[ CAS No. 402-52-8 ] {[proInfo.proName]}

Name: 402-52-8|1-Methoxy-4-(trifluoromethyl)benzene|98%
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SKU: A233289
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Quality Control of [ 402-52-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 402-52-8 ]

CAS No. :	402-52-8	MDL No. :	MFCD03094456
Formula :	C₈H₇F₃O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CFIPQRIPCRRISV-UHFFFAOYSA-N
M.W :	176.14	Pubchem ID :	600604
Synonyms :

Calculated chemistry of [ 402-52-8 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	37.94
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) :	-5.12 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.19
Log Po/w (XLOGP3) :	3.18
Log Po/w (WLOGP) :	3.87
Log Po/w (MLOGP) :	2.88
Log Po/w (SILICOS-IT) :	2.83
Consensus Log Po/w :	2.99

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.17
Solubility :	0.118 mg/ml ; 0.000671 mol/l
Class :	Soluble
Log S (Ali) :	-3.04
Solubility :	0.159 mg/ml ; 0.000902 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.41
Solubility :	0.0688 mg/ml ; 0.000391 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.02

Safety of [ 402-52-8 ]

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

Application In Synthesis of [ 402-52-8 ]

* 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 [ 402-52-8 ]
Downstream synthetic route of [ 402-52-8 ]

[ 402-52-8 ] Synthesis Path-Upstream 1~5

1
[ 124-38-9 ]
[ 402-52-8 ]
[ 4864-01-1 ]

Reference： [1] Patent: WO2011/25982, 2011, A2, . Location in patent: Page/Page column 145

2
[ 402-52-8 ]
[ 402-10-8 ]

Reference： [1] Organometallics, 2018, vol. 37, # 19, p. 3243 - 3247
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 2, p. 727 - 739
[3] Tetrahedron, 2007, vol. 63, # 41, p. 10127 - 10132

3
[ 402-52-8 ]
[ 349-67-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 12, p. 3089 - 3104

4
[ 2591-86-8 ]
[ 402-52-8 ]
[ 146539-83-5 ]

Reference： [1] Journal of Organic Chemistry, 1993, vol. 58, # 6, p. 1385 - 1392

5
[ 402-52-8 ]
[ 67589-15-5 ]

Reference： [1] Patent: WO2011/51478, 2011, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6414 - 6416

[ 402-52-8 ] Synthesis Path-Downstream 1~88

1
[ 124-41-4 ]
[ 98-56-6 ]
[ 402-52-8 ]

Reference： [1]Journal of general chemistry of the USSR,1965,vol. 35,p. 1944 - 1947
Zhurnal Obshchei Khimii,1965,vol. 35,p. 1952 - 1955
[2]Journal of the Chemical Society. Perkin transactions II,1974,p. 256 - 260

2
[ 2591-86-8 ]
[ 402-52-8 ]
[ 146539-83-5 ]

Reference： [1]Journal of Organic Chemistry,1993,vol. 58,p. 1385 - 1392

3
[ 104-92-7 ]
[ 75-63-8 ]
[ 402-52-8 ]

Reference： [1]Journal of the Chemical Society. Chemical communications,1992,p. 53 - 54

4
[ 104-92-7 ]
[ 2314-97-8 ]
[ 402-52-8 ]
[ 14038-06-3 ]
[ 100-66-3 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1980,p. 661 - 664

5
[ 75-63-8 ]
[ 696-62-8 ]
[ 402-52-8 ]

Reference： [1]Journal of the Chemical Society. Chemical communications,1992,p. 53 - 54
[2]Journal of the Chemical Society. Chemical communications,1992,p. 53 - 54

6
[ 623-12-1 ]
[ 88986-32-7 ]
[ 402-52-8 ]

Reference： [1]Journal of the Chemical Society. Chemical communications,1993,p. 1389 - 1391

7
[ 696-62-8 ]
[ 2923-18-4 ]
[ 402-52-8 ]

Reference： [1]Chemistry Letters,1981,p. 1719 - 1720

8
[ 696-62-8 ]
[ 120120-26-5 ]
[ 402-52-8 ]
[ 14038-06-3 ]

Reference： [1]Tetrahedron Letters,1991,vol. 32,p. 91 - 94
[2]Tetrahedron Letters,1991,vol. 32,p. 91 - 94

9
[ 2168-77-6 ]
[ 402-52-8 ]
4-Methoxy-thiobenzoyl fluoride [ No CAS ]

