[ CAS No. 1221171-70-5 ]

Name: 1221171-70-5|2-Chloro-6-(trifluoromethoxy)pyridine|95%
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Quality Control of [ 1221171-70-5 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 1221171-70-5 ]

CAS No. :	1221171-70-5	MDL No. :	MFCD18909427
Formula :	C₆H₃ClF₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	197.54 g/mol	Pubchem ID :	49871750
Synonyms :

Calculated chemistry of of [ 1221171-70-5 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	35.93
TPSA :	22.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.1 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.94
Log Po/w (XLOGP3) :	3.39
Log Po/w (WLOGP) :	3.89
Log Po/w (MLOGP) :	1.65
Log Po/w (SILICOS-IT) :	2.58
Consensus Log Po/w :	2.69

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.44
Solubility :	0.072 mg/ml ; 0.000364 mol/l
Class :	Soluble
Log S (Ali) :	-3.53
Solubility :	0.0578 mg/ml ; 0.000293 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.27
Solubility :	0.106 mg/ml ; 0.000535 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.92

Safety of [ 1221171-70-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1221171-70-5 ]

* 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 [ 1221171-70-5 ]
Downstream synthetic route of [ 1221171-70-5 ]

[ 1221171-70-5 ] Synthesis Path-Upstream 1~4

1
[ 1221171-69-2 ]
[ 1221171-70-5 ]

Yield	Reaction Conditions	Operation in experiment
62%	at 120℃; for 3.33333 h; Inert atmosphere	b) 2-chloro-6-(trifluoromethoxy)pyridine (1-5); To a mixture of SbF₃ (29.87 g; 167.10 mmol; 2 eq) and SbCl₅ (1.61 mL; 12.53 mmol; 0.15 eq) stirred under argon at 120°C, was added dropwise over 20 minutes 2-chloro-6- (trichloromethoxy)pyridine (20.63 g; 83.55 mmol; 1 eq). After 3 hours stirring at 120°C, the reaction mixture was cooled to room temperature and dichlorom ethane (350 mL) was added, followed by a saturated solution of sodium carbonate (350 mL) and an aqueous solution of 20percent KF (175 mL). The biphasic mixture was filtered on Celite.(R).. The 2 layers were separated and the aqueous layer was extracted with dichloromethane (5 x 100 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated to dryness. The crude obtained was purified under vacuum distillation (P = 35 mbars; T° = 81-83°C) to afford 2-chloro-6- (trifluoromethoxy)pyridine in 62 percent yield as a colorless oil.1H- MR (CDC1₃): δ (ppm) 6.96 (d, 1H); 7.27 (d, 1H); 7.75 (t, 1H).
53%	at 120 - 150℃;	2-Chloro-6-trifluoromethoxypyridine (2); 2-Chloro-6-trichloromethoxypyridine (1, 5.9 g, 23.8 mmol) was added dropwise to a molten mixture Of SbF₃ (8.7 g, 47.7 mmol, 2.0 eq) and SbCl₅ (1.0 g, 0.45 mL, 3.6 mmol, 0.15 eq) at 120 ⁰C and stirred for 3 h at 150 ⁰C. GC monitoring indicated 100percent conversion and disappearance of byproduct OCF₂Cl. The mixture was then cooled to 0 ⁰C and dissolved in dichloromethane (100 mL). The solution was quenched with saturated aqueous solution of sodium hydrogencarbonate (100 mL) and potassium fluoride (20percent, 50 mL), the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over sodium sulfate and the solvent was distilled. The crude product was distilled under vacuum to afford pure 2-chloro-6-trifiuoromethoxypyridine (2, 2.5 g, 10.1 mmol, 53percent) as a colorless oil; b.p. 42-44 ⁰C / 20 mbar. - ¹H NMR (CDCl₃, 300 MHz): δ = 7.67 (t, J = 7.9 Hz, 1 H), 7.18 (d, J = 7.7 Hz, 1 H), 6.87 (d, J= 8.0 Hz, 1 H). - ¹³C NMR (CDCl₃, 75 MHz): δ = 155.6, 149.3, 141.9, 122.2, 119.8 (q, J= 262 Hz), 111.8. - MS(EI): m/z = 197 [M⁺], 162 [M⁺-Cl].
53%	at 120 - 140℃; for 3 h;	2-Chloro-6-trichloromethoxypyridine (1, 5.9 g, 24 mmol, 1 equiv.) was added dropwise at 120 °C to a mixture of SbF3 (8.7 g, 48 mmol, 2equiv.) and SbCl5 (0.60 mL, 4.8 mmol, 0.2 equiv.) and the mixture was stirred for 3 h at 140 °C. GC monitoring indicated 100percent conversion and disappearance of the−OCF2Cl byproduct. The mixture was then cooled to room temperature and dissolved in dichloromethane (100 mL). The solution was washed with 2 M HCl (150 mL) and the aqueous layer wa sextracted with dichloromethane (2 × 50 mL). The combined organic layers were dried over sodium sulphate and the solvent was evaporated at atmospheric pressure. The crude product was distilled under reduced pressure to afford pure 2-chloro-6-trifluoromethoxypyridine (2).Colourless oil (2.5 g, 53percent yield), b.p.= 42–44 °C (20 mbar); 1H NMR(CDCl3, 300 MHz, 25 °C): δ 7.67 (t, 1H, J =7.9 Hz, H-4), 7.18 (d, 1H,J = 7.9 Hz, H-5), 6.87 (d, 1H, J =7.9 Hz, H-3) ppm; 13C NMR (CDCl3,75 MHz, 25 °C): δ 155.6 (C), 149.3 (C), 142.0 (CHarom), 122.2(CHarom), 119.8 (q, JC-F= 262.1 Hz, OCF3), 111.1 (CH); 19F NMR(CDCl3, 282 MHz, 25 °C): δ −57.2 ppm.

