[ CAS No. 198206-33-6 ] {[proInfo.proName]}

Name: 198206-33-6|1-Iodo-3-(trifluoromethoxy)benzene|97%
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SKU: A130922
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Quality Control of [ 198206-33-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 198206-33-6 ]

Product Details of [ 198206-33-6 ]

CAS No. :	198206-33-6	MDL No. :	MFCD01090992
Formula :	C₇H₄F₃IO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UQZXQSQWKJZHCD-UHFFFAOYSA-N
M.W :	288.01	Pubchem ID :	2777293
Synonyms :

Calculated chemistry of [ 198206-33-6 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	45.84
TPSA :	9.23 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) :	-5.17 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.35
Log Po/w (XLOGP3) :	4.06
Log Po/w (WLOGP) :	4.45
Log Po/w (MLOGP) :	3.17
Log Po/w (SILICOS-IT) :	3.35
Consensus Log Po/w :	3.48

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.42
Solubility :	0.0109 mg/ml ; 0.0000379 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.96
Solubility :	0.0317 mg/ml ; 0.00011 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.97
Solubility :	0.031 mg/ml ; 0.000108 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.17

Safety of [ 198206-33-6 ]

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

Application In Synthesis of [ 198206-33-6 ]

* 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 [ 198206-33-6 ]
Downstream synthetic route of [ 198206-33-6 ]

[ 198206-33-6 ] Synthesis Path-Upstream 1~5

1
[ 591-50-4 ]
[ 103962-05-6 ]
[ 175278-00-9 ]
[ 198206-33-6 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13784 - 13789[2] Angew. Chem., 2018, vol. 130, p. 13980 - 13985,6

2
[ 591-50-4 ]
[ 103962-05-6 ]
[ 175278-00-9 ]
[ 198206-33-6 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13784 - 13789[2] Angew. Chem., 2018, vol. 130, p. 13980 - 13985,6

3
[ 1535-73-5 ]
[ 198206-33-6 ]

Yield	Reaction Conditions	Operation in experiment
14%	Stage #1: With sulfuric acid; sodium nitrite In water at -5℃; for 0.25 h; Stage #2: With potassium iodide In water at 20℃;	l-Iodo-3-(trifluoromethoxy)benzene:; To 3-(trifluoromethoxy)beπzenamine (17.7 g, 100.00 mmol) was added a solution OfNaNO₂ (7.4 g, 115.62 mmol) in H₂O (80 ml). H₂SO₄ (25 g, 250.00 mmol) was added dropwise with stirring at -5 °C. The resulting solution was kept at -5 °C for 15 minutes. To this solution was added a solution of KI (20 g, 120,48 mmol) in H₂O (60 ml) dropwise, The resulting solution was stirred overnight at room temperature and extracted with EtOAc (2 X 100 mL). The combined organic layers were washed with Na₂SO₃/H₂O (2 X 50 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford 4.0 g (14percent) of l-iodo-3- (trifluoromethoxy)benzene.

Reference： [1] Patent: WO2006/55187, 2006, A1, . Location in patent: Page/Page column 99-100

4
[ 2252-44-0 ]
[ 198206-33-6 ]

Reference： [1] European Journal of Organic Chemistry, 2001, # 4, p. 691 - 695

5
[ 591-50-4 ]
[ 103962-05-6 ]
[ 175278-00-9 ]
[ 198206-33-6 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13784 - 13789[2] Angew. Chem., 2018, vol. 130, p. 13980 - 13985,6

[ 198206-33-6 ] Synthesis Path-Downstream 1~88

1
[ 2252-44-0 ]
[ 198206-33-6 ]

Reference： [1]European Journal of Organic Chemistry,2001,p. 691 - 695

2
[ 5440-69-7 ]
[ 198206-33-6 ]
2,6-bis-(3-trifluoromethoxyphenyl)-benzoic acid isopropylamide [ No CAS ]

Reference： [1]Organic Letters,2006,vol. 8,p. 4947 - 4949

3
[ 70001-43-3 ]
[ 198206-33-6 ]
2-(3-trifluoromethoxyphenyl)-4,5-dimethylbenzoic acid isopropylamide [ No CAS ]

Reference： [1]Organic Letters,2006,vol. 8,p. 4947 - 4949

4
[ 35306-75-3 ]
[ 198206-33-6 ]
3-bromo-6-(3-trifluoromethoxyphenyl)-benzoic acid isopropylamide [ No CAS ]

