[ CAS No. 453565-90-7 ] {[proInfo.proName]}

Name: 453565-90-7|3-Bromo-5-(trifluoromethoxy)benzoic acid|98%
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SKU: A223890
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Quality Control of [ 453565-90-7 ]

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Product Details of [ 453565-90-7 ]

CAS No. :	453565-90-7	MDL No. :	MFCD04116041
Formula :	C₈H₄BrF₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OYWFMHKHBDYTKB-UHFFFAOYSA-N
M.W :	285.01	Pubchem ID :	2782843
Synonyms :

Safety of [ 453565-90-7 ]

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 [ 453565-90-7 ]

* 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 [ 453565-90-7 ]
Downstream synthetic route of [ 453565-90-7 ]

[ 453565-90-7 ] Synthesis Path-Upstream 1~1

1
[ 453565-89-4 ]
[ 453565-90-7 ]

Yield	Reaction Conditions	Operation in experiment
75.5%	With sulfuric acid; sodium nitrite In sodium hydroxide; ethanol; water	3-Bromo-5-trifluoromethoxybenzoic Acid 4-Amino-3-bromo-5-trifluoromethoxybenzoic acid (1.5 g, 5 mmoles) was mixed with ethanol (15 mL) at 0° C. and then concentrated sulfuric acid (2.26 g, 10.2 mmoles) wad added. The sodium nitrite (0.38 g, 5.5 mmoles) water solution (1.2 mL) was added dropwise at 0° C. for 1 hour. After the reaction mixture was warmed to room temperature and then heated to reflux for 45 minutes, water was added. The mixture was extracted with dichloromethane. The dichloromethane layer was dried and concentrated. The residue was dissolved in 1M sodium hydroxide and extracted with ether. The aqueous solution was acidified with 2M HCl to pH=2 to give 3-bromo-5-trifluoromethoxybenzoic acid (1.08 g, 75.5percent).

Reference： [1] Patent: US2003/55085, 2003, A1,

[ 453565-90-7 ] Synthesis Path-Downstream 1~65

1
[ 453565-89-4 ]
[ 453565-90-7 ]

Yield	Reaction Conditions	Operation in experiment
75.5%	With sulfuric acid; sodium nitrite; In sodium hydroxide; ethanol; water;	3-Bromo-5-trifluoromethoxybenzoic Acid 4-Amino-3-bromo-5-trifluoromethoxybenzoic acid (1.5 g, 5 mmoles) was mixed with ethanol (15 mL) at 0 C. and then concentrated sulfuric acid (2.26 g, 10.2 mmoles) wad added. The sodium nitrite (0.38 g, 5.5 mmoles) water solution (1.2 mL) was added dropwise at 0 C. for 1 hour. After the reaction mixture was warmed to room temperature and then heated to reflux for 45 minutes, water was added. The mixture was extracted with dichloromethane. The dichloromethane layer was dried and concentrated. The residue was dissolved in 1M sodium hydroxide and extracted with ether. The aqueous solution was acidified with 2M HCl to pH=2 to give 3-bromo-5-trifluoromethoxybenzoic acid (1.08 g, 75.5%).

Reference： [1]Patent: US2003/55085,2003,A1

2
[ 453565-90-7 ]
[ 453565-91-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide;tetrakis(triphenylphosphine)palladium (0); In methanol; ethyl acetate; N,N-dimethyl-formamide;	3-Cyano-5-trifluoromethoxybenzoic Acid To an ether solution of <strong>[453565-90-7]3-bromo-5-trifluoromethoxybenzoic acid</strong> (1.08 g, 3.79 mmloes), tirmethylsilylmethyl azide was added in and stirred at room temperature for 10 minutes. The reaction was quenched with methanol and passed column with 2% ethyl acetate in hexanes to give colorless oil (0.84 g). This colorless oil was mixed with zinc cyanide (0.33 g, 2.8 mmoles) and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 467 mg, 0.404 mmol) in N,N-dimethylformamide(10 mL) under argon at 85 C. overnight. The reaction mixture was diluted with dichloromethane and washed with water twice. The dichloromethane layer was dried and concentrated. The residue was mixed with1M sodium hydroxide (8 mL) and methanol (4 mL) and stirred at room temperature for 2 hours. The mixture was acidified with 1M HCl to pH=1~2 and extracted with ethyl acetate. The ethyl acetate layer was washed with Brine and concentrated. The residue was passed column with 2% ethyl acetate in hexanes to give 3-cyano-5-trifluoromethoxybenzoic acid, which contained 3-[imino(methoxy)methyl]-5-trifluoromethoxybenzoic acid (3:1, 145 mg, 16.6%)

