171178-50-0|2,6-Difluoropyridine-3-carboxylic acid| Ambeed

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Quality Control of [ 171178-50-0 ] Purity: 96% SDS Specification

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Product Details of [ 171178-50-0 ]

CAS No. :	171178-50-0
Formula :	C₆H₃F₂NO₂
M.W :	159.09
SMILES Code :	O=C(O)C1=C(F)N=C(F)C=C1
MDL No. :	MFCD08064047
InChI Key :	IEVMFAWRTJEFCF-UHFFFAOYSA-N
Pubchem ID :	10583070

Safety of [ 171178-50-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 171178-50-0 ] 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	5.0
Num. H-bond donors	1.0
Molar Refractivity	31.11
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	50.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.94
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	1.25
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.9
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.	-0.24
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	1.6
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.09

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.95
Solubility	1.78 mg/ml ; 0.0112 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.	-1.9
Solubility	1.99 mg/ml ; 0.0125 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	-1.95
Solubility	1.81 mg/ml ; 0.0114 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.	-6.38 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.	0.56

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)	1.73

Application In Synthesis of [ 171178-50-0 ]

* 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 [ 171178-50-0 ]

[ 171178-50-0 ] Synthesis Path-Downstream 1~35

1
[ 1513-65-1 ]
[ 124-38-9 ]
[ 171178-50-0 ]

Yield	Reaction Conditions	Operation in experiment
62.9%		To a solution of 2,6-difluoropyridine (25.0 g, 217 mmol) in tetrahydrofuran (300 ml) was added dropwise 1.6 N n-butyllithium-hexane solution (163 ml) at -70 C., and the mixture was stirred at -70 C. for 1 hr. Dry ice (14.5 g, 330 mmol) was added at -70 C., and the mixture was stirred at -70 C. for 30 min, and then under ice-cooling for 1 hr. The reaction mixture was poured into ice water, and washed with ethyl acetate. The aqueous layer was adjusted to pH=3 with 3N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of diethyl ether and hexane to give the object product (21.7 g, 62.9%) as a solid. 1H-NMR (CDCl3) δ; 6.89-6.94 (1H, m), 8.48-8.57 (1H, m).
		Synthesis of 2,6-difluoronicotinic acid A 2.62 M solution of n-butyllithium in THF (29.1 mL) was added dropwise to a solution of diisopropylamine (11.7 mL) in tetrahydrofuran (310 mL) under ice-cooling in a nitrogen atmosphere, and the reaction solution was stirred under ice-cooling for one hour. After cooling the reaction solution to -78C, a solution of 2,6-difluoropyridine [CAS# 1513-65-1] (8 g) in tetrahydrofuran (10 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at -78C for three hours. Then, an excessive amount of crushed dry ice was added to the reaction solution in a nitrogen stream, and the reaction solution was stirred at -78C for 20 minutes and at room temperature for three hours. Water and diethyl ether were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid. Then, ethyl acetate was added and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 10.4 g of a crude product of the title compound. The property values of the compound are as follows. 1H-NMR (CD3OD) δ (ppm): 7.08 (dd, J = 8.4, 2.8 Hz, 1H) 8.58 (dd, J = 17.2, 8.4 Hz, 1H).
		To a stirring -78 0C solution of LDA (91.34 ml of 1.8 M in heptane/THF/ethylbenzene, 164.41 mmol) and TBDF (201 ml) was added slowly over 20 min. a solution of 2,6- difluoropyridine (18.92 g, 164.41 mmol) in THF (20 ml) so that the internal temperature stayed below -70 0C. After the addition, the reaction was stirred for 3 h at -78 0C. Dry ice (about 22 g) was treated with a stream of N2 gas before being added to the mixture over a 5 min. period. The internal temperature rose to -50 0C as a result of an exothermic reaction. Once the internal temperature stabilized back to -78 0C, it was stirred for 30 min before being gradually warmed to RT arid then stirred for 18 h. The solution was acidified to pH 2.5 with HCl (10% aqueous solution). The organic solvents were removed under vacuum, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, decanted, and concentrated under vacuum. The crude was treated with cold Et2O. The beige solid was isolated by filtration and washed twice with small amounts of cold diethyl ether to yield title compound.