Reference： [1]Organic Letters,2006,vol. 8,p. 4947 - 4949

5
[ 18368-59-7 ]
[ 198206-33-6 ]
[ 1001906-15-5 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; for 24h;	Example 195; Synthesis of 3-iodo-4-methyl-1-(3-(trifluoromethoxy)phenyl)pyridin-2? HP-one; A resealable pressure vessel was charged with copper(l) iodide (0.081 g, 0.425 mmol), 1-iodo-3-(trifluoromethoxy)benzene (0.434 ml, 2.77 mmol) and 3-bromo-4- methylpyridin-2(1H)-one (0.400 g, 2.13 mmol). To the mixture was added dioxane (3 ml.) followed by N1,N2-dimethylethane-1,2-diamine (0.092 ml, 0.851 mmol). The vessel was purged with Argon, sealed, and heated to 1100C for 24 hrs. The mixture was cooled to RT, diluted with EtOAc and washed with water and brine. The organic fraction was adsorbed onto silica gel and purified by silica gel chromatography using 15-80% Hexanes:EtOAc to afford 3-iodo-4-methyl-1- (3-(trifluoromethoxy)phenyl)pyridin-2(1 H)-one as an off-white solid. M+H+ = 396.0.
	With copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; for 24h;Sealed tube;	Example 2Synthesis of 3-iodo-4-methyl-1-(3-(trifluoromethoxy)phenyl)pyridin-2(1 H)- one <n="34"/>A resealable pressure vessel was charged with copper (I) iodide (0.081 g, 0.425 mmol), 1-iodo-3-(trifluoromethoxy) benzene (0.434 ml, 2.77 mmol) and 3-bromo-4- methylpyridin-2(1 H)-one (0.400 g, 2.13 mmol). To the mixture was added dioxane (3 mL) followed by NN2-dimethylethane-1 ,2-diamine (0.092 ml, 0.851 mmol). The vessel was purged with argon, sealed, and heated to 1100C for 24 hrs. The mixture was cooled to RT, diluted with EtOAc and washed with water and brine. The organic fraction was adsorbed onto silica gel and purified by silica gel chromatography using 15-80% Hexanes: EtOAc to afford 3-iodo-4-methyl-1- (3-(trifluoromethoxy)phenyl)pyridin-2(1 H)-one as an off-white solid. MH+ = 396.0.

Reference： [1]Patent: WO2008/11109,2008,A2 .Location in patent: Page/Page column 50
[2]Patent: WO2008/8493,2008,A2 .Location in patent: Page/Page column 32-33

6
[ 2759-55-9 ]
[ 198206-33-6 ]
4-methyl-2,6-di-(3-trifluoromethoxyphenyl)-N-propionylaniline [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 7720 - 7725

7
[ 2759-55-9 ]
[ 198206-33-6 ]
4-methyl-N-propionyl-2-(3-trifluoromethoxyphenyl)aniline [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 7720 - 7725

8
[ 103-89-9 ]
[ 198206-33-6 ]
N-acetyl-4-methyl-2,6-di-(3-trifluoromethoxyphenyl)aniline [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 7720 - 7725

9
[ 198206-33-6 ]
4-methyl-2,6-di-(3-trifluoromethoxyphenyl)aniline [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 7720 - 7725

10
[ 126378-11-8 ]
[ 198206-33-6 ]
[ 876049-04-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In acetonitrile; at 20℃; for 2.5h;	To a degassed (Ar) solution of <strong>[198206-33-6]1-iodo-3-trifluoromethoxy-benzene</strong> (0.54 ml, 3 mmol) in acetonitrile (30 ml) was added pent-4-ynoic acid benzyl ester (719 mg, 4 mmol; A. Rosowsky, R. A. Forsch, F. S. Queener, J. Med. Chem. 2003, 46, 1726-1736), PdCl2(Ph3P)2 (122 mg, 0.17 mmol), cuprous iodide (33 mg, 0.17 mmol) and triethylamine (1.45 ml, 10 mmol). The reaction mixture was stirred for 2.5 h at ambient temperature, poured into a solution of aqueous 10% KHSO4/ice water 1/1 and extracted two times with ether. The combined extracts were washed with aqueous 10% KHSO4 and aqueous 10% NaCl and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 1.13 g (3.2 mmol, 93%) of the title compound as yellow oil. MS: 349.5 (M+H)+.

Reference： [1]Patent: US2006/35956,2006,A1 .Location in patent: Page/Page column 24

11
[ 1535-73-5 ]
[ 198206-33-6 ]

Yield	Reaction Conditions	Operation in experiment
14%		l-Iodo-3-(trifluoromethoxy)benzene:; To 3-(trifluoromethoxy)be?zenamine (17.7 g, 100.00 mmol) was added a solution OfNaNO2 (7.4 g, 115.62 mmol) in H2O (80 ml). H2SO4 (25 g, 250.00 mmol) was added dropwise with stirring at -5 C. The resulting solution was kept at -5 C for 15 minutes. To this solution was added a solution of KI (20 g, 120,48 mmol) in H2O (60 ml) dropwise, The resulting solution was stirred overnight at room temperature and extracted with EtOAc (2 X 100 mL). The combined organic layers were washed with Na2SO3/H2O (2 X 50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford 4.0 g (14%) of l-iodo-3- (trifluoromethoxy)benzene.

