[ CAS No. 537050-14-9 ]

Name: 537050-14-9|2-Bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone|97%
Brand: Ambeed
SKU: A342057
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Quality Control of [ 537050-14-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 537050-14-9 ]

CAS No. :	537050-14-9	MDL No. :	MFCD03094509
Formula :	C₉H₅BrF₄O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BUNOSKWLVXNWEH-UHFFFAOYSA-N
M.W :	285.03 g/mol	Pubchem ID :	2778787
Synonyms :

Calculated chemistry of [ 537050-14-9 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	49.47
TPSA :	17.07 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) :	-5.64 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.94
Log Po/w (XLOGP3) :	3.38
Log Po/w (WLOGP) :	4.99
Log Po/w (MLOGP) :	3.65
Log Po/w (SILICOS-IT) :	4.2
Consensus Log Po/w :	3.63

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.83
Solubility :	0.0417 mg/ml ; 0.000146 mol/l
Class :	Soluble
Log S (Ali) :	-3.42
Solubility :	0.109 mg/ml ; 0.000383 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.76
Solubility :	0.00491 mg/ml ; 0.0000172 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.02

Safety of [ 537050-14-9 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P501-P260-P234-P264-P280-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P406-P405	UN#:	3261
Hazard Statements:	H314-H290	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 537050-14-9 ]

* 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 [ 537050-14-9 ]
Downstream synthetic route of [ 537050-14-9 ]

[ 537050-14-9 ] Synthesis Path-Upstream 1~1

1
[ 208173-24-4 ]
[ 537050-14-9 ]

Reference： [1] Patent: WO2009/130232, 2009, A1, . Location in patent: Page/Page column 72
[2] Patent: WO2009/130231, 2009, A1, . Location in patent: Page/Page column 92; 93

[ 537050-14-9 ] Synthesis Path-Downstream 1~58

2
[ 537050-14-9 ]
[ 104-15-4 ]
[ 1082951-17-4 ]

Yield	Reaction Conditions	Operation in experiment
85%		EXAMPLE 57; 4- {4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-l -methyl- IH- imidazol-2-yl]-piperidin-l-yl}- lH-pyrazolo[3 ,4-<i]pyrimidine p-toluenesulfonate; Cool a solution of 4-fluoro-3-(trifluoromethyl)phenacyl bromide (93% pure by etaPLC, 1000 g; 3.51 moles) and tetrahydrofuran (5 L) to <5 0C in an ice bath. Add a solution of sodium azide (239 g; 3.68 moles, 1.05 eq) in water (800 mL) drop wise over one hour at < 5 0C. After stirring at < 5 0C for one hour, separate and discard the aqueous layer. While still cold, add the organic layer slowly over 3 hours to a solution of <n="65"/>triphenylphosphine (920.2g, 3.51 moles, 1.0 eq), p-toluenesulfonic acid monohydrate (1335g, 7.02 moles, 2.0 eq), and THF (5L). Maintain the temperature at < 15 C throughout this addition and solids precipitate during the addition.Stir the reaction mixture at <20 0C for 2 hours and then filter the solid , wash with THF (3 x 2 L), and dry at 50 0C under vacuum to give 1167.4g (85%, 92% corrected for starting material purity) of 2-amino-l-(4-fluoro-3-trifluoromethyl-phenyl)-ethanone p- toluenesulfonate as a white crystalline solid.

Reference： [1]Patent: WO2008/140947,2008,A1 .Location in patent: Page/Page column 63-64

3
[ 537050-14-9 ]
[ 1082949-76-5 ]