Reference： [1] Patent: WO2012/93174, 2012, A1, . Location in patent: Page/Page column 38
[2] Patent: WO2010/40461, 2010, A1, . Location in patent: Page/Page column 17-18
[3] European Journal of Organic Chemistry, 2010, # 31, p. 6043 - 6066
[4] ChemMedChem, 2015, vol. 10, # 4, p. 715 - 726
[5] Journal of Fluorine Chemistry, 2017, vol. 203, p. 155 - 165

2
[ 16879-02-0 ]
[ 1221171-70-5 ]

Reference： [1] Journal of Fluorine Chemistry, 2017, vol. 203, p. 155 - 165

3
[ 16879-02-0 ]
[ 1221171-70-5 ]

Reference： [1] Patent: WO2012/93174, 2012, A1,

4
[ 1221171-70-5 ]
[ 135900-33-3 ]

Reference： [1] Patent: WO2016/144792, 2016, A1,

[ 1221171-70-5 ] Synthesis Path-Downstream 1~32

1
[ 75-77-4 ]
[ 1221171-70-5 ]
[ 1221172-02-6 ]

Yield	Reaction Conditions	Operation in experiment
94%		c) 6-chloro-2-(trifluoromethoxy)-3-(trimethylsilyl)pyridine (1-6); A LDA solution was prepared from n-BuLi 2.5M in hexane (22 mL; 56.80 mmol; 1.1 eq) and diisopropylamine (8 mL; 56.80 mmol; 1.1 eq) in THF (40 mL) at 0C. To the LDA solution at -78 C, a solution of <strong>[1221171-70-5]2-chloro-6-(trifluoromethoxy)pyridine</strong> (10.2 g; 51.64 mmol; 1 eq) in THF (40 mL) was added dropwise over 30 minutes. The solution was stirred at -78 C for 2 hours, after what TMSCI (7.20 mL; 56.80 mmol; 1.1 eq) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred 1 hour. Water (120 mL) was then added. The aqueous layer was extracted with diethylether (3 x 120 mL), and the combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified on silica gel using petroleum ether (100 %) as an eluent to afford 6-chloro-2- (trifluoromethoxy)-3-(trimethylsilyl)pyridine in 94 % yield as a colorless oil.1H- MR (CDC13): delta (ppm) 0.33 (s, 9H); 7.21 (d, 1H); 7.77 (d, 1H).
83.2%		[00532] An LDA solution was prepared from n-BuLi (2.5M in hexane, 9.0 mL, 22.4mmols, 1.3 eq) and diisopropylamine (2.60 g, 25.9 mmols, 1.5 eq) in THF (10 mL) at 0C. To the LDA solution was added a solution of 77 (3.40 g, 17.3 mmols, 1.0 eq) in THF(10 mL) dropwise at -78 C. The solution was stirred at -78 C for 2 hours. After TMSC1 (2.42 g, 22.4 mmols, 1.3 eq) was added dropwise, the reaction mixture was allowed to warm up to room temperature and stirred for 1 hour. Water (120 mL) was added. The aqueous layer was extracted with ethyl acetate (100 mL x 3), and the combined organic layers were dried over Na2SO4 and concentrated. The crude was purified on silica gel using petroleum ether (100 percent) as an eluent to afford the desired compound 78 (3.90 g, 14.4 mmols, 83.2%) as a yellow oil.