Reference： [1]Patent: WO2006/55187,2006,A1 .Location in patent: Page/Page column 99-100

12
[ 1759-68-8 ]
[ 198206-33-6 ]
C₂₇H₂₃F₆NO₃ [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7818 - 7821

13
[ 1107620-19-8 ]
[ 198206-33-6 ]
[ 1107619-56-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 80℃; for 2h;	A mixture of Compound 1c (60 mg, 0.25 mmol), <strong>[198206-33-6]3-(trifluoromethoxy)iodobenzene</strong> (41.6 muL, 0.26 mmol), bis(triphenylphosphine)palladium(II)dichloride (8.65 mg, 0.01 mmol), CuI (4.69 mg, 0.1 mmol) in anhydrous and degassed triethylamine (3 mL) was heated at 80 C. under a nitrogen atmosphere for 2 h in a sealed vessel. The reaction mixture was cooled, filtered on Celite, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc-Petroleum Ether 5:95) affording the title product (57 mg).MS: [M+H]+=404.351H-NMR (CDCl3delta): 2.50-2.53 (m, 2H), 2.75-2.78 (m, 2H), 3.53-3.58 (m, 4H), 5.64 (s, 1H), 6.78-6.81 (m, 1H), 7.17-7.19 (m, 1H), 7.28-7.30 (m, 1H) 7.34-7.37 (m, 2H), 8.17-8.19 (m, 1H), 8.37-8.38 (m, 1H).

Reference： [1]Patent: US2009/42841,2009,A1 .Location in patent: Page/Page column 38

14
[ 5390-04-5 ]
[ 198206-33-6 ]
[ 500709-29-5 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of 5 g (17 mmol) <strong>[198206-33-6]1-iodo-3-trifluoromethoxy-benzene</strong>, 973 mg (1 mmol) Pd(PPh3)4 and 160 mg (1 mmol) cuprous iodide in 130 ml piperidine was stirred for 30 min at 50 C. under an argon atmosphere. 2.125 g (25 mmol) 4-Pentyn-1-ol was added within 60 min at 50 C. The temperature was raised to 80 C. and the mixture was stirred for 3 h at this temperature. The reaction mixture was cooled to ambient temperature, poured into a solution of saturated aqueous 10% KHSO4/ice water 1/1 and extracted two times with tert butyl methyl ether. The combined extracts were washed with water and brine (two times) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 3.4 g of the title compound as orange oil. MS: 244.2 (M)+.

Reference： [1]Patent: US2006/4091,2006,A1 .Location in patent: Page/Page column 21-22

15
[ 107-18-6 ]
[ 198206-33-6 ]
[ 1057671-08-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4151 - 4158

16
[ 1215018-79-3 ]
[ 198206-33-6 ]
[ 1215018-84-0 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 3965 - 3972

17
C₃₈H₅₀N₃O₈Pol [ No CAS ]
[ 198206-33-6 ]
C₄₅H₅₃F₃N₃O₉Pol [ No CAS ]

Reference： [1]Chemistry - A European Journal,2010,vol. 16,p. 2692 - 2695

18
[ 35590-37-5 ]
[ 198206-33-6 ]
[ 1227402-37-0 ]

Reference： [1]Nature Chemistry,2010,vol. 2,p. 313 - 318

19
[ 1276045-27-2 ]
[ 198206-33-6 ]
[ 1276045-24-9 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; potassium carbonate; L-proline; In dimethyl sulfoxide; at 100℃; for 64h;Inert atmosphere;	General Procedure: To a solution of (S)-N-(piperidin-3-yl)cyclopropanecarboxamide hydrochloride (16, S-enantiomer HCl salt) (150 mg, 0.735 mmol) in DMSO (3 mL) was added K2CO3 (304 mg, 2.21 mmol). The mixture was stirred at rt with argon bubbling for 3 min. 1-Difluoromethoxy-3-iodo-benzene (199 mg, 0.735 mmol) was added, followed by CuI (14 mg, 0.074 mmol) and L-proline (17 mg, 0.147 mmol). The argon bubbling was continued for additional 2 min. The vial was sealed and heated at 100 oC for 64 hours. The reaction was cooled to rt, diluted with ethyl acetate (30.0 mL). The organic layer was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by CombiFlash (hexane/ethyl acetate: 100/0 to 50/50 in 10 min) to afford 46 mg (21%) of desired product 18-f.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1236 - 1242

