There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 693-98-1 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
2
[ 930-61-0 ]
[ 67-66-3 ]
[ 5053-43-0 ]
[ 4994-86-9 ]
[ 693-98-1 ]
[ 930-62-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
3
[ 930-61-0 ]
[ 67-66-3 ]
[ 4994-86-9 ]
[ 693-98-1 ]
[ 930-62-1 ]
[ 75712-73-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
4
[ 693-98-1 ]
[ 696-23-1 ]
Yield
Reaction Conditions
Operation in experiment
3.8 g
at 150℃; for 2 h;
Take concentrated sulfuric acid 20ml and 5g sodium sulfate into a three-mouth bottle,Stir at room temperature, slowly add 2-methylimidazole 5.0g,After starting to heat up, the temperature of the reaction liquid reaches 150°C.Slowly add concentrated nitric acid 5ml,The reaction was incubated for 2 hours after the addition.After the end of the reaction, it is cooled to 80°C and 5 ml of water is added.Ammonia water is used to adjust the pH to 3-4 and a large amount of solids precipitates.Filter, dry at 60°C,2-trifluoromethyl-5-nitroimidazole 3.8 g was obtained.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1274 - 1278
[2] Journal of the Chemical Society, 1919, vol. 115, p. 250
[3] Pharmaceutical Chemistry Journal, 1989, vol. 23, # 10, p. 861 - 863[4] Khimiko-Farmatsevticheskii Zhurnal, 1989, vol. 23, # 10, p. 1246 - 1248
[5] Patent: CN107556304, 2018, A, . Location in patent: Paragraph 0022
Reference：
[1] Australian Journal of Chemistry, 2004, vol. 57, # 2, p. 145 - 147
9
[ 930-61-0 ]
[ 67-66-3 ]
[ 14331-54-5 ]
[ 4994-86-9 ]
[ 693-98-1 ]
[ 75712-73-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
10
[ 110-85-0 ]
[ 288-32-4 ]
[ 290-37-9 ]
[ 616-47-7 ]
[ 109-08-0 ]
[ 13925-00-3 ]
[ 693-98-1 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 7.1, p. 1340 - 1345[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 7, p. 1483 - 1488
11
[ 123-84-2 ]
[ 290-37-9 ]
[ 109-08-0 ]
[ 123-32-0 ]
[ 13925-00-3 ]
[ 693-98-1 ]
[ 15707-23-0 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1993, vol. 29, # 11, p. 1308 - 1315[2] Khimiya Geterotsiklicheskikh Soedinenii, 1993, # 11, p. 1516 - 1525
12
[ 131543-46-9 ]
[ 75-07-0 ]
[ 74-89-5 ]
[ 616-47-7 ]
[ 1739-84-0 ]
[ 693-98-1 ]
Yield
Reaction Conditions
Operation in experiment
85.1%
With ammonium hydroxide In water at 25 - 70℃;
As shown in Fig. 1, a high-pressure microreactor in which a micro mixer was incorporated at three locations was used.An aqueous solution of methylamine (0.33 mol / L) was fed from the tank 1 through the pump 1 at a flow rate of 0.68 mL / min, an aqueous solution of acetaldehyde (0.33 mol / L) At a flow rate of 63 mL / min, from the tank 3 via the pump 3AmmoniumNear water(0.33 mol / L) was flowed at a flow rate of 1.13 mL / min, an aqueous glyoxal solution (0.33 mol / L) was flowed from the tank 4 via the pump 4 at 0.56 mL / flow rate, and a reaction pressure of 30 MPa The reaction was carried out under pressure. The final flow rate was 8.0 mL / min. The temperature of the first micromixer and the reaction tube of 2.4 m is controlled in a thermostatic chamber 1 keeping the temperature at 25 ° C. The mixture and reaction of methylamine and acetaldehyde in the first micromixer and reaction tube Was done. In the next second micromixer in which the aqueous solution and ammonia water are mixed by this mixing, they are mixed in a thermostatic chamber 2 kept at a temperature of 25 ° C., and after sufficient mixing and reaction in a 0.1 m reaction tube After that, glyoxal was mixed, after which 1Sufficient reaction was carried out in a 0 m reaction tube. Next, the temperature of the reaction part was adjusted to 70 ° C., and the reaction was carried out in a 25 m reaction tube. Finally, it was cooled down to 5 ° C. with a heat exchanger, depressurized to normal pressure via a discharge pressure valve, and the aqueous solution obtained while cooling with ice water (0 ° C. to 4 ° C.) was collected. In this case, the reaction time (residence time in the reaction part) was 37 seconds. For the analysis, if necessary diluted 10 times with ice water and analyzed immediately using a gas chromatograph. The reaction tube was made of stainless steel (SUS 316) and had an inner diameter of 0.5 mm. As a result, the objective 1,2-dimethylimidazole was obtained in a yield of 85.1percent.For measurement of the above quantitative yield, a gas chromatograph (GC 6890, hydrogen flame ionization detector) manufactured by Agilent was used and the column was HP INNOWAX manufactured by J & W Co., inner diameter 0.32 mm, film thickness 0.25 μm, length Analysis was carried out using 30 m. The yield of each product was determined by preparing a calibration curve for each compound using various concentrations of the product (1,2-dimethylimidazole, 1-methylimidazole, 2-methylimidazole, imidazole) Concentration of each product obtained was converted from a calibration curve, and the yield of each product was calculated. The respective yields were 1,2-dimethylimidazole 85.1percent, 1-methylimidazole 6.27percent, 2-methylimidazole 6.59percent and imidazole 2.06percent.
Reference：
[1] Patent: JP2016/222615, 2016, A, . Location in patent: Paragraph 0051-0052
13
[ 693-98-1 ]
[ 616-38-6 ]
[ 1739-84-0 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 120 - 145℃;
To 500 ml of the input three-mouth flask in 128g of 2 - methyl imidazole and 100 ml of DMF, oil bath heated to 120 °C, the temperature next adds by drops 280g dimethyl carbonate, control temperature at 135 - 140 °C, dropping time control in 5 - 6h, after dropping in the 145 °C preserving 2h, thermal insulation after the completion of the, gas chromatographic analysis of 2 - methyl imidazole conversion 98percent. In 4.0KPa, 90 °C conditions under reduced pressure distillation, evaporate the solvent. The use of the rectifying device, in 4.0KPa under vacuum, collecting 100 - 110 °C of distillate, high purity can be obtained of the 1, 2 - dimethyl imidazole of the finished product, yield 85percent, gas chromatographic analysis of the content of 99.5percent.
