885167-81-7|6-Bromo-5-methylnicotinaldehyde| Ambeed

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Quality Control of [ 885167-81-7 ] Purity: 95% SDS Specification

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Product Details of [ 885167-81-7 ]

CAS No. :	885167-81-7
Formula :	C₇H₆BrNO
M.W :	200.03
SMILES Code :	O=CC1=CN=C(Br)C(C)=C1
MDL No. :	MFCD08277302
InChI Key :	GLUTVVKVSPUTKQ-UHFFFAOYSA-N
Pubchem ID :	44754884

Safety of [ 885167-81-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 885167-81-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	42.29
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	29.96 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.59
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	1.7
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.96
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.	0.89
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	2.62
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.75

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.53
Solubility	0.591 mg/ml ; 0.00296 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.	-1.94
Solubility	2.27 mg/ml ; 0.0114 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	-3.22
Solubility	0.121 mg/ml ; 0.000605 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.	-6.31 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	0.0
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	2.0 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)	1.62

Application In Synthesis of [ 885167-81-7 ]

* 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 [ 885167-81-7 ]

[ 885167-81-7 ] Synthesis Path-Downstream 1~21

2
[ 885167-81-7 ]
[ 99-76-3 ]
[ 926294-89-5 ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium carbonate; In N,N-dimethyl-formamide; at 125℃; for 16h;	A mixture of -bromo-S-methylpyridine-S-carboxaldehyde (1.44 g, 7.24 mmol), 4- hydroxy-benzoic acid methyl ester (1.52 g, 10.0 mmol) and K2CO3 (1.00 g, 7.24 mmol) in DMF (20 mL) was stirred at 125 0C for 16 h. The mixture was cooled to room temperature and DMF was removed. Aqueous work-up and purification by flash chromatography on silica gel (EtOAc/hexanes, 1:3 in v/v) afforded 4-(5-formyl-3-methyl-pyridin-2-yloxy)-benzoic acid methyl ester as a white solid (0.98 g, 50%). 1H NMR (CDCl3) delta 2.44 (s, 3H), 3.93 (s, 3H), 7.22-7.25 (m, 2H), 8.05 (d, IH, J= 2.1 Hz), 8.11-8.15 (m, 2H), 8.41 (d, IH5 J= 2.1 Hz), 9.96 (S, IH).

References: [1]Patent: WO2007/22371,2007,A2 .Location in patent: Page/Page column 56.

3
[ 617703-01-2 ]
[ 885167-81-7 ]
[ 901300-03-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 17 - 60℃; for 2h;	Method 3; Preparation of t-butyl (2-[4-(5-formyl-3-methylpyridin-2-yl)benzoyl]amino}phenyl carbamate; N-(2-t-Butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)benzamide (7.69 g, 17.55 mmol-prepared as described in Method 13, page 60, of International patent publication number WO 03/087057), was added to a stirred solution of <strong>[885167-81-7]6-bromo-5-methylnicotinaldehyde</strong> (3.51 g, 17.55 mmol, see Method 4 below) in dimethoxyethane (100 ml) at ambient temperature under a nitrogen atmosphere. 1,1'Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.72 g, 0.88 mmol) was added followed by saturated aqueous sodium bicarbonate solution (50 ml) and the mixture heated at 60 C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The dichloromethane layer was washed with saturated aqueous sodium bicarbonate solution and brine, then dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 40% ethyl acetate in isohexane, to give the title compound (5.93 g, 75%); NMR Spectrum: (DMSO-d6) 1.46 (s, 9H), 2.47 (s, 3H), 7.20 (m, 2H), 7.58 (m, 2H), 7.80 (d, 2H), 8.09 (d, 2H), 8.23 (s, 1H), 8.70 (s, 1H), 9.04 (s, 1H), 9.94 (s, 1H), 10.17 (s, 1H); Mass Spectrum: M+H+432.
75%	With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 60℃; for 2h;	Method 2; Preparation of tert-butyl (2-ir4-(5-formyl-3-methylpyridin-2-yl)benzoyllamino\|phenyl) carbamate; N-(2-t-Butoxycarbonylaminophenyl)-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2,-dioxaborolan-2-yl) benzamide (7.69 g, 17.55 mmol - prepared as described in Method 13, page 60, of International patent publication number WO 03/087057), was added to a stirred solution of 6- bromo-5-methylnicotinaldehyde (3.51 g, 17.55 mmol, see Method 3 below) in dimethoxyethane (100 ml) at ambient temperature under a nitrogen atmosphere. l,rBis(diphenylphosphino)ferrocenedichloropalladium(?) (0.72 g, 0.88 mmol) was added followed by saturated aqueous sodium bicarbonate solution (50 ml) and the mixture heated at 60 C for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The dichloromethane layer was washed with saturated aqueous sodium bicarbonate solution and brine, then dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was <n="44"/>purified by flash chromatography, eluting with 40 % ethyl acetate in zs°hexane, to give the title compound (5.93 g, 75 %); NMR Spectrum: (DMSO-d6) 1.46 (s, 9H), 2.47 (s, 3H), 7.20 (m, 2H), 7.58 (m, 2H), 7.80 (d, 2H), 8.09 (d, 2H), 8.23 (s, IH), 8.70 (s, IH), 9.04 (s, IH), 9.94 (s, IH), 10.17 (s, IH); Mass Spectrum: MH-H+ 432.

References: [1]Patent: US2008/119451,2008,A1 .Location in patent: Page/Page column 35.
[2]Patent: WO2007/71956,2007,A1 .Location in patent: Page/Page column description.
[3]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2525 - 2529.