Reference： [1]Tetrahedron Letters,1990,vol. 31,p. 3357 - 3358

10
[ 421-83-0 ]
[ 100-66-3 ]
[ 402-52-8 ]
[ 454-90-0 ]
[ 395-48-2 ]

Reference： [1]Chemistry Letters,1990,p. 649 - 650
[2]Journal of the Chemical Society. Perkin transactions I,1994,p. 1339 - 1346

11
[ 383-73-3 ]
[ 100-66-3 ]
[ 402-52-8 ]
[ 454-90-0 ]
[ 395-48-2 ]

Reference： [1]Journal of Fluorine Chemistry,1990,vol. 46,p. 423 - 431
[2]Journal of Fluorine Chemistry,1990,vol. 46,p. 423 - 431

12
[ 67-56-1 ]
[ 98-56-6 ]
[ 402-52-8 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1986,vol. 105,p. 171 - 175
[2]Organic Process Research and Development,2008,vol. 12,p. 480 - 489

13
[ 402-52-8 ]
[ 402-10-8 ]

Reference： [1]Organometallics,2018,vol. 37,p. 3243 - 3247
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 727 - 739
[3]Tetrahedron,2007,vol. 63,p. 10127 - 10132

14
[ 104-92-7 ]
[ 431-47-0 ]
[ 696-62-8 ]
[ 402-52-8 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

15
[ 431-47-0 ]
[ 696-62-8 ]
[ 104-92-7 ]
[ 402-52-8 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

16
[ 431-47-0 ]
[ 696-62-8 ]
[ 402-52-8 ]
[ 100-66-3 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

17
[ 431-47-0 ]
[ 696-62-8 ]
[ 623-12-1 ]
[ 402-52-8 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

18
[ 431-47-0 ]
[ 696-62-8 ]
[ 402-52-8 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

19
[ 431-47-0 ]
[ 696-62-8 ]
[ 402-52-8 ]
[ 150-78-7 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325
[2]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

20
[ 431-47-0 ]
[ 696-62-8 ]
[ 68-12-2 ]
[ 104-92-7 ]
[ 402-52-8 ]
[ 7291-00-1 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

21
[ 431-47-0 ]
[ 696-62-8 ]
[ 68-12-2 ]
[ 402-52-8 ]
[ 7291-00-1 ]
[ 100-66-3 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

22
[ 431-47-0 ]
[ 696-62-8 ]
[ 68-12-2 ]
[ 402-52-8 ]
[ 7291-00-1 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325
[2]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

23
[ 431-47-0 ]
[ 696-62-8 ]
[ 68-12-2 ]
[ 402-52-8 ]
[ 7291-00-1 ]
[ 150-78-7 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325
[2]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

24
[ 383-63-1 ]
[ 696-62-8 ]
[ 402-52-8 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

25
[ 696-62-8 ]
[ 407-25-0 ]
[ 402-52-8 ]
[ 150-78-7 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325

26
[ 402-52-8 ]
tris(2-methoxy-5-trifluoromethylphenyl)methanol [ No CAS ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 10127 - 10132

27
[ 402-52-8 ]
tris(2-methoxy-5-trifluoromethylphenyl)methane [ No CAS ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 10127 - 10132

28
[ 104-92-7 ]
[ 402-52-8 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325
[2]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325
[3]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325
[4]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325
[5]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325
[6]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325
[7]Journal of Fluorine Chemistry,2007,vol. 128,p. 1318 - 1325
[8]Angewandte Chemie - International Edition,2012,vol. 51,p. 536 - 539

29
[ 402-52-8 ]
[ 329943-17-1 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 727 - 739

30
[ 402-52-8 ]
[ 329943-15-9 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 727 - 739

31
[ 402-52-8 ]
[ 329943-23-9 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 727 - 739

32
[ 402-52-8 ]
[ 329943-21-7 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 727 - 739

33
[ 402-52-8 ]
[ 329943-19-3 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 727 - 739

34
[ 402-52-8 ]
2-[2-(3-cyano-benzoyl)-4-trifluoromethyl-phenoxy]-N-(6-methyl-3H-benzoimidazol-5-yl)-acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 727 - 739

35
[ 402-52-8 ]
2-[2-(3-cyano-benzoyl)-4-trifluoromethyl-phenoxy]-N-(2-methyl-4-sulfamoyl-phenyl)-acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 727 - 739

36
[ 402-52-8 ]
[ 349-67-7 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 3089 - 3104

37
[ 402-52-8 ]
4-(4-chloro-benzyl)-2-(2-methoxy-5-trifluoromethyl-phenoxymethyl)-morpholine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 3089 - 3104