Yield	Reaction Conditions	Operation in experiment
100%		EXAMPLE 55; 4- {4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-l -methyl- IH- imidazol-2-yl]-piperidin- 1-yll- lH-pyrazolor3.4-</1Pvrimidine hydrochloride; Add methenamine (1.10 equiv; 231.55 mmoles; 32.46 g) to a solution of 4-fluoro-3-(trifluoromethyl)phenacyl bromide (60.00 g 1.00 equiv; 210.50 mmoles) in ethyl acetate (450 mL; 4.60 moles). Stir the mixture at room temperature overnight. Remove the solvent in vacuo and triturate the solid in MTBE. Filter and dry under reduced pressure. Add ethanol (450 mL; 7.73 moles), followed by hydrogen chloride (150 mL; 8.30 equiv; 1.75 moles) and stir the mixture at room temperature overnight. Remove the solvent in vacuo and dry the solid in vacuo at 50 0C for a week to obtain 2-Amino-l-(4- fluoro-3-trifluoromethyl-phenyl)-ethanone hydrochloride (54.23 g; 100% yield) as a white solid.
57.8%		Step 1: 2-amino-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone hydrochloride2-Bromo-1 -(4-fluoro-3-trifluoromethyl-phenyl)-ethanone (10.00 g; 35.08 mmol; 1.00 eq.) was added to a solution of 1 ,3,5,7-tetraaza-tricyclo[3.3.1 .13,7]decane (5.80 g; 41 .37 mmol; 1.18 eq.) in CCI4 100ml, stirred overnight. The prepcipate was filtered amd, collected as a white solid.The above solid was added ethanol 100ml, and then 28ml concentrated 36.5%HCI (aq) and stirred at RT over weekend, filtered off the solid. The filtrate was concentrated and solid came out. 10ml of isopropanol (contained 1 % HCI) was added, filtered and collected white solid as the titile compound 5.22g, 57.8%

Reference： [1]Patent: WO2008/140947,2008,A1 .Location in patent: Page/Page column 59
[2]Patent: WO2013/40059,2013,A1 .Location in patent: Page/Page column 38

4
[ 537050-14-9 ]
[ 7776-41-2 ]
[ 1082950-84-2 ]

Yield	Reaction Conditions	Operation in experiment
43%		Preparation 84; l-Benzyl-4-r5-(4-fluoro-3-trifluoromethyl-phenyl)- IH -imidazol-2-yli-piperazine; Heat 4-Benzylpiperazine-l-carboxamidine hemisulfate (500 mg, 1.00 equiv; 1.580 mmoles); sodium carbonate (4 equiv, 6.321 mmoles); dimethylformamide (10.5 mL), and acetone ( 110. mL) to reflux. Add 2-Bromo-l-[4-fluoro-3(trifluoromethyl)phenyl]-l- ethanone (1.00 equiv; 1.580 mmoles; 450 mg) in 4 mL acetone dropwise over 15 minutes and stir the reaction for 30 minutes, then cool to room temperature. Filter the reaction and concentrate under reduced pressure, dilute with ethyl acetate, wash with 20% sat. sodium bicarbonate, water, and saturated aqueous sodium chloride. Dry with MgSO4, filter and evaporate under reduced pressure. Purify the on silica gel with 2-5% IM NH3- MeOH/DCM to give 262.0 mg (0.678mmol, 43%) l-Benzyl-4-[5-(4-fluoro-3- trifluoromethyl-phenyl)- IH -imidazol-2-yl]-piperazine. MS (ES): m/z = 405 [M + H].

Reference： [1]Patent: WO2008/140947,2008,A1 .Location in patent: Page/Page column 34

5
[ 537050-14-9 ]
[ 1192149-31-7 ]
[ 1192148-41-6 ]