68%		I-Chloro--trifluoromethoxy-S-trimethylsilylpyridine (47); At 0 0C, diisopropylamine (0.9 g, 1.2 mL, 8.9 mmol, 1.1 eq) was added dropwise to a solution of butyllithium (1.56 M in hexane, 5.7 mL, 8.9 mmol, 1.1 eq) in THF (15 mL). At -78 0C, a solution of 2-chloro-6-trifluoromethoxy pyridine (2, 1.6 g, 8.1 mmol, 1 eq) in THF (5 mL) was added dropwise and the reaction mixture was stirred for 2 h at this temperature. Chlorotrimethylsilane (1.0 g, 1.2 mL, 8.9 mmol, 1.1 eq) was then added and the mixture was allowed to reach 25 0C before being neutralized with water (20 mL) and extracted with diethylether (3 chiltheta mL). The combined organic layers were dried over sodium sulfate before being evaporated. The crude product was distilled under vacuum to afford pure 2-chloro-6-trifluoromethoxy-5-trimethylsilylpyridine (47, 1.5 g, 5.5 mmol, 68%) as a colorless oil; b.p. 89-93 0C / 14 mbar.1H NMR (CDCl3, 300 MHz): delta = 7.78 (d, J = 7.6 Hz, 1 H), 7.22 (d, J = 7.6 Hz, 1 H), 0.34 (s, 9 H). - 13C NMR (CDCl3, 75 MHz): delta = 159.5, 149.8, 147.7, 147.3, 121.5, 120.4 (q, J= 260 Hz), -1.7.

68%		Butyllithium (1.56 M in hexanes, 5.7 mL, 8.9 mmol, 1.1 equiv.) was added dropwise at 0 C to a solution of diisopropylamine (1.2 mL,8.9 mmol, 1.1 equiv.) in THF (15 mL). A solution of <strong>[1221171-70-5]2-chloro-6-(trifluoromethoxy)pyridine</strong> 2 (1.6 g, 8.1 mmol, 1 equiv.) in THF (5 mL) was added dropwise at-78 C, and the reaction mixture was stirred for 2 h at this temperature. Chlorotrimethylsilane (1.0 g, 1.13 mL,8.9 mmol, 1.1 equiv.) was then added dropwise and the mixture was allowed to reach 25 C before being neutralised with water (20 mL) andextracted with diethyl ether (3 ×10 mL). The combined organic layerswere dried over sodium sulphate and concentrated in vacuo. The crude product was distilled under reduced pressure to afford pure 2-chloro-6-(trifluoromethoxy)-5-(trimethylsilyl)pyridine (3). Colourless oil (1.5 g,68%), b.p.= 89-93 C (14 mbar); 1H NMR (CDCl3, 300 MHz, 25 C): delta7.78 (d, 1H, J =7.6 Hz, H-3), 7.22 (d, 1H, J =7.6 Hz, H-4), 0.34 (s,9H, SiMe3) ppm.
		To a solution of LDA (0.557 mL, 1.114 mmol) in THF (3 mL) was added <strong>[1221171-70-5]2-chloro-6-(trifluoromethoxy)pyridine</strong> (0.2 g, 1.0 12 mmol) dropwise at -78 C. After addition, the mixture was stirred at -78 C for 1.5 h. Then TMS-Cl (0.142 mL, 1.114 mmol) in THF (1 mL) was added dropwise at -78 C. After addition, the mixture was stirred at 10C for 14 h with aN2 balloon. The mixture was quenched by water (10 mL) and extracted by DCM (15 mL). Organic phase was dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by combiflash(Si02, eluting with petroleum ether) to give the title compound as colorless oil.1H NMR (CDC13, 400MHz): 7.76 (d, J= 8.0 Hz, 1H), 7.22 (d, J= 7.2 Hz, 1H), 0.33 (s, 9H).