38
[ 402-52-8 ]
4,4'-(4-Methoxyphenylmethylen)bis-1-naphthol [ No CAS ]

Reference： [1]Pharmazie,1996,vol. 51,p. 89 - 92

39
[ 402-52-8 ]
protonated 2-methoxy-5-(trifluoromethyl)benzaldehyde [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1993,vol. 58,p. 1385 - 1392

40
[ 98-56-6 ]
[ 402-52-8 ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium methylate; In methanol; water;	EXAMPLE 10 Production of 4-(trifluoromethyl)anisole 200 g (1.11 mol) of 4-(trifluoromethyl)chlorobenzene, 179 g (3.31 mol) of sodium methoxide, and 600 ml of methanol were mixed together in a pressurized reaction vessel, followed by stirring for 6 hr at 150 C. under tight sealing. The resulting reaction mixture was filtered to remove precipitates. Water was added to the obtained filtrate, followed by extraction with n-hexane. The resulting organic layer was washed with water, followed by drying with magnesium sulfate anhydride and removal of the solvent by distillation. The obtained residue was purified by distillation, thereby obtaining 112 g (0.636 mol) of 4-(trifluoromethyl)anisole (yield: 57%).

Reference： [1]Patent: US2003/109574,2003,A1

41
[ 402-43-7 ]
[ 402-52-8 ]

Yield	Reaction Conditions	Operation in experiment
62.6%	With sodium methylate; In methanol;	EXAMPLE 11 Production of 4-(trifluoromethyl)anisole 100 g (0.445 mol) of 4-(trifluoromethyl)bromobenzene, 120 g (2.22 mol) of sodium methoxide, and 300 ml of methanol were mixed together in a pressurized reaction vessel, followed by stirring for 6 hr at 150 C. under tight sealing. The resulting reaction mixture was poured into water, followed by extraction with n-hexane. The resulting organic layer was washed with water, followed by drying with magnesium sulfate anhydride and removal of the solvent by distillation. The obtained residue was purified by distillation, thereby obtaining 49 g (0.278 mol) of 4-(trifluoromethyl)anisole (yield: 62.6%).

Reference： [1]Patent: US2003/109574,2003,A1

42
[ 402-52-8 ]
[ 503464-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluorormethanesulfonic acid; acetic anhydride; In water;	EXAMPLE 12 Production of 2-Methoxy-5-(trifluoromethyl)acetophenone 97.0 g (0.65 moles) of trifluoromethanesulfonic acid were put into a 200 ml three-necked flask. The flask was equipped with a reflux condenser, a dropping funnel and a thermometer and was connected with a calcium chloride tube for shielding the flask against moisture of the outside. A mixture of 22.8 g (0.13 moles) of <strong>[402-52-8]4-(trifluoromethyl)anisole</strong> and 26.5 g (0.26 moles) of acetic anhydride was added in a dropwise manner at a temperature of not higher than 30 C. to the flask under stirring. After the adding, the reaction was conducted for 3 hrs at 20-25 C. The resulting reaction liquid was poured into 300 ml of iced water. Then, 200 ml of ether were added to extract the reaction product. Then, 100 ml of ether were added to the aqueous layer to extract the reaction product again. The resulting two ether layers were combined together, followed by washing with 10% sodium hydrogencarbonate aqueous solution until the ether layer is made basic.
	With trifluorormethanesulfonic acid; acetic anhydride;	Example 249A 1-(2-methoxy-5-(trifluoromethyl)phenyl)ethan-1-one A 250 mL 3-neck round bottom flask equipped with a thermometer and an addition funnel was charged with trifluoromethanesulfonic acid (29.6 mL, 333 mmol) and then treated dropwise (?6 drops/minute) under N2 over 3 hours with a mixture of <strong>[402-52-8]4-(trifluoromethyl)anisole</strong> (11.74 g, 66.6 mmol) and acetic anhydride (12.57 mL, 133 mmol) keeping the internal temperature at or below 30 C. The resulting mixture was stirred at room temperature for 3 hours and then poured carefully into 150 mL of ice water, adding more ice during the addition to prevent the mixture from warming. The mixture was extracted with methyl tert-butyl ether (twice, 150 mL and 50 mL). The combined methyl tert-butyl ether layers were washed with saturated aqueous NaHCO3 solution 4 times (100 mL, 100 mL, 50 mL and 50 mL). The methyl tert-butyl ether layer was washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed on silica gel, eluting with a gradient of 5% to 10% ethyl acetate in heptane to provide the title compound. 1H NMR (400 MHz, CDCl3) delta ppm 8.00 (dd, J=0.8, 2.5 Hz, 1H), 7.70 (ddd, J=0.8, 2.5, 8.8 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.97 (s, 3H), 2.62 (s, 3H).