Yield	Reaction Conditions	Operation in experiment
65.9%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 3h;	To a solution of (2S,4R)-4-(7-chloro-4-methoxyisoquinolin-1-yloxy)-N-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-(2,2-difluoroethyl)cyclopropyl)-1-((S)-3,3-dimethyl-2-thioureidobutanoyl)pyrrolidine-2-carboxamide (30 mg, 0.040 mmol) and N,N-diisopropylethylamine (0.014 mL, 0.081 mmol) in DMF (1 mL) was added <strong>[537050-14-9]2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone</strong> (22.95 mg, 0.081 mmol). The formed light yellow solution was stirred at 25 C. After 3 h, the reaction mixture was diluted with MeOH (1 mL) and purified by reverse phase HPLC using solvent system and conditions as the following: solvent A=H2O, solvent B=MeOH, both containing 0.1% TFA; 15% B to 100% B 15 mins, hold at 100% B 5 mins. The combined HPLC fractions was concentrated to almost dryness, filtered, washed the cake with water. The collected cake was dried in vacuo overnight to afford the desired product (2S,4R)-4-(7-chloro-4-methoxyisoquinolin-1-yloxy)-N-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-(2,2-difluoroethyl)cyclopropyl)-1-((S)-2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide (26 mg, 0.027 mmol, 65.9% yield) as an off-white solid. 1H NMR (500 MHz, MeOD) delta 1.10-1.15 (m, 2H), 1.18 (s, 9H), 1.24-1.42 (m, 3H), 1.61-1.75 (m, 2H), 2.09-2.32 (m, 3H), 2.45 (dd, J=13.73, 6.71 Hz, 1H), 2.92-3.10 (m, 1H), 3.95 (s, 3H), 4.18 (dd, J=11.44, 3.51 Hz, 1H), 4.51 (dd, J=10.83, 6.87 Hz, 1H), 4.87-4.93 (m, 1H), 4.99 (d, J=10.99 Hz, 1H), 5.74-6.05 (m, 1H), 6.08 (br. s., 1H), 6.75-6.91 (m, 2H), 7.37 (d, J=1.83 Hz, 1H), 7.42 (s, 1H), 7.52 (dd, J=8.85, 2.14 Hz, 1H), 7.82 (ddd, J=8.39, 2.44, 2.29 Hz, 1H), 7.86-8.00 (m, 2H). LC (retention time: 3.34 min, Method A).

Reference： [1]Patent: US2009/274652,2009,A1 .Location in patent: Page/Page column 75-76

6
[ 537050-14-9 ]
[ 870-46-2 ]
[ 1192313-80-6 ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 5℃;	In a 4L round bottomed flask, 1 ,1-dimethylethyl hydrazinecarboxylate (45g, 334 mmol) was dissolved in dry DMF (1 L) followed by slow addition of DIPEA (0.059 L, 334 mmol); the system was cooled down until intrenal temperature was 50C, then a solution of 2- bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (105 g, 350 mmol) in dry DMF (0.100 L) was added dropwise. After 2 hours at O0C, the mixture was poured in to 2 L of water and extracted with diethyl ether (2x1 L); combined organics were washed with water (2x0.5L), dried on sodium sulphate and evaporated under reduced pressure (bath set at 250C) to obtain 140.6 g of 1 ,1-dimethylethyl 2-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2- oxoethyl}hydrazinecarboxylate (140.6 g, 264 mmol, 79 % yield) as crude material (pale yellow solid) used quickly without further purifications in the next step.

Reference： [1]Patent: WO2009/130232,2009,A1 .Location in patent: Page/Page column 67

7
[ 208173-24-4 ]
[ 537050-14-9 ]

Yield	Reaction Conditions	Operation in experiment
	In chloroform; ethyl acetate; for 6h;Reflux;	To a vigorously stirred refluxing solution of Cub (15.17 g, 67.9 mmol) in EA (40 ml), a solution of 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (7 g, 34.0 mmol) in dry chloroform (50 ml) was added one pot, then the reaction mixture was refluxed for 6h. The mixture was cooled down to RT, filtered over a pad of celite and evaporated. The residue was partitioned between EA and saturated NaHCO3 aqueous solution, then organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by FC on silica (eluting with Cy/EA from 10/0 to 8/2) to give 6.95 g of the title compound.NMR (1H, CDCI3): delta ppm 8.15 - 8.30 (m, 2 H), 7.30 - 7.39 (m, 1 H), 4.45 (s, 2 H).
	With copper(II) iodide; In chloroform; for 6h;Reflux;	To a vigorously stirred refluxing solution of CuI2 (15.17 g, 67.9 mmol) in EA (40 ml), a solution of 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (7 g, 34.0 mmol) in dry chloroform (50 ml) was added one pot, then the reaction mixture was refluxed for 6h. The mixture was cooled down to RT, filtered over a pad of celite and evaporated. The residue was partitioned between EA and saturated NaHCO3 aqueous solution, then organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by FC on silica (eluting with Cy/EA from 10/0 to 8/2) to give 6.95 g of the title compound. <n="95"/>NMR (1H, CDCI3): delta 8.15 - 8.30 (m, 2 H), 7.30 - 7.39 (m, 1 H), 4.45 (s, 2 H).
3.50 g	With bromine; acetic acid; at 20℃; for 18h;	1-[4-Fluoro-3-(trifluoromethyl)phenyl]ethanone (7.7 m[, 100 % purity, 49 mmol, GAS2081 73-24-4) was dissolved in acetic acid (70 m[), then a solution of bromine (2.5 m[,100% purity, 49 mmol) in acetic acid (5 m[) was added slowly. The mixture was stirredat RT for 18 h. The mixture was dried in vacuo to obtain 3.50 g of the title compound.

