52764-11-1|2,6-Dichloropyridin-3-ol| Ambeed

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Quality Control of [ 52764-11-1 ] Purity: 98% SDS Specification

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Product Details of [ 52764-11-1 ]

CAS No. :	52764-11-1
Formula :	C₅H₃Cl₂NO
M.W :	163.99
SMILES Code :	OC1=CC=C(Cl)N=C1Cl
MDL No. :	MFCD11044319
InChI Key :	CDDCESLWCVAQMG-UHFFFAOYSA-N
Pubchem ID :	104317

Safety of [ 52764-11-1 ]

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

Computational Chemistry of [ 52764-11-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	36.28
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	33.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.63
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	1.79
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.09
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.	1.02
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	2.23
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.75

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.48
Solubility	0.546 mg/ml ; 0.00333 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.	-2.1
Solubility	1.29 mg/ml ; 0.00787 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	-2.67
Solubility	0.348 mg/ml ; 0.00212 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.	-6.03 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)	1.6

Application In Synthesis of [ 52764-11-1 ]

* 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 [ 52764-11-1 ]
Downstream synthetic route of [ 52764-11-1 ]

[ 52764-11-1 ] Synthesis Path-Upstream 1~3

1
[ 148493-34-9 ]
[ 52764-11-1 ]

Yield	Reaction Conditions	Operation in experiment
91.4%	With dihydrogen peroxide In dichloromethane; water at 0 - 20℃; for 0.15 h;	Preparation of Compound 1Step 1 - Synthesis of 2,6-dichloropyridin-3-olΗ₂0₂ (1.60 g, 47.12 mmol) was added slowly to the solution of compound 2,6- dichloropyridin-3-ylboronic acid (3 g, 15.71 mmol) in CH₂CI₂ (30 mL) at 0 °C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na₂S203 aqueous (50 mL) and adjusted to pH < 7 with IN HC1. The mixture was extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (100 mL), dried over Na₂S0₄, filtered and the solvent was evaporated to provide2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4percent). 1H-NMR (CDC1₃, 400 MHz) δ 7.30 (d, / = 8.4 Hz, 1H), 7.19 (d, / = 8.4 Hz, 1H), 5.70 (br, 1H).
91.4%	With dihydrogen peroxide In dichloromethane at 0 - 20℃; for 15 h;	H202 (1.60 g, 47.12 mmol) was added slowly to the solution of compound 2,6- dichloropyridin-3-ylboronic acid (3 g, 15.71 mmol) in CH2C12 (30 mL) at 0 °C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na2S203 aqueous (50 mL) and adjusted to pH < 7 with IN HC1. The mixture was extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2S04, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4percent). 1H- MR (CDC13, 400 MHz) δ 7.30 (d, J= 8.4 Hz, 1H), 7.19 (d, J= 8.4 Hz, 1H), 5.70 (br, 1H). MS (M+H)+: 164 / 166 / 168.
91.4%	With dihydrogen peroxide In dichloromethane at 0 - 20℃; for 15 h;	Step 1-Synthesis of 2,6-dichloropyridin-3-ol H₂O₂ (1.60 g, 47.12 mmol) was added slowly to the solution of compound 2,6-dichloropyridin-3-ylboronic acid (3 g, 15.71 mmol) in CH₂Cl₂ (30 mL) at 0° C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na₂S₂O₃ aqueous (50 mL) and adjusted to pH<7 with 1N HCl. The mixture was extracted with EtOAc (40 mL*3). The organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4percent). ¹H-NMR (CDCl₃, 400 MHz) δ 7.30 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 5.70 (br, 1H). MS (M+H)⁺: 164/166/168.

References: [1] Tetrahedron, 2005, vol. 61, # 6, p. 1417 - 1421.
[2] Patent: WO2013/33900, 2013, A1, . Location in patent: Page/Page column 27.
[3] Patent: WO2013/33971, 2013, A1, . Location in patent: Page/Page column 32-33.
[4] Patent: US2014/213571, 2014, A1, . Location in patent: Paragraph 0223.

2
[ 6636-78-8 ]
[ 52764-11-1 ]

References: [1] Patent: US4404020, 1983, A, .
[2] Patent: US4067725, 1978, A, .