Reference： [1]Patent: US2003/55085,2003,A1

3
[ 453565-90-7 ]
[ 1026201-95-5 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate C7: 3-Bromo-5-("trifluoromethoxy)benzyl methanesulfonateStep 1 : r3-Bromo-5-(trifluoromethoxy)phenyllmethanolTo a solution of LAH (100 mL, IM in Et2O, 100 mmol) that had been cooled to -700C, a solution of <strong>[453565-90-7]3-bromo-5-(trifluoromethoxy)benzoic acid</strong> (12.0 g, 42.1 mmol) was added slowly. The mixture was then slowly warmed to RT and stirred overnight. After recooling to -70C, the reaction was quenched with H2O (4 mL), 2N NaOH (4 mL), more H2O (8 mL), and then warmed to RT. The mixture was then filtered through CELITE, MgSO4 was added, and the EPO <DP n="55"/>mixture was filtered again. The solvent was removed in vacuo to yield the title compound as a colorless oil. LRMS ESI+ (M+H)+ 272.2.

Reference： [1]Patent: WO2008/57209,2008,A1 .Location in patent: Page/Page column 53-54

4
[ 110-91-8 ]
[ 453565-90-7 ]
[ 1163141-85-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,10-Phenanthroline; caesium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 175℃; for 6.0h;Microwave irradiation;	3-Bromo-5-(trifluoromethoxy)benzoic acid (1 g, 3.51 mmol), morpholine (0.957g, 10.5 mmol), copper(I) iodide (0.134 g, 0.702 mmol), cesium carbonate (2.51 g, 7.72 mmol), and 1,10-phenanthroline (0.221 g, 1.228 mmol) were suspended in DMSO (10 mL) in a 20 mL vial. The reaction mixture was heated under microwave irradiation at 175 0C for 6 h. The reaction mixture was added to chilled water, acidified to pH 3 using aqueous 6 N HCl and extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with 1 M aqueous citric acid (3 x 50 mL) and brine, and concentrated. The residue was purified by preparative HPLC to give the title compound as a brown oil (0.350 g). LCMS m/z = 292.3 [M + H]+.

Reference： [1]Patent: WO2009/78983,2009,A1 .Location in patent: Page/Page column 115

5
[ 123-75-1 ]
[ 453565-90-7 ]
[ 1163141-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,10-Phenanthroline; caesium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 150℃; for 6.0h;Microwave irradiation;	3-Bromo-5-(trifluorornethoxy)benzoic acid (1.0 g, 3.51 mmol), pyrrolidine (0.499 g, 7.02 mmol), copper(I) iodide (0.100 g, 0.526 mmol), cesium carbonate (2.51 g, 7.72 mmol), and 1,10-phenanthroline (0.158 g, 0.877 mmol) were suspended in DMSO (10 mL) in a 20 mL vial. The reaction mixture was heated under microwave irradiation at 150 0C for 6 h. The reaction mixture was added to chilled water, brought to pH 3 using aqueous 6 N HCl and extracted with EtOAc (2 x 100 mL). The organic layer was washed with 1 M aqueous citric acid (3 x 50 mL). The organic layer was washed with brine, and concentrated. The residue was purified by preparative HPLC to give the title compound as a yellow solid (0.230 g). LCMS m/z = 276.1 [M + H]+; 1H NMR (400 MHz, DMSO-J6) delta ppm 1.95-1.98 (m, 4H), 3.25-3.28 (m, 4H), 6.63 (s, IH), 6.98 (s, IH), 7.06 (s, IH).

