399-88-2|3-Fluoro-4-methylpyridine| Ambeed

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Structure of 399-88-2

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Quality Control of [ 399-88-2 ] Purity: 97% SDS Specification

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Product Details of [ 399-88-2 ]

CAS No. :	399-88-2
Formula :	C₆H₆FN
M.W :	111.12
SMILES Code :	CC1=C(F)C=NC=C1
MDL No. :	MFCD04114226
InChI Key :	WZMOEPZZTTWDIA-UHFFFAOYSA-N
Pubchem ID :	345367

Safety of [ 399-88-2 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H225-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338
Class:	3
UN#:	1993
Packing Group:	Ⅲ

Computational Chemistry of [ 399-88-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	8
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	29.16
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	12.89 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.61
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	1.32
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.95
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.	1.24
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	2.28
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.68

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.92
Solubility	1.35 mg/ml ; 0.0121 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.	-1.19
Solubility	7.15 mg/ml ; 0.0643 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	-2.63
Solubility	0.261 mg/ml ; 0.00235 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.	-6.04 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	2.0
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)	1.21

Application In Synthesis of [ 399-88-2 ]

* 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 [ 399-88-2 ]

[ 399-88-2 ] Synthesis Path-Downstream 1~55

1
[ 399-88-2 ]
[ 393-53-3 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 1729,1731.

3
[ 3430-27-1 ]
aq.-ethanolic tetrafluoroboric acid [ No CAS ]
[ 399-88-2 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 1729,1731.

4
[ 372-47-4 ]
[ 74-88-4 ]
[ 399-88-2 ]

Yield	Reaction Conditions	Operation in experiment
47%		3-Fluoro-4-methylpyridine To a cooled (-780C) solution of Lambda/,Lambda/-diisopropylamine (15.92mL, 113.4mmol) in THF (14OmL) a solution of BuLi 2.5M in hexane (45.4ml, 113.4 mmol) was added dropwise over 30 minutes under an atmosphere of Argon. The mixture was stirred for 30 min. at - 780C and a solution of 3-fluoropyridine (1 Og1 103.1 mmol) in THF (5ml) was added. After 1h at -780C, the mixture was treated with MeI (7 ml, 113.4mmol) and then was allowed to reach 250C. A solution of NaHCO3 saturated (30ml) was added and the aqueous phase was extracted with diethyl ether. The organic layer was dried (MgSO4) and upon distillation the product was collected as a colourless liquid, bp 1300C, yield 5.3 g (47percent) delta 1 H-NMR (CDCI3): 8.25 (s, 1 H), 8.18 (m, 1 H), 7.02 (m, 1 H). ESI/MS m/e: 112 ([M+H]+, C6H6FN)
	With diisopropylamine;	3-Fluoro-4-methylpyridine (5-1) To a stirred solution of LDA (5.5 mmol) at -78° C., was added 3-fluoropyridine (486 mg, 5.0 mmol) dropwise. After stirring for 4h at -78° C., methyl iodide was added dropwise (0.343 mL, 5.5 mmol). The reaction was quenched after stirring at -78° C. for 2 h, by the addition of 20 mL of sat. aq. NH4Cl. This mixture was extracted with EtOAc (3*25 mL), the combined organics dried and concentrated to afford the product as a yellow solid 5-1: 1H NMR (CDCl3) delta 8.36 (br s, 1H), 8.27 (d, 1H, 4.8 Hz), 7.15 (br dd, 1H, 5.7, 5.7 Hz), 2.32 (s, 3H).
		To a solution of diisopropylamine in THF (200 mL) was added a 2.44 M H-BuLi in THF (116 mL) at 0 0C and the mixture was stirred at 0 0C for 20 min. The mixture was cooled to -60 0C and a solution of 3-fluoropyridine (25.0 g) in THF (100 mL) was added. The mixture was stirred at -60 0C for 3 h and a solution of iodomethane (17.6 mL) in THF (100 mL) was added. The mixture was stirred at -60 0C for 30 min and the reaction was quenched with saturated aqueous NH4CI (100 mL). The aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure to give a colorless oil (14.6 g). To a solution of the above oil (14.6 g) in CHCl3 (145 mL) was added a suspension of m-chloroperbenzoic acid (34.8 g) in CHCl3 (145 mL) at 0 0C and the mixture was stirred at ambient temperature for 3 h. To the mixture was added saturated aqueous Na2S2psi3 and the organic layer was separated. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was washed with IM aqueous NaOH and saturated aqueous NaCl, dried over MgSO4, filtered, concentrated under reduced pressure EPO <DP n="102"/>and purified by medium-pressure liquid chromatography (silica gel, 2percent to 4percent MeOH in CHCl3) to give the title compound (3.47 g).1HNMR (SOO MHz, CDCl3, delta): 2.28-2.32 (m, 3H), 7.06-7.13 (m, IH), 7.96-8.00 (m, IH), 8.11 (dd,J= 4.9, 1.8 Hz, IH); ESI MS m/z 150 (M++23, 100percent).