20
[ 66790-20-3 ]
[ 198206-33-6 ]
[ 1310492-08-0 ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 9286 - 9289

21
[ 934615-47-1 ]
[ 198206-33-6 ]
C₂₉H₂₅ClF₃NO₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7124 - 7130

22
[ 198206-33-6 ]
C₂₈H₂₃ClF₃NO₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7124 - 7130

23
[ 198206-33-6 ]
C₃₅H₃₆ClF₃N₂O₅ [ No CAS ]
C₃₅H₃₆ClF₃N₂O₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7124 - 7130

24
[ 619-44-3 ]
[ 198206-33-6 ]
methyl 3'-(trifluoromethoxy)biphenyl-4-carboxylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11157 - 11161,5
Angewandte Chemie,2012,vol. 124,p. 11319 - 11323,5

25
[ 680596-79-6 ]
[ 198206-33-6 ]
[ 1429345-59-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 1.5h;Inert atmosphere; Microwave irradiation;	Intermediate 15A. 8-(3-(trifluoromethoxy)phenyl)-l,4-dioxaspiro[4.5]dec-7-ene[00192] To a solution of 4,4,5,5-tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)- 1,3,2-dioxaborolane (150 mg, 0.560 mmol) in dioxane (2.5 mL) was added l-iodo-3- (trifluoromethoxy)benzene (195 mg, 0.680 mmol), bis(triphenylphosphine)palladium (II) chloride (20 mg, 0.028 mmol) and a solution of sodium carbonate (179 mg, 1.69 mmol) in water (1.127 mL). The reaction mixture was degassed, refilled with Ar three times, subject to microwave irradiation at 110 C for 90 min. The reaction mixture was diluted with H20 and the aqueous phase extracted with DCM twice. The combined organic portions were dried over MgS04, filtered, concentrated under reduced pressure and purified by flash chromatography (EtOAc/Hexanes 0-50% over 20 min, column 4g, flow rate 40 mL/min) to give Intermediate 15A (119 mg, 0.400 mmol, 70.0% yield) as a clear oil. XH NMR (400 MHz, CHLOROFORM-d) delta ppm1.93 (2 H, t, J=6.4 Hz), 2.48 (2 H, d, J=3.8 Hz), 2.59 - 2.71 (2 H, m), 4.02 (4 H, s), 5.96 - 6.1 1 (1 H, m), 7.03 - 7.1 1 (1 H, m), 7.22 (1 H, s), 7.27 - 7.36 (2 H, m).

Reference： [1]Patent: WO2013/48928,2013,A1 .Location in patent: Paragraph 00192

26
[ 198206-33-6 ]
[ 1429345-60-7 ]

Reference： [1]Patent: WO2013/48928,2013,A1

27
[ 198206-33-6 ]
[ 1429345-61-8 ]

Reference： [1]Patent: WO2013/48928,2013,A1

28
[ 10075-50-0 ]
[ 198206-33-6 ]
[ 1610800-64-0 ]

Yield	Reaction Conditions	Operation in experiment
29%		l-Iodo-3-(trifluoromethyl)benzene (2.204 g, 7.65 mmol) was added to a solution of 5- bromo- lH-indole (1.5 g, 7.65 mmol) and copper(I) bromide (0.110 g, 0.765 mmol) in DMF (30 mL) followed by potassium carbonate (2.1 15 g, 15.30 mmol) and the mixture was stirred at 100 C for 10 min. NaOH (0.0131 g, 0.765 mmol) and copper(II) acetate (0.138 g, 0.765 mmol) were then added at 1 10 C, and the reaction mixture was stirred for 16 h. Insoluble solids were filtered, the filtrate was concentrated, and the residue was partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo to afford the title compound (0.8 g, 29%), which was carried on to the next step without any further purification. ESI-MS m/z = 356 (M+H)+.
	With copper diacetate; potassium carbonate; copper(I) bromide; sodium hydroxide; In N,N-dimethyl-formamide; at 100 - 110℃; for 16.1667h;	5-Bromo-1-(3-(trifluoromethoxy)phenyl)-1H-indole (2A) 1-Iodo-3-(trifluoromethyl)benzene (2.204 g, 7.65 mmol) was added to a solution of 5-bromo-1H-indole (1.5 g, 7.65 mmol) and copper(I) bromide (0.110 g, 0.765 mmol) in DMF (30 mL) followed by potassium carbonate (2.115 g, 15.30 mmol) and the mixture was stirred at 100 C. for 10 min. NaOH (0.0131 g, 0.765 mmol) and copper(II) acetate (0.138 g, 0.765 mmol) were then added at 110 C., and the reaction mixture was stirred for 16 h. Insoluble solids were filtered, the filtrate was concentrated, and the residue was partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulphate and filtered, and the filtrate was concentrated in vacuo to afford the title compound (0.8 g, 29%), which was carried on to the next step without any further purification. ESI-MS m/z=356 (M+H)+.

