

23
[ 3764-01-0 ]
[ 3034-41-1 ]
[ 1208893-80-4 ]

Yield	Reaction Conditions	Operation in experiment
		2, 6-Dichloro-Lambda/-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lEta-imidazole (Intermediate 5, 1.0 g, 7.87 mmol) was dissolved in ethanol (12.82 ml) and Pd/C (10 wt%, Degussa, 0.209 g, 0.20 mmol) was added. The reaction was subjected to 1 atm of hydrogen for 3 hours. TLC analysis indicated that the reaction was completed and the reaction mixture was filtered through Celite and cooled to 00C. TEA (2.193 ml, 15.74 mmol) and 2,4,6-trichloropyrimidine (0.722 ml, 6.29 mmol) were added and the reaction was allowed to slowly warm to rt overnight. LCMS confirmed formation of the desired product. The reaction mixture was then filtered leaving a tan solid (1.526 g) which was confirmed by LCMS to be the title compound with 99% purity. The material was used in a subsequent step without any further purification. LCMS: 245 [M+H]+.

Reference： [1]Patent: WO2010/20810,2010,A1 .Location in patent: Page/Page column 66-67

24
[ 3034-41-1 ]
[ 19646-07-2 ]
[ 1208893-84-8 ]

Yield	Reaction Conditions	Operation in experiment
		2-Chloro-5-methoxy-N-(l-methyl-lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 400 mg, 3.15 mmol) was dissolved in ethanol (4.063 mL) and Pd/C (10 wt%, Degussa, 84 mg, 0.08 mmol) was added. The reaction was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite and TEA (0.877 mL, 6.29 mmol) and 2,4-dichloro-5-methoxypyrimidine (563 mg, 3.15 mmol) were added. The reaction was subsequently heated to reflux overnight. The volatiles were concentrated in vacuo leaving a rust solid (1.140 g). This material was purified utilizing ISCO (0-10% MeOEta/DCM). Concentration of the fractions in vacuo provided the title compound as a yellow solid (603 mg). LCMS: 240 [M+Eta]+.

Reference： [1]Patent: WO2010/20810,2010,A1 .Location in patent: Page/Page column 67

25
[ 870065-73-9 ]
[ 3034-41-1 ]
[ 1208893-79-1 ]

Yield	Reaction Conditions	Operation in experiment
		,5-Difluoro-6-[(l-methyl-lH-imidazol-4-yl)aminolnicotinonitrile l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 500 mg, 3.93 mmol) was dissolved in ethanol (7.868 mL) and Pd/C (10 wt%, Degussa, 105 mg, 0.10 mmol) was added. The reaction mixture was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite and the filtrate was cooled to O0C. <strong>[870065-73-9]2,5,6-trifluoronicotinonitrile</strong> (497 mg, 3.15 mmol) and TEA (1.097 mL, 7.87 mmol) were added and the reaction mixture was allowed to warm to rt slowly overnight. The reaction mixture was filtered providing the title compound as a yellow solid (566 mg). LCMS: 236 [M+Eta]+.

Reference： [1]Patent: WO2010/20810,2010,A1 .Location in patent: Page/Page column 66

26
[ 3034-41-1 ]
[ 2927-71-1 ]
[ 1208893-88-2 ]

Yield	Reaction Conditions	Operation in experiment
		2-Chloro-5-fluoro-Lambda/-(l -methyl- lH-imidazol-4-yl)pyrimidin-4-amine l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 400 mg, 3.15 mmol) was dissolved in ethanol (4.063 mL) and Pd/C (10 wt%, Degussa, 84 mg, 0.08 mmol) was added. The reaction was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite and TEA (0.877 mL, 6.29 mmol) and 2,4-dichloro-5-fluoropyrimidine (525 mg, 3.15 mmol) were added. The reaction was stirred at rt overnight. The reaction mixture was filtered providing the title compound as a white solid (495 mg). LCMS: 228 [M+Eta]+.

Reference： [1]Patent: WO2010/20810,2010,A1 .Location in patent: Page/Page column 68

27
[ 616-47-7 ]
[ 3034-41-1 ]
[ 3034-42-2 ]
[ 19183-15-4 ]

Reference： [1]Synthesis,2011,p. 2859 - 2864

28
[ 3034-41-1 ]
[ 20485-39-6 ]
[ 1387556-73-1 ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 6158 - 6162
[2]Journal of Organic Chemistry,2012,vol. 77,p. 7677 - 7683

29
[ 3034-41-1 ]
[ 89088-69-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 144 - 158
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 265 - 285

30
[ 3034-41-1 ]
[ 25554-84-1 ]
[ 20041-97-8 ]

Reference： [1]Organic Letters,2018,vol. 20,p. 1413 - 1416

31
[ 3034-41-1 ]
[ 25554-84-1 ]
[ 7464-68-8 ]
[ 20041-97-8 ]

Reference： [1]Organic Letters,2018,vol. 20,p. 1413 - 1416

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