Reference： [1]Patent: WO2012/93174,2012,A1 .Location in patent: Page/Page column 38-39
[2]Patent: WO2016/144792,2016,A1 .Location in patent: Paragraph 00532
[3]Patent: WO2010/40461,2010,A1 .Location in patent: Page/Page column 46-47
[4]European Journal of Organic Chemistry,2010,p. 6043 - 6066
[5]Journal of Fluorine Chemistry,2017,vol. 203,p. 155 - 165
[6]Patent: WO2019/5588,2019,A1 .Location in patent: Page/Page column 52; 53

2
[ 124-38-9 ]
[ 1221171-70-5 ]
[ 1221171-91-0 ]

Yield	Reaction Conditions	Operation in experiment
69%		6-Chloro-2-trifluoromethoxy nicotinic acid (37); At 0 0C, diisopropylamine (1.3 g, 1.8 mL, 12.6 mmol, 1 eq) was added dropwise to a solution of butyllithium (1.56 M in hexane, 8.3 mL, 12.6 mmol, 1 eq) in THF (25 mL). At -100 0C, a solution of <strong>[1221171-70-5]2-chloro-6-trifluoromethoxypyridine</strong> (2, 2.5 g, 12.6 mmol, 1 eq) in THF (5 mL) was added dropwise and the reaction mixture was stirred for 4 h at - 85 0C. The mixture was then poured onto an excess of freshly crushed dry ice before being treated with an aqueous solution of sodium hydroxide (5%, 25 mL). The resulting aqueous layer was collected, washed with diethylether (15 mL) and acidified to pH 4 by dropwise addition of hydrochloric acid (6 N, 8 mL). After extraction with ethyl acetate (3 x 20 mL), the combined organic layers were dried over sodium sulfate before being evaporated to afford pure 6-chloro-2-trifluoromethoxy nicotinic acid (37, 1.9 g, 7.9 mmol, 69%) as a white powder; m.p. 139-142 0C.1H NMR (CDCl3, 300 MHz): delta = 8.32 (d, J = 8.2 Hz, 1 H), 7.29 (d, J= 8.2 Hz, 1 H). -19F NMR (CDCl3, 282 MHz): delta = -56.5 - 13C NMR (CDCl3, 75 MHz): delta = 167.5, 154.2, 153.4, 145.3, 122.1, 119.3 (q, 7 = 260 Hz), 113.5. - C7H3ClF3NO3 (241): calcd. (%) C 34.81, H 1.25, N 5.80; found C 34.88, H 1.32, N 5.78.

Reference： [1]Patent: WO2010/40461,2010,A1 .Location in patent: Page/Page column 41-42
[2]European Journal of Organic Chemistry,2010,p. 6043 - 6066

3
[ 1221171-70-5 ]
[ 1221172-10-6 ]

Yield	Reaction Conditions	Operation in experiment
48%		2-Bromo-6-trifluoromethoxypyridine (55); A solution of <strong>[1221171-70-5]2-chloro-6-trifluoromethoxypyridine</strong> (2, 7.0 g, 35.4 mmol) in hydrobromic acid (33% in acetic acid, 100 mL) was heated for 3 days at 100 0C. The reaction mixture was cooled down to 0 0C before being slowly neutralized by addition of saturated aqueous solution of sodium hydrogencarbonate (500 mL). After extraction with ethyl acetate (4 x 100 mL), the combined organic layers were dried over sodium sulfate before being evaporated. The crude oil was distilled under vacuum (67-69 0C / 15 mbar) to afford pure 2-bromo-6-trifluoromethoxypyridine (2, 4.2 g, 17.3 mmol, 48%) as a colorless oil.1H NMR (CDCl3, 300 MHz): delta = 7.58 (t, J = 7.9 Hz, 1 H), 7.37 (d, J = 7.7, 1 H), 6.92 (d, J = 8.0, 1 H). - 19F NMR (CDCl3, 282 MHz): delta = -56.5 - 13C NMR (CDCl3, 75MHz): delta = 154.5, 141.0, 138.1, 125.1, 119.0 (q, J= 260 Hz), 110.1.

