58602-02-1|2,6-Difluoro-3-nitropyridine| Ambeed

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Quality Control of [ 58602-02-1 ] Purity: 97% SDS Specification

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Product Details of [ 58602-02-1 ]

CAS No. :	58602-02-1
Formula :	C₅H₂F₂N₂O₂
M.W :	160.08
SMILES Code :	O=[N+](C1=CC=C(F)N=C1F)[O-]
MDL No. :	MFCD11044323
InChI Key :	GFDZKTFHLUFNPC-UHFFFAOYSA-N
Pubchem ID :	11389546

Safety of [ 58602-02-1 ]

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

Computational Chemistry of [ 58602-02-1 ] 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	0.0
Molar Refractivity	32.98
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	58.71 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.9
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	1.55
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.11
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.	0.95
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	0.15
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.13

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.15
Solubility	1.14 mg/ml ; 0.00713 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.	-2.39
Solubility	0.648 mg/ml ; 0.00405 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	-1.95
Solubility	1.78 mg/ml ; 0.0111 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.	-6.18 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	3.0 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)	2.13

Application In Synthesis of [ 58602-02-1 ]

* 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.

Upstream synthesis route of [ 58602-02-1 ]
Downstream synthetic route of [ 58602-02-1 ]

[ 58602-02-1 ] Synthesis Path-Upstream 1~7

1
[ 16013-85-7 ]
[ 58602-02-1 ]

Yield	Reaction Conditions	Operation in experiment
45%	With cesium fluoride In dimethyl sulfoxide at 90℃; for 0.5 h;	General procedure: To asolution of 3-bromo-2,6-dichloropyridine (4.70 g, 20.7 mmol) in DMSO (103 ml)was added cesium fluoride (12.6 g, 82.9 mmol) at room temperature. The mixturewas stirred at 80 °C under air for 8 h. The mixture was poured into water atroom temperature and extracted with Et₂O. The organic layer wasseparated, washed with water and brine, dried over Na₂SO₄and concentrated in vacuo. (400 Torr, 40 °C). The residue was purified bycolumn chromatography (silica gel, eluted with EtOAc in hexane) to give 3-bromo-2,6-difluoropyridine (3B) (2.58 g, 64percent) as colorless oil. ¹H NMR (CDCl₃)δ: 6.79 1H,dd, J = 8.3, 3.0 Hz), 8.03 (1H, ddd, J = 8.4, 8.4 7.0 Hz). ¹⁹F NMR(CDCl₃) δ: -69.3 Hz, -63.8 Hz. The compound 4B-8B were prepared in a manner similarto that described for 3B.

References: [1] Collection of Czechoslovak Chemical Communications, 1991, vol. 56, # 11.1, p. 2420 - 2429.
[2] Tetrahedron Letters, 2015, vol. 56, # 44, p. 6043 - 6046.

2
[ 1513-65-1 ]
[ 58602-02-1 ]

References: [1] Journal of Organic Chemistry, 2003, vol. 68, # 2, p. 267 - 275.
[2] Journal of Organic Chemistry, 1991, vol. 56, # 9, p. 3006 - 3009.
[3] Patent: US4144341, 1979, A, .

3
[ 1513-65-1 ]
[ 7664-93-9 ]
[ 58602-02-1 ]

References: [1] Patent: US2002/28807, 2002, A1, .

4
[ 1513-65-1 ]
[ 58602-02-1 ]

References: [1] Patent: EP2181992, 2010, A1, .

5
[ 16013-85-7 ]
[ 58602-02-1 ]

References: [1] Tetrahedron, 2001, vol. 57, # 4, p. 739 - 750.

6
[ 58602-02-1 ]
[ 7439-89-6 ]
[ 108118-69-0 ]

References: [1] Patent: EP2181992, 2010, A1, .

7
[ 58602-02-1 ]
[ 108118-69-0 ]

References: [1] Collection of Czechoslovak Chemical Communications, 1991, vol. 56, # 11.1, p. 2420 - 2429.