Reference：
[1] Synthesis, 1986, # 5, p. 382 - 383
[2] Liebigs Annalen der Chemie, 1987, p. 77 - 80
[3] Patent: CN106045912, 2016, A, . Location in patent: Paragraph 0020; 0021; 0023; 0024; 0025; 0026; 0027
14
[ 693-98-1 ]
[ 74-88-4 ]
[ 1739-84-0 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1991, vol. 27, # 10, p. 1140 - 1144[2] Khimiya Geterotsiklicheskikh Soedinenii, 1991, vol. 27, # 10, p. 1414 - 1418
[3] Archiv der Pharmazie, 1988, vol. 321, # 4, p. 193 - 197
15
[ 67-56-1 ]
[ 693-98-1 ]
[ 1739-84-0 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1995, # 1, p. 9 - 10
[2] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1994, vol. 30, # 5, p. 547 - 550[3] Khimiya Geterotsiklicheskikh Soedinenii, 1994, # 5, p. 624 - 628
16
[ 79-20-9 ]
[ 107-15-3 ]
[ 534-26-9 ]
[ 1739-84-0 ]
[ 693-98-1 ]
Reference：
[1] J. Appl. Chem. USSR (Engl. Transl.), 1991, vol. 64, # 7.2, p. 1446 - 1447[2] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1991, vol. 64, # 7, p. 1590 - 1591
[3] J. Appl. Chem. USSR (Engl. Transl.), 1991, vol. 64, # 7.2, p. 1446 - 1447[4] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1991, vol. 64, # 7, p. 1590 - 1591
[5] J. Appl. Chem. USSR (Engl. Transl.), 1991, vol. 64, # 7.2, p. 1446 - 1447[6] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1991, vol. 64, # 7, p. 1590 - 1591
17
[ 693-98-1 ]
[ 74-88-4 ]
[ 1739-84-0 ]
[ 36432-31-2 ]
Reference：
[1] Chemische Berichte, 1883, vol. 16, p. 488
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1994, vol. 30, # 5, p. 547 - 550[2] Khimiya Geterotsiklicheskikh Soedinenii, 1994, # 5, p. 624 - 628
20
[ 930-61-0 ]
[ 67-66-3 ]
[ 14331-54-5 ]
[ 4994-86-9 ]
[ 693-98-1 ]
[ 75712-73-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
21
[ 930-61-0 ]
[ 67-66-3 ]
[ 123-32-0 ]
[ 4994-86-9 ]
[ 693-98-1 ]
[ 75712-73-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
22
[ 930-61-0 ]
[ 67-66-3 ]
[ 4994-86-9 ]
[ 4472-45-1 ]
[ 693-98-1 ]
[ 75712-73-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
23
[ 930-61-0 ]
[ 67-66-3 ]
[ 5053-43-0 ]
[ 4994-86-9 ]
[ 693-98-1 ]
[ 930-62-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
24
[ 930-61-0 ]
[ 67-66-3 ]
[ 4994-86-9 ]
[ 693-98-1 ]
[ 930-62-1 ]
[ 75712-73-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
25
[ 693-98-1 ]
[ 67-66-3 ]
[ 4994-86-9 ]
[ 54198-89-9 ]
[ 95-58-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
26
[ 693-98-1 ]
[ 116-16-5 ]
[ 54198-89-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
27
[ 693-98-1 ]
[ 650-51-1 ]
[ 54198-89-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
28
[ 693-98-1 ]
[ 67-66-3 ]
[ 4994-86-9 ]
[ 54198-89-9 ]
[ 95-58-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
29
[ 930-61-0 ]
[ 67-66-3 ]
[ 5053-43-0 ]
[ 95-58-9 ]
[ 693-98-1 ]
[ 930-62-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
30
[ 693-98-1 ]
[ 67-66-3 ]
[ 4994-86-9 ]
[ 54198-89-9 ]
[ 95-58-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
31
[ 930-61-0 ]
[ 67-66-3 ]
[ 4994-86-9 ]
[ 4472-45-1 ]
[ 693-98-1 ]
[ 75712-73-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
32
[ 693-98-1 ]
[ 100-44-7 ]
[ 13750-62-4 ]
Yield
Reaction Conditions
Operation in experiment
38%
Stage #1: With potassium carbonate In acetonitrile at 20℃; for 0.25 h; Stage #2: at 70℃; for 72 h;
10 mmol of 2-methyl-1H-imidazole was added to a suspensionof potassium carbonate (10 mmol) in acetonitrile (10 mL), and then stirred for 15 min at r.t. 10 mmol of1-(chloromethyl)benzene was added to the reaction mixture and the mixture was heated to 70°C and kept for 72 h. After completion of the reaction, the solvent was removed and the residue was dissolved in EtOAc (20 mL), washed with H2O(2×10 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: CHCl3)to afford the desired product. Yield 38percent; yellow oil; UV-Vis (chloroform, λ, nm): 290; IR spectrum (KBr, ν, cm–1): 2939,1712, 1508, 1434, 1365, 1272, 1118, 983, 721; 1H NMR (250.13 MHz, CDCl3) δ: 7.43-7.32 (m, 5H), 7.17-7.14 (m, 2H), 6.99(d, J = 1.3 Hz, 1H), 6.84 (d, J = 1.2 Hz, 1H), 5.11 (s, 2H), 2.27 (s, 3H); 13C NMR (62.9 MHz, CDCl3) δ: 144.3, 138.0, 129.3,128.1, 127.5, 127.1, 120.9, 49.2, 13.4.
60.5%
With hydrogenchloride; sodium hydroxide In <i>N</i>-methyl-acetamide; water
(i) 1-Benzyl-2-methylimidazole To a slurry of 2.4 g (0.1 mole) of sodium hydride in 50 ml of dimethylformamide under a nitrogen atmosphere was added, with stirring, 8.2 g (0.1 mole) of 2-methylimidazole. A slow exothermic reaction occurred, the temperature reaching 43° C. When the exotherm subsided, the reaction was warmed on a steam bath to 70°-75° C. for a half-hour and then at 95° C. for 15 minutes to complete the reaction as evidenced by cessation of gas evolution. It was then cooled to 68° C. and 12.7 g (0.1 mole) of benzyl chloride added dropwise. An exothermic reaction occurred, the temperature reaching 95° C. After stirring for a half-hour following completion of addition, the reaction was poured into 600 ml of water and the product extracted with ethyl acetate (2*200 ml). The combined extracts were washed successively with water (1*400 ml), saturated aqueous sodium chloride solution (1*100 ml), then with 6N HCl (1*50 ml). The HCl wash was extracted with ether (1*25 ml) and then made basic by addition of sodium hydroxide. The yellow oil which separated was extracted into ether, the extract dried (MgSO4) and evaporated under reduced pressure to give a pale yellow oil. Yield, 11.5 g (60.5percent). NMR indicates the compound was obtained as the monohydrate. It was used as is in the hydroxymethylation reaction.