Reference： [1]Patent: WO2009/78983,2009,A1 .Location in patent: Page/Page column 114

6
[ 288-88-0 ]
[ 453565-90-7 ]
[ 1163141-28-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; N,N`-dimethylethylenediamine;copper(l) iodide; In N,N-dimethyl-formamide; at 130℃; for 15.0h;	To a solution of <strong>[453565-90-7]3-bromo-5-(trifluoromethoxy)benzoic acid</strong> (0.50 g, 1.754 mmol), IH-1,2,4-triazole (0.33 g, 4.387 mmol) and V ,N2-dimethylethane-l,2-diamine (0.062 g, 0.702 mmol) in DMF (5 mL) was added copper(I) iodide (0.067 g, 0.351 mmol) and tripotassium phosphate (0.819 g, 3.86 mmol). The reaction mixture was stirred at 130 0C for 15 h. The mixture was diluted with ethyl acetate (20 mL), Celite was added, and the mixture was filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound as a white solid (0.13 g). LCMS m/z = 274.2 [M + H]+; 1H nuMR (400 MHz, DMSO- d6) delta ppm 7.83 (s, IH), 8.23 (s, IH), 8.33 (s, IH), 8.45 (s, IH), 9.54 (s, IH), 13.88 (bs, IH).

Reference： [1]Patent: WO2009/78983,2009,A1 .Location in patent: Page/Page column 99

7
[ 453565-90-7 ]
[ 1163141-31-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; sodium azide; N,N`-dimethylethylenediamine;copper(l) iodide; In N,N-dimethyl-formamide; at 135℃; for 15.0h;	To a solution of <strong>[453565-90-7]3-bromo-5-(trifluoromethoxy)benzoic acid</strong> (0.50 g, 1.754 mmol), sodium azide (0.303 g, 4.66 mmol) and lambda^,N2-dimethylethane-l,2-diamine (0.062 g, 0.702 mmol) in DMF (5 mL) was added copper(I) iodide (0.067 g, 0.351 mmol) and tripotassium phosphate (0.819 g, 3.86 mmol). The resulting brown mixture was stirred in a sealed vial at 135 0C for 15 h (caution-gas evolution). The mixture was diluted with ethyl acetate (20 mL), Celite was added, and the mixture was filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound as an orange solid (0.23 g). LCMS m/z = 222.2 [M + H]+.
450 mg	With potassium phosphate; copper(l) iodide; sodium azide; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 135℃; for 18.0h;	A mixture of <strong>[453565-90-7]3-bromo-5-(trifluoromethoxy)benzoic acid</strong> (0.5 g, 1.754 mmol), sodium azide (0.303 g, 4.66 mmol), N1 ,N2-dimethylethane-1 ,2-diamine (0.062 g, 0.702 mmol), copper(l) iodide (0.067 g, 0.351 mmol) and K3P04 (0.819 g, 3.86 mmol) in DMF (5 mL) was heated at 135C for 18h. The mixture was cooled, EtOAc (20 mL) and Celite (2 g) was added then filtered. The filtrate was evaporated under reduced pressure to give a black oil. Repeat in duplicate. The crude product was loaded onto a column of SAX (Discovery DSC-SAX, a polymer-bound quaternary amine) in MeOH. The column was washed with MeOH and then the product was eluted with 5% AcOH in MeOH. The resultant mixture was concentrated in vacuo then loaded onto a column of SCX in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the subtitle compound (450 mg) as a yellow powder. 1 H NMR (400MHz; DMSO-d6) delta 7.15 (s, 1 H), 6.87 (s, 1 H), 6.57 (s, 1 H), 5.63 (br s, 2H) LCMS m/z 222 (M+H)+ (ES+); 220 (M-H)" (ES")
450 mg	With potassium phosphate; copper(l) iodide; sodium azide; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 135℃; for 18.0h;	A mixture of <strong>[453565-90-7]3-bromo-5-(trifluoromethoxy)benzoic acid</strong> (0.5 g, 1.754 mmol), sodium azide (0.303 g, 4.66 mmol), N1,N2-dimethylethane-1,2-diamine (0.062 g, 0.702 mmol), copper(I) iodide (0.067 g, 0.351 mmol) and K3PO4 (0.819 g, 3.86 mmol) in DMF (5 mL) was heated at 135 C. for 18 h. The mixture was cooled, EtOAc (20 mL) and Celite (2 g) was added then filtered. The filtrate was evaporated under reduced pressure to give a black oil. Repeat in duplicate. The crude product was loaded onto a column of SAX (Discovery DSC-SAX, a polymer-bound quaternary amine) in MeOH. The column was washed with MeOH and then the product was eluted with 5% AcOH in MeOH. The resultant mixture was concentrated in vacuo then loaded onto a column of SCX in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the sub-title compound (450 mg) as a yellow powder. 1H NMR (400 MHz; DMSO-d6) delta 7.15 (s, 1H), 6.87 (s, 1H), 6.57 (s, 1H), 5.63 (br s, 2H) LCMS m/z 222 (M+H)+ (ES+); 220 (M-H)- (ES-)