Reference： [1]Patent: WO2010/40461,2010,A1 .Location in patent: Page/Page column 50-51
[2]European Journal of Organic Chemistry,2010,p. 6043 - 6066

4
[ 1221171-70-5 ]
[ 1221172-16-2 ]

Yield	Reaction Conditions	Operation in experiment
		5-amino-<strong>[1221171-70-5]2-chloro-6-trifluoromethoxypyridine</strong> (39); At 0 0C, diisopropylamine (1.7 g, 2.4 mL, 16.7 mmol, 1.1 eq) was added dropwise to a solution of butyllithium (1.56 M in hexane, 10.7 mL, 16.7 mmol, 1.1 eq) in THF (25 mL). At -78 0C, a solution of <strong>[1221171-70-5]2-chloro-6-trifluoromethoxypyridine</strong> (2, 3.0 g, 15.2 mmol,1 eq) in THF (7 mL) was added dropwise followed after 2 h by benzenesulfonyl azide(3.3 g, 18.2 mmol, 1.2 eq). The reaction mixture was allowed to reach 25 0C before being treated with a saturated aqueous solution of ammonium chloride (30 mL) and extracted with diethylehter (3 x 20 mL). The combined organic layers were dried over sodium sulfate and evaporated to afford a crude red oil of 5-azido-2-chloro-6- trifluoromethoxy pyridine. It was then dissolved in anhydrous diethylether (100 mL) and added dropwise to a suspension of lithium aluminium hydride (690 mg, 18.2 mmol, 1.2 eq) in diehtylether (100 mL). The reaction mixture was heated under reflux for 5 h before being treated with water (100 mL) and extracted with diethylether (3 * 80 mL). The combined organic layers were dried over sodium sulfate before being evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate/cyclohexane (3:7) as eluent which afforded pure 5-amino-2-chloro-6- trifluoromethoxy pyridine (39, 2.3 g, 10.8 mmol, 71%) as yellow crystals; m.p. 42-45 0C.1H NMR (CDCl3, 300 MHz): delta = 6.98 (d, J = 8.2 Hz, 1 H), 6.95 (d, J = 8.2 Hz, 1 H), 3.83 (bs, 2 H). - 19F NMR (CDCl3, 282 MHz): delta = -56.5 - 13C NMR (CDCl3, 75 MHz): delta = 142.5, 135.3, 131.1, 126.3, 122.7, 120.1 (q, J = 262 Hz). - C6H4ClF3N2O (212): calcd. (%) C 33.90, H 1.90, N 13.18; found C 33.54, H 2.06, N 13.00.

Reference： [1]Patent: WO2010/40461,2010,A1 .Location in patent: Page/Page column 42-43
[2]European Journal of Organic Chemistry,2010,p. 6043 - 6066

5
[ 1221171-70-5 ]
[ 1221171-95-4 ]