Reference：
[1] Asian Journal of Chemistry, 2014, vol. 26, # 8, p. 2381 - 2388
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 22, p. 6495 - 6499
[3] Journal of Structural Chemistry, 2016, vol. 57, # 4, p. 835 - 839[4] Zh. Strukt. Kim., 2016, vol. 57, # 4, p. 873 - 876,4
[5] Patent: US4560690, 1985, A,
Reference：
[1] Journal of the American Society for Mass Spectrometry, 2012, vol. 23, # 5, p. 823 - 833
35
[ 693-98-1 ]
[ 100-39-0 ]
[ 13750-62-4 ]
[ 91473-32-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1988, vol. 25, p. 1845 - 1847
36
[ 693-98-1 ]
[ 10325-70-9 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 6 - 10[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 1, p. 9 - 14
37
[ 693-98-1 ]
[ 100-11-8 ]
[ 56643-86-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1799 - 1810
[2] Patent: US5298520, 1994, A,
[3] Journal of Medicinal Chemistry, 1990, vol. 33, # 5, p. 1312 - 1329
[4] Patent: US5510362, 1996, A,
38
[ 693-98-1 ]
[ 18994-90-6 ]
[ 56643-86-8 ]
Reference：
[1] Patent: US6048884, 2000, A,
39
[ 109-65-9 ]
[ 693-98-1 ]
[ 13435-22-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: With potassium hydroxide In N,N-dimethyl-formamide for 0.25 h; Green chemistry Stage #2: for 12 h; Green chemistry
0.82 g of 2-methylimidazole (10 mmol) was dissolved in N,N-dimethylformamide (20 mL), heated to 40 ° C, and 0.84 g of potassium hydroxide (15 mmol) was added.After stirring for 15 min, 1.438 g of bromo n-butane (10.5 mmol) was added dropwise. After the addition was completed, the reaction was continued for 12 h.Cool to room temperature, dilute with water, extract 3 times with dichloromethane, combine the organic phase, wash 3 times with water,Adding water-removing agent anhydrous sodium sulfate to the organic phase, after standing for 1 h, suction filtration, and removing the solvent to obtain 1-butyl-2-methylimidazole, the yield is 97percent;
Reference：
[1] Patent: CN108440416, 2018, A, . Location in patent: Paragraph 0030; 0031
[2] Journal of Materials Chemistry A, 2014, vol. 2, # 12, p. 4413 - 4421
[3] New Journal of Chemistry, 2012, vol. 36, # 3, p. 702 - 722
[4] Chemical Communications, 2018, vol. 54, # 50, p. 6879 - 6882
[5] Bioscience, Biotechnology and Biochemistry, 2000, vol. 64, # 4, p. 919 - 923
40
[ 693-98-1 ]
[ 350-46-9 ]
[ 73225-15-7 ]
Yield
Reaction Conditions
Operation in experiment
89%
With caesium carbonate In N,N-dimethyl-formamide at 100℃; Inert atmosphere
A mixture of l-fluoro-4-nitrobenzene (10 g, 70.9 mmol), 2-methyl-lH- imidazole (5.8 g, 70.9 mmol), and Cs2C03 (34.7 g, 106.4 mmol) in degassed DMF (200 mL) was heated at 100°C under nitrogen overnight. When TLC indicated that l-fluoro-4-nitrobenzene was consumed, the reaction mixture was concentrated in vacuo. The residue was diluted with water (300 mL), and a grey precipitate was formed and was isolated to give 2-methyl-l-(4- nitrophenyl)-lH-imidazole (12.8 g, yield 89percent).
88%
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 18 h;
5 To 1 -fluoro-4-nitrobenzene (11.0 g, 0.078 mol) in DMF (40 mL) were added 2- methyl-lH-imidazole (6.41 g, 0.078 mol) and potassium carbonate (16.16 g, 0.117 mol) and the reaction stirred at 500C for 18 h. Residual solids were filtered off and the solvent removed from the filtrate. The residues were dissolved in ethyl acetate/water and extracted into ethyl acetate. The solvent was removed and, the residues triturated with 10 diethyl ether to give the title compound (13.93 g, 88percent) as an off-white solid. δη (DMSO- d6) 8.38 (2H, d, J8.8 Hz), 7.78 (2H, d, J9.1 Hz), 7.46 (IH, s), 6.99 (IH, s), 2.38 (3H, s). LCMS (ES+) 204.0 (M+H+).
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 4, p. 597 - 609
[2] Patent: WO2011/75478, 2011, A1, . Location in patent: Page/Page column 53
[3] Patent: WO2009/71888, 2009, A1, . Location in patent: Page/Page column 83
[4] Patent: US5298520, 1994, A,
[5] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1799 - 1810
[6] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[7] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1729 - 1744
[8] Patent: US5128351, 1992, A,
[9] Patent: US5077409, 1991, A,
[10] Patent: EP991638, 2005, B1, . Location in patent: Page/Page column 52
41
[ 693-98-1 ]
[ 586-78-7 ]
[ 73225-15-7 ]
Yield
Reaction Conditions
Operation in experiment
80%
With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube
General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
Reference：
[1] Organic Letters, 2009, vol. 11, # 15, p. 3294 - 3297
[2] Chemistry - A European Journal, 2009, vol. 15, # 36, p. 8971 - 8974
[3] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[4] Patent: US6020357, 2000, A,
[5] Patent: EP946508, 2009, B1, . Location in patent: Page/Page column 64-65
42
[ 636-98-6 ]
[ 693-98-1 ]
[ 73225-15-7 ]
Reference：
[1] New Journal of Chemistry, 2014, vol. 38, # 9, p. 4267 - 4274
[2] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 1971 - 1976
[3] Organic and Biomolecular Chemistry, 2017, vol. 15, # 26, p. 5503 - 5512
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 6 - 10[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 1, p. 9 - 14
46
[ 693-98-1 ]
[ 2926-29-6 ]
[ 33468-67-6 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 18, p. 5809 - 5812
47
[ 693-98-1 ]
[ 33468-67-6 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 40, p. 14315 - 14321
48
[ 693-98-1 ]
[ 2314-97-8 ]
[ 81769-59-7 ]
[ 33468-67-6 ]
Reference：
[1] Journal of Organic Chemistry, 1982, vol. 47, # 15, p. 2867 - 2872
49
[ 123-84-2 ]
[ 290-37-9 ]
[ 109-08-0 ]
[ 123-32-0 ]
[ 13925-00-3 ]
[ 693-98-1 ]
[ 15707-23-0 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1993, vol. 29, # 11, p. 1308 - 1315[2] Khimiya Geterotsiklicheskikh Soedinenii, 1993, # 11, p. 1516 - 1525
50
[ 693-98-1 ]
[ 6966-10-5 ]
[ 70759-03-4 ]
Reference：
[1] Synthesis, 2004, # 15, p. 2540 - 2544
51
[ 80242-42-8 ]
[ 693-98-1 ]
[ 5550-12-9 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 5, p. 1810 - 1813
52
[ 693-98-1 ]
[ 27387-31-1 ]
[ 51-80-9 ]
[ 99614-02-5 ]
Yield
Reaction Conditions
Operation in experiment
81.5%
With acetyl chloride In toluene; acetonitrileHeating / reflux
Example 11: Synthesis of ls239-tetrahydro-9-methyl-3-[(2-methyl-lH- imidazole-1-yl methyl]-4H-carbazol-4-one To the solution of 36 ml of acetyl chloride in 50 ml of actonitrile and 750 ml of toluene, was slowly added 51 ml of N, N, N', N'- tetramethyldiaminomethane at 0°C, which was then stirred for 10min. 50 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one and 100 g of 2-methyl imidazole was subsequently added to the reaction mixture, which was then stirred under reflux. After completion of reaction, the reaction mixture was evaporated, and then 150 ml of water was added to the resulting residue. The resulting solid was filtered and washed, and then dried under a reduced pressure. The resulting solid was suspended in 350 ml of methanol, and then 0.7g of active carbon was added to thereto, which was then stirred for 1 hour under reflux. The resulting mixture was filtered and washed with methanol, which was then stirred for 3 hours at room temperature. The resulting solid was filtered and dried to give 60 g of pure white title compound (yield 81.5percent).