With bromine; acetic acid; at 20℃;Inert atmosphere;

1 -[4-Fluoro-3-(trifluoromethyl)phenyl]ethanone (380 muIota_, 100 % purity, 2.4 mmol, CAS 208173-24-4) was dissolved in acetic acid (3.7 mL) at room temperature. Bromine (120 muIota_, 100 % purity, 2.4 mmol) was added dropwise into the reaction mixture, which was stirred overnight, its colour turned from brown to orange. The mixture was concentrated under reduced pressure and used as crude material in the next step.

Reference： [1]Patent: WO2009/130232,2009,A1 .Location in patent: Page/Page column 72
[2]Patent: WO2009/130231,2009,A1 .Location in patent: Page/Page column 92; 93
[3]Patent: WO2019/25554,2019,A1 .Location in patent: Page/Page column 152
[4]Patent: WO2019/25562,2019,A1 .Location in patent: Page/Page column 227; 239

8
[ 537050-14-9 ]
[ 1192313-85-1 ]
[ 1192313-86-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; at 20℃;	To a stirred solution of 1 ,1-dimethylethyl 4-({5-[(ethyloxy)carbonyl]-1 H-pyrazol-3-yl}oxy)-1- piperidinecarboxylate (P58, 0.81 g, 2.387 mmol) in DMF (8 ml_), at RT, 2-bromo-1-[4- fluoro-3-(trifluoromethyl)phenyl]ethanone (P57bis, 0.75 g, 2.63 mmol) and sodium carbonate (0.55 g, 5.19 mmol) were subsequently added and the reaction mixture was stirred overnight. Ether and cold water were added, the organic phase was washed with water, brine, dried over Na2SO4 and the solvent removed under reduced pressure. The residue was purified by FC on silica (eluting with Cy/EA from 1/0 to 7/3) to give 0.69 g of the title compound as a white foam.NMR (1H, CDCI3): delta ppm 8.11 - 8.31 (m, 2 H) 7.37 (t, 1 H), 6.33 (s, 1 H), 5.83 (s, 2 H), 4.68 (dt, 1 H), 4.27 (q, 2 H), 3.64 - 3.81 (m, 2 H), 3.20 - 3.37 (m, 2 H), 1.88 - 2.08 (m, 2 H), 1.68 - 1.86 (m, 2 H), 1.42 - 1.53 (m, 9 H), 1.32 (t, 3 H). MS(m/z): 544.16 [MH]+.

Reference： [1]Patent: WO2009/130232,2009,A1 .Location in patent: Page/Page column 72-73

9
[ 537050-14-9 ]
ethyl 3⁽⁵⁾-iodopyrazole-5⁽³⁾-carboxylate [ No CAS ]
[ 1192313-67-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere of N2;	To a suspension of ethyl 3-iodo-I H-pyrazole-S-carboxylate (750 mg, P41 ) and sodium carbonate (359 mg) in dry DMF (7 ml.) under N2 atmosphere, 2-bromo-1-[4-fluoro-3- (trifluoromethyl)phenyl]ethanone (964 mg) was adedd and the mixture was stirred at RT for 3h. The reaction mixture was diluted with Et2O and washed with water. The organic phase was dried, evaporated under vacum and the crude was purified by Si flash chromatography (eluting with Cy/ AcOEt 9:1 ) to give the title compound (0.85 g).MS ( m/z): 471 [MH]+.

