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Chemical Structure| 693-98-1
Chemical Structure| 693-98-1
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Product Citations

Abraha, Yuel W. ; Tsai, Chih-Wei ; Langner, Ernst H. G. DOI:

Abstract: Several ZIFs and their functionalised derivatives have been reported as efficient catalytic materials for the fixation of CO2 in the bid to reduce global warming, caused by the persistent use of fossil fuels. However, the major challenge of using these ZIFs at large scales requires the scalability of their synthesis. Herein, a series of Zn-based zeolite imidazolate frameworks (ML-ZIFs) with mixed linkers (2-methylimidazole and 2-nitroimidazole) were synthesized via an easily scalable procedure. The products were characterised by PXRD, TGA, TEM, N2 isotherms, digestive 1H NMR and evaluated as catalysts for CO2 fixation. All ML-ZIFs are thermally stable, highly porous with SOD or frl topologies and particle sizes of 44-360 nm. ML-ZIF 3 with [Zn(mIm)0.87(nIm)1.13] composition resulted in the highest CO2 uptake of 91 cm3g-1. ML-ZIF 4 (Zn(mIm)1.44(nIm)0.56) led to the highest catalytic activity (684 h-1) by a ZIF derivative in the cycloaddition of CO2 to epichlorohydrin substrate.

Keywords: Scalable ; ZIFs ; Catalysts ; CO2 fixation

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Product Details of [ 693-98-1 ]

CAS No. :693-98-1 MDL No. :MFCD00005190
Formula : C4H6N2 Boiling Point : -
Linear Structure Formula :(CH3)N2C3H3 InChI Key :LXBGSDVWAMZHDD-UHFFFAOYSA-N
M.W : 82.10 Pubchem ID :12749
Synonyms :
Chemical Name :2-Methyl-1H-imidazole

Calculated chemistry of [ 693-98-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 6
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 : 23.55
TPSA : 28.68 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.47 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.81
Log Po/w (XLOGP3) : 0.46
Log Po/w (WLOGP) : 0.72
Log Po/w (MLOGP) : -0.47
Log Po/w (SILICOS-IT) : 1.56
Consensus Log Po/w : 0.62

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.26
Solubility : 4.56 mg/ml ; 0.0555 mol/l
Class : Very soluble
Log S (Ali) : -0.63
Solubility : 19.2 mg/ml ; 0.234 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.51
Solubility : 2.55 mg/ml ; 0.0311 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 693-98-1 ]

Signal Word:Danger Class:8
Precautionary Statements:P501-P260-P270-P202-P201-P264-P280-P308+P313-P308+P311-P303+P361+P353-P301+P330+P331-P363-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P405 UN#:3263
Hazard Statements:H302-H314-H360-H371-H373-H341-H351 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 693-98-1 ]

* 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 [ 693-98-1 ]
  • Downstream synthetic route of [ 693-98-1 ]

[ 693-98-1 ] Synthesis Path-Upstream   1~68

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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
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
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YieldReaction ConditionsOperation 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
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Reference: [1] Patent: WO2015/198107, 2015, A1, . Location in patent: Page/Page column 3
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Reference: [1] Tetrahedron, 1998, vol. 54, # 38, p. 11525 - 11536
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Reference: [1] Tetrahedron, 1998, vol. 54, # 38, p. 11525 - 11536
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Reference: [1] Australian Journal of Chemistry, 2004, vol. 57, # 2, p. 145 - 147
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
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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
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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
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YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation 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
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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
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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
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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
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Reference: [1] Chemische Berichte, 1883, vol. 16, p. 488
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Reference: [1] Bull. Russ. Acad. Sci. Div. Chem. Sci. (Engl. Transl.), 1992, vol. 41, # 4, p. 932 - 940,728 - 734
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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
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
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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
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
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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
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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
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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
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
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YieldReaction ConditionsOperation 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,
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Reference: [1] Tetrahedron Letters, 1987, vol. 28, # 5, p. 515 - 516
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Reference: [1] Journal of the American Society for Mass Spectrometry, 2012, vol. 23, # 5, p. 823 - 833
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Reference: [1] Journal of Heterocyclic Chemistry, 1988, vol. 25, p. 1845 - 1847
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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
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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,
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Reference: [1] Patent: US6048884, 2000, A,
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YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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
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  • [ 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
  • 43
  • [ 693-98-1 ]
  • [ 100-00-5 ]
  • [ 73225-15-7 ]
Reference: [1] Synthetic Communications, 2012, vol. 42, # 1, p. 114 - 121
[2] Synlett, 2008, # 19, p. 3068 - 3072
  • 44
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  • [ 24067-17-2 ]
  • [ 73225-15-7 ]
Reference: [1] Chemistry Letters, 2010, vol. 39, # 7, p. 764 - 765
  • 45
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  • [ 53342-27-1 ]
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
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  • [ 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
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  • [ 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
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  • [ 27387-31-1 ]
  • [ 51-80-9 ]
  • [ 99614-02-5 ]
YieldReaction ConditionsOperation 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).

