1256345-66-0|(6-Chloro-2-fluoropyridin-3-yl)boronic acid| Ambeed

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Quality Control of [ 1256345-66-0 ] Purity: 98% SDS Specification

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Product Details of [ 1256345-66-0 ]

CAS No. :	1256345-66-0
Formula :	C₅H₄BClFNO₂
M.W :	175.35
SMILES Code :	FC1=NC(Cl)=CC=C1B(O)O
MDL No. :	MFCD11504861
InChI Key :	AYPTVURLQVNETR-UHFFFAOYSA-N
Pubchem ID :	46739261

Safety of [ 1256345-66-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P280-P305+P351+P338-P310

Computational Chemistry of [ 1256345-66-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	39.03
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	53.35 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
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	1.15
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-0.03
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.	-0.3
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	-0.05
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.15

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.99
Solubility	1.8 mg/ml ; 0.0102 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.86
Solubility	2.39 mg/ml ; 0.0136 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	-1.81
Solubility	2.73 mg/ml ; 0.0156 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	No
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.	-6.55 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	1.0
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)	2.39

Application In Synthesis of [ 1256345-66-0 ]

* 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 [ 1256345-66-0 ]

[ 1256345-66-0 ] Synthesis Path-Downstream 1~18

1
[ 1407167-77-4 ]
[ 1256345-66-0 ]
[ 1407167-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90℃; for 3.0h;	Step 10 Preparation of 5-(6-chloro-2-fluoropyridin-3-yl)-l-(cyclopropylmethyI)-4- (trifluoromethyl)-l/-r-benzotriazoIe:1 -(Cyclopropylmethyl)-4-(trifluoromethyl)- lH-benzotriazol-5-yl trifluoromethanesulfonate (221 mg, 0.568 mmol) and <strong>[1256345-66-0](6-chloro-2-fluoropyridin-3-yl)boronic acid</strong> (130 mg, 0.738 mmol, 1.3 equiv) were dissolved in degassed dioxane (5.6 mL) and treated with potassium phosphate (0.37 mL, 2 M aqueous, 0.74 mmol, 1.3 equiv) and palladiumtetrakis(triphenylphosphine) (98 mg, 0.085 mmol, 0.15 equiv). The mixture was placed into a preheated oil bath at 90 C for 3 hours, cooled to ambient temperature, diluted with ethyl acetate (40 mL) and washed with sodium bicarbonate (2 x 30 mL, aqueous saturated). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 70:30; hexanes : ethyl acetate), providing the titled compound.
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 3.0h;	l-(Cyclopropylmethyl)-4-(trifluoromethyl)-lH-benzotriazol-5-yl trifluoromethanesulfonate (221 mg, 0.568 mmol) and <strong>[1256345-66-0](6-chloro-2-fluoropyridin-3-yl)boronic acid</strong> (130 mg, 0.738 mmol, 1.3 equiv) were dissolved in degassed dioxane (5.6 mL) and treated with potassium phosphate (0.37 mL, 2 M aqueous, 0.74 mmol, 1.3 equiv) and palladiumtetrakis(triphenylphosphine) (98 mg, 0.085 mmol, 0.15 equiv). The mixture was placed into a preheated oil bath at 90 C for 3 hours, cooled to ambient temperature, diluted with ethyl acetate (40 mL) and washed with sodium bicarbonate (2 x 30 mL, aqueous saturated). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 70:30; hexanes : ethyl acetate), providing the titled compound.

References: [1]Patent: WO2012/151140,2012,A1 .Location in patent: Page/Page column 24.
[2]Patent: WO2012/151136,2012,A1 .Location in patent: Page/Page column 24; 27.

2
[ 1256345-66-0 ]
[ 883107-68-4 ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide; sodium hydroxide; at 0 - 20℃;	A suspension of <strong>[1256345-66-0](6-chloro-2-fluoropyridin-3-yl)boronic acid</strong> (1.3 g, 7.41 mmol) in NaOH (4.45 ml, 22.24 mmol) at 0 C was treated all at once with hydrogen peroxide (0.500 ml, 8.15 mmol). The mixture was stirred at ambient temperature overnight. The resulting solution was quenched with ice water, acidified with 3 N aqueous hydrochloric acid to pH = 5, and extracted three times with ethyl acetate. The pooled organics were dried over sodium sulfate and concentrated under reduced pressure to afford 6-chloro-2-fluoropyridin-3-ol (1.08 g, 7.32 mmol, 99% crude yield) as a waxy solid that was used without further purification. LCMS (ESI) m/e 148.0 (M+H)+, calcd C5H4ClFNO, 148.0]; LC/MS retention time (method D): tR=
	With dihydrogen peroxide; sodium hydroxide; at 0 - 20℃;	A suspension of <strong>[1256345-66-0](6-chloro-2-fluoropyridin-3-yl)boronic acid</strong> (1.3 g, 7.41 mmol) in NaOH (4.45 ml, 22.24 mmol) at 0 C was treated all at once with hydrogen peroxide (0.500 ml, 8.15 mmol). The mixture was stirred at ambient temperature overnight. The resulting solution was quenched with ice water, acidified with 3 N aqueous hydrochloric acid to pH = 5, and extracted three times with ethyl acetate. The pooled organics were dried over sodium sulfate and concentrated under reduced pressure to afford 6-chloro-2-fiuoropyridin-3-ol (1.08 g, 7.32 mmol, 99% crude yield) as a waxy solid that was used without further purification. LCMS (ESI) m/e 148.0 (M+H)+, calcd C5H4CIFNO, 148.0]; LC/MS retention time (method D): fe. = 0.83 min.