75%
Stage #1: at 120 - 130℃; for 8 h; Stage #2: With sodium hydroxide In water
Example 8: Synthesis of 12s3 " 9-tetrahydro-9-methyl-3-[(2-methel-lH- imidazole-1-vl) methyl]-4H-carbazol-4-one At-10°C, 4 ml of N, N, N', N'-tetramethyldiaminomethane was slowly added to 46 ml of trifluoroacetic acid, which was then stirred for 30 min. 2.0 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one and 8 g of 2-methyl imidazole was added to the reaction mixture, which was then stirred for about 8 hours at 120-130°C. After completion of reaction, the reaction mixture was cooled at room temperature, and then IN aq. sodium hydroxide was added thereto. The resulting solid was filtered and washed with water, and then dried. The resulting solid was suspended in 80 ml of methanol, and then 0.28 g of active carbon was added thereto, which was then stirred under reflux for 1 hour. The resulting mixture was filtered and washed with methanol, and then evaporated to give 2.2 g of 1, 2,3, 9-tetrahydro-9-methyl-3-[(2-methyl-lH- imidazol-1-yl) methyl]- 4H-carbazol-4-one (yield 75percent).
66%
With chloro-trimethyl-silane In DMF (N,N-dimethyl-formamide) at 90℃; for 10 h;
Example 2: Synthesis of 1, 23*9-tetrahydro-9-methyl-3-r (2-methyl-lH- imidazole-1yl) methyll-4H-carbazol-4-one 2.0 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one, 1.65 g of 2- methyl imidazole and 2 ml of N, N, N', N'-tetramethyldiaminomethane were suspended in 20 ml of N, N-dimethylformamide, and then 4 ml of chlorotrimethylsilane was slowly added thereto. The reaction mixture was stirred at 90 °C for 10 hours. 100ml of water was added to the reaction mixture. The resulting solid was filtered and dried, which was then suspended in acetone and stirred for 3 hours, and then filtered and dried under a reduced pressure to give 1.93 g of title compound (yield 66percent).
60%
With chloro-trimethyl-silane In acetonitrile for 10 h; Heating / reflux
Example 1 : Synthesis of 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-lH- imidazole-1-yl) methyll-4H-carbazol-4-one 2.0 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one, 1.65 g of 2- methyl imidazole and 2 ml of N, N, N', N'-tetramethyldiaminomethane were suspended in 30 ml of acetonitrile, and then 4 ml of chlorotrimethylsilane was slowly added thereto. The reaction mixture was stirred under reflux for 10 hours. The reaction mixture was concentrated to remove the solvent, and then 40 ml of water was added to the resulting residue. The resulting solid was filtered and dried, which was then suspended in acetone and stirred for 3 hours, and then filtered and dried under a reduced pressure to give 1.76 g of title compound (yield 60percent).
58%
With acetyl chloride In toluene for 10 h; Heating / reflux
Example 7: Synthesis of 123*9-tetrahydro-9-methyl-3-r (2-methyl-lH- imidazole-1-yl methyl]-4H-carbazol-4-one 2.0 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one, 2 ml of N, N, N', N'-tetramethyl- diaminomethane were suspended in 30 ml of toluene, and then 1.4 ml of acetyl chloride was slowly added thereto, which was then stirred for 10 min. 1.65g of 2-methyl imidazole was added to the reaction mixture, which was then stirred under reflux for 10 hours. The reaction mixture was concentrated to remove the solvent, and then 150ml dichloromethane and 50ml of IN aq. sodium hydroxide were added to the resulting residue. The resulting organic layer was separated and dried over MgS04, and then evaporated. The resulting solid was suspended in acetone, which was then stirred for 3 hours, and then filtered and dried to give 1.70 g of title compound (yield 58percent).
55%
With aluminum (III) chloride In acetonitrile for 10 h; Heating / reflux
Example 4: Synthesis of 123, 9-tetrahydro-9-methyl-3-r (2-methyl-lH- imidazole-1-yDmethyl]-4H-carbazol-4-one 2.0 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one, 1.65 g of 2- methyl imidazole and 2 ml of N, N, N', N'-tetramethyldiaminomethane were suspended in 30 ml of acetonitrile, and then 1.4 g of aluminum chloride was slowly added thereto. The reaction mixture was stirred under reflux for 10 hours. 150 ml dichloromethane and 50 ml of IN aq. sodium hydroxide were added to the reaction mixture. The resulting organic layer was separated and dried over MgS04, and then evaporated. The resulting solid was suspended in acetone and stirred for 3 hours, and then filtered and dried under a reduced pressure to give 1.61 g of title compound (yield 55percent).
