1003-91-4|2,4,5-Tribromo-1-methylimidazole| Ambeed

CAS No. :	1003-91-4
Formula :	C₄H₃Br₃N₂
M.W :	318.79
SMILES Code :	CN1C(Br)=C(Br)N=C1Br
MDL No. :	MFCD00955564
InChI Key :	KAMDVXMJRMNDCQ-UHFFFAOYSA-N
Pubchem ID :	629187

Safety of [ 1003-91-4 ]

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

Computational Chemistry of [ 1003-91-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	5
Fraction Csp3	0.25
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	0.0
Molar Refractivity	46.59
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	17.82 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.18
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.09
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.71
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.97
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.53
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.49

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.17
Solubility	0.0213 mg/ml ; 0.0000669 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.13
Solubility	0.235 mg/ml ; 0.000738 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.33
Solubility	0.148 mg/ml ; 0.000465 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.05 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.14

Application In Synthesis of [ 1003-91-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1003-91-4 ]

[ 1003-91-4 ] Synthesis Path-Downstream 1~50

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[ 616-47-7 ]
[ 1003-50-5 ]
[ 1003-91-4 ]

References: [1]Journal of the Chemical Society,1924,vol. 125,p. 1569.

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[ 1003-91-4 ]

Yield	Reaction Conditions	Operation in experiment
29%	With bromine; sodium acetate; In acetic acid; at 20℃; for 2.5h;	To a solution of N-methylimidazole (1.64 g, 19.97 mmol) and sodium acetate (25 g, 300 mmol) in acetic acid (180 mL) at room temperature was added bromine (9.6 g, 60.07 mmol) dropwise as a solution in 20 mL acetic acid. The resulting mixture was stirred for 2.5 h at room temperature. Acetic acid was removed in vacuo, the residue was suspended in 500 mL water and stirred at room temperature for 10 minutes. The resultant precipitate was filtered, washed with water and dried under high vacuum to give 2,4,5-tribromo-l-methyl- lH-imidazole (1.82 g, 29percent - some product remained in the mother liquor) as a light yellow powder. Used without further characterization. To a suspension of the tribromide (1.82 g, 5.71 mmol) in 45 mL water was added sodium sulfite (13 g, 103 mmol) and the resulting mixture was stirred at rapid reflux for 24 h. After cooling to room temperature, organics were extracted with ether (3 chi 75 mL), dried over magnesium sulfate, filtered and concentrated to give 1.61 g of a mixture of tri-, di- and monobromoimidazoles. This mixture was re-subjected to the reduction conditions (same quantity of sodium sulfite) using 15 mL of 3: 1 water/acetic acid as solvent and heating in a sealed vessel at 130 °C for 60 h. After cooling to room temperature, the pH of the reaction mixture was adjusted to 9-10 by addition of 2 N sodium hydroxide. Organics were extracted with ether (3 chi 50 mL), dried over magnesium sulfate, filtered and concentrated to give crude 4-bromo-l -methyl- lH-imidazole (571 mg, ca. 62percent). Used without further characterization.. 