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[ CAS No. 457097-93-7 ]

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CAS No. :	457097-93-7	MDL No. :	MFCD15527567
Formula :	C₉H₈F₃NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	235.16 g/mol	Pubchem ID :	53419671
Synonyms :

Safety of [ 457097-93-7 ]

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 [ 457097-93-7 ]

Upstream synthesis route of [ 457097-93-7 ]
Downstream synthetic route of [ 457097-93-7 ]

[ 457097-93-7 ] Synthesis Path-Upstream 1~5

1
[ 175278-22-5 ]
[ 67-56-1 ]
[ 457097-93-7 ]

Yield	Reaction Conditions	Operation in experiment
96.2%	Stage #1: at -5 - -4℃; for 1 h; Stage #2: at 15 - 30℃; for 72 h;	Thionyl chloride (2.68g, 0.023 mol) was added dropwise to methanol (12 mL) at -5° C via a syringe keeping the temperature at or below -4° C. The resulting mixture was stirred at or below -5° C for 1 hr., then 4-amino- 3-(trifluoromethoxy)benzoic acid (0.5g, 0.003 mol) [Alfa Aesar] was added in one portion. The reaction mixture was stirred at ambient temperature for 3 days after which the mixture was concentrated in vacuo. Water (10 mL) was added to the residue and sodium bicarbonate (0.46g, 5.4 mmol) was added in one portion and the mixture was stirred at ambient temperature for 30 min. The mixture was extracted several times with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 1.02g (96.2percent) of methyl 4-amino-3-(trifiuoromethoxy)berrzoate as a red oil that slowly sodified to a brown solid on cooling. MS: m/z 236.1 (MH⁺). 1H NMR (500 MHz, DMSO-d₆): δ 3.771 (s, 3H), 6.329 (s, 2H), 6.834 (d, 1H), 7.6181 (s, 1H), 7.655 (dd, 1H).
95%	With hydrogenchloride In 1,4-dioxane at 20℃; for 72 h;	A. Methyl 4-amino-3-(trifluoromethoxy)benzoate A mixture of 4-amino-3-(trifluoromethoxy)benzoic acid (8.88 g 40.2 mmol), MeOH (142 mL) and hydrochloric acid in 1,4-dioxane (4.0 M, 142 mL, 568 mmol) was stirred at room temperature for 72 h. After removal of the organic solvent the pH of the residue was adjusted to pH 8 and the aqueous layer was extracted with ethyl acetate (50 mL*3). The combined organic layers were dried and concentrated under vacuum to afford the title compound (9.3 g, 39.6 mmol, 95percent yield). MS (ESI) m/z 236.1 [M+1]⁺.

Reference： [1] Patent: WO2014/165816, 2014, A1, . Location in patent: Page/Page column 92
[2] Patent: US2015/175557, 2015, A1, . Location in patent: Paragraph 0300
[3] Patent: EP2017263, 2009, A1, . Location in patent: Page/Page column 213
[4] Patent: US2013/115194, 2013, A1, . Location in patent: Paragraph 0335
[5] Patent: US2013/287731, 2013, A1, . Location in patent: Paragraph 0284; 0285

2
[ 67-56-1 ]
[ 175278-09-8 ]
[ 201230-82-2 ]
[ 457097-93-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	at 100℃; for 36 h;	To a solution of 4-bromo-2-(trifluoromethoxy)aniline (10 g, 50.21 mmol) in methanol (150 mL) in a pressure tank reactor was added TEA (11.84 g, 117.01 mmol), Pd(dppf)Ci₂ CH₂Q₂ (2.4 g, 2.94 mmol). Then the reactor was charged with CO (g) (20 atm). The resulting reaction was stirred for 1.5 days at 100°C. Then it was diluted with water (200 mL), extracted with ethyl acetate (3 x 100 mL) and the organic layers combined and dried in an oven under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 :50) to afford methyl 4- amino-3-(trifluoromethoxy)benzoate as yellow solid (5 g, 54percent).