Preparation of 1, 23*9-Tetrahydro-9-methYl-3- [ (2-methyl-1 H-imidazol-1-yPmethyl]-4H-carbazol-4-onc; Example 1; 3- [ (Dimethylamino) methyl]-1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (10 g, 34 mmol) and 2-methylimidazole (16.8 g, 205 mmol, 6.0 eq. ) were suspended in mixture of water (75 ml) and dimethyl formamide (37.5 ml). The reaction mixture was heated to reflux (102-103°C) and stirred for a further 6 hours at this temperature. The reaction mixture was cooled to 5-10°C and stirred for half an hour at this temperature. The precipitated crude ondansetron base was filtered and washed with cold water (3x 90 ml) and dried under vacuum at 60 °C to give ondansetron base (9.68 g, 96.4 percent yield) in 98.9percent HPLC purity. Example 2; 3- [(Dimethylamino) methyl]-1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (12 kg, 41 mol) and 2-methylimidazole (20.2 kg, 246 mol, 6 eq. ) were suspended in mixture of water (120 L) and DMF (30 L). The reaction mixture was heated to reflux (100-102°C) and stirred for 5 hours at this temperature. The reaction mixture was cooled to 5-10 °C and stirred for half an hour. The precipitated crude ondansetron base was filtered and washed with cold water (2x110 L) and dried under vacuum at 60 °C to give ondansetron base (10 kg, 83percent yield) in 97.3percent HPLC purity. The major impurity was the exomethylene carbazolone which amounted to 2.6percent of the crude ondansetron mixture.
Example 8 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one prepared in any one of Examples 1 to 7,5. 89 g of 2-methyl imidazole and 1 g of montmorillonite K10 were added to 100ml of toluene, and then the reaction mixture was stirred under reflux for 6 hours. After completion of reaction, the solvent was distilled off, and then chloroform was added to the resulting residue and the catalyst was filtered off. The filtrate was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The resulting solid was purified with ethyl acetate to give 6.94 g of the title compound as white solid (yield 99percent).
94%
for 3 - 4 h; Heating / reflux
Example 4 Synthesis of Ondansetron Without Using Alumina In this reaction, we examined the feasibility of producing ondansetron from 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one without alumina as a catalyst. The crude 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one from Example 3 (145 grams, 0.69 mol) and 2-methylimidazole (71 grams; 0.86 mol) were added to toluene (800 mL), and the mixture was heated to reflux temperature. After about 3-4 hours (TLC indicated that 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one had been substantially consumed), the reaction was cooled to room temperature. The resulting precipitate was isolated by filtration to provide 190 grams (0.65 mol; 94percent yield) of crude ondansetron. Accordingly, ondansetron was prepared from 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one in a yield of about 94percent after heating for about 3-4 hours. Note that alumina was not used as a catalyst. In addition, the ondansetron was isolated from the reaction mixture quickly and efficiently by filtering the reaction mixture.
91%
for 2 h; Heating / reflux
Example 13 The same procedures as described in Example 10 were repeated, except that toluene was employed instead of acetonitrile, to give 6.32 g of the title compound (yield 91percent).
90%
for 6 h; Heating / reflux
Example 9 The suspension of 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H- carbazol-4-one prepared in any one of Examples 1 to 7,5. 89 g of 2-methyl imidazole and 1 g of montmorillonite KSF in 100ml of toluene was stirred under reflux for 6 hours. After completion of reaction, the reaction solvent was distilled off, and then chloroform was added to the resulting residue, and then the catalyst was filtered off. The filtrate was washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness. The resulting solid was purified with ethyl acetate to give 6.3 g of the title compound as white solid (yield 90percent).
88.3%
for 2 h; Heating / reflux
Example 11 The same procedures as described in Example 10 were repeated, except that tetrahydrofuran was employed instead of acetonitrile, to give 6.14 g of the title compound (yield 88.3percent).
84.2%
for 2 h; Heating / reflux
Example 10 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one prepared in any one of Examples 1 to 7 and 11 g of 2-methyl-1-trimethylsilyl imidazole was suspended in 25 ml of acetonitrile. 23. 7ml of 1N tetra-n- butylammonium fluoride solution was added dropwise for 10 min under reflux, and then the reaction mixture was stirred for 2 hours. After cooling to room temperature, 100 ml of water was added to the reaction mixture, and then stirred for 30 min. The resulting solid was filtered and washed with 100 ml of water to give 5.85 g of the title compound as a white solid (yield 84.2percent).
80%
for 2 h; Heating / reflux
Example 12 The same procedures as described in Example 10 were repeated, except that 1.4-dioxane was employed instead of acetonitrile, to give 5.56 g of the title compound (yield 80percent).
With aluminum (III) chloride In acetonitrile for 10 h; Heating / reflux
Example 6: Synthesis of 123s9-tetrahydro-9-methyl-3-[(2-methyl-lH- imidazole-1-yl) methvl]-4H-carbazol-4-one 2.0 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one, 1.65 g of 2- methyl imidazole and 274 g of dipiperidinomethane were suspended in 30 ml of acetonitrile, and then 2 g of aluminum chloride was slowly added thereto. The reaction mixture was stirred under reflux for 10 hours. 150 ml dichloromethane and 50 ml of IN aq. sodium hydroxide were added to the reaction mixture. The resulting organic layer was separated and dried over MgS04, and then evaporated. The resulting solid was suspended in acetone and stirred for 3 hours, and then filtered and dried under a reduced pressure to give 2.05 g of title compound (yield 70percent).
68%
With chloro-trimethyl-silane In DMF (N,N-dimethyl-formamide) at 90℃; for 8 h;
Example 5: Synthesis of 1239-tetrahydro-9-methyl-3-r (2-methyl-lH- imidazole-l-yl . methyl]-4H-carbazol-4-one 2.0 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one, 1.65 g of 2- methyl imidazole and 2.74 g of dipiperidinomethane were suspended in 20 ml of N, N-dimethylformamide, and then 4 ml of chlorotrimethylsilane was slowly added thereto. The reaction mixture was stirred for 8 hours at 90 °C. 100 ml of water was added to the reaction mixture. The resulting solid was filtered and dried, which was then suspended in acetone and stirred for 3 hours, and then filtered and dried under a reduced pressure to give 1.99 g of title compound (yield 68percent).
Step 1 9-Methyl-3- (2-methyl-imidazol-1ylmethyl)-1,2,3,9-tetrahydro-carbazol-4-one: At about 70° C., a solution of 2-(oxazolidin-3-yl)ethanol (372 mg, 3.18 mmol, 1.50 equiv) and n-butanol (50 mL) was added to a mixture of 9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one (420 mg, 2.11 mmol, 1.00 equiv), methanesulfonic acid (324 mg, 3.38 mmol, 1.60 equiv) and n-butanol (50 mL). The resulting mixture was stirred at about 80° C. for about 30 minutes, and then stirred at about 120° C. for about 2.5 hours. 2-Methyl-1H-imidazole (870 mg, 10.6 mmol, 5.00 equiv) was then added to the mixture. After stifling the mixture at about 120° C. for about 6 hours, the mixture was concentrated in vacuo and the resulting residue was resuspended in methanol. The resulting solids were collected by filtration and washed with water and methanol. The solids were then purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether (1:1)), to give the title product as a light yellow solid (200 mg, yield=32percent).