Reference： [1]Patent: US2003/109574,2003,A1
[2]Patent: US2018/99932,2018,A1 .Location in patent: Paragraph 2166

43
[ 865-33-8 ]
[ 98-56-6 ]
[ 402-52-8 ]

Yield	Reaction Conditions	Operation in experiment
83%Chromat.	In N,N-dimethyl-formamide; at 100℃; for 16h;Product distribution / selectivity;	Direct coupling of aryl halides with alkoxides and aryloxides was investigated by using Ni-plm catalyst B using similar reaction conditions as C-S coupling. High activities of Ni-plm catalyst B towards coupling aryl halides with all primary, secondary and tertiary alkoxides to form the associated esters were observed (Table 2) . Activities are considered relative to other comparative catalysts. Good yields with less than 1% catalyst loading is considered as high activity.

Reference： [1]Patent: WO2008/136770,2008,A1 .Location in patent: Page/Page column 24-25

44
[ 865-33-8 ]
[ 100-00-5 ]
[ 402-52-8 ]

Yield	Reaction Conditions	Operation in experiment
98%Chromat.	nickel 1,3-dibenzylimidazolidene; In N,N-dimethyl-formamide; at 100℃; for 16h;Product distribution / selectivity;	Homogeneous C-O coupling reactions catalyzed by Ni-NHC complexes were investigated. As with the C-S coupling reactions, the activities of the catalysts were observed to be dependent on the type of ligands and the ligand/Ni ratio (Table 6) . The activity of the Ni-NHC catalysts was observed to decrease in the following order: Ni-c (ligand/Ni ratio = 2) > Wi-e (ligand/Ni ratio = 2) > Ni-c (ligand/Ni ratio = 1) > Ni-a (ligand/Ni ratio = 1) . The homogeneous Ni-c catalysts were observed to have higher activities than the heterogeneous system. It is well known that the bulky NHC ligand in Pd-NHC catalyst is very important for achieving high activity in Suzuki coupling reactions. However, stereo effect was not obvious in the Ni-NHC catalysts. It was observed that electronic effect appeared to be more important for improving the catalyst performance. Ni- (c)2 and Ni- (e) 2 showed excellent activities towards the coupling of aryl halides with alkoxides and aryloxides .

Reference： [1]Patent: WO2008/136770,2008,A1 .Location in patent: Page/Page column 35-36

45
[ 696-62-8 ]
[ 81290-20-2 ]
[ 402-52-8 ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 8600 - 8601
[2]Organic Letters,2014,vol. 16,p. 4268 - 4271

46
[ 402-52-8 ]
[ 100-52-7 ]
[ 791113-36-5 ]