Reference： [1]Patent: WO2009/130232,2009,A1 .Location in patent: Page/Page column 62-63

10
[ 537050-14-9 ]
[ 1192313-21-5 ]
[ 1192313-58-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;	To a solution of ethyl 3-[(3-[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1 H-pyrazole- 5-carboxylate (3 g, prepared with an analogous procedure to that described in P2) and Na2CO3 (1.16 g) in DMF (20 ml.) <strong>[537050-14-9]2-bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone</strong> (3.12 g, commercially available) was added . The mixture was stirred at 600C for 8h. After cooling the mixture was diluted with Et2O and washed with water and brine. The organic phase was separated from the aqueous phase, dried over Na2SO4 and the solvent <n="61"/>evaporated under vacuum. The crude was purified by flash chromatography (eluentAcOEt:Cy=2:8) to give of the title compound (2.5 g).MS ( m/z): 533 [MH]+.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5044 - 5049
[2]Patent: WO2009/130232,2009,A1 .Location in patent: Page/Page column 58-59

11
[ 537050-14-9 ]
[ 1082951-17-4 ]

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 982 - 1002

12
[ 537050-14-9 ]
[ 77287-34-4 ]
[ 1226802-64-7 ]

Yield	Reaction Conditions	Operation in experiment
47%	at 180℃; for 3h;	Preparation 64 4-(4-Fluoro-3-(trifluoromethyl)phenyl)-1H-imidazole Charge <strong>[537050-14-9]2-bromo-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethanone</strong> (40.0 g; 0.14 mol; 1.0 equiv) and formamide (175 mL; 4.38 mol; 31.3 equiv) in a pressure vessel. Heat at 180 C. for 3 h. Quench with saturated sodium bicarbonate solution and filter through Celite. Extract with EA and wash the organic layer with water and brine. Concentrate and purify on silica column with 0-10% MeOH-EA to give the title compound. (15.2 g; 47.0%). (ES+): m/z=231 (M+H).

Reference： [1]Patent: US2010/120801,2010,A1 .Location in patent: Page/Page column 16

13
[ 537050-14-9 ]
[ 100-97-0 ]
Br^(1-)*C₁₅H₁₇F₄N₄O⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; at 20℃;	Preparation 4 2-Amino-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone, hydrochloride To a solution of <strong>[537050-14-9]2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone</strong> (60.00 g 1.00 equiv; 210.50 mmoles (mmol)) in ethylacetate (EA) (450 mL; 4.60 moles (mol)), add 1,3,5,7-tetraazatricyclo-[3.3.1.13,7]decane (Methenamine, 1.10 equiv; 231.55 mmol; 32.46 g) and stir at RT overnight. Remove the solvent in vacuo and triturate the solid with methyl-t-butylether (MTBE), filter and dry in vacuo. Add ethanol (450 mL; 7.73 mol) followed by hydrogen chloride (36.5 wt/wt % in water) (150 mL; 8.30 equiv; 1.75 mol) and stir the mixture overnight. Remove the solvent in vacuo and dry the solid in vacuo at 50 C. for 1 week to give the title compound (54.23 g; 100% yield) as a white solid with some amount of ammonium salt. 1H NMR (300 MHz, DMSO): 8.69-8.59 (m, 4H), 8.07-8.01 (m, 1H), 4.95 (d, J=5.2 Hz, 2H). Use the solid as is.

Reference： [1]Patent: US2010/120801,2010,A1 .Location in patent: Page/Page column 9

14
[ 537050-14-9 ]
C₉H₅F₄N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium azide; In tetrahydrofuran; at 20℃;Product distribution / selectivity;	Preparation 1 2-Amino-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone, 4-methylbenzenesulfonate Add sodium azide (1.76 g; 1.05 equivalents (equiv)) in one portion to a solution of <strong>[537050-14-9]2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone</strong> (9.19 g; 1.00 equiv) in THF (50 mL). Stir the mixture at room temperature (RT) overnight. Filter the solids and wash with THF. Add the crude azide to a solution of triphenylphosphine (1.06 equiv; 8.64 g) and p-toluenesulfonic acid (2.2 equiv; 12.0 g) in THF (50 mL) under 20 C. Stir the mixture overnight. Filter the solid, and then wash with THF to obtain 5.5 g of the title compound. MS(ES): m/z=217.2 [M+H].