Reference：
[1] Patent: US2010/119623, 2010, A1,
60
[ 693-98-1 ]
[ 99614-02-5 ]
Reference：
[1] Patent: US4695578, 1987, A,
61
[ 108-74-7 ]
[ 693-98-1 ]
[ 27387-31-1 ]
[ 99614-02-5 ]
Yield
Reaction Conditions
Operation in experiment
54%
With chloro-trimethyl-silane In toluene; acetonitrileHeating / reflux
Example 10: Synthesis of 1*23*9-tetrahydro-9-methyl-3-[(2-methyl-lH- imidazole-1-yl) methel]-4H-carbazol-4-one To the solution 19.5 g of 1, 3, 5-trimethylhexahydro-1, 3,5-triazine in 20 ml of actonitrile and 150 ml of toluene, was slowly added 19 ml of chlorotrimethylsilane, which was then stirred for lOmin. lOg of 1,2, 3,9- tetrahydro-9-methyl-4H-carbazol-4-one and 8.2g of 2-methyl imidazole was subsequently added to the reaction mixture, which was then stirred under reflux. After completion of reaction, the reaction mixture was evaporated, and then 200 ml of water was added to the resulting residue, which was then stirred for 2 hours at room temperature. The resulting solid was filtered and washed with water to give 7.95 g of light yellow title compound (yield 54percent).
51%
Heating / reflux
Example 9: Synthesis of 12s39-tetrahydro-9-methel-3-[(2-methyl-lH- imidazole-1-yl) methyll-4H-carbazol-4-one To the solution of 7.1 ml of 1, 3, 5-trimethylhexahydro-1, 3,5-triazine in 150ml of toluene, was slowly added 4 ml of trifluoroacetic acid, which was then stirred for 10min. lOg of 1,2, 3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 20 g of 2-methyl imidazole were subsequently added to the reaction mixture, which was then stirred under reflux. After completion of reaction, the reaction mixture was evaporated, and then 200 ml of water was added to the resulting residue, which was then stirred for 2 hours at room temperature. The resulting solid was filtered and washed with excess water to give 7.5 g of light yellow title compound (yield 51percent).
With triethylsilane; palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere;
General procedure: A 16 mL vial with a PTFE/silicone septum and a nitrogen-bubbler line was charged with N-benzylbenzimidazole (208.1 mg, 1.0 mmol), Pd/C (10 wt %, dry powder, reduced) (20 mg) and THF (5 mL). The mixture was treated at rt with triethylsilane (320 muL, 2.0 mmol) and then stirred under nitrogen for 14 h at rt. The mixture was filtered through a 0.45 muM PTFE syringe filter and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (0 to 10% MeOH/ dichloromethane) to afford benzimidazole as a colorless solid (117.6 mg, 0.996 mmol 99%). The reactions generally exhibit an induction period of 5 to 30 min as indicated by the initiation of gas release (i.e., bubbling) from the reaction mixture. The use of Pd/C on a dry matrix is imperative as wet Pd/C results in decreased yield or no reaction.
0.82 g of 2-methylimidazole (10 mmol) was dissolved in N,N-dimethylformamide (20 mL), heated to 40 C, and 0.84 g of potassium hydroxide (15 mmol) was added.After stirring for 15 min, 1.438 g of bromo n-butane (10.5 mmol) was added dropwise. After the addition was completed, the reaction was continued for 12 h.Cool to room temperature, dilute with water, extract 3 times with dichloromethane, combine the organic phase, wash 3 times with water,Adding water-removing agent anhydrous sodium sulfate to the organic phase, after standing for 1 h, suction filtration, and removing the solvent to obtain 1-butyl-2-methylimidazole, the yield is 97%;
2-cyano-4-fluoronitrobenzene (9.8 g, 59 mmol) and 2-methylimidazole (14.5 g, 177 mmol) were dissolved in dry acetonitrile (300 mL), the reaction mixture was then heated at 9O0C for 5 hours.The solution was cooled at r.t. and the solvent evaporated, the residue was partitioned between AcOEt/0.5N HCl (5/1), the separated organic phase was washed with water, brine and then evaporated. The orange residue was crystallized from acetone/hexane to provide 12.8 g (95%) of the titled compound. When not dry acetonitrile is used some amide is ob- <n="30"/>tained as side-product.1H-NMR (300 MHz, CDCl3) ppm: 2.47 (s, 3H), 7.70 (d, IH), 7.12 (d, IH), 7.73 (dd, IH), 7.83 (d, IH), 8.46 (d, IH).
3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl acetamide; at 145℃; for 19h;
A mixture of 3-fluoro-5- (trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH; 17 g, 89 MMOL) and 2-methylimidazole (Fluka, Buchs, Switzerland; 22.2 g, 270 MMOL) in N, N- dimethylacetamide (80 mL) is stirred at 145C for 19 h. The solvent is evaporated off under reduced pressure and the residue is dissolved in ethyl acetate (200 mL). The solution is washed with brine (200 mL), dried (NA2SO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ether-hexane to afford the title compound as yellow crystalline solid, m. p. 132-134C.
In N,N-dimethyl acetamide; at 145℃; for 19h;
A mixture of [3-FLUORO-5- (TRIFLUOROMETHYL)-BENZONITRILE (LANCASTER] Synthesis GmbH; 17 g, 89 [MMOL)] and 2-methylimidazole (Fluka, Buchs, Switzerland ; 22.2 g, 270 [MMOL)] in N, N- dimethylacetamide (80 mL) is stirred at [145C] for 19 h. The solvent is evaporated off under reduced pressure and the residue is dissolved in ethyl acetate (200 mL). The solution is washed with brine (200 mL), dried [(NA2SO4)] and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ether-hexane to afford the title compound as yellow crystalline solid, m. p. [132-134C.]
