473917-15-6|3-Fluoro-4-(trifluoromethoxy)benzaldehyde| Ambeed

CAS No. :	473917-15-6
Formula :	C₈H₄F₄O₂
M.W :	208.11
SMILES Code :	O=CC1=CC=C(OC(F)(F)F)C(F)=C1
MDL No. :	MFCD06660201
InChI Key :	RQLRUBHAAVGRPW-UHFFFAOYSA-N
Pubchem ID :	2783358

Safety of [ 473917-15-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of [ 473917-15-6 ]

* 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.

Downstream synthetic route of [ 473917-15-6 ]

[ 473917-15-6 ] Synthesis Path-Downstream 1~52

1
[ 473917-15-6 ]
C₁₇H₂₆N₆O₂*ClH [ No CAS ]
[ 76-05-1 ]
[ 1251528-86-5 ]

Yield	Reaction Conditions	Operation in experiment
		Building block D1 (0.08 g) and <strong>[473917-15-6]3-fluoro-4-trifluoromethoxy benzaldehyde</strong> (0.05 g) were dissolved in 25% MeOH in DCM (4 ml) and the resulting solution stirred at room temperature for 30 min. Sodium cyanoborohydride (0.02 g) was then added in one portion and the whole allowed to react overnight. The solvent was evaporated under reduced pressure, 10% aq. K2CO3 (3 ml) and DCM (5 ml) were added, the layers separated, the organic phase dried over Na2SO4 and evaporated to dryness. The resulting crude was then purified by preparative LC-MS to afford the target compound as a TFA salt (0.03 g). HPLC (Rt)=7.01 min (method P)The following examples are synthesized in analogy to the preparation of example 197

References: [1]Patent: US2010/261687,2010,A1 .Location in patent: Page/Page column 93.

2
[ 187235-66-1 ]
[ 473917-15-6 ]
[ 1321963-48-7 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5639 - 5659.

3
[ 473917-15-6 ]
[ 886499-04-3 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5639 - 5659.
[2]Patent: WO2016/41892,2016,A1 .

4
[ 473917-15-6 ]
[ 1321963-41-0 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5639 - 5659.

5
[ 473917-15-6 ]
[ 886498-99-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 3h;	(3-Fluoro-4-(trifluoromethoxy)phenyl)methanol. NaBH4 (1.36 g, 36.0 mmol) is added in portions to a sol. of 3- fluoro-4-(thfluoromethoxy)benzaldehyde (5.00 g, 24.0 mmol) in MeOH (80 mL) at 0 C. The mixture is stirred for 3 h while warming up to rt. Water is added carefully and the solvents are partially removed under reduced pressure. The residue is extracted with CH2CI2 (2x). The combined org. layers are dried over MgS04, filtered, and the solvents are removed under reduced pressure to yield the crude title product. LC-MS: tR = 0.77 min., conditions 3.

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5639 - 5659.
[2]Patent: WO2016/41892,2016,A1 .Location in patent: Page/Page column 42.

6
[ 473917-15-6 ]
[ 1418296-87-3 ]
[ 1418296-95-3 ]

Yield	Reaction Conditions	Operation in experiment
55%	With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃; for 1h;Inert atmosphere;	Step 1: 3-{(Z)-1-Fluoro-2-[3-fluoro-4-(trifluoromethoxy)phenyl]vinyl}-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (racemate) Under argon and at 0 C., 48.0 ml (48.0 mmol) of a 1 M solution of lithium hexamethyldisilazide in THF were added to a solution of 7.91 g (20.0 mmol) of the compound from Example 2A and 4.16 g (20.0 mmol) of <strong>[473917-15-6]3-fluoro-4-(trifluoromethoxy)benzaldehyde</strong> in 350 ml of THF. After 1 h of stirring at 0 C., 600 ml of saturated aqueous ammonium chloride solution were added, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by column chromatography (silica gel, mobile phase cyclohexane/ethyl acetate 9:1). Drying under high vacuum gave 4.40 g (55% of theory, purity 98%) of the title compound. 1H NMR (400 MHz, CDCl3, delta/ppm): 7.50 (d, 1H), 7.35-7.21 (m, 2H), 6.39 (d, 1H), 6.29 (s, 1H), 5.30 (dd, 1H), 4.08 (d, 1H), 3.71-3.63 (m, 1H), 2.55-2.42 (m, 1H), 2.38 (s, 3H), 2.18-2.09 (m, 1H), 2.01-1.93 (m, 1H), 1.80-1.56 (m, 3H). LC/MS (Method 2, ESIpos): Rt=1.71 min, m/z=389 [M+H]+.