References: [1]Patent: WO2007/17096,2007,A1 .Location in patent: Page/Page column 70-71.
[2]Journal of Medicinal Chemistry,2003,vol. 46,p. 461 - 473.
[3]Patent: US6455532,2002,B1 .
[4]Patent: US6350745,2002,B1 .Location in patent: Page column 15;16.
[5]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 98-99.

5
[ 399-88-2 ]
[ 33252-59-4 ]

Yield	Reaction Conditions	Operation in experiment
	With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 0 - 20℃; for 3h;	To a solution of diisopropylamine in THF (200 mL) was added a 2.44 M H-BuLi in THF (116 mL) at 0 0C and the mixture was stirred at 0 0C for 20 min. The mixture was cooled to -60 0C and a solution of 3-fluoropyridine (25.0 g) in THF (100 mL) was added. The mixture was stirred at -60 0C for 3 h and a solution of iodomethane (17.6 mL) in THF (100 mL) was added. The mixture was stirred at -60 0C for 30 min and the reaction was quenched with saturated aqueous NH4CI (100 mL). The aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure to give a colorless oil (14.6 g). To a solution of the above oil (14.6 g) in CHCl3 (145 mL) was added a suspension of m-chloroperbenzoic acid (34.8 g) in CHCl3 (145 mL) at 0 0C and the mixture was stirred at ambient temperature for 3 h. To the mixture was added saturated aqueous Na2S2psi3 and the organic layer was separated. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was washed with IM aqueous NaOH and saturated aqueous NaCl, dried over MgSO4, filtered, concentrated under reduced pressure EPO <DP n="102"/>and purified by medium-pressure liquid chromatography (silica gel, 2percent to 4percent MeOH in CHCl3) to give the title compound (3.47 g).1HNMR (SOO MHz, CDCl3, delta): 2.28-2.32 (m, 3H), 7.06-7.13 (m, IH), 7.96-8.00 (m, IH), 8.11 (dd,J= 4.9, 1.8 Hz, IH); ESI MS m/z 150 (M++23, 100percent).

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 461 - 473.
[2]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 98-99.
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3636 - 3643.

6
[ 399-88-2 ]
[ 312904-99-7 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 461 - 473.

7
[ 399-88-2 ]
2-aminomethyl-3-fluoro-4-methylpyridine dihydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 461 - 473.

8
[ 399-88-2 ]
3-Fluoro-4-methyl-2-pyridylmethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 461 - 473.

9
[ 399-88-2 ]
2-[3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-N-(3-fluoro-4-methyl-pyridin-2-ylmethyl)-acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 461 - 473.

10
[ 399-88-2 ]
2-[3-(2,2-difluoro-2-phenyl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-N-(3-fluoro-4-methyl-pyridin-2-ylmethyl)-acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 461 - 473.

11
[ 399-88-2 ]
3-fluoro-4-methyl-2-pyridylmethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-cyanopyrazin-2-one-1-acetamide hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 461 - 473.

12
[ 399-88-2 ]
[ 343-72-6 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 1729,1731.

13
[ 23056-33-9 ]
[ 399-88-2 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 1729,1731.

14
[ 21901-41-7 ]
[ 399-88-2 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 1729,1731.

15
[ 21901-40-6 ]
[ 399-88-2 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 1729,1731.