Yield	Reaction Conditions	Operation in experiment
78%		2-Chloro-5-iodo-6-trifluoromethoxy pyridine (41); At 0 0C, diisopropylamine (2.2 g, 3.1 mL, 22.2 mmol, 1.1 eq) was added dropwise to a solution of butyllithium (1.56 M in hexane, 14.2 mL, 22.2 mmol, 1.1 eq) in THF (35 mL). At -78 0C, a solution of <strong>[1221171-70-5]2-chloro-6-trifluoromethoxypyridine</strong> (2, 4.0 g, 20.2 mmol,1 eq) in THF (10 mL) was added dropwise followed after 2 h by a solution of iodide (5.7 g, 22.2 mmol, 1.1 eq) in THF (10 mL). The reaction mixture was allowed to reach 25 0C before being treated with a saturated aqueous solution of sodium sulfite (30 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate before being evaporated. The crude dark oil was distilled under vacuum (b.p. 103-106 0C / 16 mbar) to afford pure 2-chloro-5-iodo-6- trifluoromethoxypyridine (41, 5.1 g, 15.7 mmol, 78%) as colorless needles; m.p. 33-350C.1H NMR (CDCl3, 300 MHz): delta = 8.11 (d, J = 8.1 Hz, 1 H), 7.03 (d, J= 8.1 Hz, I H). - 19F NMR (CDCl3, 282 MHz): delta = -57.1 - 13C NMR (CDCl3, 75 MHz): delta = 154.9, 151.7, 148.8, 142.0, 123.3, 120.4 (q, J = 264 Hz).
65.2%		To a solution of LDA (2 M, 2.5 mL) in THF ( 27.0 mL) was added dropwise a solution of <strong>[1221171-70-5]2-chloro-6-(trifluoromethoxy)pyridine</strong> (900 mg, 4.6 mmol) in THF (9.0 mL) at -78C under N2. The mixture was stirred at -78C for 2 h. A solution of I2 (1.3 g, 5.0 mmol, 1.0 mL) in THF (9.0 mL) was added at -78C. Then the mixture was slowly warmed to 25C and stirred for 12 h. The reaction was quenched with saturated H4C1 (15.0 mL) and extracted with ethyl acetate (15.0 mL chi 3). The combined organic phase was washed with brine (15 mL chi 3), dried over anhydrous Na2S04, filtered and concentrated to give a residue. The residue was purified by prep-TLC (Si02) to give 6-chloro-3-iodo-2-(trifluoromethoxy)pyridine (1.2 g, 3.0 mmol, 65.2% yield). 1H MR (400MHz, CHLOROFORM-i ) delta 8.10 (d, J= 8.1 Hz, 1H), 7.03 (d, J= 8.1 Hz, 1H).
61.07%		To a cooled solution of <strong>[1221171-70-5]2-chloro-6-(trifluoromethoxy)pyridine</strong> (0.3 g, 1.51 mmol) in anhydrous THF (2 ml.) was added LDA (2M in THF, 0.9 ml_, 1 .82 mmol) dropwise over 5 min and the resulting solution was stirred for 2 h at -78C. Iodine (0.5 g, 1 .97 mmol) in anhydrous TFIF (1 ml.) was then added dropwise over 5 min at -78C and stirred for an hour at same temperature. The reaction mixture was then quenched with saturated aq.NFUCI solution (5 ml_). Crude was extracted with EtOAc (10 mL X 2) and combined organic phases were washed with Na2S2C>3 (2M, 10 mL), dried over sodium sulphate, evaporated under reduced pressure to afford a title compound as colourless liquid (0.30g, 61 .07 %), Rf = 0.6 (05% EtOAc in n-Hexane); 1H NMR (300 MHz, Chloroform-d) d 8.09 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.2 Hz, 1 H).

Reference： [1]Patent: WO2010/40461,2010,A1 .Location in patent: Page/Page column 43-44
[2]European Journal of Organic Chemistry,2010,p. 6043 - 6066
[3]Patent: WO2018/222918,2018,A1 .Location in patent: Paragraph 00215
[4]Patent: WO2019/244049,2019,A1 .Location in patent: Paragraph 00246

6
[ 1221171-69-2 ]
[ 1221171-70-5 ]