Reference： [1]Patent: WO2014/81994,2014,A1 .Location in patent: Page/Page column 31
[2]Patent: US2014/148437,2014,A1 .Location in patent: Paragraph 0174-0176

29
[ 198206-33-6 ]
[ 1610800-66-2 ]

Reference： [1]Patent: US2014/148437,2014,A1
[2]Patent: WO2014/81994,2014,A1

30
[ 198206-33-6 ]
[ 1610800-68-4 ]

Reference： [1]Patent: US2014/148437,2014,A1
[2]Patent: WO2014/81994,2014,A1

31
[ 198206-33-6 ]
[ 1610800-70-8 ]

Reference： [1]Patent: US2014/148437,2014,A1
[2]Patent: WO2014/81994,2014,A1

32
[ 198206-33-6 ]
[ 1610800-72-0 ]

Reference： [1]Patent: US2014/148437,2014,A1
[2]Patent: WO2014/81994,2014,A1

33
[ 198206-33-6 ]
[ 1610800-00-4 ]

Reference： [1]Patent: US2014/148437,2014,A1
[2]Patent: WO2014/81994,2014,A1

34
[ 201230-82-2 ]
[ 6638-79-5 ]
[ 198206-33-6 ]
[ 1203575-93-2 ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 5727 - 5732

35
C₁₁H₁₁FN₂ [ No CAS ]
[ 198206-33-6 ]
2-((3-fluoro-1-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)ethynyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); at 100℃; for 1h;Inert atmosphere;	To a solution of 1(21mg, 0.11mmol) and 2(35mg, 0.15mmol) was added Pd(dba)2 (6mg, 0.01mmol), Xantphos (6mg,0.01mmol) and Cs2CO3(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N2 several times. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 100 C for 1h, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (10mg, yield: 39%). LCMS: m/z, 351.1 (M+H)+; 1H NMR (400 MHz, CDCl3): delta 2.39~2.70(m, 2H), 3.47~3.51(m, 2H), 3.75-3.82(m, 2H), 6.27~6.29(m, 1H), 6.37~6.39(m, 1H), 6.50~6.52(m, 1H), 7.14-7.25 (m, 2H), 7.43-7.46 (m, 1H), 7.62-7.66 (m, 1H), 8.55~8.57(m, 1H).

Reference： [1]Patent: WO2014/124560,2014,A1 .Location in patent: Page/Page column 73; 74

36
2-((3-fluoroazetidin-3-yl)ethynyl)pyridine [ No CAS ]
[ 198206-33-6 ]
2-((3-fluoro-1-(3-(trifluoromethoxy)phenyl)azetidin-3-yl)ethynyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); at 100℃; for 1h;Inert atmosphere;	To a solution of 1 (17.6mmol, 0.1mmol) and 2 (36mg, 0.15mmol) was added Pd(dba)2 (6mg,0.01mmol), Xantphos 6mg,0.01mmol) and Cs2CO3(98mg,0.3mmol). The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 100 C for 1h, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (10mg, yield: 30%). LCMS: m/z, 336.1 (M+H)+; 1HNMR (400 MHz, CDCl3): delta 4.17~4.45 (m, 4H), 6.13~6.24 (m, 1H), 6.27~6.33 (m, 1H), 6.57~6.60 (m, 1H), 7.14~7.25 (m, 2H), 7.42~7.44 (m, 1H), 7.61~7.65(m, 1H). 8.54~8.55 (m, 1H).

Reference： [1]Patent: WO2014/124560,2014,A1 .Location in patent: Page/Page column 41; 42

37
[ 198206-33-6 ]
[ 1057671-55-2 ]