4-Butyl-l -methyl- lH-imidazole (95 mg, 22 percent) was synthesized as in Example 3.1 using 4-bromo-l -methyl- lH-imidazole (571 mg, ca. 3.53 mmol) in place of 5-bromo-2- formylfuran and propylboronic acid (372 mg, 4.24 mmol) in place of hexylboronic acid. Used without further characterization. To a solution of diisopropylamine (0.13 mL, 0.918 mmol) in 2 mL anhydrous tetrahydrofuran at - 0°C was added -butyllithium (0.34 mL, 2.5 M in hexanes) dropwise. The solution was stirred while warming to -20 °C over 20 minutes. After cooling to -78 °C, 4-butyl-l -methyl- lH-imidazole (95 mg, 0.765 mmol) was added dropwise as a solution in 2 mL anhydrous tetrahydrofuran. The resulting solution was stirred for 40 minutes at -78 °C. Dimethylformamide (0.24 mL, 3.06 mmol) was added and the solution stirred while warming to room temperature. The reaction mixture was poured into 15 mL of 1 N hydrochloric acid and stirred for 5 minutes. The pH of the reaction mixture was adjusted to 7-8 by careful addition of saturated sodium bicarbonate solution. Organics were extracted with dichloromethane (3 chi 20 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-50percent ethyl acetate in hexanes) to give l -methyl-4-propyl-lH-imidazole-2-carbaldehyde (9 mg, 8percent) as an off-white solid. Used without further characterization
63.76 g	With N-Bromosuccinimide; In chloroform; at 20℃; for 1.5h;	2-(2-Ethynyl-1 -methyl-1 H-imidazol-4-yl)-thiazole To a solution of compound N-methylimidazole (65.6 g, 0.8 mol) in CHCl3 (1 .5 L), N-bromosuccinimide (NBS; 476g,2.4 mol) was added in portion and then the mixture was stirred at roomtemperature for 1 .5 hour, filtered and concentrated, the residue was purifiedby column chromatography over silica gel (eluent: EA/PE 1/10) to afford 2,4,5-Tribromo-1 -methyl-1H-imidazole (63.76 g, 0.2 mol), which was dissolved in in dry THF (2L) andEtMgBr (220 ml_, 0.22 mol) was added slowly under N2 atmosphere at ambient temperature during 3 hourand stirred for another 2 hour. Then about 100ml_ water was added and filtered,concentrated and the residue was extracted with ethyl acetate, purified bycolumn chromatography over silica gel (eluent : EA/PE 1/10) to afford 2,4-dibromo-1 -methyl-1 H-imidazole (20 g, yield:41 .7percent). To a solution of 2,4-dibromo-1-methyl-1 H-imidazole (6 g, 25.6 mmol) in THF (26 ml_) was added Cul (0.2 g,1mmol), Et3N (12 ml_,86 mmol),Pd(dppf)CI2 (417 mg, 0.5 mmol),Ethynyl-trimethyl-silane (4.2 ml_,29.6 mmol), then the mixture was heated to40°C and stirred at this temperature for 40min. Then filtered, concentrated andpurified by column chromatography over silica gel (eluent: EA/PE 1/50), collectthe desire fraction and concentrated to give 4-Bromo-1-methyl-2-trimethylsilanylethynyl-1 H-imidazole (3.95 g, yield: 60percent). To a solution of 4-Bromo-1-methyl-2-trimethylsilanylethynyl-1 H-imidazole (5.14 g, 20 mmol) in toluene(100 ml_) , 2-Tributylstannanyl- thiazole (8.3 g, 22 mmol) was added followedwith Pd(PPh3) (1 .2 g, 1 mmol), then themixture was refluxed for 6 hour, when cooled, the mixture was filtered, thefiltrate was concentrated and purified by chromatography over silica gel (eluent :EA/PE 1/20 to 1/10) to afford 2-(1-Methyl-2-trimethylsilanylethynyl-1 H-imidazol-4-yl)-thiazole (2.5 g, yield:48percent). To the mixture of 2-(1 -Methyl -2-trimethylsilanylethynyl-1H-imidazol-4-yl)-thiazole in MeOH (50 ml_), Na2CO3 (1 .5 g, 18 mmol) was added quickly and stirred the mixture forabout one minutes, then filtered, concentrated and purified by column chromatographyover silica gel (eluent: EA PE 1/5) to afford 2-(2-Ethynyl-1 -methyl-1H-imidazol-4-yl)-thiazole (2 g, yield: 80percent). 1H NMR (CDCI3 400 MHz TMS):53.40 (s, 1 H), 3.80 (s, 3H), 7.27 (s, 1 H), 7.53 (s, 1 H), 7.26-7.27 (d, J=4.0Hz, 1 H).
95 g	With bromine; sodium acetate; acetic acid; at 20℃; for 2.5h;	To a solution of Example 69a (82 g, 1.0 mol) and sodium acetate (125 g, 1.52 mol) in acetic acid (2.0 L) at room temperature was added bromine (480 g, 30 mmol) dropwise as a solution in 1.0L acetic acid. The resulting mixture was stirred for 2.5 h at room temperature. Acetic acid was removed in vacuo; the residue was suspended in 1.5L water and stirred at room temperature for 10 minutes. The resultant precipitate was filtered, washed with water and dried under high vacuum to give Example 69b (95.0 g, contained 30percent isomer) as light yellow powder. LCMS [M+H]+=319.1