Reference： [1] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175

3
[ 175278-22-5 ]
[ 457097-93-7 ]

Reference： [1] Patent: US2012/114600, 2012, A1,

4
[ 175278-22-5 ]
[ 186581-53-3 ]
[ 457097-93-7 ]

Reference： [1] Patent: US2003/69284, 2003, A1,

5
[ 457097-93-7 ]
[ 886500-50-1 ]

Reference： [1] Patent: WO2014/66795, 2014, A1,

[ 457097-93-7 ] Synthesis Path-Downstream 1~25

1
[ 175278-22-5 ]
[ 186581-53-3 ]
[ 457097-93-7 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; methanol; hexane; ethyl acetate;	Step 1: 4-Amino-3-trifluoromethoxy-benzoic acid methyl ester. To a stirred solution of <strong>[175278-22-5]4-amino-3-trifluoromethoxy-benzoic acid</strong> (1.2 g, 5.4 mmol) in 16 mL of 4:1 THF:MeOH at 0 C. was added TMS -diazomethane (2solution in hexane, 6 mL, 12 mmol) dropwise and conversion was monitored by TLC in 2/3 EtOAc/hexane. When complete, the reaction was concentrated to a white solid corresponding to the methyl ester (1.27 g, quantitative).

Reference： [1]Patent: US2003/69284,2003,A1

2
[ 457097-93-7 ]
[ 7693-46-1 ]
[ 457097-94-8 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane;	Step 2: 4-(4-Nitro-phenoxycarbonylamino)-3-trifluoromethoxy-benzoic acid methyl ester. To a stirred solution of <strong>[457097-93-7]4-amino-3-trifluoromethoxy-benzoic acid methyl ester</strong> (1.38 gm, 5.9 mmol) in 18 mL CH2Cl2 at 0 C. under nitrogen was added pyridine (521 muL, 6.4 mmol) followed by p-nitrophenylchloroformate (1.18 gm, 5.9 mmol). After 4 hours at 0 C. the reaction was diluted to 60 mL with CH2C12 and washed 260 mL with 2HCl, 160 mL with H2O and 1*60 mL with saturated NaCl. The organics were dried (MgSO4), filtered and concentrated to a white solid, corresponding to the carbamate (2.1 gm, 89 %).

Reference： [1]Patent: US2003/69284,2003,A1

3
[ 175278-22-5 ]
[ 67-56-1 ]
[ 457097-93-7 ]

Yield	Reaction Conditions	Operation in experiment
96.2%		Thionyl chloride (2.68g, 0.023 mol) was added dropwise to methanol (12 mL) at -5 C via a syringe keeping the temperature at or below -4 C. The resulting mixture was stirred at or below -5 C for 1 hr., then 4-amino- 3-(trifluoromethoxy)benzoic acid (0.5g, 0.003 mol) [Alfa Aesar] was added in one portion. The reaction mixture was stirred at ambient temperature for 3 days after which the mixture was concentrated in vacuo. Water (10 mL) was added to the residue and sodium bicarbonate (0.46g, 5.4 mmol) was added in one portion and the mixture was stirred at ambient temperature for 30 min. The mixture was extracted several times with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 1.02g (96.2%) of methyl 4-amino-3-(trifiuoromethoxy)berrzoate as a red oil that slowly sodified to a brown solid on cooling. MS: m/z 236.1 (MH+). 1H NMR (500 MHz, DMSO-d6): delta 3.771 (s, 3H), 6.329 (s, 2H), 6.834 (d, 1H), 7.6181 (s, 1H), 7.655 (dd, 1H).
95%	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 72h;	A. Methyl 4-amino-3-(trifluoromethoxy)benzoate A mixture of <strong>[175278-22-5]4-amino-3-(trifluoromethoxy)benzoic acid</strong> (8.88 g 40.2 mmol), MeOH (142 mL) and hydrochloric acid in 1,4-dioxane (4.0 M, 142 mL, 568 mmol) was stirred at room temperature for 72 h. After removal of the organic solvent the pH of the residue was adjusted to pH 8 and the aqueous layer was extracted with ethyl acetate (50 mL*3). The combined organic layers were dried and concentrated under vacuum to afford the title compound (9.3 g, 39.6 mmol, 95% yield). MS (ESI) m/z 236.1 [M+1]+.
		To a methanol solution (10 mL) of <strong>[175278-22-5]4-amino-3-trifluoromethoxybenzoic acid</strong> (WO 2002/070494) (220 mg), thionyl chloride (76 muL) was added, and the mixture was stirred for 2 hours at reflux. Thionyl chloride (76 muL) was further added, followed by stirring overnight at reflux. The resultant mixture was left to stand to cool to room temperature and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction twice, each with ethyl acetate. The extracts were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure, whereby the title compound (224 mg) was yielded. 1H-NMR(CDCl3)delta: 3.87(3H,s), 4.30(2H,s), 6.77(1H,d,J=8.6Hz), 7.78-7.84(2H,m). MS (ESI) m/z : 236 (M+H)+.