Reference： [1]Patent: WO2014/143799,2014,A2

38
[ 107-19-7 ]
[ 198206-33-6 ]
[ 1093173-10-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In diethylamine; for 20h;Inert atmosphere;	A mixture of propargyl alcohol (1.0g, 18mmol), 1-Iodo-3-trifluoromethoxy-benzene (5.14g, 18mmol), copper iodide (0.342g, 1.8mmol), dichlorobis (triphenylphosphine) palladium (II) (0.632g, 0.9mmol), diethylamine (30ml) was degassed for 10min. and stirred for 20hat 25-25C. Excess of diethyl amine was distilled off under vacuum. The residue was diluted with water (50ml) and extracted with ethyl acetate (3×50ml). The organic layer was washed with brine solution and dried over Na2SO4. The solvent was evaporated and the crude product was purified by column chromatography (10% Ethyl acetate in hexane) to obtain pure 3-(3-Trifluoromethoxy-phenyl)-prop-2-yn-1-ol (3.8g, 100%). 1HNMR (CDCl3): delta 1.71 (t, J=6Hz, 1H); 4.52 (d, J=6Hz, 2H); 7.20 (d, J=7.2Hz, 1H); 7.28-7.39 (m, 3H).
80.2%	With morpholine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In toluene; at 80℃;Inert atmosphere;	Step 1 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-l-ol To a solution of l -iodo-3-(trifluoromethoxy)benzene (0.5 g, 1.73 mmol) in toluene (10 mL) was added prop-2-yn-l-ol (0.1 5 g, 2.62 mmol) and morpholine (0.5 mL). Then cuprous iodide (4 mg, 0.02mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02mmol) were added to the mixture under nitrogen. The reaction was heated at 80 C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with ethyl acetate/petroleum ether (1 :6 to 1 :3) to give 3-(3- (trifluoromethoxy)phenyl)prop-2-yn-l-ol (0.3 g, 80.2 %) as a yellow oil. LCMS retention time 1.552 min.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 134,p. 218 - 229
[2]Patent: WO2014/143799,2014,A2 .Location in patent: Page/Page column 395; 396

39
2-(diethoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-c]pyridine [ No CAS ]
[ 198206-33-6 ]
2-(diethoxymethyl)-7-{3-(trifluoromethoxy)phenyl}furo[3,2-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; for 12h;Reflux; Inert atmosphere;	A solution prepared by dissolving 2-(diethoxymethyl)-7-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)furo[3,2-c]pyridine (1.0 mmol) obtained in Reference Example 2 in tetrahydrofuran/water (4/1, v/v, 5 ml) was added with <strong>[198206-33-6]1-iodo-3-(trifluoromethoxy)benzene</strong> (1.2 mmol), sodium carbonate (2.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.0 mol%), and stirred under reflux for 12 hours under a nitrogen atmosphere. The organic layer was separated and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1, v/v) to obtain the title compound as light brown oil (yield: 89%). 1H NMR (CDCl3, 300 MHz) delta 8.90(s, 1H), 8.67(s, 1H), 7.82-7.72(m, 2H), 7.56(dd, 1H), 7.30(d, 1H), 6.97(s, 1H), 5.71(s, 1H), 3.76-3.66(m, 4H), 1.29(t, 6H)
89%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; for 12h;Reflux; Inert atmosphere;	Example 383 (E)-3-Methyl-4-([7-{3-(trifluoromethoxy)phenyl}furo[3,2-c]pyridin-2-yl]-methylene)-1H-pyrazol-5(4H)-one Step 1: Synthesis 2-(diethoxymethyl)-7-{3-(trifluoromethoxy)phenyl}furo[3,2-c]pyridine A solution prepared by dissolving 2-(diethoxymethyl)-7-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)furo[3,2-c]pyridine (1.0 mmol) obtained in Reference Example 2 in tetrahydrofuran/ water (4/1, v/v, 5 ml) was added with <strong>[198206-33-6]1-iodo-3-(trifluoromethoxy)benzene</strong> (1.2 mmol), sodium carbonate (2.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.0 mol %), and stirred under reflux for 12 hours under a nitrogen atmosphere. The organic layer was separated and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1, v/v) to obtain the title compound as light brown oil (yield: 89%). 1H NMR (CDCl3, 300 MHz) delta 8.90 (s, 1H), 8.67 (s, 1H), 7.82-7.72 (m, 2H), 7.56 (dd, 1H), 7.30 (d, 1H), 6.97 (s, 1H), 5.71 (s, 1H), 3.76-3.66 (m, 4H), 1.29 (t, 6H)

Reference： [1]Patent: EP2876109,2015,A1 .Location in patent: Paragraph 0579-0580
[2]Patent: US2015/191478,2015,A1 .Location in patent: Paragraph 0676-0677

40
[ 198206-33-6 ]
(E)-5-(3-(trifluoromethoxy)styryl)-1,3,4-oxathiazol-2-one [ No CAS ]

Reference： [1]ChemistryOpen,2015,vol. 4,p. 342 - 362

41
[ 79-06-1 ]
[ 198206-33-6 ]
(E)-3-(3-(trifluoromethoxy)phenyl)acrylamide [ No CAS ]