References: [1]Synthesis,1988,p. 767 - 771.
[2]Tetrahedron Letters,2006,vol. 47,p. 1949 - 1951.
[3]Polish Journal of Chemistry,1981,vol. 55,p. 1659 - 1665.
[4]Chemische Berichte,1991,vol. 124,p. 1639 - 1650.
[5]Patent: WO2013/192352,2013,A1 .Location in patent: Page/Page column 116; 117.
[6]Chemische Berichte,1883,vol. 16,p. 546 Anm. 1.
[7]Patent: WO2013/50527,2013,A1 .Location in patent: Page/Page column 38; 39; 40.
[8]Patent: WO2017/218960,2017,A1 .Location in patent: Paragraph 00638.

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[ 616-47-7 ]

References: [1]Chemische Berichte,1877,vol. 10,p. 1370.

4
[ 2034-22-2 ]
[ 77-78-1 ]
[ 1003-91-4 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1983,p. 735 - 739.
[2]Angewandte Chemie,1981,vol. 93,p. 601 - 602.
[3]Tetrahedron Letters,2006,vol. 47,p. 1949 - 1951.

5
[ 75-77-4 ]
[ 1003-91-4 ]
[ 133227-92-6 ]

References: [1]Chemische Berichte,1991,vol. 124,p. 1639 - 1650.

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[ 1003-91-4 ]
[ 624-92-0 ]
[ 145083-26-7 ]

References: [1]Journal of Organic Chemistry,1993,vol. 58,p. 7952 - 7954.
[2]Tetrahedron Letters,1992,vol. 33,p. 5865 - 5868.

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[ 1003-91-4 ]
[ 420-37-1 ]
C₃N₂(CH₃)2Br₃⁽¹⁺⁾*BF₄^(1-)=(C₃N₂(CH₃)2Br₃)BF₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In dichloromethane; at 20℃;Inert atmosphere; Schlenk technique;	<strong>[1003-91-4]2,4,5-tribromo-1-methyl-imidazole</strong> (1) (0.5g, 1.56mmol) and trimethyloxonium tetrafluoroborate (0.25g, 1.72mmol) in a Schlenk flask was charged with dichloromethane (30mL). The mixture was stirred overnight at room temperature to afford a colorless solid. The volatiles were removed in vacuum and the resulted solid was washed with diethyl ether (2×15mL) and dried under vacuum to give 3 as colorless powder. Yield: 0.60g (91percent). Mp: 304°C. 1H NMR (DMSO-d6, 500MHz, delta, ppm): 3.78 (s, 6H, N?CH3). 13C NMR (DMSO-d6, 125MHz, delta, ppm): 38.1 (N?CH3), 112.0 (4,5-C?Br), 124.9 (C2?Br). IR (KBr, cm?1): 1637(m), 1554(m), 1504(s), 1445(m), 1396(m), 1329(m), 1295(m), 1056(vs), 1034(vs), 813(w), 641(w), 522(w). ESI MS: m/z 332.8081 [M?(BF4) ]+.

References: [1]Journal of Organometallic Chemistry,2017,vol. 851,p. 104 - 114.
[2]Angewandte Chemie,1981,vol. 93,p. 601 - 602.
[3]Angewandte Chemie,1981,vol. 93,p. 601 - 602.