[ 58602-02-1 ] Synthesis Path-Downstream 1~35

1
[ 1513-65-1 ]
[ 58602-02-1 ]

Yield	Reaction Conditions	Operation in experiment
	In sulfuric acid;	STEP A: 2,6-difluoro-3-nitropyridine To a stirred solution of 20 g. of 2,6-difluoropyridine in 100 ml. of concentrated sulfuric acid at about 20 C., was added 75 ml. of 90% fuming nitric acid over 20 minutes. The mixture was kept at room temperature overnight, warmed to 35 C. over 15 minutes and held at this temperature for 10 minutes. The solution was cooled and poured into ice. The oil was extracted with 400 ml. of ether and the ether extract was washed with bicarbonate solution until all of the acid was neutralized. The ether was dried, evaporated and the residue was distilled at 0.1 mm. The only fraction came over at 50 C.
	With dihydrogen peroxide; nitric acid; at 0 - 60℃; for 3h;	To a solution of 2,6-difluoropyridine (5.00 g, 43.4 mmol) in Conc.HN03 (36.3 mL, 869 mmol) was added concentrated H2S04 (34.7 mL, 652 mmol) slowly at 0 C and the reaction mixture was heated at 60 C for 3h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled at room temperature, poured into crushed ice (120 mL) and extracted with DCM (2 c 100 mL). The organic layer was separated, washed with an aqueous saturated NaHC03 solution (120 mL), dried over anhydrous Na2S04 and concentrated under vacuum to afford 2,6-difluoro-3-nitropyridine X-12a (3.20 g crude) as a yellow oil. (0877) This compound was used as such for the next reaction without further purification. 1 H NMR (400 MHz, DMSO-cfe) d 7.47 (dd, J=8.80, 2.45 Hz, 1 H) 8.91 -9.00 (m, 1 H).

References: [1]Journal of Organic Chemistry,2003,vol. 68,p. 267 - 275.
[2]Journal of Organic Chemistry,1991,vol. 56,p. 3006 - 3009.
[3]Patent: US4144341,1979,A .
[4]Patent: WO2019/243303,2019,A1 .Location in patent: Page/Page column 59; 74.

2
[ 16013-85-7 ]
[ 58602-02-1 ]

Yield	Reaction Conditions	Operation in experiment
45%	With cesium fluoride; In dimethyl sulfoxide; at 90℃; for 0.5h;	General procedure: To asolution of 3-bromo-2,6-dichloropyridine (4.70 g, 20.7 mmol) in DMSO (103 ml)was added cesium fluoride (12.6 g, 82.9 mmol) at room temperature. The mixturewas stirred at 80 C under air for 8 h. The mixture was poured into water atroom temperature and extracted with Et2O. The organic layer wasseparated, washed with water and brine, dried over Na2SO4and concentrated in vacuo. (400 Torr, 40 C). The residue was purified bycolumn chromatography (silica gel, eluted with EtOAc in hexane) to give 3-bromo-2,6-difluoropyridine (3B) (2.58 g, 64%) as colorless oil. 1H NMR (CDCl3)delta: 6.79 1H,dd, J = 8.3, 3.0 Hz), 8.03 (1H, ddd, J = 8.4, 8.4 7.0 Hz). 19F NMR(CDCl3) delta: -69.3 Hz, -63.8 Hz. The compound 4B-8B were prepared in a manner similarto that described for 3B.

References: [1]Collection of Czechoslovak Chemical Communications,1991,vol. 56,p. 2420 - 2429.
[2]Tetrahedron Letters,2015,vol. 56,p. 6043 - 6046.

3
[ 58602-02-1 ]
[ 50534-24-2 ]
[ 179557-98-3 ]

References: [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 3769 - 3789.

4
[ 58602-02-1 ]
[ 7006-50-0 ]
[ 181579-38-4 ]

References: [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 3769 - 3789.

5
[ 58602-02-1 ]
[ 139087-05-1 ]

References: [1]Collection of Czechoslovak Chemical Communications,1991,vol. 56,p. 2420 - 2429.

6
[ 58602-02-1 ]
[ 139087-03-9 ]

References: [1]Collection of Czechoslovak Chemical Communications,1991,vol. 56,p. 2420 - 2429.

7
[ 58602-02-1 ]
[ 139087-07-3 ]

References: [1]Collection of Czechoslovak Chemical Communications,1991,vol. 56,p. 2420 - 2429.

8
[ 58602-02-1 ]
[ 139087-12-0 ]

References: [1]Collection of Czechoslovak Chemical Communications,1991,vol. 56,p. 2420 - 2429.

9
[ 58602-02-1 ]
[ 139087-11-9 ]

References: [1]Collection of Czechoslovak Chemical Communications,1991,vol. 56,p. 2420 - 2429.
[2]Collection of Czechoslovak Chemical Communications,1991,vol. 56,p. 2420 - 2429.

10
[ 58602-02-1 ]
[ 139087-10-8 ]

References: [1]Collection of Czechoslovak Chemical Communications,1991,vol. 56,p. 2420 - 2429.