References: [1]Patent: US2013/150325,2013,A1 .Location in patent: Paragraph 0431; 0432; 0433; 0434.

7
[ 473917-15-6 ]
[ 53947-84-5 ]
(E)-2-[[3-(3-fluoro-4-trifluoromethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With piperidine; In toluene; for 0.5h;Dean-Stark; Reflux;	Piperidine (0.12 mL, 1.2 mmol) was added toa solution of 3-trifluoromethoxy-4-methoxybenzaldehyde (0.26g, 1.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (7) (0.25 g, 1.1 mmol) in toluene (5 mL). The reaction flask wasfitted with a Dean-Stark apparatus and heated to reflux for 30 min. Thereaction was then cooled to rt and the resulting suspension was filtered andwashed with toluene. The piperidinium salt was dissolved in MeOH (5 mL) andwater (2 mL) and the solution was acidified with 20% aqueous AcOH. Theprecipitate was filtered and the crude product was recrystallised fromEtOH/water affording (E)-2-[[3-(3-fluoro-4-trifluoromethoxyphenyl)-1-oxo-2-propenyl]amino]benzoicacid (0.27 g, 66%) as a pale yellow crystalline solid;mp 264-266 C; deltaH (500 MHz, DMSO-d6) 7.02 (d, J = 15.6 Hz, 1H, CH=CHCO), 7.18 (t, J3,4 = J4,5= 8.0 Hz, 1H, H4), 7.58-6.82 (m, 4H, H3, H5,H5?, H6?), 7.98-8.01 (m, 2H, H2?,CH=CHCO), 8.61 (d, J5,6 = 8.0 Hz, 1H, H6), 11.37 (s, 1H, NH), 13.61 (br s, 1H, CO2H); deltaC (125 MHz, DMSO-d6) 116.5 (d, J= 19 Hz), 116.8, 120.0 (q, J = 256Hz), 120.4, 123.0, 124.2, 125.2, 125.7, 131.1, 134.0, 135.8 (d, J = 13 Hz), 136.1, 138.7, 140.6, 153.7(d, J = 249 Hz), 163.3, 169.4; HRMS(ESI) calculated for C17H11F4NO4[M+H]+ 370.0697, found 370.0696; nmax 754, 1168, 1250, 1584, 1659, 1677,2874, 3064, 3312 cm-1.

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6868 - 6873.

8
[ 886498-89-1 ]
[ 473917-15-6 ]

References: [1]Patent: EP2848618,2015,A1 .

9
3-fluoro-N-methoxy-N-methyl-4-(trifluoromethoxy)benzamide [ No CAS ]
[ 473917-15-6 ]

Yield	Reaction Conditions	Operation in experiment
3.55 g	With diisobutylaluminium hydride; In tetrahydrofuran; toluene; at 0 - 35℃;	E) 3-fluoro-4-(trifluoromethoxy)benzaldehyde To a solution of 3-fluoro-N-methoxy-N-methyl-4-(trifluoromethoxy)benzamide (10.0 g) in tetrahydrofuran (101 mL) was added 1.5 M diisobutylaluminium hydride/toluene solution (27.4 mL) at 0C. The reaction mixture was stirred overnight at room temperature, saturated aqueous ammonium chloride solution and 6 M hydrochloric acid was successively added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.55 g). 1H NMR (300 MHz, DMSO-d6) delta 7.71-7.97 (2H, m), 7.97-8.10 (1H, m), 10.02 (1H, d, J = 1.9 Hz).

References: [1]Patent: EP2848618,2015,A1 .Location in patent: Paragraph 0798.