Reference: [1] Patent: WO2005/37822, 2005, A1, . Location in patent: Page/Page column 11
[2] Patent: WO2005/37822, 2005, A1, . Location in patent: Page/Page column 10
[3] Patent: WO2005/37822, 2005, A1, . Location in patent: Page/Page column 7
[4] Patent: WO2005/37822, 2005, A1, . Location in patent: Page/Page column 7
[5] Patent: WO2005/37822, 2005, A1, . Location in patent: Page/Page column 9-10
[6] Patent: WO2005/37822, 2005, A1, . Location in patent: Page/Page column 8
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  • [ 693-98-1 ]
  • [ 99614-02-5 ]
YieldReaction ConditionsOperation in experiment
83% at 5 - 103℃; for 5.5 - 6.5 h; 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.
Reference: [1] Patent: WO2003/93281, 2003, A1, . Location in patent: Page/Page column 15; 16
[2] Patent: US6544550, 2003, B1,
[3] Patent: US4753789, 1988, A,
[4] Patent: US4835173, 1989, A,
[5] Patent: US4983621, 1991, A,
[6] Patent: US4847281, 1989, A,
[7] Patent: EP411900, 1991, A2,
[8] Patent: EP269452, 1989, A3,
[9] Patent: US4695578, 1987, A,
[10] Patent: EP269452, , A2, [10] Patent: , 1988, ,
  • 54
  • [ 693-98-1 ]
  • [ 99614-64-9 ]
  • [ 99614-02-5 ]
YieldReaction ConditionsOperation in experiment
99% for 6 h; Heating / reflux 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).

Reference: [1] Patent: WO2005/37823, 2005, A1, . Location in patent: Page/Page column 11
[2] Patent: US2006/41004, 2006, A1, . Location in patent: Page/Page column 8
[3] Patent: WO2005/37823, 2005, A1, . Location in patent: Page/Page column 13
[4] Patent: WO2005/37823, 2005, A1, . Location in patent: Page/Page column 12
[5] Patent: WO2005/37823, 2005, A1, . Location in patent: Page/Page column 12
[6] Patent: WO2005/37823, 2005, A1, . Location in patent: Page/Page column 12
[7] Patent: WO2005/37823, 2005, A1, . Location in patent: Page/Page column 12
[8] Heterocycles, 1997, vol. 45, # 10, p. 2041 - 2043
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  • [ 1630-73-5 ]
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Reference: [1] Patent: WO2004/46116, 2004, A1, . Location in patent: Page 13
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Reference: [1] Patent: WO2004/46116, 2004, A1, . Location in patent: Page 12
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Reference: [1] Patent: WO2004/46116, 2004, A1, . Location in patent: Page 12-13
  • 58
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  • [ 27387-31-1 ]
  • [ 99614-02-5 ]
YieldReaction ConditionsOperation in experiment
70% 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).
Reference: [1] Patent: WO2005/37822, 2005, A1, . Location in patent: Page/Page column 9
[2] Patent: WO2005/37822, 2005, A1, . Location in patent: Page/Page column 9
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  • [ 27387-31-1 ]
  • [ 71-36-3 ]
  • [ 99614-02-5 ]
YieldReaction ConditionsOperation in experiment
32% With methanesulfonic acid In methanol 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,
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Reference: [1] Patent: US4695578, 1987, A,
  • 61
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  • [ 27387-31-1 ]
  • [ 99614-02-5 ]
YieldReaction ConditionsOperation 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).
Reference: [1] Patent: WO2005/37822, 2005, A1, . Location in patent: Page/Page column 11
[2] Patent: WO2005/37822, 2005, A1, . Location in patent: Page/Page column 10-11
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Reference: [1] Patent: WO2006/46253, 2006, A1, . Location in patent: Page/Page column 18-19
[2] Patent: WO2006/46253, 2006, A1, . Location in patent: Page/Page column 19
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