Yield	Reaction Conditions	Operation in experiment
62%	With antimonypentachloride; antimony(III) fluoride; at 120℃; for 3.33333h;Inert atmosphere;	b) 2-chloro-6-(trifluoromethoxy)pyridine (1-5); To a mixture of SbF3 (29.87 g; 167.10 mmol; 2 eq) and SbCl5 (1.61 mL; 12.53 mmol; 0.15 eq) stirred under argon at 120C, was added dropwise over 20 minutes 2-chloro-6- (trichloromethoxy)pyridine (20.63 g; 83.55 mmol; 1 eq). After 3 hours stirring at 120C, the reaction mixture was cooled to room temperature and dichlorom ethane (350 mL) was added, followed by a saturated solution of sodium carbonate (350 mL) and an aqueous solution of 20% KF (175 mL). The biphasic mixture was filtered on Celite. The 2 layers were separated and the aqueous layer was extracted with dichloromethane (5 x 100 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated to dryness. The crude obtained was purified under vacuum distillation (P = 35 mbars; T = 81-83C) to afford 2-chloro-6- (trifluoromethoxy)pyridine in 62 % yield as a colorless oil.1H- MR (CDC13): delta (ppm) 6.96 (d, 1H); 7.27 (d, 1H); 7.75 (t, 1H).
53%	With antimony(III) fluoride;antimonypentachloride; at 120 - 150℃;	2-Chloro-6-trifluoromethoxypyridine (2); 2-Chloro-6-trichloromethoxypyridine (1, 5.9 g, 23.8 mmol) was added dropwise to a molten mixture Of SbF3 (8.7 g, 47.7 mmol, 2.0 eq) and SbCl5 (1.0 g, 0.45 mL, 3.6 mmol, 0.15 eq) at 120 0C and stirred for 3 h at 150 0C. GC monitoring indicated 100% conversion and disappearance of byproduct OCF2Cl. The mixture was then cooled to 0 0C and dissolved in dichloromethane (100 mL). The solution was quenched with saturated aqueous solution of sodium hydrogencarbonate (100 mL) and potassium fluoride (20%, 50 mL), the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over sodium sulfate and the solvent was distilled. The crude product was distilled under vacuum to afford pure 2-chloro-6-trifiuoromethoxypyridine (2, 2.5 g, 10.1 mmol, 53%) as a colorless oil; b.p. 42-44 0C / 20 mbar. - 1H NMR (CDCl3, 300 MHz): delta = 7.67 (t, J = 7.9 Hz, 1 H), 7.18 (d, J = 7.7 Hz, 1 H), 6.87 (d, J= 8.0 Hz, 1 H). - 13C NMR (CDCl3, 75 MHz): delta = 155.6, 149.3, 141.9, 122.2, 119.8 (q, J= 262 Hz), 111.8. - MS(EI): m/z = 197 [M+], 162 [M+-Cl].
53%	With antimonypentachloride; antimony(III) fluoride; at 120 - 140℃; for 3h;	2-Chloro-6-trichloromethoxypyridine (1, 5.9 g, 24 mmol, 1 equiv.) was added dropwise at 120 C to a mixture of SbF3 (8.7 g, 48 mmol, 2equiv.) and SbCl5 (0.60 mL, 4.8 mmol, 0.2 equiv.) and the mixture was stirred for 3 h at 140 C. GC monitoring indicated 100% conversion and disappearance of the-OCF2Cl byproduct. The mixture was then cooled to room temperature and dissolved in dichloromethane (100 mL). The solution was washed with 2 M HCl (150 mL) and the aqueous layer wa sextracted with dichloromethane (2 × 50 mL). The combined organic layers were dried over sodium sulphate and the solvent was evaporated at atmospheric pressure. The crude product was distilled under reduced pressure to afford pure 2-chloro-6-trifluoromethoxypyridine (2).Colourless oil (2.5 g, 53% yield), b.p.= 42-44 C (20 mbar); 1H NMR(CDCl3, 300 MHz, 25 C): delta 7.67 (t, 1H, J =7.9 Hz, H-4), 7.18 (d, 1H,J = 7.9 Hz, H-5), 6.87 (d, 1H, J =7.9 Hz, H-3) ppm; 13C NMR (CDCl3,75 MHz, 25 C): delta 155.6 (C), 149.3 (C), 142.0 (CHarom), 122.2(CHarom), 119.8 (q, JC-F= 262.1 Hz, OCF3), 111.1 (CH); 19F NMR(CDCl3, 282 MHz, 25 C): delta -57.2 ppm.

Reference： [1]Patent: WO2012/93174,2012,A1 .Location in patent: Page/Page column 38
[2]Patent: WO2010/40461,2010,A1 .Location in patent: Page/Page column 17-18
[3]European Journal of Organic Chemistry,2010,p. 6043 - 6066
[4]ChemMedChem,2015,vol. 10,p. 715 - 726
[5]Journal of Fluorine Chemistry,2017,vol. 203,p. 155 - 165

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