Reference： [1]ChemistryOpen,2015,vol. 4,p. 342 - 362

42
C₁₉H₂₀N₂O₄ [ No CAS ]
[ 198206-33-6 ]
5-benzyl-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenoxy) quinazoline-2,4(1H,3H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With 2-Picolinic acid; potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 80℃; for 18h;Inert atmosphere;	Step 8 5-benzyl-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenoxy)quinazoline-2,4(1H,3H)-dione To a solution of 5-benzyl-6-hydroxy-3-(4-hydroxybutyl)-l-methylquinazoline-2,4 (1H,3H)- dione (14 mg, 0.041 mmol) in DMSO (2 mL) was added l-iodo-3-(trifluoromethoxy)benzene (24 mg, 0.082 mmol), K2P04 (17 mg, 0.082 mmol), picolinic acid (1 mg, 0.004 mmol) and Cul (1 mg, 0.004 mmol). The reaction was heated at 80C for 18 h, cooled to RT and diluted with EA (20 mL) and water (10 mL). The organic layer was dried over Na2SC>4 and concentrated to give a residue which was purified by Prep TLC eluted with PE/EA (1 : 1) to give 5-benzyl-3-(3- hydroxypropyl)-l-methyl-6-(3-(trifluoromethoxy)phenoxy) quinazoline-2,4(lH,3H)-dione (8 mg, 50% yield) as a white solid. 1H NMR (CD3OD) delta: 7.47-7.43 (m, 2H), 7.35 (t, J = 8.0 Hz, (0280) 1H), 7.13-7.06 (m, 5H), 6.97-6.95 (m, 1H), 6.81-6.80 (m, 1H), 6.67 (s, 1H), 4.80 (s, 2H), 4.15 (t, J = 7.2 Hz, 2H), 3.65 (s, 3H), 3.61 (t, J = 3.2 Hz, 2H), 1.90-1.85 (m, 2H). LCMS: MH+ 501 and TR = 3.175 min.

Reference： [1]Patent: WO2016/23826,2016,A1 .Location in patent: Page/Page column 38; 39

43
5-(4-fluorobenzyl)-6-hydroxy-3-(3-hydroxypropyl)-1-methylquinazoline-2,4(1H,3H)-dione [ No CAS ]
[ 198206-33-6 ]
5-(4-fluorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenoxy)-quinazoline-2,4(1H,3H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11.5%	With 2-Picolinic acid; potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 85℃; for 18h;Inert atmosphere;	Step 2 5-(4-fluorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenoxy)- quinazoline-2,4(1H,3H)-dione To a solution of 5-(4-fluorobenzyl)-6-hydroxy-3-(3-hydroxypropyl)-1-methylquinazoline-2,4 (1H,3H)-dione (30 mg, 0.084 mmol) in DMSO (2 mL) was added picolinic acid (5 mg, 0.041 mmol), K3PC>4 (80 mg, 0.377 mmol) and Cul (10 mg, 0.053 mmol). The reaction was degassed with nitrogen (3x), heated at 85C for 18h, cooled to RT then diluted with EA (10 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over a2S04, concentrated to a residue and purified by Prep HPLC then dried to give 5-(4-fluorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy) phenoxy)quinazoline-2,4(1H,3H)-dione (5 mg, 1 1.5% yield) as a white solid. 1H NMR (CD3OD) delta: 7.43-7.37 (q, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.10-7.06 (m, 2H), 6.90 (d, J = 9.2 Hz, 1H), 6.80-6.73 (m, 3H), 6.60 (s, 1H), 4.71 (s, 2H), 4.10 (t, J = 7.2 Hz, 2H), 3.59 (s, 3H), 3.55 (t, J = 6.4 Hz, 2H), 1.86-1.79 (m, 2H). LCMS: MH 519 and TR = 3.299 min.

Reference： [1]Patent: WO2016/23826,2016,A1 .Location in patent: Page/Page column 47; 48; 49

44
[ 73183-34-3 ]
[ 198206-33-6 ]
2,2'-(4-(trifluoromethoxy)-1,2-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2016,vol. 138,p. 8408 - 8411

45
[ 198206-33-6 ]
(Sp)-neopentyl(phenyl)-m-trifluoromethoxyphenylphosphine oxide [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2016,vol. 138,p. 13183 - 13186

46
[ 198206-33-6 ]
neopentyl(phenyl)-m-trifluoromethoxyphenylphosphine oxide [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2016,vol. 138,p. 13183 - 13186

47
[ 109-63-7 ]
[ 179113-90-7 ]
[ 198206-33-6 ]
bis(3-trifluoromethoxyphenyl)iodonium tetrafluoroborate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2016,vol. 138,p. 13183 - 13186

48
C₁₇H₂₀N₂O [ No CAS ]
[ 198206-33-6 ]
C₂₄H₂₃F₃N₂O₂ [ No CAS ]
C₂₄H₂₃F₃N₂O₂ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 15387 - 15391
Angew. Chem.,2016,vol. 128,p. 15613 - 15617,5

49
[ 16872-09-6 ]
[ 198206-33-6 ]
C₉H₁₅B₁₀F₃O [ No CAS ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 17542 - 17546