Yield	Reaction Conditions	Operation in experiment
54.8%		All glassware was dried in the oven at 105C overnight and assembled hot under nitrogen. Under a nitrogen atmos- phere in a 4-neck, 3 L flask, a solution of 4-tri- fluoromethylanisole (97.75 g ; 0. 555 mol) in 1300 mL anhy- drous tetrahydrofuran was stirred mechanically in a dry ice-acetone bath. A 2.5 M solution of n-Butyllithium in hexane (269 mL; 0.672 mol) was added dropwise at FROM-67C to-71C over a period of 56 min. The addition funnel was rinsed with anhydrous THF (2 x 50 mL). After stirring in the dry ice-acetone bath for 32 min, this bath was replaced with an ice bath. The light orange solution was allowed to warm to 0C in the ice bath over a period of 97 min to give a dark amber solution. A solution of benzaldehyde (68. 5 g ; 0.646 mol, Aldrich) in 200 mL an- hydrous THF was added dropwise at 0-10C (mainly 7-9C) over a period of 49 min. As the addition proceeded, the color of the. reaction solution changed from the dark amber to a light orange. The addition funnel was rinsed with anhydrous THF (2 x 50 mL) and the ice bath was removed. The light orange solution was stirred under nitrogen for 1 h as the temperature increased from 5. 5C to 17. 5C. The light orange solution was cooled again in an ice bath. 20% Aqueous NH4CL (500 mL) was added dropwise at 7-11C over 13 min. The resulting mixture was extracted with ether (2000 mL). The ether extract was washed successively with water (1000 mL), 10% aqueous NAHCO3 (1000 mL) and then saturated brine (1000 mL). The ether layer was dried over MGS04, filtered and concentrated on a rotary evaporator at 45C to give a light yellow oily solid; 160.65 g. GC showed a high boiling component along with some starting 4- trifluoromethylanisole and benzaldehyde. This oily solid was slurried in hexane (200 mL) and cooled in the refrig- erator overnight. The slurry was suction filtered and the light yellow solid was crushed with a spatula. The cake was then washed with hexane (250 mL) to give a light yellow crystalline solid; 116.0 g. GC showed 86. 5% product with some residual low boiling point components. The yellow filtrate was con- centrated on a rotary evaporator at 35C to give a yellow viscous oil; 39.2 g. GC showed mostly low boiling point components with some residual product (17. 7%). The solid was stirred magnetically at room temperature in a mixture of hexane (250 mL) and diethyl ether (50 mL) for 45 min. The slurry was suction filtered and washed with hexane to give a white, crystalline solid ; 82. 85 G. mp = 83-85C. H-NMR and 13C-NMR were consistent with the desired alcohol. GC showed only the desired alcohol. The ether-hexane filtrate was concentrated on a rotary evaporator at 35C to give a yellow slush ; 33.0 g. GC showed impure alcohol (69%). Each filtrate was slurried in hexane (100 ML) and ether (25 mL) to give white solid. The samples were stoppered and allowed to stand at room tem- perature. The two slurries were suction filtered into the same Buchner funnel and rinsed with 4: 1 hexane: ether (50 mL) to give a white solid; 3.0 g. mp = 82-85C. 1H-NMR showed the desired alcohol with a slightly higher level of impurities. GC showed 99% of the desired alcohol. This solid was combined with the first crop. Total yield = 85.85 g (54.8% yield).

Reference： [1]Patent: WO2004/96751,2004,A1 .Location in patent: Page 11; 12-14

47
[ 6919-61-5 ]
[ 402-52-8 ]
[ 72083-15-9 ]

Yield	Reaction Conditions	Operation in experiment
57%		Example 17 3-14- [3- (2-BENZOYL-4-TRIFLUOROMETHYL-PHENOXY)-BUTOXY]-2-METHYL-PHENYLL-PROPIONIC acid Step A (2-Methoxy-5-trifluoromethyl-phenyl)-phenyl-methanone; A 1.6 M solution of n-BuLi in hexanes (0.51 mL, 0.82 mmol) is added dropwise for about 20 min to N, N, N, N-tetramethylenediamine (0.12 mL, 0. 80 mmol) at -20C UNDER N2 After 20 min, p-trifluoromethylanisole (0.10 g, 0.57 mmol) in THF (0.2 mL) is added dropwise for 15 min at-20 C under N2. After IH, N-methoxy-N-methyl- benzamide (0.12 mL, 0.79 mL) is added dropwise in 10 min AT-20 C UNDERN2. After 2h, a 1 M HCl (0.9 mL) is added. The mixture is extracted with EtOAc, and organic phases are combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (90: 10) provides the title compound (0.09 g, 0.32 mmol, 57%): ES+ (M/E) 281.08 (M+H) + ; RR 0.20 hexanes : EtOAc (90: 10).

Reference： [1]Patent: WO2005/19151,2005,A1 .Location in patent: Page/Page column 127

48
[ 402-52-8 ]
[ 108-24-7 ]
[ 503464-99-1 ]