3
[ 2402-78-0 ]
[ 52764-11-1 ]

References: [1] Tetrahedron, 2005, vol. 61, # 6, p. 1417 - 1421.

[ 52764-11-1 ] Synthesis Path-Downstream 1~26

2
[ 148493-34-9 ]
[ 52764-11-1 ]

Yield	Reaction Conditions	Operation in experiment
91.4%	With dihydrogen peroxide; In dichloromethane; water; at 0 - 20℃; for 0.15h;	Preparation of Compound 1Step 1 - Synthesis of 2,6-dichloropyridin-3-olEta202 (1.60 g, 47.12 mmol) was added slowly to the solution of compound 2,6- dichloropyridin-3-ylboronic acid (3 g, 15.71 mmol) in CH2CI2 (30 mL) at 0 C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na2S203 aqueous (50 mL) and adjusted to pH < 7 with IN HC1. The mixture was extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2S04, filtered and the solvent was evaporated to provide2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4%). 1H-NMR (CDC13, 400 MHz) delta 7.30 (d, / = 8.4 Hz, 1H), 7.19 (d, / = 8.4 Hz, 1H), 5.70 (br, 1H).
91.4%	With dihydrogen peroxide; In dichloromethane; at 0 - 20℃; for 15h;	H202 (1.60 g, 47.12 mmol) was added slowly to the solution of compound 2,6- dichloropyridin-3-ylboronic acid (3 g, 15.71 mmol) in CH2C12 (30 mL) at 0 C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na2S203 aqueous (50 mL) and adjusted to pH < 7 with IN HC1. The mixture was extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2S04, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4%). 1H- MR (CDC13, 400 MHz) delta 7.30 (d, J= 8.4 Hz, 1H), 7.19 (d, J= 8.4 Hz, 1H), 5.70 (br, 1H). MS (M+H)+: 164 / 166 / 168.
91.4%	With dihydrogen peroxide; In dichloromethane; at 0 - 20℃; for 15h;	Step 1-Synthesis of 2,6-dichloropyridin-3-ol H2O2 (1.60 g, 47.12 mmol) was added slowly to the solution of compound <strong>[148493-34-9]2,6-dichloropyridin-3-ylboronic acid</strong> (3 g, 15.71 mmol) in CH2Cl2 (30 mL) at 0 C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na2S2O3 aqueous (50 mL) and adjusted to pH<7 with 1N HCl. The mixture was extracted with EtOAc (40 mL*3). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4%). 1H-NMR (CDCl3, 400 MHz) delta 7.30 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 5.70 (br, 1H). MS (M+H)+: 164/166/168.

References: [1]Tetrahedron,2005,vol. 61,p. 1417 - 1421.
[2]Patent: WO2013/33900,2013,A1 .Location in patent: Page/Page column 27.
[3]Patent: WO2013/33971,2013,A1 .Location in patent: Page/Page column 32-33.
[4]Patent: US2014/213571,2014,A1 .Location in patent: Paragraph 0223.

3
[ 2402-78-0 ]
[ 52764-11-1 ]

References: [1]Tetrahedron,2005,vol. 61,p. 1417 - 1421.

4
[ 52764-11-1 ]
[ 535-11-5 ]
[ 62804-93-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In acetonitrile;	EXAMPLE 1 2-[(2,6-dichloro-3-pyridyl)oxy]propionic acid ethyl ester 164 g (1 mole) of 2,6-dichloro-3-pyridinol, 1500 ml of acetonitrile, 253.4 g (1.4 moles) of 2-bromopropionic acid ethyl ester and 127.2 (1.2 moles) of sodium carbonate were refluxed for 3 hours. The reaction mixture was then cooled, filtered and concentrated in a rotary evaporator. The residue was taken up in ether and washed with 2 N sodium hydroxide solution. After drying with magnesium sulphate and concentration of the solution by evaporation, distillation was performed, with a clear oil distilling at 110-140/0.1 torr; yield: 200 g; nD25:1.5200. Crystallisation from benzene/petroleum ether yielded a product having the melting point 41-46. The 2,6-dichloro-3-pyridinol required as starting material was produced as follows:
	With sodium carbonate; In acetonitrile;	b. 2-[(2,6-dichloro-3-pyridyl)oxy]propionic acid ethyl ester 164 g (1 mole) of 2,6-dichloro-3-pyridinol, 1500 ml of acetonitrile, 253.4 g (1.4 moles) of 2-bromopropionic acid ethyl ester and 127.2 (1.2 moles) of sodium carbonate are refluxed for 3 hours. The reaction mixture is then cooled, filtered, and concentrated in a rotary evaporator. The residue is taken up in ether and washed with 2N sodium hydroxide solution. After drying with magnesium sulphate, the solution is concentrated by evaporation and distilled in vacuo; a clear oil distills at 110-140/0.1 torr; yield: 200 g; i nD25: 1.5200. Crystallisation from benzene/petroleum ether yields a product having a melting point of 41-46;