	With hydrogenchloride; In 1,4-dioxane; at 20℃;	Preparation 14 4-Bromo-3-trifluoromethoxy-benzoic acid methyl ester A mixture of <strong>[175278-22-5]4-amino-3-(trifluoromethoxy)benzoic acid</strong> (504.1 mg, 2.28 mmol), methanol (7.6 mL) and 4.0 M HCl in 1,4-dioxane (5.7 mL) was stirred at RT over the weekend, concentrated, evaporated with EtOAc (3*10 mL), and dried under vacuum to give a brownish solid
	With hydrogenchloride; In 1,4-dioxane; at 20℃;Inert atmosphere;	Preparation 14 4-Bromo-3-trifluoromethoxy-benzoic acid methyl ester A mixture of <strong>[175278-22-5]4-amino-3-(trifluoromethoxy)benzoic acid</strong> (504.1 mg, 2.28 mmol), methanol (7.6 mL) and 4.0 M HCl in 1,4-dioxane (5.7 mL) was stirred at RT over the weekend, concentrated, evaporated with EtOAc (310 mL), and dried under vacuum to give a brownish solid. The solid was dissolved in a mixture of acetonitrile (23 mL) and water (2.3 mL). Copper(II) bromide (595 mg, 2.66 mmol) and tert-butyl nitrite (0.39 mL, 3.32 mmol) were added to the reaction mixture which was heated at 70 C. for 1.5 h, cooled to RT and diluted with EtOAc (70 mL). The organic layer was washed with saturated sodium bicarbonate (215 mL), brine (2*15 mL), dried over sodium sulfate, filtered and concentrated to give a brownish oil, which was purified by silica gel chromatography (24 g silica gel, 0-50% EtOAc/Hexanes). Desired fractions were combined and concentrated to give the title intermediate (281 mg, 41% yield) as a yellowish oil.

Reference： [1]Patent: WO2014/165816,2014,A1 .Location in patent: Page/Page column 92
[2]Patent: US2015/175557,2015,A1 .Location in patent: Paragraph 0300
[3]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 213
[4]Patent: US2013/115194,2013,A1 .Location in patent: Paragraph 0335
[5]Patent: US2013/287731,2013,A1 .Location in patent: Paragraph 0284; 0285

