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[ CAS No. 1003-91-4 ] {[proInfo.proName]}

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Chemical Structure| 1003-91-4
Chemical Structure| 1003-91-4
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Product Details of [ 1003-91-4 ]

CAS No. :1003-91-4 MDL No. :MFCD00955564
Formula : C4H3Br3N2 Boiling Point : -
Linear Structure Formula :- InChI Key :KAMDVXMJRMNDCQ-UHFFFAOYSA-N
M.W : 318.79 Pubchem ID :629187
Synonyms :

Calculated chemistry of [ 1003-91-4 ]

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 : 17.82 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.05 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.18
Log Po/w (XLOGP3) : 3.09
Log Po/w (WLOGP) : 2.71
Log Po/w (MLOGP) : 1.97
Log Po/w (SILICOS-IT) : 2.53
Consensus Log Po/w : 2.49

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -4.17
Solubility : 0.0213 mg/ml ; 0.0000669 mol/l
Class : Moderately soluble
Log S (Ali) : -3.13
Solubility : 0.235 mg/ml ; 0.000738 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.33
Solubility : 0.148 mg/ml ; 0.000465 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.14

Safety of [ 1003-91-4 ]

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

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.

  • Upstream synthesis route of [ 1003-91-4 ]
  • Downstream synthetic route of [ 1003-91-4 ]

[ 1003-91-4 ] Synthesis Path-Upstream   1~6

  • 1
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YieldReaction ConditionsOperation in experiment
571 mg for 24 h; Reflux 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 χ 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 χ 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 χ 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.
Reference: [1] Patent: WO2013/192352, 2013, A1, . Location in patent: Page/Page column 117
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YieldReaction ConditionsOperation in experiment
29% With bromine; sodium acetate In acetic acid at 20℃; for 2.5 h; 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 χ 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 χ 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 χ 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 1.5 h; 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 at 20℃; for 2.5 h; 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
Reference: [1] Synthesis, 1988, # 10, p. 767 - 771
[2] Tetrahedron Letters, 2006, vol. 47, # 12, p. 1949 - 1951
[3] Polish Journal of Chemistry, 1981, vol. 55, # 7/8, 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
  • 3
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YieldReaction ConditionsOperation in experiment
94%
Stage #1: at 50℃; for 1 h;
Stage #2: at 0 - 50℃; for 16 h;
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) δ 3.62 (s, 3H). MS (ESI) m/z 316.77 [M+H]+.
Reference: [1] Synlett, 2010, # 12, p. 1779 - 1782
[2] Patent: WO2017/87837, 2017, A1, . Location in patent: Paragraph 00314
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, # 4, p. 735 - 739
[2] Angewandte Chemie, 1981, vol. 93, # 6/7, p. 601 - 602
[3] Tetrahedron Letters, 2006, vol. 47, # 12, p. 1949 - 1951
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Reference: [1] Journal of the Chemical Society, 1924, vol. 125, p. 1569
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Reference: [1] Journal of the Chemical Society, 1924, vol. 125, p. 1569
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