11
[ 58602-02-1 ]
[ 139087-08-4 ]

References: [1]Collection of Czechoslovak Chemical Communications,1991,vol. 56,p. 2420 - 2429.

12
[ 1513-65-1 ]
[ 7664-93-9 ]
[ 58602-02-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	With nitric acid;	a 2,6-Difluoro-3-nitropyridine To a mixture of concentrated sulphuric acid (600 mL) and fuming nitric acid (90%, 400 mL) in a ice-bath (internal temperature maintained at 5-10 C.) was added drop-wise 2,6-difluoropyridine (200 g, 1.74 mol). The resulting mixture was stirred overnight at room temperature. The mixture was poured slowly into 3 kg of ice and extracted with Et2O (22 L). The combined organic layers were washed with aqueous 1.5 N NaOH (21 L), then with aqueous saturated NaHCO3 (400 mL) or until pH is around 8-9. The organic layers were dried over MgSO4, filtrated and concentrated under reduced pressure until constant weight (to remove unreacted 2,6-difluoropyridine: 10-12%). The title compound was obtained as a yellow liquid (207.3 g, 74% yield).

References: [1]Patent: US2002/28807,2002,A1 .

13
[ 58602-02-1 ]
[ 75-04-7 ]
[ 380378-98-3 ]

Yield	Reaction Conditions	Operation in experiment
82%	In tetrahydrofuran; hexane; ethyl acetate;	b 2-(Ethylamino)-6-fluoro-3-nitropyridine To a solution of <strong>[58602-02-1]2,6-difluoro-3-nitropyridine</strong> (45.7 g, 285 mmol) in THF (500 mL) at -40 C. was added drop-wise a solution of ethylamine (25.7 g, 570 mmol) in THF (250 mL). After 30 min, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated. The resulting yellow solid was purified by flash chromatography (15% EtOAc in hexane) to give the title compound (43.2 g, 82% yield) as a yellow solid.

References: [1]Patent: US2002/28807,2002,A1 .

14
[ 58602-02-1 ]
[ 1115-59-9 ]
ethyl DL-2-[6-fluoro-3-nitropyridyl-2-amino]propionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile;	Step A <strong>[58602-02-1]2,6-difluoro-3-nitropyridine</strong> (14.68g,91.8mmol) was added to a mixture of DL-alanine ethyl ester hydrochloride (14.09g 92mmol) and potassium carbonate (25.3g, 183mmol) in acetonitrile (200ml) and the mixture stirred for 2 hours at room temperature. The reaction mixture was poured into water and extracted several times with ethyl acetate; the combined extracts were dried (MgSO4) and the solvent removed in vacuo leaving a viscous orange-yellow residue which solidified on standing. The solid was triturated with hexane and the solvent removed from the hexane soluble fraction leaving ethyl DL-2-[6-fluoro-3-nitropyridyl-2-amino]propionate as a yellow solid m.p. 49-51 C.

References: [1]Patent: US5133798,1992,A .

15
[ 58602-02-1 ]
[ 14268-66-7 ]
[ 61964-27-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In ethanol; water;	STEP B: 6-Fluoro-2-(3,4-methylenedioxyanilino)-3-nitropyridine In 75 ml. of ethanol was dissolved 3.2 g. (0.002 mole) of <strong>[58602-02-1]2,6-difluoro-3-nitropyridine</strong> followed by 1.68 g. (0.02 mole) of sodium bicarbonate. To this stirred mixture, was added a solution of 2.74 g. (0.02 mole) of 3,4-(methylenedioxy) aniline in 50 ml. of ethanol dropwise over 45 minutes at room temperature. After one hour, 100 ml. of water was added and the deep-red crystalline solid product was collected. A small amount was crystallized from ethanol and melted at 161-162 C.

References: [1]Patent: US4144341,1979,A .

16
4-carbobenzoxypiperazine-2-carboxylic acid hydrochloride [ No CAS ]
[ 58602-02-1 ]
1-(6-fluoro-3-nitro-2-pyridinyl)-4-carbobenzoxypiperazine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dimethyl sulfoxide; triethylamine;	EXAMPLE 4 1-(6-Fluoro-3-nitro-2-pyridinyl)-4-carbobenzoxypiperazine-2-carboxylic acid In a similar procedure to that described in Example 1, from 6.0 g. of <strong>[58602-02-1]2,6-difluoro-3-nitropyridine</strong>, 9.0 g. of 4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, 20 ml. of triethylamine and 150 ml. of dimethyl sulfoxide, there is obtained 14 g. of the title product as a viscous orange glass. Thin layer chromatographic analysis of this material shows essentially one spot.