450 mg

With potassium phosphate; copper(l) iodide; sodium azide; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 135℃; for 18.0h;

(i) 3-Amino-5-(trifluoromethoxy)benzoic acid A mixture of <strong>[453565-90-7]3-bromo-5-(trifluoromethoxy)benzoic acid</strong> (0.5 g, 1.754 mmol), sodium azide (0.303 g, 4.66 mmol), N1,N2-dimethylethane-1,2-diamine (0.062 g, 0.702 mmol), copper(I) iodide (0.067 g, 0.351 mmol) and K3PO4 (0.819 g, 3.86 mmol) in DMF (5 mL) was heated at 135 C. for 18 h. The mixture was cooled, EtOAc (20 mL) and Celite (2 g) was added then filtered. The filtrate was evaporated under reduced pressure to give a black oil. Repeat in duplicate. The crude product was loaded onto a column of SAX (Discovery DSC-SAX, a polymer-bound quaternary amine) in MeOH. The column was washed with MeOH and then the product was eluted with 5% AcOH in MeOH. The resultant mixture was concentrated in vacuo then loaded onto a column of SCX in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the sub-title compound (450 mg) as a yellow powder. 1H NMR (400 MHz; DMSO-d6) delta 7.15 (s, 1H), 6.87 (s, 1H), 6.57 (s, 1H), 5.63 (br s, 2H) LCMS m/z 222 (M+H)+ (ES+); 220 (M-H)- (ES-)

Reference： [1]Patent: WO2009/78983,2009,A1 .Location in patent: Page/Page column 100
[2]Patent: WO2014/33447,2014,A2 .Location in patent: Page/Page column 66
[3]Patent: US2015/210722,2015,A1 .Location in patent: Paragraph 0731; 0732
[4]Patent: US2016/340375,2016,A1 .Location in patent: Paragraph 0826; 0827; 0828

8
[ 453565-90-7 ]
[ 1163141-52-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; tert-butyl XPhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 100℃; for 2.0h;	3-Bromo-5-(trifluoromethoxy)benzoic acid (0.500 g, 1.754 mmol), i-tert- butyl(2',4',6'-triisopropylbiphenyl-2-yl) phosphine (0.060 g, 0.080 mmole), tris(dibenzylideneacetone) dipalladium(O) (0.032 g, 0.035 mmol) and potassium hydroxide (0.394 g, 7.02 mmol) were dissolved in dioxane (5.00 mL) and water (5.00 mL) in a 50 mL round bottomed flask under N2. The reaction was heated to 100 0C for 2 h. The product was poured into 1 M HCl and extracted into EtOAc (2 x 20 mL), filtered by vacuum filtration through Celite, then washed with saturated NaCl (20 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a white solid (0.300 g). LCMS m/z = 223.2 [M + H]+.
1.71 g	With tris-(dibenzylideneacetone)dipalladium(0); sodium hydroxide; tert-butyl XPhos; In 1,4-dioxane; water; at 100℃; for 2.5h;Inert atmosphere;	A solution of 3-bromo-5-(trifluoromethoxy)ben- zoic acid (3200 mg, 11.23 mmol) and NaOH (2520 mg, 44.9 mmol) in water (30 mE) and dioxane (30 mE) was degassed for 5 minutes prior to the addition of Pd2(dba)3 (206 mg, 0.225 mmol) and di-tert-butyl(2?,4?,6?-triisopropyl-[ 1,1 ?-biphenyl]-2-yl)phosphine (215 mg, 0.505 mmol). The resulting mixture was degassed for a thrther 2 minutes and then heated under a nitrogen atmosphere at 100 C. for 2.5 h. The mixture was diluted with water (150 mE) and washed with diethyl ether (3x75 mE). The aqueous layer was then acidified with HC1 (1 M, 33 mE) to pH 3 and extracted with ethyl acetate (3x75 mE). The combined organic layers were washed with saturated brine (50 mE), dried over MgSO4, filtered, and concentrated under reduced pressure to afford a yellow oil. The oil was redissolved in diethyl ether (10 mE) and diluted with isohexane (30 mE). The resulting precipitate was collected by filtration and washed with isohexane (10 mE) to yield the sub-title compound (1.71 g) as a tan solid.?H NMR (400 MHz, DMSO-d6) oe 13.34 (bs, 1H),10.57 (bs, 1H), 7.36 (dd, 1H), 7.28-7.20 (m, 1H), 6.99-6.90 (m, 1H)