References: [1]Patent: US4404020,1983,A .
[2]Patent: US4067725,1978,A .

5
[ 6636-78-8 ]
[ 52764-11-1 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorine; In N-methyl-acetamide; water;	(a) 2,6-dichloro-3-pyridinol 100 g (0.77 mole) of 2-chloro-3-pyridinol (I) was dissolved in 350 ml of dimethylformamide. 70 ml of chlorine (measured at -80; 0.93 mole) was introduced in the course of 1.5 hours into the stirred solution at 0. The reaction mixture was then stirred for 1.5 hours at 20 C. and subsequently concentrated in a rotary evaporator (bath: 50; 10 torr). 400 ml of water and 100 ml of ether were added to the residue; the two phases were separated and the aqueous phase was extracted 5 times with 100 ml of ether each time. The combined ether phases were washed with water and dried. The solvent was removed in vacuo; the semisolid residue was stirred with 1.6 liters of water, and the resulting suspension was adjusted to pH 3. The suspension was heated to boiling, and after a few minutes the solution was decanted from an oily residue. The solution was purified with active charcoal, and the yellow product obtained on cooling was recrystallized from water; m.p. 136-138 C.; yield 42 g.
	With chlorine; In N-methyl-acetamide; water;	a. 2,6-dichloro-3-pyridinol 100 g (0.77 mole) of 2-chloro-3-pyridinol is dissolved in 350 ml of dimethylformamide. In the course of 1.5 hours, 70 ml of chlorine (measured at -80; 0.93 mole) is introduced at 0 into the stirred solution. The reaction mixture is subsequently stirred for 1.5 hours at 20 C and afterwards concentrated in a rotary evaporator (bath: 50; 10 torr). To the residue are added 400 ml of water and 100 ml of ether. The two phases are separated, and the aqueous phase is extracted 5 times with 100 ml of ether each time.

References: [1]Patent: US4404020,1983,A .
[2]Patent: US4067725,1978,A .

6
[ 52764-11-1 ]
[ 2315-36-8 ]
[ 62843-76-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; dimethyl sulfoxide;	EXAMPLE 1 N,N-diethyl-(2,6-dichloro-3-pyridyl)-oxy-acetic acid amide A solution of 4.6 g of sodium methylate (0.2 mole) in 50 ml of absolute methanol is slowly added at room temperature to 33.4 g (0.2 mole) of <strong>[52764-11-1]2,6-dichloropyridin-3-ol</strong>. There is then added, with gentle heating, 100 to 150 ml of dimethylsulphoxide until the cloudy solution becomes clear. The solution is then heated to 80-90 and methanol is distilled off. The reaction solution is cooled and an addition is slowly made dropwise at 0-10 C of a solution of 60 g (0.2 mole) of chloroacetic acid diethylamide (dissolved in 300 ml of dimethylsulphoxide). After the dropwise addition is completed, the reaction mixture is stirred at room temperature for a further hour. The solvent is distilled off under reduced pressure; the oil remaining is taken up in ether, washed with water, dried and freed from solvent to leave N,N-diethyl-(2,6-dichloro-3-pyridyl)-oxy-acetic acid amide, which boils at 137/0.4 torr; yield: 35 g (62% of theory).

References: [1]Patent: US4067725,1978,A .