		12.3 ml of N,N-diisopropylamine was mixed with 100 ml of THF. Thereafter, 50 ml of a hexane solution containing 1.6 mol/liter n-butyllithium was mixed therewith at -78C. The obtained mixture was stirred at -78C for 20 minutes. Thereafter, 10.1 g of 2,6-difluoropyridine dissolved in 50 ml of THF was added to the reaction mixture at -78C over 10 minutes. The obtained mixture was stirred for 30 minutes. Thereafter, dry ice was added to the reaction mixture, and the obtained mixture was stirred for 4 hours, while the temperature thereof was gradually raised to a room temperature. Thereafter, water was added to the reaction mixture, followed by partition with MTBE. Subsequently, concentrated hydrochloric acid was added to the water layer, so that the pH thereof was adjusted to pH 1, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, and it was then dried over sodium sulfate, followed by concentration under reduced pressure. The obtained residue was washed with a mixed solvent of hexane and MTBE, so as to obtain 8.69 g of 2,6-difluoronicotinic acid.2,6-difluoronicotinic acid [Show Image] 1H-NMR (DMSO-D6) δ: 7.30 (1H, dd, J = 8.2, 2.4 Hz), 8.59 (1H, dd, J = 8.2, 4.1 Hz).
		Example 8; Synthesis of Aldehyde ReagentsAldehyde reagents that are used in making compounds are prepared according to the following protocols. In these reactions, the unprotected aldehyde isolated after step 5, or the subsequently Boc-protected aldehyde may be used in preparation of compounds.(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 57 is prepared in six steps from 2,6-difluoro-pyridine 39 as shown in Scheme 8. Step 1-Preparation of 2,6-difluoro-nicotinic acid (51)In a round bottom flask, to 2,6-difluoro-pyridine (39, 7.10 g, 61.7 mmol) in 150.0 mL of tetrahydrofuran under an atmosphere of nitrogen at -78 C., n-butyllithium (26.0 mL, 2.50 M in hexane, 65.0 mmol) is slowly added. After 30 minutes, 3.0 g of dry ice is added and an hour later the reaction is allowed to warm to room temperature. The reaction is poured into water, extracted with ethyl acetate and the aqueous layer is adjusted to pH 4-5 with 1 N hydrochloric acid. This is extracted with ethyl acetate and the organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (51, 5.6 g).

References: [1]European Journal of Organic Chemistry,2004,p. 1018 - 1024.
[2]Patent: US2009/318412,2009,A1 .Location in patent: Page/Page column 24.
[3]Journal of Medicinal Chemistry,1996,vol. 39,p. 1823 - 1835.
[4]Chemical and Pharmaceutical Bulletin,1997,vol. 45,p. 1027 - 1038.
[5]Patent: EP2019094,2009,A1 .Location in patent: Page/Page column 111.
[6]Patent: WO2007/48070,2007,A2 .Location in patent: Page/Page column 118.
[7]Patent: EP2248423,2010,A1 .Location in patent: Page/Page column 273; 278-279.
[8]Patent: US2011/263595,2011,A1 .Location in patent: Page/Page column 86-87.

2
[ 171178-50-0 ]
[ 171178-51-1 ]

Yield	Reaction Conditions	Operation in experiment
3.05 g	With thionyl chloride; In 1,2-dichloro-ethane; at 70℃; for 3h;	To a dichloroethane solution (28.0 mL) of <strong>[171178-50-0]2,6-difluoropyridine-3-carboxylic acid</strong> (3.41 g) was added thionyl chloride (9.16 mL) at room temperature, and the reaction mixture was stirred at 70C for 3 h After cooling to room temperature, the solvent was evaporated under reduced pressure. To a diethyl ether solution (46.0 mL) of the residue was added 28% aqueous ammonia (4.60 mL) at 0C and the mixture was stirred for 10 min. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (3.05 g). MS(ESI)m/z; 159[M+H]+

References: [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 1823 - 1835.
[2]Patent: EP3372601,2018,A1 .Location in patent: Paragraph 0912; 0913.

3
[ 171178-50-0 ]
[ 859174-38-2 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In dichloromethane; for 3h;Heating / reflux;	2,6-Difluoro-nicotinoyl chloride. A mixture of <strong>[171178-50-0]2,6-difluoronicotinic acid</strong> (6.2 g), thionyl chloride (15 mL) and CH2Cl2 (100 mL) was heated to reflux for 3 h. The mixture was evaporated to dryness, CH2Cl2, was added and evaporated to dryness to afford 1.1 g of the <strong>[171178-50-0]2,6-difluoronicotinic acid</strong> chloride. This material used without further purification.
	With thionyl chloride; In dichloromethane; for 1.5h;Heating / reflux;	EXAMPLE 1 Synthesis of 2-(2-fluoro,5-chloro)phenyl-7-fluoro-pyrido-8-pyrimidone. (Entry 7, Table II) 2,6 difluoronicotinic acid, (0.479 g, 3.012 mmol) was suspended in 30 mL dry methylene chloride and treated with thionyl chloride (2.5 mL, 34.27 mmol), under reflux for 90 minutes. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure on a rotary evaporator, the residue obtained was further dried under high vacuum to give 2,6 difluoronicotinoyl chloride.
	With thionyl chloride; for 2h;Inert atmosphere; Reflux;	2,6-Difluoronicotinic acid (10.6 g, 66.6 mmol) and thionyl chloride (35 mF, 480 mmol) were combined under nitrogen and heated to gentle reflux for 2 h. The solution was concentrated to dryness under reduced pressure. Toluene (100 mF) was added to the crude and it was evaporated to dryness once more. The crude acid chloride was dissolved in DCM (50 mF) under nitrogen and cooled in an ice bath. A mixture of triethylamine (25 mF, 180 mmol) and benzyl alcohol (7.25 ml, 70.1 mmol) in DCM (50 mF) was added dropwise over 10 min. 0.1 N HC1 (100 mF) was added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure to provide benzyl 2,6-difluoronicotinate (50A) which was used without purification. m/z (ESI): 250.0 (M+H)+.