Reference： [1]Patent: US2010/120801,2010,A1 .Location in patent: Page/Page column 9
[2]Organic Process Research and Development,2012,vol. 16,p. 982 - 1002

15
[ 537050-14-9 ]
[ 1044560-96-4 ]
[ 1226804-40-5 ]

Yield	Reaction Conditions	Operation in experiment
33%		Preparation 144 (R)-3-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylamino]-piperidine-1-carboxylic acid benzyl ester hydrochloride Combine <strong>[537050-14-9]2-bromo-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethanone</strong> (1.00 equiv; 22.57 mmol; 6.43 g) in 15 mL DMF dropwise to a solution of (R)-3-amino-piperidine-1-carboxylic acid benzyl ester (1 equiv; 22.57 mmol; 5.29 g) and TEA (1 equiv; 22.57 mmol; 3.15 mL) in DMF (30 mL). Stir 10 min. Dilute with EA, wash 3* with brine, dry over MgSO4, filter, add 1 equiv 1M HCl in ether and evaporate to give 10.56 g orange residue. Dissolve in IPA (100 mL), cool in ice bath, filter the solids, rinse with diethyl ether, dry in a vacuum oven at 40 C. to provide the title compound (3.49 g; 7.35 mmol; 33%). MS (ES+): m/z=439 (M+H).

Reference： [1]Patent: US2010/120801,2010,A1 .Location in patent: Page/Page column 23

16
[ 537050-14-9 ]
[ 40611-79-8 ]
[ 1192688-03-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5044 - 5049

17
[ 537050-14-9 ]
[ 1083051-56-2 ]

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 982 - 1002
[2]Organic Process Research and Development,2012,vol. 16,p. 982 - 1002

18
[ 537050-14-9 ]
4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidine dihydrochloride [ No CAS ]

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 982 - 1002

19
[ 537050-14-9 ]
[ 1082949-99-2 ]

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 982 - 1002
[2]Patent: WO2013/40059,2013,A1

20
[ 537050-14-9 ]
[ 1082950-48-8 ]

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 982 - 1002
[2]Patent: WO2013/40059,2013,A1

21
[ 537050-14-9 ]
[ 1082950-60-4 ]

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 982 - 1002

22
[ 512822-50-3 ]
[ 537050-14-9 ]
3-methylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-[2-(4-fluoro-3-trifluoromethylphenyl)-2-oxoethyl] ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetone; at 20℃; for 0.5h;	To a solution of 2-bromo-1 -(4-fluoro-3-trifluoromethyl-phenyl)-ethanone (1000.00 mg; 3.51 mmol; 1 .00 eq.) and 3-methyl-piperidine-1 ,4-dicarboxylic acid 1 -tert-butyl ester (981 .62 mg; 4.03 mmol; 1 .15 eq.) in 10ml acetone, was added cesium carbonate (1714.6 mg; 5.26 mmol; 1 .50 eq.). The resulting mixture was stirred at RT for 30min. LC-MS showed the reaction was done with the desired product formed. The reaction solution was poured to 50 ml of ethyl acetate and washed with 5% NaHC03 aqueous solution, then brine. The organic phase was dried and concentrated to afford the title compound, which was directly used for the next step reaction. LC-MS (M+H = 448, obsd = 448).

Reference： [1]Patent: WO2014/143612,2014,A1 .Location in patent: Page/Page column 32-33

23
[ 537050-14-9 ]
1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-carboxylic acid [ No CAS ]
3-fluoropiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-[2-(4-fluoro-3-trifluoromethylphenyl)-2-oxoethyl] ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.75 g	With triethylamine; In acetonitrile; at 20℃; for 1.5h;	2- Bromo-1 -(4-fluoro-3-trifluoromethyl-phenyl)-ethanone (2.23 g; 8.07 mmol; 1 .0 eq.) was added to a solution of 3-fluoro-piperidine-1 ,4-dicarboxylic acid 1 -tert-butyl ester (2.0 g; 8.07 mmol; 1 .0 eq.) and triethylamine (1.36 ml; 9.68 mmol; 1 .20 eq.) in acetonitrile (20 ml) at rt in one portion. The resulting mixture was stirred at rt for 1 .5 h. The reaction mixture was diluted with 60 ml of ethyl acetate, washed with saturated sodium bicarbonate solution once and brine twice. The organic layer was dried over MgS04 and then concentrated to yield the title compound as light brown solid (3.75 g, 103% yield).