10
[ 473917-15-6 ]
tert-butyl (cyano(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)carbamate [ No CAS ]

References: [1]Patent: EP2848618,2015,A1 .
[2]Patent: EP2848618,2015,A1 .
[3]Patent: US2016/159808,2016,A1 .
[4]Patent: EP3061754,2016,A1 .

11
[ 473917-15-6 ]
tert-butyl (2-amino-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-oxoethyl)carbamate [ No CAS ]

References: [1]Patent: EP2848618,2015,A1 .
[2]Patent: EP2848618,2015,A1 .
[3]Patent: US2016/159808,2016,A1 .
[4]Patent: EP3061754,2016,A1 .

12
[ 473917-15-6 ]
tert-butyl (3-amino-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-oxopropyl)carbamate [ No CAS ]

References: [1]Patent: EP2848618,2015,A1 .

13
[ 473917-15-6 ]
tert-butyl (2-cyano-1-(3-fluoro-4-(trifluoromethoxy)phenyl)ethyl)carbamate [ No CAS ]

References: [1]Patent: EP2848618,2015,A1 .

14
[ 473917-15-6 ]
2-amino-2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetic acid [ No CAS ]

References: [1]Patent: EP2848618,2015,A1 .
[2]Patent: EP2848618,2015,A1 .

15
[ 473917-15-6 ]
2-((tert-butoxycarbonyl) amino)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetic acid [ No CAS ]

References: [1]Patent: EP2848618,2015,A1 .
[2]Patent: EP2848618,2015,A1 .
[3]Patent: EP2848618,2015,A1 .
[4]Patent: EP2848618,2015,A1 .

16
[ 473917-15-6 ]
methyl 2-((tert-butoxycarbonyl) amino)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetate [ No CAS ]

References: [1]Patent: EP2848618,2015,A1 .
[2]Patent: EP2848618,2015,A1 .
[3]Patent: EP2848618,2015,A1 .
[4]Patent: EP2848618,2015,A1 .
[5]Patent: US2016/159808,2016,A1 .
[6]Patent: EP3061754,2016,A1 .

17
[ 473917-15-6 ]
tert-butyl (1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-hydroxy-2-methylpropyl)carbamate [ No CAS ]

18
[ 141-82-2 ]
[ 473917-15-6 ]
3-amino-3-(3-fluoro-4-(trifluoromethoxy)phenyl)propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.48 g	With ammonium acetate; In ethanol; at 80℃; for 20h;	A) 3-amino-3-(3-fluoro-4-(trifluoromethoxy)phenyl)propanoic acid To a solution of <strong>[473917-15-6]3-fluoro-4-(trifluoromethoxy)benzaldehyde</strong> (2.08 g) in ethanol (40 mL) were added malonic acid (1.35 g) and ammonium acetate (1.16 g) at room temperature, and the mixture was stirred at 80C for 20 hr. The reaction mixture was filtered, and the obtained solid was washed with ethanol to give the title compound (1.48 g). MS (API+): [M+H]+ 268.1.
2.84 g	With ammonium acetate; In ethanol; at 80℃; for 15h;Inert atmosphere;	A) 3-amino-3-(3-fluoro-4-(trifluoromethoxy)phenyl)propanoic acid A mixed solution of <strong>[473917-15-6]3-fluoro-4-(trifluoromethoxy)benzaldehyde</strong> (4.16 g), ammonium acetate (3.08 g) and malonic acid (2.08 g) in ethanol (50 mL) was stirred under a nitrogen atmosphere at 80 C. for 15 hr. After cooling the reaction mixture, the resulting solid was collected by filtration, and washed with ethanol and then diisopropyl ether to give the title compound (2.84 g). MS (API+): [M+H]+268.1.

References: [1]Patent: EP2848618,2015,A1 .Location in patent: Paragraph 1286.
[2]Patent: US2016/159808,2016,A1 .Location in patent: Paragraph 1303; 1304.