With thionyl chloride; for 2h;Inert atmosphere; Reflux;

2,6-Difluoronicotinic acid (10.6 g, 66.6 mmol) and thionyl chloride (35 mL, 480 mmol) were combined under nitrogen and heated to gentle reflux for 2 h. The solution was concentrated to dryness under reduced pressure. Toluene (100 mL) was added to the crude and it was evaporated to dryness once more. The crude acid chloride was dissolved in DCM (50 mL) under nitrogen and cooled in an ice bath. A mixture of triethylamine (25 mL, 180 mmol) and benzyl alcohol (7.25 mL, 70.1 mmol) in DCM (50 mL) was added dropwise over 10 min, and the mixture was stirred at rt for 30 min. Then, 0.1 N HCl (100 mL) was added and the phases mixed and separated. The organic phase was taken, dried with magnesium sulfate, and evaporated to dryness under reduced pressure to provide benzyl 2,6-difluoronicotinate which was used without purification. m/z (ESI): 250.0 (M+H)+.

References: [1]Chemical and Pharmaceutical Bulletin,1997,vol. 45,p. 1027 - 1038.
[2]Patent: WO2006/100310,2006,A1 .Location in patent: Page/Page column 29.
[3]Patent: US2005/176957,2005,A1 .Location in patent: Page/Page column 5.
[4]Patent: WO2020/132653,2020,A1 .Location in patent: Paragraph 0257-0258.
[5]Patent: WO2021/26100,2021,A1 .Location in patent: Paragraph 0326-0327.

4
[ 155601-65-3 ]
[ 171178-50-0 ]

References: [1]Journal of Heterocyclic Chemistry,1997,vol. 34,p. 789 - 795.

5
[ 67-56-1 ]
[ 171178-50-0 ]
[ 117671-02-0 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2-Preparation of 2,6-difluoro-nicotinic acid methyl ester (52)In a round bottom flask, 2,6-difluoro-nicotinic acid (51, 5.60 g, 35.2 mmol), 60.0 mL of methanol and sulfuric acid (1.0 mL, 19.0 mmol) are combined and heated to reflux overnight. The reaction is poured into water, adjusted to pH around 9 with 1M aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound as a yellow oil (52, 3.5 g).

References: [1]Chemical and Pharmaceutical Bulletin,2000,vol. 48,p. 1847 - 1853.
[2]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1551 - 1554.
[3]Patent: US2011/263595,2011,A1 .Location in patent: Page/Page column 86-87.

6
[ 685517-67-3 ]
[ 171178-50-0 ]

References: [1]European Journal of Organic Chemistry,2004,p. 1018 - 1024.

7
[ 171178-50-0 ]
[ 187480-11-1 ]

References: [1]Chemical and Pharmaceutical Bulletin,2000,vol. 48,p. 1847 - 1853.
[2]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1551 - 1554.

8
[ 171178-50-0 ]
methyl 6-fluoro-2-methylaminopyridine-3-carboxylate [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,2000,vol. 48,p. 1847 - 1853.
[2]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1551 - 1554.

9
[ 171178-50-0 ]
[ 187480-13-3 ]

References: [1]Chemical and Pharmaceutical Bulletin,2000,vol. 48,p. 1847 - 1853.
[2]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1551 - 1554.

10
[ 171178-50-0 ]
[ 187480-17-7 ]

References: [1]Chemical and Pharmaceutical Bulletin,2000,vol. 48,p. 1847 - 1853.
[2]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1551 - 1554.

11
[ 171178-50-0 ]
[ 187480-15-5 ]

References: [1]Chemical and Pharmaceutical Bulletin,2000,vol. 48,p. 1847 - 1853.
[2]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1551 - 1554.

12
[ 171178-50-0 ]
[ 210697-20-4 ]