Yield	Reaction Conditions	Operation in experiment
67%	trifluorormethanesulfonic acid; at 20℃; for 3h;Inert atmosphere;	Example 11 B: 2'-methoxy-5'-trifluoromethyl-acetophenone was prepared as follow {US2003/0109574): in a water bath at room temperature, to a solution of trifluoromethane sulfonic acid (5 ml, 56.7 mmol) under argon was slowly added a solution of 4-trifiuoromethyl-anisol (2.0 g, 1 1.35 mmol) in acetic anhydride (2.15 ml, 22.7 mmol). The resulting dark mixture was stirred for 3 hours at room temperature then poured onto ice water (26 ml). The product was extracted several times with ether. The ethereal layer was washed with a 10% solution of sodium hydrogenocarbonate, water, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography ove . silica gel (gradient cydohexane/dichloromethane: 0-50%) to yield 2'-methoxy-5'-trifluoromethyi- acetophenone (1.7 g, 67%) as a white solid.1 H NMR : CDCI3 delta (ppm): 8.00 (d, J = 2.3 Hz, 1 H), 7.71 (dd, J = 8.8 Hz, J = 2.3 Hz, 1 H), 7.05 (d, J = 8.7 Hz, 1 H), 3.98 (s, 3H), 2.63 (s, 3H).
59.1%	With trifluorormethanesulfonic acid; at 0 - 30℃;	Intermediate 4: 1-[2-(methyloxy)-5-(trifluoromethyl)phenyl]ethanone; At 00C, to the trifluoromethane sulfonic acid (30.9 ml, 348 mmol), was added dropwise a solution of 1-(methyloxy)-4-(trifluoromethyl)benzene, intermediate 3, (12.25 g, 69.5 mmol) in acetic anhydride(13.15 ml, 139 mmol). The temperature was maintained under 300C. The reaction was then stirred at room temperature for one night. The reaction was gently hydrolysed with addition of ice and extracted with Et2O. The combined organic phases were washed with a saturated solution of hydrogeno sodium carbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (cHex/EtOAc: 90/10 to 60/40) to give the title compound 1-[2-(methyloxy)-5-(trifluoromethyl)phenyl]ethanone (8.968 g, 41.1 mmol, 59.1 % yield) as a yellow oil. 1H NMR (CDCI3) £7.95 (d, 1 H), 7.6 (dd, 1 H), 6.95 (d, 1 H), 3.95 (s, 3H), 2.55 (s, 3H).
39%	With trifluorormethanesulfonic acid; at 0 - 20℃;	A mixture of 7 (24.0 g, 136 mmol) and Ac2O (25.7 mL, 272 mmol) was added to CF3SO3H (60.2 mL, 680 mmol) dropwise at 0 C. After stirring for 2 h at room temperature, the reaction mixture was poured into ice-water and extracted with ether. The extract was washed with 1 M NaOH and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography eluting with hexane/AcOEt (5/1) followed by silica gel column chromatography eluting with hexane/AcOEt (9/1) to give 8 (11.7 g, 39% yield) as colorless crystals.

Reference： [1]Patent: WO2011/51478,2011,A1 .Location in patent: Page/Page column 56
[2]Patent: WO2010/15652,2010,A2 .Location in patent: Page/Page column 32
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6414 - 6416

49
C₂₆H₃₁F₃N₂OPd [ No CAS ]
[ 402-52-8 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 2878 - 2879

50
[ 402-52-8 ]
[ 75-24-1 ]
[ 5396-38-3 ]

Reference： [1]Chemical Communications,2009,p. 6011 - 6013

51
[ 696-62-8 ]
potassium trimethoxy(trifluoromethyl)boranuide [ No CAS ]
[ 402-52-8 ]

Reference： [1]Chemistry - A European Journal,2011,vol. 17,p. 2689 - 2697

52
[ 124-38-9 ]
[ 402-52-8 ]
[ 4864-01-1 ]

Yield	Reaction Conditions	Operation in experiment
		2-methoxy-5-(trifluoromethyl)benzoic acid (12-3). nBuLi (276 mL, 2.5 M, 0.69 mol, 1.1 equiv) and KOtBu (77 g, 0.69 mol, 1.1 equiv) were added to a THF solution (1 L) of crude 12-2 (110 g) at -78 0C. The reaction was stirred at -78 0C for 4 h. Dry CO2 was bubbled into the solution at -78 0C for 1 h. The reaction was allowed to warm to 25 0C over 0.5 h. NaOH (6N, 300 mL) and H2O were added to the resulting reaction mixture. The mixture was extracted with t-butylmethyl ether (400 mL x 2). The aqueous layer was acidified with HCl (6N) to pH 1 and extracted with EtOAc (300 mL x 4). The combined EtOAc extracts were concentrated and re- dissolved in CH2Cl2. The solution was dried (Na2SO4), filtered through a pad of Celite and concentrated. Flash chromatography on silica gel (1:1 PE/EtOAc) yielded 82 g of compound 12-3 (53% for 2 steps): 1H NMR (400 MHz, CDCl3) delta 8.45 (s, 1 H), 7.81 (d, J= 8.0 Hz5 1 H), 7.16 (d, J= 8.0 Hz5 1 H), 4.13 (s, 3 H); MS (ESI) m/z 221.0 (M+H).

Reference： [1]Patent: WO2011/25982,2011,A2 .Location in patent: Page/Page column 145

53
[ 402-52-8 ]
[ 1268462-82-3 ]