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃;
Example 15; 2- [4- (2-Chloro-pyridin-4-ylethynyl)-2,5-dimethyl-1 H-imidazol-1-yl] -5-methyl-pyridine; Step 1: 5-Methyl-2-(2-methyl-imidazol-1-yl)-pyridine 2-Methylimidazole (2.0 g, 24 mmol) and <strong>[2369-19-9]<strong>[2369-19-9]2-Fluoro-5-methylpyridin</strong>e</strong> (5.41 g, 49 mmol) were dissolved in 40 ml dimethyl formamide. Cesium carbonate (23.8 g, 73 mmol) was added and the reaction mixture was stirred at 100C overnight. The reaction mixture was poured into 100 mL water and extracted three times with ethyl acetate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The desired compound was obtained as a brown oil (4.0 g, 95%), MS: m/e = 174.1 (M+H+).
Method 26; 3-r4-Metliyl-lH"-imidazol-l-yl)-5-(trifluoromethyl)benzonitrileTo a solution of <strong>[149793-69-1]3-fluoro-5-(trifluoromethyl)benzonitrile</strong> (5.0 g, 26.4 mmol) in 25 ml of DMA was added 2-methyl imidazole (6.5 g, 79.3 mmol). The reaction mixture was stirred for 15 h at 145 C. The reaction was allowed to cool to room temperature and was quenched with 50 ml of brine and extracted three times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to yield the crude EPO <DP n="42"/>product. The crude residue was purified by column chromatography (hexanes/EtOAc) to give 4.0 g (61%) of the title compound as a white solid, m/z 251.
4-amino-2-(2-methyl-1H-imidazol-1-yl)-5-nitrobenzotrifluoride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
In N,N-dimethyl-formamide;
a. 4-Amino-2-(2-methyl-1H-imidazol-1-yl)-5-nitrobenzotrifluoride To a solution of 20.0 g (~83 mmol) 4-amino-2-chloro-5-nitrobenzotrifluoride in 50 ml dry N,N-dimethylformamide was added 30 g (~370 mmol) 2-methylimidazole, and stirring was continued at 180 C. for 30 h. The reaction mixture was poured into 400 ml water to give the title compound (14.7 g; 62%). M.p. 222-225 C.
General procedure: Compounds 1-18 were synthesized using the following generalprocedure reported by Salvio et al. [41]. A mixture of potassium carbonate(2.0 g, 14.4 mmol), imidazole derivatives 27-28 (32.9 mmol)and compounds 29-37 (4.7 mmol) in dry acetonitrile (50 ml) was heatedunder reflux and the progress of the reaction was monitored byTLC. Then the solvent was evaporated under the vacuum and the residuewas dissolved in DCM (100 ml) *. The organic layer was washedwith saturated sodium bicarbonate aqueous solution (2×50 ml),passed through diatomaceous earth, dried over sodium sulfate, evaporatedunder the vacuum, and purified by flash column chromatography(ethyl acetate-hexane 0-100%)** to give the products 1-18.*Note 1: Ethyl acetate (200 ml) was used for compounds 17 and 18.**Note 2: Compounds 17 and 18 (ethyl acetate-methanol 0-100%).
38%
10 mmol of 2-methyl-1H-imidazole was added to a suspensionof potassium carbonate (10 mmol) in acetonitrile (10 mL), and then stirred for 15 min at r.t. 10 mmol of1-(chloromethyl)benzene was added to the reaction mixture and the mixture was heated to 70C and kept for 72 h. After completion of the reaction, the solvent was removed and the residue was dissolved in EtOAc (20 mL), washed with H2O(2×10 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: CHCl3)to afford the desired product. Yield 38%; yellow oil; UV-Vis (chloroform, lambda, nm): 290; IR spectrum (KBr, nu, cm-1): 2939,1712, 1508, 1434, 1365, 1272, 1118, 983, 721; 1H NMR (250.13 MHz, CDCl3) delta: 7.43-7.32 (m, 5H), 7.17-7.14 (m, 2H), 6.99(d, J = 1.3 Hz, 1H), 6.84 (d, J = 1.2 Hz, 1H), 5.11 (s, 2H), 2.27 (s, 3H); 13C NMR (62.9 MHz, CDCl3) delta: 144.3, 138.0, 129.3,128.1, 127.5, 127.1, 120.9, 49.2, 13.4.
11.5 g (60.5%)
With hydrogenchloride; sodium hydroxide; In N-methyl-acetamide; water;
(i) 1-Benzyl-2-methylimidazole To a slurry of 2.4 g (0.1 mole) of sodium hydride in 50 ml of dimethylformamide under a nitrogen atmosphere was added, with stirring, 8.2 g (0.1 mole) of 2-methylimidazole. A slow exothermic reaction occurred, the temperature reaching 43 C. When the exotherm subsided, the reaction was warmed on a steam bath to 70-75 C. for a half-hour and then at 95 C. for 15 minutes to complete the reaction as evidenced by cessation of gas evolution. It was then cooled to 68 C. and 12.7 g (0.1 mole) of benzyl chloride added dropwise. An exothermic reaction occurred, the temperature reaching 95 C. After stirring for a half-hour following completion of addition, the reaction was poured into 600 ml of water and the product extracted with ethyl acetate (2*200 ml). The combined extracts were washed successively with water (1*400 ml), saturated aqueous sodium chloride solution (1*100 ml), then with 6N HCl (1*50 ml). The HCl wash was extracted with ether (1*25 ml) and then made basic by addition of sodium hydroxide. The yellow oil which separated was extracted into ether, the extract dried (MgSO4) and evaporated under reduced pressure to give a pale yellow oil. Yield, 11.5 g (60.5%). NMR indicates the compound was obtained as the monohydrate. It was used as is in the hydroxymethylation reaction.
1-(4-bromo-3-fluorobenzyl)-2-methylimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N-methyl-acetamide; ethyl acetate;
Step B Preparation of 1-(4-bromo-3-fluorobenzyl)-2-methylimidazole To a solution of the product from Step A (ca. 42 mmol) in 50 mL of dimethylformamide was added 2-methylimidazole (3.47 g, 82.1 mmol) and potassium carbonate (7.53 g, 54.6 mmol). After stirring for two hours, the mixture was poured into EtOAc and washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting solid was taken up in 100 mL of EtOAc, and excess HCl gas was bubbled through the solution. The precipitate was removed by filtration, partitioned between dichloromethane and dilute NaHCO3 solution, and the water phase was extracted repeatedly with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide the desired product as a pale yellow oil.
A mixture of <strong>[32608-29-0]2,4-dichloro-8-methoxy-quinoline</strong> (0.20 g, 0.88 mmol) and 2-methyl-lH- imidazole (0.11 g, 1.3 mmol) in NMP (0.20 mL) was heated to 140C for 20 h. The solvent was removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound as the TFA salt. MS (m/z):419.0 [M+H+].