References: [1]Patent: WO2015/153720,2015,A1 .Location in patent: Page/Page column 139; 140.
[2]Patent: WO2017/59085,2017,A1 .Location in patent: Page/Page column 138; 139.

3
[ 1256345-66-0 ]
[ 1335218-41-1 ]

References: [1]Patent: WO2015/153720,2015,A1 .

4
[ 1256345-66-0 ]
6-chloro-2-fluoro-3-(methoxymethoxy)-4-methylpyridine [ No CAS ]

References: [1]Patent: WO2015/153720,2015,A1 .
[2]Patent: WO2017/59085,2017,A1 .

5
[ 1256345-66-0 ]
6-fluoro-5-(methoxymethoxy)-2’,4-dimethyl-2,4‘-bipyridine [ No CAS ]

References: [1]Patent: WO2015/153720,2015,A1 .
[2]Patent: WO2017/59085,2017,A1 .

6
[ 1256345-66-0 ]
6-fluoro-2’,4-dimethyl-[2,4‘-bipyridin]-5-ol [ No CAS ]

References: [1]Patent: WO2015/153720,2015,A1 .
[2]Patent: WO2017/59085,2017,A1 .

7
[ 1256345-66-0 ]
(S)-tert-butyl (1-((6-fluoro-2’,4-dimethyl-[2,4‘-bipyridin]-5-yl)oxy)-2, 4-dimethylpentan-2-yl)carbamate [ No CAS ]

References: [1]Patent: WO2015/153720,2015,A1 .
[2]Patent: WO2017/59085,2017,A1 .

8
[ 1256345-66-0 ]
(S)-1-((6-fluoro-2’,4-dimethyl-[2,4’-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine [ No CAS ]

References: [1]Patent: WO2015/153720,2015,A1 .
[2]Patent: WO2017/59085,2017,A1 .

9
[ 20885-12-5 ]
[ 1256345-66-0 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of LDA (1M in THF) (8.36 ml, 8.36 mmol) at -78 C was treated dropwise with a solution of 2-chloro-6-fluoropyridine (1.0 g, 7.60 mmol) in THF (2 mL). The mixture was maintained at -78 C for 1 h and then treated with a solution of triisopropyl borate (1.765 ml, 7.60 mmol) in THF (1 mL). The reaction mixture was treated with water (4 mL) and concentrated under reduced pressure to afford (6- chloro-2-fluoropyridin-3-yl)boronic acid (1.33 g, 7.60 mmol, 100% crude yield) as a pale orange waxy solid that was used without further purification. LCMS (ESI) m/e 176.0 (M+H)+, calcd C5H5BClFNO2, 176.0]; LC/MS retention time (method D): tR = 0.71 min.

References: [1]Patent: WO2015/153720,2015,A1 .Location in patent: Page/Page column 139.

10
[ 20885-12-5 ]
[ 5419-55-6 ]
[ 1256345-66-0 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of LDA (1M in THF) (8.36 ml, 8.36 mmol) at -78 C was treated dropwise with a solution of 2-chloro-6-fluoropyridine (1.0 g, 7.60 mmol) in THF (2 mL). The mixture was maintained at -78 C for 1 h and then treated with a solution of triisopropyl borate (1.765 ml, 7.60 mmol) in THF (1 mL). The reaction mixture was treated with water (4 mL) and concentrated under reduced pressure to afford (6- chloro-2-fluoropyridin-3-yl)boronic acid (1.33 g, 7.60 mmol, 100% crude yield) as a pale orange waxy solid that was used without further purification. LCMS (ESI) m/e 176.0 (M+H)+, calcd C5H5BCIFNO2, 176.0]; LC/MS retention time (method D): fe. = 0.71 min.

References: [1]Patent: WO2017/59085,2017,A1 .Location in patent: Page/Page column 138; 139.

11
[ 1256345-66-0 ]
C₁₉H₁₇ClN₂OS [ No CAS ]