50
[ 120-72-9 ]
[ 198206-33-6 ]
C₁₅H₁₀F₃NOSe [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.9%	With selenium; potassium phosphate; copper(II) oxide; In dimethyl sulfoxide; at 90℃; for 20h;Inert atmosphere;	To a solution of the compound of the above formula (II) in the organic solvent DMSO in the reaction vessel at room temperature,Compounds, elemental Se, CuO powder and K3P0.412H20. Wherein the molar ratio of the compound of the formula (II) to the compound of the formula (III) is 1: 1.5, the molar ratio of the compound of the formula (Pi) to the element Se is 1: 2.5, the molar ratio of the compound of the formula (II) to CuO is 1: 0.15 The molar ratio of the compound of formula (II) to K3P04 · 12H20 was 1: 1.5, then charged with nitrogen and replaced twice so that the reaction atmosphere was a nitrogen atmosphere; then the temperature was raised to 90 C with stirring and incubated for 20 hours.After the post-treatment, the product (I) as a brown liquid was obtained in a yield of 88.9% and a purity of 98.3%

Reference： [1]Patent: CN104387311,2016,B .Location in patent: Paragraph 0088-0091

51
[ 17629-26-4 ]
[ 198206-33-6 ]
3,5-dimethyl-2-[(3-(trifluoromethoxy)phenyl)ethyl]-1H-pyrazole [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 3630 - 3634
Angew. Chem.,2017,vol. 129,p. 3684 - 3688,5

52
[ 100-13-0 ]
[ 198206-33-6 ]
C₁₅H₁₀F₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutylammomium bromide; potassium acetate; palladium diacetate; In N,N-dimethyl-formamide; at 80℃; for 5h;Inert atmosphere; Sealed tube;	General procedure: To a solution of tetrabutylammonium bromide (1.100 g, 3.33 mmol), potassium acetate (0.586 g, 3.57 mmol), and palladium acetate (0.025 g, 0.11 mmol) in DMF (20 mL) were added substituted iodobenzene (2.21 mmol) and 4-nitrostyrene (2.44 mmol). The reaction mixture was recharged with argon and stirred at 80C for 5 h in a sealed tube. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10:3) to afford the intermediate substituted (E)-1-nitro-4-styrylbenzene. To a solution of stannous chloride (2.087 g, 11.05 mmol) in EtOH (20 mL) was added substituted (E)-1-nitro-4-styrylbenzene (2.21 mmol). The reaction mixture was stirred at reflux temperaturefor 4.0 h. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane/methanol, 10:0.1) to afford pure product.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 382 - 392

53
[ 100-13-0 ]
[ 198206-33-6 ]
(E)-4-(3-(trifluoromethoxy)styryl)aniline [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 382 - 392

54
[ 637-69-4 ]
[ 198206-33-6 ]
(E)-1-(4-methoxystyryl)-3-(trifluoromethoxy)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30.6%	With tetrabutylammomium bromide; potassium acetate; palladium diacetate; In N,N-dimethyl-formamide; at 80℃; for 5h;Inert atmosphere; Sealed tube;	General procedure: To a solution of tetrabutylammonium bromide (1.100 g, 3.33mmol), potassium acetate (0.586 g, 3.57 mmol), and palladium acetate (0.025 g, 0.11mmol) in DMF (20 mL) were added substituted iodobenzene (2.21mmol) and substituted styrene (2.44 mmol). The reaction mixture was recharged with argon and stirred at 80C for 5 h in a sealed tube. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10:3) to afford pure product.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 382 - 392

55
[ 2628-16-2 ]
[ 198206-33-6 ]
(E)-4-(3-(trifluoromethoxy)styryl)phenol [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 382 - 392

56
[ 2628-16-2 ]
[ 198206-33-6 ]
C₁₇H₁₃F₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutylammomium bromide; potassium acetate; palladium diacetate; In N,N-dimethyl-formamide; at 80℃; for 5h;Inert atmosphere; Sealed tube;	General procedure: To a solution of tetrabutylammonium bromide (1.100 g, 3.33 mmol), potassium acetate (0.586 g, 3.57 mmol), and palladium acetate (0.025 g, 0.11 mmol) in DMF (20 mL) were added substituted iodobenzene (2.21 mmol) and 4-acetyloxystyrene (2.44 mmol). The reaction mixture was recharged with Argon and stirred at 80C for 5 h in a sealed tube. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10:3) to afford the intermediate substituted (E)-4-styrylphenyl acetate. To a solution of triethylamine (2.0 mL) in MeOH (5 mL) was added substituted (E)-4-styrylphenyl acetate (1.36 mmol). The reaction mixture was stirred at reflux temperaturefor 3 h. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane/methanol, 10:0.3) to afford pure product.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 382 - 392

57
[ 198206-33-6 ]
[ 1188541-00-5 ]