1186637-43-3|3-Bromo-6-methoxypicolinonitrile| Ambeed

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Quality Control of [ 1186637-43-3 ] Purity: 98% SDS Specification

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Product Details of [ 1186637-43-3 ]

CAS No. :	1186637-43-3
Formula :	C₇H₅BrN₂O
M.W :	213.03
SMILES Code :	N#CC1=NC(OC)=CC=C1Br
MDL No. :	MFCD08062835
InChI Key :	QDGRHOJWSDHVSS-UHFFFAOYSA-N
Pubchem ID :	53485627

Safety of [ 1186637-43-3 ]

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

Computational Chemistry of [ 1186637-43-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	43.14
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	45.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.03
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	1.9
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.72
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.	0.68
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	1.98
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.66

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.7
Solubility	0.43 mg/ml ; 0.00202 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.	-2.49
Solubility	0.694 mg/ml ; 0.00326 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	-3.1
Solubility	0.17 mg/ml ; 0.000798 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.	-6.25 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	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)	2.0

Application In Synthesis of [ 1186637-43-3 ]

* 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 [ 1186637-43-3 ]

[ 1186637-43-3 ] Synthesis Path-Downstream 1~17

1
[ 1186637-40-0 ]
[ 74-88-4 ]
[ 1186637-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	With silver carbonate; In toluene; at 20.0℃;Darkness;	A solution of <strong>[1186637-40-0]3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile</strong> (from Example 15/Step 2) (1.0 eq.), silver carbonate (1.3 eq.), and iodomethane (1.2 eq.) in toluene (0.2 M) was stirred in the dark at room temperature overnight. The solvent was concentrated en vacuo, and the resulting residue was purified by a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give 3-bromo-6-methoxypicolinonitrile.
	With silver carbonate; In toluene; at 20.0℃;In the dark;	A solution of 3-bromo-6-oxo-l,6-dihydropyndine-2-carbonitrile (from Example 15 /Step 2) (1.0 eq.), silver carbonate (1.3 eq.), and iodomethane (1.2 eq.) in toluene (0.2 M) was stirred in the dark at room temperature overnight. The solvent was concentrated en vacuo, and the resulting residue was purified by a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give 3-bromo-6-methoxypicolinonitrile.

References: [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 67.
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 175.

2
[ 1186637-43-3 ]
[ 115377-94-1 ]
[ 1186635-17-5 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; at 100.0℃;	A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and <strong>[1186637-43-3]3-bromo-6-methoxypicolinonitrile</strong> (from step 1) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100 C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-50% ethyl acetate in hexane to give 3-methoxybenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (acetone d-6): delta 8.91 (d, 1H), 8.34 (d, 1H), 7.63 (d, 1H), 7.51-7.53 (dd, 1H), 7.27-7.33 (m, 2H), 6.65 (br, 2H), 4.11 (s, 3H). LRMS [M+H]=226.1
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 100.0℃;	A solution of 2-(te/i-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and <strong>[1186637-43-3]3-bromo-6-methoxypicolinonitrile</strong> (from step 1) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol%) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 1000C and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-50% ethyl acetate in hexane to give 3- methoxybenzo[f][l,7]naphthyridin-5-amme as a yellow solid. 1H NMR (acetone J-6): delta 8.91 (d, IH), 8.34 (d, IH), 7.63 (d, IH), 7.51-7.53 (dd, IH), 7.27-7.33 (m, 2H), 6.65 (br, 2H), 4.11 (s, 3H). LRMS [M+H] = 226.1

References: [1]Patent: US9408907,2016,B2 .Location in patent: Page/Page column 67.
[2]Patent: WO2009/111337,2009,A1 .Location in patent: Page/Page column 175.

3
[ 446284-14-6 ]
[ 7677-24-9 ]
[ 1186637-43-3 ]

Yield	Reaction Conditions	Operation in experiment
82.7%	With triethylamine; In acetonitrile; at 80.0℃; for 15.0h;Inert atmosphere;	Step 2: preparation of 3-Bromo-6-methoxypicolinonitrile (3D): To a stirred solution of 2D (28 g, 137.9 mmol) in MeCN (60 ml) was added TMSCN (54.6 g, 551.6mmol) and TEA (41.8 g, 413.7). The mixture was stirred at 80C for 15 h under N2. After the reaction mixture was concentrated and water (60 mL) was added, it was extracted with EtOAc (80 mL X 2), dried over Na2S04, concentrated and purified by column (PE:EtOAc = 3:1) to give the product as white solid (24.4 g, 82.7%). NMR (400MHz, CDC13) delta 8.16 (d, J= 9.2 Hz, 1H), 7.15 (d, J= 8.8 Hz, 1H), 3.86 (s, 3H).
	With triethylamine; In acetonitrile; at 100.0℃; for 14.0h;	To a solution of 5-bromo-2-methoxypyridine 1-oxide (1eq) in CH3CN was added TEA (3eq) followed by TMSCN (4eq). The reaction was warmed to 100 C for 14h, and then cooled and quenched with saturated aqueous NaHCO3 and diluted with EtOAc. The layers were separated, and the organic layer was washed with sat. aq. NaHCO3, brine, dried (MgSO4) and concentrated in vacuo to give the title compound which was purified by chromatography on SiO2 (0793) (EtOAc/hex) to give the title compound. ESI-MS (m/z): 213.19 [M+1]+.

References: [1]Patent: WO2013/113669,2013,A1 .Location in patent: Page/Page column 74.
[2]Patent: WO2017/139603,2017,A1 .Location in patent: Page/Page column 122.

4
[ 13472-85-0 ]
[ 1186637-43-3 ]