16
[ 6635-86-5 ]
[ 399-88-2 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 1729,1731.

17
[ 21901-18-8 ]
[ 399-88-2 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 1729,1731.

18
[ 23056-39-5 ]
[ 399-88-2 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 1729,1731.

19
[ 399-88-2 ]
DCM-MeOH [ No CAS ]
[ 33252-59-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; water;	3-Fluoro-4-methylpyridine-N-oxide. (5-2) To a stirred solution of 3.17 g (28.6 mmol) of <strong>[399-88-2]3-fluoro-4-methylpyridine</strong> in 5-1 35 mL of dichloromethane was added 4.83 g NaHCO3 (57.5 mmol, in 10 mL H2O). This mixture was cooled to 0° C., and 9.85 g of MCPBA (57.1 mmol) was added in three portions over 15 min. The reaction was allowed to warm to room temperature overnight. The layers of the biphasic mixture were separated and the aqueous phase was washed with chloroform (3*100 mL). The combined organic layers were dried over MgSO4 and the solvents removed at reduced pressure to give an oil that was chromatographed on SiO2 using 95:5 DCM-MeOH to give 5-2 as a white solid: 1H NMR (CDCl3) delta 8.13 (d, 1H, 4.6 Hz), 7.99 (d, 1H, 6.6 Hz), 7.09 (br dd, 1H, 7.6, 7.6 Hz), 2.30 (s, 3H).

References: [1]Patent: US6455532,2002,B1 .

20
[ 399-88-2 ]
[ 7677-24-9 ]
[ 312904-99-7 ]

References: [1]Patent: US6350745,2002,B1 .Location in patent: Page column 16.

21
[ 695-34-1 ]
[ 399-88-2 ]

References: [1]Journal of Fluorine Chemistry,2011,vol. 132,p. 541 - 547.

22
[ 399-88-2 ]
[ 471909-36-1 ]

References: [1]Journal of Fluorine Chemistry,2011,vol. 132,p. 541 - 547.

23
[ 399-88-2 ]
[ 40273-47-0 ]

References: [1]Journal of Fluorine Chemistry,2011,vol. 132,p. 541 - 547.

24
[ 399-88-2 ]
[ 100-52-7 ]
[ 177600-62-3 ]

References: [1]Journal of Fluorine Chemistry,2011,vol. 132,p. 541 - 547.

25
[ 3430-27-1 ]
[ 399-88-2 ]

References: [1]Journal of Fluorine Chemistry,2011,vol. 132,p. 541 - 547.

26
[ 399-88-2 ]
[ 451-46-7 ]
[ 1383377-54-5 ]

Yield	Reaction Conditions	Operation in experiment
89%		Step 6: Preparation of 1-(4-fluorophenyl)-2-(3-fluoropyridin-4-yl)ethanoneLithium hexamethyldisilazide (1.0M in THF, 17.9 mL, 17.9 mmol) was cooled to 0° C. and <strong>[399-88-2]3-fluoro-4-methylpyridine</strong> (1.00 g, 0.926 mmol) in THF (50 mL) was added dropwise, keeping the solution temperature below 5° C. The mixture was then stirred for 1 hour at 0° C. and ethyl 4-fluorobenzoate in THF (50 mL) was added dropwise. The reaction was allowed to warm slowly to rt with stirring overnight. Aqueous ammonium chloride was added and the mixture was poured into EtOAc. The organic phase was separated dried (Na2SO4) and concentrated. Silica gel chromatography using a 10-50percent EtOAc/heptanes gradient yielded 1.83 g (89percent) of Ex 1-Step 6 product as a white solid: LCMS m/z 234.4 (M+1); 1H NMR (400 MHz, MeOH-d4) delta 8.41 (d, J=1.7 1H), 8.32 (d, J=4.8, 1H), 8.14 (dd, J=8.9, 5.4, 2H), 7.38 (dd, J=5.9, 5.1, 1H), 7.25 (dd, J=9.0, 9.0, 2H), 4.52 (s, 2H).

References: [1]Patent: US2012/157440,2012,A1 .Location in patent: Page/Page column 27.

27
[ 399-88-2 ]
[ 1383376-92-8 ]