Reference： [1]Patent: WO2009/78983,2009,A1 .Location in patent: Page/Page column 106
[2]Patent: US2017/291917,2017,A1 .Location in patent: Paragraph 0856; 0857

9
[ 453565-90-7 ]
[ 75-24-1 ]
[ 916420-51-4 ]

Yield	Reaction Conditions	Operation in experiment
		3-Bromo-5-(trifluoromethoxy)benzoic acid (1.0 g, 3.51 mmol) was dissolved in THF (10 mL). Nitrogen was bubbled through the solution for 10 min. Palladium tetrakis(triphenylphosphine) (0.182 g, 0.158 mmol) was added followed by a 2.0 M hexanes solution of trimethylaluminium (5.26 mL, 10.53 mmol). The resulting orange solution was heated under microwave irradiation in a sealed thick-walled glass tube with stirring at 100 0C for 2 h. The orange solution was carefully added to 1 M HCl (75 mL). The mixture was extracted with DCM (2 x 50 mL). The combined organic extracts were back extracted with 2 M NaOH (50 mL). The basic aqueous solution was filtered and acidified to pH 2 with 6 M HCl. The resulting precipitate was collected by filtration, and dried under reduced pressure to afford the title compound as a white solid (0.63 g). LCMS m/z = 221.1 [M + H]+; 1H NMR (400 MHz, DMSO-J6) delta ppm 2.42 (s, 3H), 7.49 (s, IH), 7.61 (s, IH), 7.80 (s, IH), 13.40 (bs, IH).

Reference： [1]Patent: WO2009/78983,2009,A1 .Location in patent: Page/Page column 101

10
[ 453565-90-7 ]
[ 1092461-36-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; for 2.0h;Reflux;	General procedure: A mixture of various carboxylic acids (1.0mmol), an excess of thionyl chrolide (5mL) was refluxed for 2h and concentrated in vacuo to give corresponding acyl chloride (quant).
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 23℃;	To a cooled (0 0C) mixture of <strong>[453565-90-7]3-bromo-5-(trifluoromethoxy)benzoic acid</strong> (1.425 g, 5.00 mmol) in DCM (10.00 mL) was added oxalyl chloride (0.481 mL, 5.50 mmol) followed by one drop of DMF. The reaction mixture was stirred for 2 h while warming to room temperature and concentrated under reduced pressure to give the title compound without further purification.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;	INTERMEDIATE 12[3 -Bromo-5 -(trifluoromethoxy )pheny 11 (pyrrolidin- 1 -y DmethanoneOxalyl chloride (3 mL) was added to a solution/suspension of 3 -bromo-5 - (trifluoromethoxy)benzoic acid (1.5 g, 5.26 mmol) and DMF (2 drops) in DCM (20 mL) at r.t. The mixture was stirred for 2 h. The mixture was concentrated in vacuo, adding DCM (20 mL) to assist removal of oxalyl chloride. The residue was dissolved in DCM (20 mL) and added to a stirred solution of pyrrolidine (3 mL) in DCM (20 mL), pre- cooled in an ice-water bath. The mixture was stirred, allowed to warm to r.t., and then left to stand for 18 h. The mixture was washed with water (20 mL) and adsorbed onto silica. The residue was purified by column chromatography (SiO2, 20 to 100% EtOAc in heptane) to give the title compound (1.68 g, 94%) as a colourless oil. 6H (CDCl3) 7.61 (s, IH), 7.44 (s, IH), 7.32 (s, IH), 3.64 (t, 2H), 3.41 (t, 2H), 1.87-2.05 (m, 4H). LCMS (ES+) 340 (M+H)+, RT 3.78 minutes.