Reference： [1]Patent: WO2014/143612,2014,A1 .Location in patent: Page/Page column 31

24
[ 537050-14-9 ]
C₁₂H₇F₄N₃OS [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5481 - 5486

25
[ 537050-14-9 ]
[ 37566-39-5 ]
C₁₁H₄BrF₄N₃S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5481 - 5486

26
[ 537050-14-9 ]
5-bromo-N’-hydroxy-6-methoxypicolinimidamide [ No CAS ]
(Z)-5-bromo-N’-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-oxoethoxy)-6-methoxypicolinimidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		bromo-iV-hydroxy-6-methoxypicolinimidamide (573 mg, 2.33 mmol) in acetonitrile (15 mL) was added to PS-BEMP (2.2 mmollg, 1.27 g, 2.8 mmol). The mixture was stirred at room temperature for 5 minutes before the addition of 2-bromo- i-(3- fluoro-4-(trifluoromethyl)phenyl)ethanone (1 g, 3.5 mmol) in acetonitrile (5 mL). The reaction mixture was stirred for 2.5 hours, filtered, and the solvent was removed under reduced pressure to afford crude (Z)-5-bromo-N?-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-2oxoethoxy)-6-methoxypicolinimidamide which was used directly in the next step. UPLC (basic, 1.25 mm): RT 0.94 mi [MHj+ 450.2, purity 55%.

Reference： [1]Patent: WO2016/201168,2016,A1 .Location in patent: Paragraph 0350

27
[ 537050-14-9 ]
[ 105-45-3 ]
methyl 2-acetyl-4-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxobutanoate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 1714 - 1717

28
[ 537050-14-9 ]
methyl 1-(2-(tert-butyl)phenyl)-5-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methyl-1H-pyrrole-3-carboxylate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 1714 - 1717

29
[ 537050-14-9 ]
(R)-methyl 1-(2-(tert-butyl)phenyl)-5-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methyl-1H-pyrrole-3-carboxylate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 1714 - 1717

30
[ 537050-14-9 ]
(Z)-5-bromo-N’-hydroxy-6-methoxypicolinimidamide [ No CAS ]
(Z)-5-bromo-N’-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-oxoethoxy)-6-methoxypicolinimidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 0.0833333h;Microwave irradiation; Inert atmosphere;	[0446] To a stirred solution of (Z)-5-bromo-iV-hydroxy-6-methoxypicolinimidamide (1 g, 4 mmol) in DMF (10 mL) at room temperature under an argon atmosphere were added potassium carbonate (840 mg, 6 mmol) and 2-bromo-1-(4-fluoro-3-(trifluoromethyl) phenyl) ethan-1-one (1.4 g, 5 mmol). The reaction mixture was stirred at 60 C for 5 mm. After consumption of starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain (Z)-5-bromo-iV-(2-(4-fluoro-3- (trifluoromethyl) phenyl)-2-oxoethoxy)-6-methoxypicolinimidamide (1.6 g, crude) as brown semi solid used in the next step without further purification. LCMS: 25.5%; 449.9 (M+1); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 tim); RT 2.73 mm; mobile phase: 0.025% Aq TFA+5% ACN: ACN+5% 0.025% Aq TFA; T/B%: 0.01/5, 0.5/5, 3/100, 5/100; flow rate:1.2 mL/min) (Gradient); TLC: 40% EtOAc/ Hexane (R1: 0.6)

Reference： [1]Patent: WO2017/31325,2017,A1 .Location in patent: Paragraph 0446

31
[ 537050-14-9 ]
tert-butyl (S)-2-((3-(4-thioureidophenyl)-1,2,4-oxadiazol-5-yl)-methyl)pyrrolidine-1-carboxylate [ No CAS ]
tert-butyl (S)-2-((3-(4-((4-(4-fluoro-3-(trifluoromethyl)phenyl)-thiazol-2-yl)amino)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 3933 - 3957

32
[ 537050-14-9 ]
[ 1192313-68-0 ]