7
[ 52764-11-1 ]
[ 75-61-6 ]
[ 1258190-77-0 ]

Yield	Reaction Conditions	Operation in experiment
58%		3-(Bromodifluoromethoxy)-2,6-dichloropyridine (15); At 0 0C, sodium hydride (60%, 1.8 g, 45.7 mmol, 1.5 eq) is added portion wise to a solution of <strong>[52764-11-1]2,6-dichloro-3-hydroxypyridine</strong> (5.0 g, 30.5 mmol) in DMF (50 mL). The reaction mixture is then vigorously stirred for 1 h at 25 0C and 30 min at 55C. At 0 0C, a solution of dibromodifluoromethane (25.7 g, 11.2 mL, 122 mmol, 4 eq) in DMF (10 mL) is added dropwise and the reaction mixture is allowed to reach 25 0C during 2 h. At 0 0C, potassium tert-butoxide (3.6 g, 33.5 mmol, 1.1 eq) is then added portion wise and the reaction mixture is vigorously stirred for 16 h at 70 0C in a closed reactor. After addition of water (100 mL) the organic phase is separated and the aqueous layer is extracted with diethyl ether (3 * 50 mL). The combined organic layers are dried over sodium sulfate before being evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate / cyclohexane (2 : 98) as eluent which afforded pure 3-(bromodifluoromethoxy)-2,6-dichloropyridine (15, 4.1 g, 17.7 mmol, 58 %) as a pale yellow oil.1H NMR (CDCl3, 300 MHz): delta = 7.60 (d, J = 8.5 Hz, 1 H), 7.26 (d, J = 8.5 Hz, 1 H). - 13C NMR (CDCl3, 75 MHz): delta = 148.1, 144.4, 143.2, 133.4, 124.3, 114.7 (t, J= 113 Hz). - MS(EI): m/z = 292 [M+], 212 [M+-Br].

References: [1]Patent: WO2010/40461,2010,A1 .Location in patent: Page/Page column 26.
[2]European Journal of Organic Chemistry,2010,p. 6043 - 6066.

8
[ 52764-11-1 ]
[ 463-71-8 ]
C₆H₂Cl₃NOS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In chloroform; water; at 0℃;	2,6-Dichloro-3-trichloromethoxypyridine (3); At 0 0C, thiophosgene (4.3 g, 2.9 mL, 36.6 mmol, 1 eq) in chloroform (22 mL) is added dropwise to a solution of <strong>[52764-11-1]2,6-dichloro-3-hydroxypyridine</strong> (6.0 g, 36.6 mmol) in aqueous sodium hydroxide (5%, 32 mL). The reaction mixture is vigorously stirred for 2 h at 0 0C before being extracted with chloroform (3 x 20 mL). The combined organic layers are washed with diluted hydrochloric acid (1 N, 20 mL) and water (20 mL), dried over sodium sulfate before being filtrated. At 25 0C, the filtrate is then saturated with chlorine until the reaction mixture begins to warm up. After 2 h at 25 0C, another excess of chlorine is added until a yellow solution is obtained. After 24 h at 25 0C excess of chlorine is removed by a stream of Ar gas and the solvent is evaporated. The crude pale yellow oil is distilled under vacuum to afford pure 2,6- dichloro-3-trichloromethoxypyridine (3, 7.1 g, 25.4 mmol, 70%) as colorless crystals; b.p. 78- 81 0C / 0.5 mbar; m.p. 41-43 0C.1H NMR (CDCl3, 300 MHz): delta = 8.02 (d, J = 8.5 Hz, 1 H), 7.37 (d, J = 8.5 Hz, 1 H). - 13C NMR (CDCl3, 75 MHz): delta = 144.7, 143.4, 132.9, 123.6, 115.0, 112.2. - MS(EI): m/z = 281 [M+], 245 [M+-Cl].

References: [1]Patent: WO2010/40461,2010,A1 .Location in patent: Page/Page column 18.
[2]European Journal of Organic Chemistry,2010,p. 6043 - 6066.

9
[ 17228-74-9 ]
[ 52764-11-1 ]
[ 75-45-6 ]
[ 1214379-42-6 ]
[ 1214349-42-4 ]

References: [1]European Journal of Organic Chemistry,2010,p. 6043 - 6066.