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[ 1003-91-4 ]
[ 624-92-0 ]
[ 68-12-2 ]
[ 145083-36-9 ]

References: [1]Tetrahedron Letters,1992,vol. 33,p. 5865 - 5868.

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[ 1003-91-4 ]
[ 624-92-0 ]
[ 68-12-2 ]
[ 145083-27-8 ]

References: [1]Tetrahedron Letters,1992,vol. 33,p. 5865 - 5868.

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[ 1003-91-4 ]
[ 1003-50-5 ]

References: [1]Synthesis,1988,p. 767 - 771.
[2]Journal of the Chemical Society. Perkin transactions I,1989,p. 1139 - 1145.
[3]Chemische Berichte,1991,vol. 124,p. 1639 - 1650.

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[ 1003-91-4 ]
[ 124-38-9 ]
[ 158585-80-9 ]

References: [1]Journal of Organic Chemistry,1994,vol. 59,p. 5524 - 5526.

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[ 64-17-5 ]
sodium amalgam [ No CAS ]
[ 616-47-7 ]

References: [1]Chemische Berichte,1877,vol. 10,p. 1370.

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[ 2034-22-2 ]
CH₃X [ No CAS ]
[ 1003-91-4 ]

References: [1]Tetrahedron Letters,1992,vol. 33,p. 5865 - 5868.

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[ 74-88-4 ]
silver salt of 2.4.5-tribromo-imidazole [ No CAS ]
[ 1003-91-4 ]

References: [1]Chemische Berichte,1877,vol. 10,p. 1370.

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[ 616-47-7 ]
[ 67-66-3 ]
[ 7726-95-6 ]
[ 1003-50-5 ]
[ 1003-91-4 ]

References: [1]Journal of the Chemical Society,1924,vol. 125,p. 1569.

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[ 1003-91-4 ]
[ 106-95-6 ]
1-allyl-4,5-dibromo-3-methyl-3H-imidazol-1-ium; bromide [ No CAS ]
1-allyl-2,4,5-tribromo-3-methyl-3H-imidazol-1-ium; bromide [ No CAS ]

References: [1]Journal of Organic Chemistry,2004,vol. 69,p. 6511 - 6513.

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[ 1003-91-4 ]
[ 106-95-6 ]
1-allyl-4,5-dibromo-3-methyl-3H-imidazol-1-ium; bromide [ No CAS ]
4,5-dibromo-1-(2,3-dibromo-propyl)-3-methyl-3H-imidazol-1-ium; bromide [ No CAS ]

References: [1]Journal of Organic Chemistry,2004,vol. 69,p. 6511 - 6513.

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[ 2034-22-2 ]
[ 74-88-4 ]
[ 1003-91-4 ]

Yield	Reaction Conditions	Operation in experiment
94%		Step 1. 2,4,5-Tribromo-l-methyl-lH-imidazole (0975) [00314] To a suspension of sodium hydride (0.787 g, 19.69 mmol) in DMF (15 mL) was added 2, 4, 5-tribromo-lH-imidazole (5 g, 16.41 mmol) in DMF (10 mL) at ambient temperature. The mixture was stirred at 50 °C for 1 h, cooled to 0 °C, and treated with methyl iodide (1.128 ml, 18.05 mmol). The mixture was warmed to 50 °C and stirred 16 h, the DMF was removed under reduced pressure and EtOAc was added. The mixture was washed with water, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (eluting with a gradient of 10-80percent EtOAc/hexanes) afforded 4.87 g (94percent) of 2,4,5-tribromo-l -methyl- lH-imidazole. 1H MR (300 MHz, CDC13) delta 3.62 (s, 3H). MS (ESI) m/z 316.77 [M+H]+.

References: [1]Synlett,2010,p. 1779 - 1782.
[2]Patent: WO2017/87837,2017,A1 .Location in patent: Paragraph 00314.

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[ 5720-05-8 ]
[ 1246624-41-8 ]