19
[ 7677-24-9 ]
[ 473917-15-6 ]
2-amino-2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.4 g		D) 2-amino-2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetonitrile 3-Fluoro-4-(trifluoromethoxy)benzaldehyde (10 g) was dissolved in 2 M ammonia/methanol solution (96 mL), titanium(IV) tetraisopropoxide (15.5 mL) was added thereto under ice-cooling. The reaction mixture was stirred at the same temperature for 15 min, trimethylsilanecarbonitrile (9.61 mL) was added thereto, and the mixture was stirred at room temperature for 20 hr. The solvent was evaporated under reduced pressure, and to the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The insoluble substance was filtered off using Celite, and the filtrate was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.4 g). 1H NMR (300 MHz, CDCl3) delta 2.01 (2H, brs), 4.93 (1H, s), 7.29-7.53 (3H, m).
9.4 g		C) 2-amino-2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetonitrile 3-Fluoro-4-(trifluoromethoxy)benzaldehyde (10 g) was dissolved in 2M ammonia/methanol solution (96 mL), and titanium (IV) tetraisopropoxide (15.5 mL) was added under ice-cooling. The reaction mixture was stirred at the same temperature for 15 min, trimethylsilane carbonitrile (9.61 mL) was added, and the mixture was stirred at room temperature for 20 hr. The solvent was evaporated under reduced pressure, and to the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The insoluble material was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.4 g). 1H NMR (300 MHz, CDCl3) delta 2.01 (2H, br s), 4.93 (1H, s), 7.29-7.53 (3H, m).
9.4 g		3-Fluoro-4-(trifluoromethoxy)benzaldehyde (10 g) was dissolved in 2 M ammonia/methanol solution (96 mL), and titanium(IV) tetraisopropoxide (15.5 mL) was added under ice-cooling. The reaction mixture was stirred at the same temperature for 15 min, trimethylsilane carbonitrile (9.61 mL) was added, and the mixture was stirred at room temperature for 20 hr. The solvent was evaporated under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue. Insoluble material was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.4 g). 1H NMR (300 MHz, CDCl3) delta 2.01 (2H, brs), 4.93 (1H, s), 7.29-7.53 (3H, m).

References: [1]Patent: EP2848618,2015,A1 .Location in patent: Paragraph 1257.
[2]Patent: US2016/159808,2016,A1 .Location in patent: Paragraph 1165; 1166.
[3]Patent: EP3061754,2016,A1 .Location in patent: Paragraph 0438.

20
potassium cyanide [ No CAS ]
[ 473917-15-6 ]
2-amino-2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium carbonate; In ethanol; water; at 50 - 60℃; for 4h;	F) 2-amino-2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetic acid To a mixture of <strong>[473917-15-6]3-fluoro-4-(trifluoromethoxy)benzaldehyde</strong> (3.50 g) and ammonium carbonate (4.36 g) in a mixed solvent of ethanol (21 mL) and water (8 mL) was slowly added an aqueous solution (13 mL) of potassium cyanide (1.37 g) at 50C. The mixture was stirred at 60C for 4 hr, and cooled to room temperature, and the ethanol was evaporated under reduced pressure. The pH of the residue was adjusted to 1 with conc. hydrochloric acid at 0C, and the mixture was left overnight at freezer. The resulting solid was collected by filtration, and washed with water. To an aqueous solution (100 mL) of potassium hydroxide (3.96 g) was added the obtained solid at room temperature, and the mixture was stirred at 90C for 60 hr, cooled to room temperature, and neutralized with conc. hydrochloric acid. The resulting solid was collected by filtration, and washed with water to give the title compound (937 mg). 1H NMR (300 MHz, DMSO-d6) delta 4.34 (1H, s), 7.22-7.42 (1H, m), 7.45-7.66 (2H, m).

References: [1]Patent: EP2848618,2015,A1 .Location in patent: Paragraph 0799.

21
[ 473917-15-6 ]
C₁₅H₁₇F₄NO₅ [ No CAS ]

References: [1]Patent: EP2848618,2015,A1 .

22
[ 473917-15-6 ]
1-amino-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-methylpropan-2-ol hydrochloride [ No CAS ]

References: [1]Patent: US2016/159808,2016,A1 .
[2]Patent: EP3061754,2016,A1 .

23
[ 473917-15-6 ]
N-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-hydroxy-2-methylpropyl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]