References: [1]Patent: US4138564,1979,A .

17
[ 1513-65-1 ]
Tetramethylammonium nitride [ No CAS ]
[ 58602-02-1 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoromethanesulfonic acid anhydride; In dichloromethane;	Synthesis of 2,6-difluoro-3-nitropyridine Tetramethylammonium nitride (4.5 g) was suspended in dichloromethane (10 ml), and a solution of trifluoromethanesulfonic anhydride (5.56 ml) in dichloromethane (5 ml) was added dropwise at room temperature. After stirring at room temperature for 1.5 hours, a solution of 2,6-difluoropyridine (2 ml) in dichloromethane (5 ml) was added at room temperature, and the reaction solution was heated under reflux overnight. After leaving to cool, the reaction solution was poured into an ice-cooled saturated sodium bicarbonate solution. Dichloromethane was added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the organic layer was concentrated under reduced pressure to obtain the title compound (3.84 g). The property values of the compound are as follows. 1H-NMR (CDCl3) delta (ppm): 7.03-7.07 (m, 1H), 8.66-8.73 (m, 1H).

References: [1]Patent: EP2181992,2010,A1 .

18
[ 58602-02-1 ]
N-benzyl-6-(benzyloxy)-3-nitropyridin-2-amine [ No CAS ]

References: [1]Tetrahedron Letters,2015,vol. 56,p. 6043 - 6046.

19
[ 58602-02-1 ]
[ 100-46-9 ]
N-benzyl-6-fluoro-3-nitropyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 0.5h;	General procedure: To asolution of 3-chloro-2,6-difluoropyridine (449 mg, 3.00 mmol) and K2CO3(829 mg, 6.00 mmol) in DMSO (15 mL) was added benzylamine(338 mg, 3.15 mmol) at room temperature. The mixture was stirred at roomtemperature under air for 2 h. The mixture was poured into water at roomtemperature and extracted with EtOAc. The organic layer was separated, washedwith water and brine, dried over MgSO4 and concentrated in vacuo.The residue was purified by column chromatography (silica gel, eluted withEtOAc in hexane) to give N-benzyl-3-chloro-6-fluoropyridin-2-amine(2D) (468 mg, 66 %) and N-benzyl-5-chloro-6-fluoropyridin-2-amine (2E) (63.0 mg, 8.9 %).

References: [1]Tetrahedron Letters,2015,vol. 56,p. 6043 - 6046.

20
[ 58602-02-1 ]
tert-butyl 4-[5-nitro-6-(2-oxo-3-[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl]-3-phenylpiperazine-1-carboxylate [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2497 - 2501.

21
[ 58602-02-1 ]
1-[3-nitro-6-(2-phenylpiperazin-1-yl)pyridin-2-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2497 - 2501.

22
[ 58602-02-1 ]
3-[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one [ No CAS ]
1-(6-fluoro-3-nitropyridin-2-yl)-3-[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate; In dimethyl sulfoxide; for 0.5h;	General procedure: 3-[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8) (5.00 g, 18.8 mmol) and 2,3,6-trifluoropyridine (1) (3.51 g, 26.4 mmol) in DMSO (100 ml) was added K2CO3 (5.21 g, 37.7 mmol) at room temperature. The mixture was stirred at 130 C for 30 min. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give 1-(3,6-difluoropyridin-2-yl)-3-[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12) (7.04 g, 18.6 mmol, 99 %) as a white solid.

References: [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2497 - 2501.

23
[ 58602-02-1 ]
[ 69999-53-7 ]

References: [1]Patent: US4138564,1979,A .

24
[ 58602-02-1 ]
[ 88-18-6 ]
2-[2-(tert-butyl)phenoxy]-6-fluoro-3-nitropyridine [ No CAS ]
6-[2-(tert-butyl)phenoxy]-2-fluoro-3-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%; 35%	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 14h;	General procedure: 2-Halo-3-nitropyridine (1 eq, 7.3mmol) in DMF (6mL) was treated with 2-isopropylphenol (1 eq, 7.3mmol) and Cs2CO3 (1.5 eq, 10.9mmol) and heated at 70C for 14h. Afterwards, the reaction mixture was cooled to room temperature, and DMF was evaporated. The residue was dissolved in ethyl acetate (EA, 20mL) and washed with 5% LiCl aq sol. (3×7mL) and brine (3×7mL). Drying (MgSO4) and removal of solvent afforded a brown solid which was recrystallized from ethanol to afford the corresponding ether as yellow needles.