5-Bromo-1-methyl-1H-imidazole

Cat.NO.:A182178 Purity:97%

Product Details of [ 1003-21-0 ]

CAS No. :	1003-21-0
Formula :	C₄H₅BrN₂
M.W :	161.00
SMILES Code :	CN1C=NC=C1Br
MDL No. :	MFCD01632218
InChI Key :	HATLLUIOEIXWGD-UHFFFAOYSA-N
Pubchem ID :	1515258

Safety of [ 1003-21-0 ]

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

Computational Chemistry of [ 1003-21-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	7
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	31.19
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.	1.45
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	1.04
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.18
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.	0.4
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	1.14
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.04

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.02
Solubility	1.53 mg/ml ; 0.00951 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.0
Solubility	15.9 mg/ml ; 0.0989 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-1.64
Solubility	3.71 mg/ml ; 0.023 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	No
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.	-6.54 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	2.0
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<1.0
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)	1.75

Application In Synthesis of [ 1003-21-0 ]

* 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 [ 1003-21-0 ]

[ 1003-21-0 ] Synthesis Path-Downstream 1~2

1
[ 1003-21-0 ]
[ 116332-54-8 ]
[ 1450738-79-0 ]

Yield	Reaction Conditions	Operation in experiment
		A clear colorless solution of 5-bromo-N-methyl-imidazole (47.7 g, 296 mmol) in THF (500 mL) was placed in an ice bath and ethylmagnesium bromide in diethyl ether (3.0 M, 98.7 mL, 296 mmol) was added via syringe fairly rapidly, over 17 min. The thick suspension was stirred at room temperature for 20 min. The mixture was again cooled in an ice water bath before addition of neat <strong>[116332-54-8]4-fluoro-N-methoxy-N-methylbenzamide</strong> (45.2 g, 247 mmol, Intermediate 49, step a). The resulting suspension was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous NH4Cl (100 mL) followed by water (200 mL). The pH was adjusted to 7 by addition of 1 N aqueous HCl, the mixture was partially concentrated to remove THF, and was extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was triturated with EtOAc:heptane(1:1, 150 mL) to afford the title compound as a white crystalline solid.

References: [1]Patent: US2014/107097,2014,A1 .Location in patent: Paragraph 0422; 0423.

2
[ 1003-21-0 ]
[ 156353-01-4 ]
(1-methyl-1H-imidazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A clear colorless solution of 5-bromo-1-methyl-1H-imidazole (1.12 g, 6.93 mmol) in THF (10 mL) was placed in an ice bath and ethylmagnesium bromide (3.0 M in Et2O, 2.31 mL, 6.93 mmol) was added via syringe. The reaction mixture was stirred for 20 minutes at room temperature. N-Methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (1.0 g, 5.8 mmol, Intermediate 1: step a, Procedure A) was added neat by syringe (using 1 mL THF rinse to quantitate transfer), and the resulting white suspension was stirred at room temperature for 2 days. The mixture was diluted with saturated aqueous NH4Cl followed by water, then was extracted with EtOAc (3*). The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography two times (1-4% MeOH-DCM first column; 40-60% CH3CN-DCM second column) to provide the title compound as a white crystalline solid.
		lntermediate 1: step b (1-Methyl-lH-imidazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone A clear colorless solution of 5-bromo-l-methyl-lH-imidazole (1.12 g, 6.93 mmol) in THF (10 mL) was placed in an ice bath and ethylmagnesium bromide (3.0 M in Et20, 2.31 mL, 6.93 mmol) was added via syringe. The reaction mixture was stirred for 20 minutes at room temperature. N-Methoxy~N-methyltetrahydro-2H~pyran-4~ca.rboxamide (1.0 g, 5.8 mmol. Intermediate 1 : step a. Procedure A) was added neat by syringe (using 1 mL THF rinse to quantitate transfer), and the resulting white suspension was stirred at room temperature for 2 days. The mixture was diluted with saturated aqueous NH4C1 followed by water, then was extracted with EtOAc (3 x). The organic phase was dried (Na2S04), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography two times (1 -4% MeOH-DCM first column; 40-60% CH CN-DCM second column) to provide the title compound as a white crystalline solid.

References: [1]Patent: US2015/105366,2015,A1 .Location in patent: Paragraph 0186; 0187.
[2]Patent: WO2015/57205,2015,A1 .Location in patent: Page/Page column 59.

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