1196146-82-3|5-Bromo-2-chloro-4-hydroxypyridine| Ambeed

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Quality Control of [ 1196146-82-3 ] Purity: 95% SDS Specification

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Product Details of [ 1196146-82-3 ]

CAS No. :	1196146-82-3
Formula :	C₅H₃BrClNO
M.W :	208.44
SMILES Code :	OC1=CC(Cl)=NC=C1Br
MDL No. :	MFCD13189877
InChI Key :	HKPSSVMYMKAABY-UHFFFAOYSA-N
Pubchem ID :	72212503

Safety of [ 1196146-82-3 ]

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

Computational Chemistry of [ 1196146-82-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	38.97
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	33.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.43
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	2.15
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.2
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.	1.19
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	2.27
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.85

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.98
Solubility	0.218 mg/ml ; 0.00105 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.	-2.48
Solubility	0.694 mg/ml ; 0.00333 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	-2.92
Solubility	0.248 mg/ml ; 0.00119 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.	-6.04 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	1.0 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)	1.78

Application In Synthesis of [ 1196146-82-3 ]

* 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 [ 1196146-82-3 ]

[ 1196146-82-3 ] Synthesis Path-Downstream 1~21

1
[ 1196146-82-3 ]
[ 1895-39-2 ]
5-bromo-2-chloro-4-(difluoromethoxy)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2.0h;	To solution of <strong>[1196146-82-3]5-bromo-2-chloro-pyridin-4-ol</strong> (800 mg, 3.84 mmol) in DMF (10 ml) were added sodium chlorodifluoroacetate (700 mg, 4.61 mmol) and Cs2CO3 (1.87 g, 5.76 mmol) and the RM was heated at 100 C. for 2 h. The RM was treated with ice cold water and was extracted with diethyl ether. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reduced pressure to get a crude compound which was purified by CC (SiO2, EtOAc/Hex) to afford the desired compound (600 mg, 60%).
	With caesium carbonate; In N,N-dimethyl-formamide; at 110 - 115℃;	A solution of <strong>[1196146-82-3]5-bromo-2-chloropyridin-4-ol</strong> (200 g 0.960 mol, Intermediate 56) and sodium chlorodifluoroacetate (264 g, 1.73 mol) in DMF (1 L) was added dropwise to a 110-115 C. suspension of Cs2CO3 (469 g, 1.44 mol) in DMF (1 L), and the resulting mixture was stirred at 110-115 C. After the reaction went to completion, mixture was allowed to cool to 50-60 C., and then it was poured into ice water. The resulting mixture was extracted twice with MTBE, and the combined organic layers were washed with water and then concentrated. The concentrate was purified by distillation to afford the title compound as a colorless liquid (bp 75-78 C. at 1-2 mmHg).
	With caesium carbonate; In N,N-dimethyl-formamide; at 110 - 115℃;	A solution of <strong>[1196146-82-3]5-bromo-2-chloropyridin-4-ol</strong> (200 g 0.960 mol, Intermediate 53) and sodium chlorodifluoroacetate (264 g, 1.73 mol) in DMF (1.0 L) was added dropwise to a 110-115 C. suspension of Cs2CO3 (469 g, 1.44 mol) in DMF (1.0 L), and the resulting mixture was stirred at 110-115 C. After the reaction went to completion, mixture was allowed to cool to 50-60 C., and then it was poured into ice water. The resulting mixture was extracted twice with MTBE, and the combined organic layers were washed with water and then concentrated. The concentrate was purified by distillation to afford the title compound as a colorless liquid (bp 75-78 C. at 1-2 mmHg).

References: [1]Patent: US2015/166505,2015,A1 .Location in patent: Paragraph 0407; 048.
[2]Patent: US2019/382350,2019,A1 .Location in patent: Paragraph 0309.
[3]Patent: US2019/382373,2019,A1 .Location in patent: Paragraph 0284-0285.

2
[ 1196146-82-3 ]
5-[4-(difluoro-methoxy)-6-ethoxy-pyridin-3-yl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid amide [ No CAS ]

References: [1]Patent: US2015/166505,2015,A1 .

3
[ 1196146-82-3 ]
C₁₂H₁₀ClF₂N₃O₃ [ No CAS ]

References: [1]Patent: US2015/166505,2015,A1 .

4
[ 1196146-82-3 ]
C₁₄H₁₅F₂N₃O₄ [ No CAS ]

References: [1]Patent: US2015/166505,2015,A1 .

5
[ 17368-12-6 ]
[ 1196146-82-3 ]

References: [1]Patent: US2019/382373,2019,A1 .

6
3,5-dibromo-2-chloropyridin-4-ol [ No CAS ]
[ 1196146-82-3 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In tetrahydrofuran; at -78℃; for 0.166667h;	n-Butyl lithium (2.71 L, 2.5 M, 6.8 mol) was added dropwise to a stirring -78 C. solution of 3,5-dibromo-2-chloropyridin-4-ol (1130 g, 3.93 mol, Intermediate 55) in THF (13.6 L), and the resulting mixture was stirred at -78 C. for 10 min. After this time, water (2 L) was added dropwise to the reaction mixture, and then the mixture was allowed to warm to 0-5 C. The mixture was then washed three times with 2 N aqueous HCl, and the combined aqueous washes were back-extracted twice with EtOAc. All the organic layers were then combined and concentrated. The concentrate was stirred as a slurry in heptane at 25-30 C. for 3 h, filtered, and then dried under vacuum to afford the title compound as a light-yellow solid.
	With n-butyllithium; In tetrahydrofuran; at -78℃; for 0.166667h;	n-Butyllithium (2.71 L, 2.5 M, 6.8 mol) was added dropwise to a stirring -78 C. solution of 3,5-dibromo-2-chloropyridin-4-ol (1.13 kg, 3.93 mol, Intermediate 52) in THF (13.6 L), and the resulting mixture was stirred at -78 C. for 10 min. After this time, water (2 L) was added dropwise to the reaction mixture, and then it was allowed to warm to 0-5 C. The mixture was then washed three times with 2 N aqueous HCl, and the combined aqueous washes were back-extracted twice with EtOAc. All the organic layers were then combined and concentrated. The concentrate was slurried with heptane at 25-30 C., stirred for 3 h, filtered, and then dried under vacuum to afford the title compound as a light-yellow solid.

References: [1]Patent: US2019/382350,2019,A1 .Location in patent: Paragraph 0307.
[2]Patent: US2019/382373,2019,A1 .Location in patent: Paragraph 0282-0283.

7
[ 1196146-82-3 ]
4-chloro-5-(4-(difluoromethoxy)-6-(3,3,3-trifluoro-2,2-dimethylpropyl)pyridin-3-yl)-1-ethyl-N-(((1r,4r)-4-sulfamoylcyclohexyl)methyl)-1H-pyrazole-3-carboxamide [ No CAS ]