10
[ 52764-11-1 ]
[ 1418153-16-8 ]

References: [1]European Journal of Organic Chemistry,2012,p. 6940 - 6952.

11
[ 74-96-4 ]
[ 52764-11-1 ]
[ 1418153-04-4 ]

References: [1]European Journal of Organic Chemistry,2012,p. 6940 - 6952.

12
[ 52764-11-1 ]
[ 1426960-48-6 ]

References: [1]Patent: WO2013/33900,2013,A1 .
[2]Patent: US2014/213571,2014,A1 .
[3]Patent: WO2013/33971,2013,A1 .

13
[ 52764-11-1 ]
[ 1426960-49-7 ]

References: [1]Patent: WO2013/33900,2013,A1 .
[2]Patent: US2014/213571,2014,A1 .
[3]Patent: WO2013/33971,2013,A1 .

14
[ 52764-11-1 ]
[ 1426960-50-0 ]

References: [1]Patent: WO2013/33900,2013,A1 .
[2]Patent: US2014/213571,2014,A1 .
[3]Patent: WO2013/33971,2013,A1 .

15
[ 52764-11-1 ]
[ 1426960-32-8 ]

References: [1]Patent: WO2013/33900,2013,A1 .
[2]Patent: US2014/213571,2014,A1 .
[3]Patent: US2014/213571,2014,A1 .
[4]Patent: WO2013/33971,2013,A1 .
[5]Patent: WO2013/33971,2013,A1 .

16
[ 52764-11-1 ]
[ 74-88-4 ]
[ 1214340-74-5 ]

Yield	Reaction Conditions	Operation in experiment
96.0%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;	To a solution of <strong>[52764-11-1]2,6-dichloropyridin-3-ol</strong> (16.3 g, 0.1 mol) and K2C03 (41.4 g, 0.3 mol) in DMF (200 mL) were added Mel (21.3 g, 0.15 mol). The mixture was allowed to stir at 80 C for 2 hours. The mixture was then diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layer was washed with brine (200 mL x 3), dried over Na2S04, filtered and the solvent was evaporated to provide 2,6-dichloro-3-methoxypyridine (17.0 g, yield: 96.0%). 1H-NMR (CDC13, 400 MHz) delta 7.12-7.18 (m, 2H), 3.86 (s, 3H).
96%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;	To a solution of <strong>[52764-11-1]2,6-dichloropyridin-3-ol</strong> (16.3 g, 0.1 mol) and K2C03 (41.4 g, 0.3 mol) in DMF (200 mL) were added Mel (21.3 g, 0.15 mol). The mixture was allowed to stir at 80 C for 2 hours. The mixture was then diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layer was washed with brine (200 mL x 3), dried over Na2S04, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloro-3-methoxypyridine (17.0 g, yield: 96.0%). 1H- MR (CDC13; 400 MHz) delta 7.12-7.18 (m, 2H), 3.86 (s, 3H). MS (M+H)+: 178 / 180 / 182.
96%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;	Step 2-Synthesis of 2,6-dichloro-3-methoxypyridine To a solution of <strong>[52764-11-1]2,6-dichloropyridin-3-ol</strong> (16.3 g, 0.1 mol) and K2CO3 (41.4 g, 0.3 mol) in DMF (200 mL) were added MeI (21.3 g, 0.15 mol). The mixture was allowed to stir at 80 C. for 2 hours. The mixture was then diluted with water (200 mL) and extracted with EtOAc (200 mL3). The organic layer was washed with brine (200 mL3), dried over Na2SO4, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloro-3-methoxypyridine (17.0 g, yield: 96.0%). 1H-NMR (CDCl3, 400 MHz) delta 7.12?7.18 (m, 2H), 3.86 (s, 3H). MS (M+H)+: 178/180/182.

References: [1]Patent: WO2013/33900,2013,A1 .Location in patent: Page/Page column 27.
[2]Patent: WO2013/33971,2013,A1 .Location in patent: Page/Page column 33.
[3]Patent: US2014/213571,2014,A1 .Location in patent: Paragraph 1.2.

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[ 52764-11-1 ]
[ 1427034-61-4 ]