With sodium hydroxide; In water; at 20℃; for 0.333333h;Micellar solution;
General procedure: To the reaction vessel containing benzimidazole or imidazole (1mmol), alkyl halide (1mmol), 50% NaOH (0.5mL) and anionic surfactant sodium dodecyl sulfate (5mol%) was added and the reaction mixture was vigorously stirred at room temperature or 60C. After the completion of reaction (TLC) followed by standard workup using ethyl acetate as extracting solvent the crude product was purified over silica-gel (60-120 mesh) using ethyl acetate-hexane (3:7) as eluent to afford pure products. Identities of the products were judged by the comparison of melting point, IR data, 1H NMR, 13C NMR and HRMS analyses.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1h;Microwave irradiation;
Intermediate 513-Fluoro-4-(2-methyl-1 H-imidazol-1 -yl)-benzoic acidTo a solution of <strong>[144267-96-9]ethyl 3,4-difluorobenzoate</strong> (1 .5 g) in N,N-dimethylformaide (12 mL) is added 2-methylimidazole (1 .3 g) and K2CO3 (2.2 g) and the mixture is heated at 140 C in a microwave oven for 1 h. After cooling to room temperature, water and ethyl acetate are added and the organic layer is dried (MgS04) and concentrated. The residue is purified by chromatography (ethyl acetate/hexane 0: 1?1 :0). The ester is dissolved in methanol (30 mL) and 4 M aqueous NaOH (3 mL) is added and the mixture is stirred at room temperature for 1 h. The mixture is neutralized with 6 M aqueous HCI, concentrated and then acidified with 6 M aqueous HCI. The precipitate is filtered off washing with a small amount of water and dried by suction to give the title compound.
With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 1h;Microwave irradiation;
To a solution of <strong>[144267-96-9]ethyl 3,4-difluorobenzoate</strong> (1.5 g) in N,N-dimethylformaide (12 mL) is added 2-methylimidazole (1.3 g) and K2CO3 (2.2 g) and the mixture is heated at 140 C. in a microwave oven for 1 h. After cooling to room temperature, water and ethyl acetate are added and the organic layer is dried (MgSO4) and concentrated. The residue is purified by chromatography (ethyl acetate/hexane 0:1?1:0). The ester is dissolved in methanol (30 mL) and 4 M aqueous NaOH (3 mL) is added and the mixture is stirred at room temperature for 1 h. The mixture is neutralized with 6 M aqueous HCl, concentrated and then acidified with 6 M aqueous HCl. The precipitate is filtered off washing with a small amount of water and dried by suction to give the title compound.
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 12h;
To 2-methylimidazole (500.0 mg, 6.090 mmol) in DMF (10 mL) potassium carbonate (1.683 g, 12.180 mmol) and <strong>[454-16-0]4-fluoro-3-methoxynitrobenze</strong> (1.042 g, 6.090 mmol) are added and the resulting mixture is stirred at 85° C. for 12 h in a pressure tube. Afterwards the solvent is removed in vacuo, sodium bicarbonate solution (9percent) is added and extracted with EA. The combined organic layers are washed with sat. sodium chloride solution, dried, filtered and evaporated to get the product.
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 12h;High pressure;
To 2-methyl imidazole (500.0 mg, 6.090 mmol) in DMF (10 mL) potassium carbonate (1 .683 g, 12.180 mmol) and <strong>[454-16-0]4-fluoro-3-methoxynitrobenze</strong> (1 .042 g, 6.090 mmol) are added and the resulting mixture is stirred at 85 °C for 12 h in a pressure tube. Afterwards the solvent is removed in vacuo, sodium bicarbonate solution (9 percent) is added and extracted with EA. The combined organic layers are washed with sat. sodium chloride solution, dried, filtered and evaporated to get the product. MS (ESI+): m/z = 234 [M+H]+
2-methyl-3-(2-(2-methyl-1H-imidazol-1-yl)ethyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;
General procedure: A creamy white solid of 3-(2-chloroethyl)- 2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidin-4-one (5) (1.0eq) in N,N-dimethylformamide was taken, pottasium carbonate (3.0 eq) was added to the reaction mixture and then the appropriate aliphatic/ aromatic/heterocyclic amines (1.0 eq) were added and the reaction mixture was heated at 80 °C for 8h. The progress of the reaction was monitored by TLC. Upon completion, the solvent was removed by water wash and extracted with ethyl acetate. The organic layer was washed with 10percent ammonium chloride solution and finally water wash was given to organic layer and dried with anhydrous sodium sulphate. The solvent was evaporated to get crude product which was purified by column chromatography over silica gel (60-120mesh) using hexane: ethyl acetate(8:2) as an eluent.
1-cyclopropyl-6-fluoro-7-(2-methyl-1H-imidazol-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
In acetonitrile; for 54h;Reflux;
A mixture of 7 (200mg, 0.754mmol) and 11 (185mg, 2.25mmol) in 11mL of anhydrous CH3CN was refluxed with drying tube. After 54h, the resulting suspension was filtered and the solid was washed first with CH3CN (3×3mL) and later with water (3×3mL). The solid was dried under high vacuum to afford pure fluoroquinolone 5 (174mg, 71percent) as an off white solid, mp 290.5?292°C. IR (cm?1) 3148.64; 3114.24; 3033.28; 2973.71; 1727.08; 1615.01; 1553.18; 1491.91; 1461.72cm?1. NMR 1H (300MHz, DMSO) delta 14.67 (s, 1H); 8.82 (s, 1H); 8.47 (d, J=6.5Hz; 1H); 8.30 (d; J=10.0Hz; 1H); 7.47 (br s, 1H); 7.05 (d; J=1.3Hz; 1H); 3.94?3.78 (m, 1H); 2.33 (s, 3H); 1.38?1.14 (m, 4H). HRMS (ESI-TOF) m/z: [M+H]+ calculated for C17H14FN3O3 328.1092. Found 328.1106.
Take 0.5 mol of 2-methylimidazole,0.525 mol of <strong>[627-42-9]2-chloroethyl methyl ether</strong> (structural formula) and 80 ml of absolute ethanol,After mixing and dissolving and transferring into a 250 ml hydrothermal kettle, reacting at 140 C for 48 h;The brown oil obtained by the reaction was washed three times with a mixed solvent of 100 ml of anhydrous ethanol and anhydrous diethyl ether (1:4, v/v), and then mixed with 0.5 mol of triethylamine and transferred into a 250 ml hydrothermal kettle at 130 C. The reaction was carried out for 16 hours; the white salt impurities formed by the reaction were removed by suction filtration, the filtrate was collected, and the filtrate was subjected to distillation under reduced pressure.The fraction was collected, 1-methoxyethyl-2-methylimidazole. The yield was 82%.
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