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[ CAS No. 537050-14-9 ]

{[proInfo.proName]} ,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

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Chemical Structure| 537050-14-9

Chemical Structure| 537050-14-9

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Quality Control of [ 537050-14-9 ]

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Product Details of [ 537050-14-9 ]

CAS No. :	537050-14-9	MDL No. :	MFCD03094509
Formula :	C₉H₅BrF₄O	Boiling Point :	249.7°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	285.03 g/mol	Pubchem ID :	2778787
Synonyms :

Calculated chemistry of 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 1~33

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 ]

Reference： [1]Patent: WO2009/130232,2009,A1

33
[ 537050-14-9 ]
C₁₃H₈F₄IN₃O₂ [ No CAS ]

Reference： [1]Patent: WO2009/130232,2009,A1

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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