1214337-05-9|Methyl 6-chloro-5-fluoropicolinate| Ambeed

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Quality Control of [ 1214337-05-9 ] Purity: 97% SDS Specification

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Product Details of [ 1214337-05-9 ]

CAS No. :	1214337-05-9
Formula :	C₇H₅ClFNO₂
M.W :	189.57
SMILES Code :	O=C(OC)C1=NC(Cl)=C(F)C=C1
MDL No. :	MFCD14698137
InChI Key :	LZGCVVSRZHFYPF-UHFFFAOYSA-N
Pubchem ID :	46311229

Safety of [ 1214337-05-9 ]

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

Computational Chemistry of [ 1214337-05-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	40.48
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	39.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.84
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	2.1
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.08
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.	1.36
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	1.93

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.58
Solubility	0.503 mg/ml ; 0.00265 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.	-2.55
Solubility	0.53 mg/ml ; 0.0028 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	-3.0
Solubility	0.19 mg/ml ; 0.001 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.	-5.97 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	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)	1.93

Application In Synthesis of [ 1214337-05-9 ]

* 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 [ 1214337-05-9 ]

[ 1214337-05-9 ] Synthesis Path-Downstream 1~15

1
[ 107504-07-4 ]
[ 1214337-05-9 ]

References: [1]Patent: WO2011/139107,2011,A2 .
[2]Patent: CN110698471,2020,A .

2
[ 1346555-30-3 ]
[ 1214337-05-9 ]

Yield	Reaction Conditions	Operation in experiment
79%	With trichlorophosphate; for 4.0h;Reflux; Inert atmosphere;	Step 2: Synthesis of methyl 6-chloro-5-fluoropicolinate [512] 5-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (100 mg, 0.584 mmol) was dissolved in POCl3 (2 ml), and then heated at reflux under nitrogen stream for 4 hours. The resulting reaction liquid was slowly added to ice (15 g), and then extracted with MC (30 ml x 2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (20% EtOAc/Hexanes), to obtain 88 mg of white solid (79%).
4 g	With trichlorophosphate; at 70.0℃; for 16.0h;	Dissolve 5-fluoro-2- (methoxycarbonyl) pyridine 1-oxide (crude from the previous step, 51.6 mmol) in phosphorus trichloride (30 mL), heat to 70 C for 16 hours, and pour into ice water. Extracted with 3 × 200 mL of dichloromethane, combined the organic phases, concentrated, and column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain the compound (4.0 g, yield: 40.8%).

References: [1]Patent: WO2011/139107,2011,A2 .Location in patent: Page/Page column 83.
[2]Patent: CN110698471,2020,A .Location in patent: Paragraph 0138; 0146-0148.

3
[ 1214337-05-9 ]
[ 860296-24-8 ]

Yield	Reaction Conditions	Operation in experiment
80%		Step 3: Synthesis of 6-chloro-5-fluoropicolinic acid [514] Methyl 6-chloro-5-fluoropicolinate (1.35 g, 7.095 mmol) was dissolved in THF:H20 = 6:1 (42 ml), followed by addition of lithium hydroxide monohydrate (596 mg, 14.19 mmol), and then the resulting mixture was stirred at room temperature for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, dissolved by addition of distilled water (20 ml), acidified by slow addition of 1N aqueous HCl solution, and then extracted with 5% MeOH/MC (30 ml x 2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 1.04 g of white solid (80%). [515]

References: [1]Patent: WO2011/139107,2011,A2 .Location in patent: Page/Page column 83-84.

4
[ 1214337-05-9 ]
(3R,4R,5S)-3-amino-1-(3-[(6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol trifluoroacetic acid salt [ No CAS ]

References: [1]Patent: WO2016/196244,2016,A1 .

5
[ 1214337-05-9 ]
[ 1395992-69-4 ]

References: [1]Patent: WO2016/196244,2016,A1 .

6
[ 1214337-05-9 ]
[ 1395992-76-3 ]

References: [1]Patent: WO2016/196244,2016,A1 .

7
[ 1214337-05-9 ]
(6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-yl)methanol [ No CAS ]

References: [1]Patent: WO2016/196244,2016,A1 .

8
[ 1214337-05-9 ]
6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carbaldehyde [ No CAS ]

References: [1]Patent: WO2016/196244,2016,A1 .

9
[ 1214337-05-9 ]
[ 957065-87-1 ]
[ 1355011-30-1 ]

Yield	Reaction Conditions	Operation in experiment
47%	With bis(tri-t-butylphosphine)palladium(0); N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water; at 120.0℃; for 2.0h;Inert atmosphere;	A mixture of <strong>[1214337-05-9]methyl 6-chloro-5-fluoropyridine-2-carboxylate</strong> (from Frontier Scientific, Inc., 1.90 g, 10.0 mmol), (2,6-difluoro-4-hydroxyphenyl)boronic acid (2.00 g, 11.5 mmol), NN-diisopropylethylamine (3.4 mL, 20. mmol) in 1,4-dioxane (17 mL) and water (1.0 mL) was purged with nitrogen, followed by addition of bis(tri-/- butylphosphine)palladium (0.51 g, 1.0 mmol). The reaction mixture was degassed and recharged with nitrogen for three cycles, and then heated at 120 C with stirring for 2 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with EtOAc in hexanes (gradient: 0-50%) to afford the desired product (1.34 g, 47%). LCMS calc. for C13H9F3NO3 (M+H)+: 284.1 ; Found: 284.0.

References: [1]Patent: WO2016/196244,2016,A1 .Location in patent: Page/Page column 183-184.

10
[ 274-80-6 ]
[ 1214337-05-9 ]
6-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-5-fluoropicolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.2%	With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; at 120.0℃; for 3.0h;	Methyl 6-chloro-5-fluoropicolinate (3.2 g, 16.7 mmol),[1,2,4] triazolo [4,3-a] pyridine (1.8 g, 15.1 mmol) was dissolved in 1,4-dioxane (40 mL), and dichloroditriphenylphosphine palladium ( 1.06g, 1.5mmol), cesium carbonate (9.6g, 29.5mmol), microwave heating to 120 C, 3 hours, filtration, concentration, column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain the compound (500mg, Yield: 12.2%).

References: [1]Patent: CN110698471,2020,A .Location in patent: Paragraph 0138; 0149-0151.

11
[ 107504-08-5 ]
[ 1214337-05-9 ]