4
[ 457097-93-7 ]
[ 957206-36-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With tert.-butylnitrite; copper(ll) bromide; In water; acetonitrile; at 75℃; for 1.5h;	B. Methyl 4-bromo-3-(trifluoromethoxy)benzoate To a mixture of <strong>[457097-93-7]methyl 4-amino-3-(trifluoromethoxy)benzoate</strong> (9.3 g, 39.6 mmol) and tert-butylnitrite (6.77 mL, 57.6 mmol) in acetonitrile (300 mL) and water (30 mL) was added cupric bromide (10.3 g, 46.2 mmol). The resulting reaction mixture was stirred at 75 C. for 1.5 h. The reaction was treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to afford the title compound (10.6 g, 35.6 mmol, 90% yield). MS (ESI) m/z 299.1, 300.1 [M+1]+.
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 70℃; for 1.5h;	To an acetonitrile solution (10 mL) of <strong>[457097-93-7]4-amino-3-trifluoromethoxybenzoic acid methyl ester</strong> (224 mg), copper(II) bromide (255 mg) and tert-butyl nitrite (169 muL) were added, and the mixture was stirred for 1.5 hours at 70C. The reaction mixture was left to stand to cool to room temperature. Saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction thrice, each with ethyl acetate. The extracts were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure, whereby the title compound (200 mg) was yielded. 1H-NMR (CDCl3) delta: 3.94(3H,s),7.73(1H,d,J=8.3Hz),7.84(1H,dd,J=1.7,8.3Hz),7.95-7.96(1H,m). MS(ESI)m/z:299(M+H)+.
	With tert.-butylnitrite; copper(I) bromide; In water; acetonitrile; at 70℃; for 1.5h;	Preparation 14 4-Bromo-3-trifluoromethoxy-benzoic acid methyl ester A mixture of 4-amino-3-(trifluoromethoxy)benzoic acid (504.1 mg, 2.28 mmol), methanol (7.6 mL) and 4.0 M HCl in 1,4-dioxane (5.7 mL) was stirred at RT over the weekend, concentrated, evaporated with EtOAc (310 mL), and dried under vacuum to give a brownish solid. The solid was dissolved in a mixture of acetonitrile (23 mL) and water (2.3 mL). Copper(II) bromide (595 mg, 2.66 mmol) and tert-butyl nitrite (0.39 mL, 3.32 mmol) were added to the reaction mixture which was heated at 70 C. for 1.5 h, cooled to RT and diluted with EtOAc (70 mL). The organic layer was washed with saturated sodium bicarbonate (215 mL), brine (2*15 mL), dried over sodium sulfate, filtered and concentrated to give a brownish oil, which was purified by silica gel chromatography (24 g silica gel, 0-50% EtOAc/Hexanes). Desired fractions were combined and concentrated to give the title intermediate (281 mg, 41% yield) as a yellowish oil.

Reference： [1]Patent: US2015/175557,2015,A1 .Location in patent: Paragraph 0301
[2]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 213
[3]Patent: US2013/115194,2013,A1 .Location in patent: Paragraph 0336

5
[ 457097-93-7 ]
[ 501-53-1 ]
[ 1123171-87-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In 1,4-dioxane; water; at 0 - 25℃; for 16h;	c) 4-Benzyloxycarbonylamino-3-trifluoromethoxy-benzoic acid methyl ester To a solution of <strong>[457097-93-7]4-amino-3-trifluoromethoxy-benzoic acid methyl ester</strong> (4.9 g, 20.8 mmol) and NaHCO3 (5.24 g, 62.4 mmol) in dioxane-water 5:1 (90 mL) is added at 0-5 C. benzyl chloroformate (4.4 mL, 31.3 mmol). After addition the reaction mixture is stirred at 25 C. for 16 h. The reaction mixture is diluted with CH2Cl2 and washed with water, dried over MgSO4 and evaporated. The title compound is obtained after purification by flash-chromatography on silica gel (hexane-EtOAc 30:1 to 10:1) as a colorless oil: TLC (hexane-EtOAc 4:1) Rf=0.52; ESIMS [M-H]-=368.

Reference： [1]Patent: US2009/54427,2009,A1 .Location in patent: Page/Page column 14