4
[ 4394-85-8 ]
[ 3430-18-0 ]
[ 885167-81-7 ]

Yield	Reaction Conditions	Operation in experiment
74%		Method 4; Preparation of 6-bromo-5-methylnicotinaldehyde; 2,5-Dibromo-3-picoline (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran at 0 C. The solution was stirred for 2 hours at 0 C. and then for 1 hour at ambient temperature. A solution of 4-formylmorpholine (2.1 ml, 20.3 mmol) in tetrahydrofuran (25 ml) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solution concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10% ethyl acetate in isohexane, to give the title compound (3.0 g, 74%); NMR Spectrum: (DMSO-d6) 2.44 (s, 3H), 8.19 (s, 1H), 8.73 (s, 1H), 10.09 (s, 1H).
74%		Method 3; Preparation of 6-bromo-5-methvmicotmaldehvde; 2,5-Dibromo-3-picoline (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran at 0 0C. The solution was stirred for 2 hours at 0 0C and then for 1 hour at ambient temperature. A solution of 4-formylmorpholine (2.1 ml, 20.3 mmol) in tetrahydrofuran (25 ml) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solution concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10 % ethyl acetate in isohexane, to give the title compound (3.0 g, 74 %); NMR Spectrum: (DMSO-d6) 2.44 (s, 3H), 8.19 (s, IH), 8.73 (s, IH), 10.09 (s, IH).
		Under an argon atmosphere, a solution of 2 M isopropylmagnesium chloride in THF (5.5 ml) was cooled to -78 C., and a solution of 2,5-dibromo-3-methylpyridine (2.5 g) in THF (10 ml) was added dropwise. After stirring at the same temperature for 30 minutes, a solution of morpholine-4-carboaldehyde (1.26 g) in THF (5 ml) was added dropwise thereto, followed by elevating the temperature to 0 C. over 30 minutes, followed by stirring at 0 C. for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 6-bromo-5-methyl nicotine aldehyde (1.42 g).

References: [1]Patent: US2008/119451,2008,A1 .Location in patent: Page/Page column 35.
[2]Patent: WO2007/71956,2007,A1 .Location in patent: Page/Page column description.
[3]Patent: US2012/184520,2012,A1 .Location in patent: Page/Page column 24.

5
[ 67-56-1 ]
[ 885167-81-7 ]
[ 1210451-92-5 ]

References: [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 9286 - 9289.

6
[ 885167-81-7 ]
[ 1260657-97-3 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 6415 - 6418.

7
[ 885167-81-7 ]
[ 1315282-48-4 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 6415 - 6418.

8
[ 885167-81-7 ]
[ 1260657-98-4 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 6415 - 6418.

9
[ 885167-81-7 ]
C₄₂H₅₄Br₂N₁₀O₄ [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 6415 - 6418.

10
[ 885167-81-7 ]
C₅₂H₆₀Br₂N₁₂O₄ [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 6415 - 6418.

11
[ 885167-81-7 ]
[ 1210451-92-5 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 6415 - 6418.

12
[ 885167-81-7 ]
[ 2181-42-2 ]
[ 1400997-49-0 ]

Yield	Reaction Conditions	Operation in experiment
26%		EXAMPLE 120(RS)-N-(5-Bromopyridin-2-yl)-3-methyl-5-(morpholin-2-yl)pyridin-2-aminea) (RS)-2-Bromo-3-methyl-5-(oxiran-2-yl)pyridineTo a stirred suspension of sodium hydride (1.01 g) in THF (20 ml) was added dropwise over 5 min a solution of trimethylsulfonium iodide (4.69 g) in DMSO (20 ml). The reaction mixture was stirred for 5 min and then cooled to 0 C. A solution of <strong>[885167-81-7]6-bromo-5-methylnicotinaldehyde</strong> (4.6 g, CAS 885167-81-7) in THF (15 ml) was added dropwise. The reaction mixture was stirred at 0 C. for 30 min and then at room temperature overnight. The mixture was then poured into EtOAc/Et2O (1:1) and washed with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford (RS)-2-bromo-3-methyl-5-(oxiran-2-yl)pyridine (1.26 g, 26%) as a colourless oil. MS (ISP): 216.1 ([{81 Br}M+H]+), 214.1 ([{79Br}M+H]+).
26%		To a stirred suspension of sodium hydride (1.01 g) in THF (20 ml) was added dropwise over 5 min a solution of trimethylsulfonium iodide (4.69 g) in DMSO (20 ml). The reaction mixture was stirred for 5 minand then cooled to 0 C. A solution of <strong>[885167-81-7]6-bromo-5-methylnicotinaldehyde</strong> (4.6 g, CAS 885167-81-7) in THF (15 ml) was added dropwise. The reaction mixture was stirred at 0 C for 30 min and then at room temperature overnight. The mixture was then poured into EtOAc/Et20 (1: 1) and washed with saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford (RS)-2-bromo-3-methyl-5-(oxiran-2- yl)pyridine (1.26 g, 26%) as a colourless oil. MS (ISP): 216.1 ([{ 81Br}M+H]+), 214.1([{79Br}M+H]+).

References: [1]Patent: US2012/245172,2012,A1 .Location in patent: Page/Page column 56.
[2]Patent: WO2012/126922,2012,A1 .Location in patent: Page/Page column 100; 101.

13
[ 885167-81-7 ]
[ 1400996-14-6 ]