Reference： [1]Chinese Chemical Letters,2013,vol. 24,p. 673 - 676
[2]Patent: WO2009/94157,2009,A1 .Location in patent: Page/Page column 66
[3]Patent: WO2010/52448,2010,A2 .Location in patent: Page/Page column 38-39

11
[ 557-21-1 ]
[ 453565-90-7 ]
[ 453565-91-8 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; for 20.0h;Inert atmosphere; Reflux;	Example 41A 3-Cyano-5-(trifluoromethoxy)benzoic acid A mixture of 2.0 g (7.02 mmol) of <strong>[453565-90-7]3-bromo-5-(trifluoromethoxy)benzoic acid</strong>, 906 mg (7.72 mmol) of zinc cyanide and 486 mg (0.42 mmol) of tetrakis(triphenylphosphine)palladium(0) in 23 ml of DMF was initially degassed and then, under an atmosphere of argon, heated under reflux for 4 h. A further 243 mg (0.21 mmol) of tetrakis(triphenylphosphine)palladium(0) and 453 mg (3.86 mmol) of zinc cyanide were then added, and the mixture was stirred under reflux for another 16 h. The reaction was then concentrated to a volume of about 5 ml under reduced pressure and stirred into 100 ml of 0.1 M aqueous sodium hydroxide solution. The solid formed was filtered off, the filtrate was adjusted to pH 1 with concentrated hydrochloric acid and the precipitate formed was filtered off again. The filtrate was extracted twice with in each case 50 ml of tert-butyl methyl ether, and the combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The product was isolated by preparative HPLC (Method 20). Evaporation of the product fractions and drying of the residue under high vacuum gave 75 mg (92% pure, 4% of theory) of the title compound. 1H NMR (400 MHz, DMSO-d6, delta/ppm): 13.99 (br, 1H), 8.35 (t, 1H), 8.33 (br, 1H), 8.11 (br, 1H). LC/MS (Method 4, ESIneg): Rt=0.85 min, m/z=230 [M-H]-.

Reference： [1]Patent: US2013/190290,2013,A1 .Location in patent: Paragraph 0846; 0847; 0848; 0849

12
[ 453565-90-7 ]
[ 1447018-03-2 ]

Reference： [1]Chinese Chemical Letters,2013,vol. 24,p. 673 - 676

13
[ 453565-90-7 ]
[ 1573025-67-8 ]

Reference： [1]Patent: WO2014/33447,2014,A2
[2]Patent: US2015/210722,2015,A1
[3]Patent: US2016/340375,2016,A1

14
[ 453565-90-7 ]
[ 1573025-02-1 ]

Reference： [1]Patent: WO2014/33447,2014,A2

15
[ 453565-90-7 ]
[ 1192347-82-2 ]
3-bromo-N-(5-chloro-2-ethane sulfonyl-benzyl)-5-trifluoromethoxy-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 20.0h;	N-(5-Chloro-2-ethanesulfonyl-benzyl)-3-trifluoromethyl-benzamide DIPEA (0.016 ml, 0.091 mmol) was added to a suspension of 5-chloro-2-ethanesulfonyl-benzylamine hydrochloride (Compound a3, 20.5 mg, 0.076 mmol), 3-(trifluoromethyl)benzoic acid (18.0 mg, 0.095 mmol), and WSCDI (18.9 mg, 0.099 mmol) in DCM (1.5 ml), followed by stirring for 20 hours. DCM was added to the reaction mixture. After washing with water, the organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to yield the title compound (26.9 mg, 87%) as a colorless solid. LCMS: m/z 406 [M+H]+ HPLC retention time: 0.83 min (analysis condition A)

Reference： [1]Patent: EP2842939,2015,A1 .Location in patent: Paragraph 0203; 0204; 0205

16
[ 453565-90-7 ]
3-((4-((4-(3-(3-(tert-butyl)-1-(3-((dimethylphosphoryl)methyl)phenyl)-1H-pyrazol-5-yl)-ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-5-(trifluoromethoxy)benzamide [ No CAS ]

Reference： [1]Patent: US2015/210722,2015,A1
[2]Patent: US2016/340375,2016,A1

17
[ 453565-90-7 ]
benzyl 3-(2-(2-(2-(tert-butoxy)-2-oxoethoxy)ethoxy)ethoxy)-5-(trifluoromethoxy)benzoate [ No CAS ]