6
[ 175278-22-5 ]
[ 457097-93-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; methanol;	(a) 4-Amino-3-trifluoromethoxy-benzoic acid methyl ester A mixture of <strong>[175278-22-5]4-amino-3-(trifluoromethoxy)benzoic acid</strong> (5 g, 22.61 mmol), methanol (75 mL) and 4.0 M HCl in 1,4-dioxane (56.53 mL, 226.1 mmol) was stirred at RT for 2 days. The reaction mixture was concentrated and the resulting residue was evaporated with EtOAc (3*20 mL) and dried under vacuum to provide the HCl salt of the title intermediate (6.9 g).
	With thionyl chloride; In methanol; at 60℃; for 16h;	To a solution of <strong>[175278-22-5]4-amino-3-(trifluoromethoxy)benzoic acid</strong> (10.0 g, 45.3 mmol) in MeOH (120 mL) was added SOd2 (10 mL) for dropwise, the reaction was stirred at 60 C for about 16 h. The reaction was cooled to ambient temperature, concentrated under reduced pressure to remove solvent, the residue was partitioned between EA (80 mL) and H20 (20 mL), the organic phase was washed with sat. NaHCO3 (20 mL x 2) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product as a brown solid(9.8 g, 92.2%). MS (ESI) m/e [M+1] 236.0.

Reference： [1]Patent: US2012/114600,2012,A1
[2]Patent: WO2019/34009,2019,A1 .Location in patent: Paragraph 0205-0207

7
[ 457097-93-7 ]
4'-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylic acid trifluoroacetic acid salt [ No CAS ]

Reference： [1]Patent: US2013/115194,2013,A1

8
[ 457097-93-7 ]
[ 1433280-21-7 ]

Reference： [1]Patent: US2013/115194,2013,A1

9
[ 457097-93-7 ]
[ 1433280-40-0 ]

Reference： [1]Patent: US2013/115194,2013,A1

10
[ 457097-93-7 ]
[ 1433280-59-1 ]

Reference： [1]Patent: US2013/115194,2013,A1
[2]Patent: WO2019/34009,2019,A1

11
[ 457097-93-7 ]
[ 1433280-60-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-chloro-succinimide; In N,N-dimethyl acetamide; acetonitrile; at 20 - 60℃; for 1h;	(b) 4-Amino-3-chloro-5-trifluoromethoxy-benzoic acidmethyl ester The product of the previous step (200.0 mg, 0.74 mmol) was dissolved in a mixture of ACN (9.44 mL) and DMA (0.944 mL) at RT. To this stirred solution was added N-chlorosuccinimide (108.2 mg, 0.81 mmol). The resulting mixture was heated at 60 C. for 1 h, cooled to RT and partitioned between EtOAc (20 mL) and saturated sodium bicarbonate (4 mL). The organic layer was washed with saturated sodium bicarbonate (4 mL) and brine (4 mL), dried over sodium sulfate, filtered, and concentrated to give a yellowish oil, which was purified by silica gel chromatography (12 g silica gel, 0-40% EtOAc/hexanes) to give the title intermediate as a white solid (173.8 mg, 88% yield). Structure confirmed by NMR.
4.8 g	With N-chloro-succinimide; In N,N-dimethyl acetamide; acetonitrile; at 70℃; for 2h;	To a solution of <strong>[457097-93-7]methyl 4-amino-3-(trifluoromethoxy)benzoate</strong> (4.7 g, 20.0 mmol) in CH3CN (100 mL) was added DMAC (10 mL) and NCS (2.94 g, 22.0 mmol), the reaction was warmed to 70 C, stirred for about 2 h. The reaction was cooled to ambient temperature, concentrated under reduced pressure to remove CH3CN, the residue was diluted with EA (80 mL), the solution was washed with H20 (20 mL x 5) and brine (20 mL), dried over anhydrous Na2504, filtered, concentrated and purified by column chromatography on silica gel (200-300 mesh, eluent PE: EA= 4: 1) to give the product as a yellow solid (4.8 g, 89.0%). MS (ESI) m/e [M+1] 270.0.

Reference： [1]Patent: US2013/115194,2013,A1 .Location in patent: Paragraph 0456
[2]Patent: WO2019/34009,2019,A1 .Location in patent: Paragraph 0205; 0208-0209

12
[ 457097-93-7 ]
[ 1433280-61-5 ]

Reference： [1]Patent: US2013/115194,2013,A1
[2]Patent: WO2019/34009,2019,A1

13
[ 457097-93-7 ]
[ 1433280-62-6 ]

Reference： [1]Patent: US2013/115194,2013,A1

14
[ 457097-93-7 ]
((S)-1-{(2S,4S)-2-[4-(4'-{6-[(2R,5S)-4-((S)-2,2-dimethyl-cyclopropanecarbonyl)-2,5-dimethyl-piperazin-1-yl]-pyridin-3-ylcarbamoyl}-2'-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester di-trifluoroacetic acid salt [ No CAS ]

Reference： [1]Patent: US2013/115194,2013,A1

15
[ 457097-93-7 ]
((S)-1-{(2S,4S)-2-[4-(4'-{6-[(R)-4-((S)-2,2-dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridin-3-ylcarbamoyl}-2'-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester di-trifluoroacetic acid salt [ No CAS ]

Reference： [1]Patent: US2013/115194,2013,A1

16
[ 457097-93-7 ]
{(S)-2-methyl-1-[(2S,4S)-2-(4-{4'-[6-((R)-2-methyl-piperazin-1-yl)-pyridin-3-ylcarbamoyl]-2'-trifluoromethoxy-biphenyl-4-yl}-1H-imidazol-2-yl)-4-methylsulfanyl-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester tri-hydrochloride [ No CAS ]

Reference： [1]Patent: US2013/115194,2013,A1

17
[ 457097-93-7 ]
((S)-1-{(2S,4S)-2-[4-(4'-{6-[(R)-4-((S)-2,2-dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridin-3-ylcarbamoyl}-2'-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methylsulfanyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester di-trifluoroacetic acid salt [ No CAS ]

Reference： [1]Patent: US2013/115194,2013,A1

18
[ 457097-93-7 ]
[ 1433281-30-1 ]

Reference： [1]Patent: US2013/115194,2013,A1

19
[ 457097-93-7 ]
methyl ((S)-2-((2S,4S)-2-(4-(2'-chloro-4'-((6-((R)-2-methyl-4-pivaloylpiperazin-1-yl)pyridin-3-yl)carbamoyl)-6'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate di-trifluoroacetic acid salt [ No CAS ]

Reference： [1]Patent: US2013/115194,2013,A1

20
[ 457097-93-7 ]
C₃₀H₃₃F₃N₄O₆ [ No CAS ]

Reference： [1]Patent: US2013/115194,2013,A1

21
[ 457097-93-7 ]
4'-{2-[(2S,4S)-4-methanesulfinyl-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylic acid trifluoroacetic acid salt [ No CAS ]

Reference： [1]Patent: US2013/115194,2013,A1

22
[ 457097-93-7 ]
[ 1433280-63-7 ]

Reference： [1]Patent: US2013/115194,2013,A1

23
[ 457097-93-7 ]
(R)-4-bromo-3-chloro-N-(6-(2-methylpiperazin-1-yl)pyridin-3-yl)-5-(trifluoromethoxy)-benzamide di-hydrochloride [ No CAS ]

Reference： [1]Patent: US2013/115194,2013,A1

24
[ 457097-93-7 ]
C₄₅H₅₅F₃N₈O₇ [ No CAS ]

Reference： [1]Patent: US2013/115194,2013,A1

25
[ 67-56-1 ]
[ 175278-09-8 ]
[ 201230-82-2 ]
[ 457097-93-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; at 100℃; under 15201.0 Torr; for 36h;	To a solution of <strong>[175278-09-8]4-bromo-2-(trifluoromethoxy)aniline</strong> (10 g, 50.21 mmol) in methanol (150 mL) in a pressure tank reactor was added TEA (11.84 g, 117.01 mmol), Pd(dppf)Ci2 CH2Q2 (2.4 g, 2.94 mmol). Then the reactor was charged with CO (g) (20 atm). The resulting reaction was stirred for 1.5 days at 100C. Then it was diluted with water (200 mL), extracted with ethyl acetate (3 x 100 mL) and the organic layers combined and dried in an oven under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 :50) to afford methyl 4- amino-3-(trifluoromethoxy)benzoate as yellow solid (5 g, 54%).

Reference： [1]Patent: WO2014/66795,2014,A1 .Location in patent: Paragraph 0175

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere