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[ CAS No. 886371-22-8 ]

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2D 3D

Chemical Structure| 886371-22-8

Chemical Structure| 886371-22-8

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Quality Control of [ 886371-22-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 886371-22-8 ]

SDS Specification

Alternatived Products of [ 886371-22-8 ]

Product Details of [ 886371-22-8 ]

CAS No. :	886371-22-8	MDL No. :	MFCD02260845
Formula :	C₈H₃Cl₂F₃O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HXPJKNUPFSLMBO-UHFFFAOYSA-N
M.W :	243.01 g/mol	Pubchem ID :	24726839
Synonyms :

Calculated chemistry of [ 886371-22-8 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	46.85
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) :	-4.96 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.95
Log Po/w (XLOGP3) :	3.98
Log Po/w (WLOGP) :	5.0
Log Po/w (MLOGP) :	3.37
Log Po/w (SILICOS-IT) :	4.03
Consensus Log Po/w :	3.67

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.04
Solubility :	0.0222 mg/ml ; 0.0000914 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.04
Solubility :	0.0222 mg/ml ; 0.0000913 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.47
Solubility :	0.00822 mg/ml ; 0.0000338 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.44

Safety of [ 886371-22-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 886371-22-8 ]

* 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 [ 886371-22-8 ]
Downstream synthetic route of [ 886371-22-8 ]

[ 886371-22-8 ] Synthesis Path-Upstream 1~2

1
[ 106-46-7 ]
[ 431-47-0 ]
[ 886371-22-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at 0℃; for 2.5 h;	Example 1: l-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone A solution of 1 ,4-dichlorobenzene (20 g, 136 mmol) in anhydrous THF (200 mL) was cooled to -78 °C. n-BuLi (150 mmol in 60 mL hexane) was added. The mixture was stirred for 1 h, followed by addition of methyl trifluoroacetate (18 mL, 179 mmol) in 30 min. The mixture was allowed to warm up to 0 °C and then stirred for 2 h. Pre-cooled saturated aqueous ammonium chloride solution (100 mL) was added. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (200 mL). The water phase was extracted with ethyl acetate (200 mL). The two ethyl acetate phases were combined and then washed with brine (200 mL). The phases were separated. The organic phase was dried over Na₂S0₄ and then filtrated. The filtrate was concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate / hexane (1/10 v/v) to afford after isolation and drying l-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone as an orange oil (28.5 g, 86 percent yield).1H NMR (400 MHz, CDC1₃) delta 7.67 (s, 1H), 7.56 to 7.50 (m, 2H).
86%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at -78 - 0℃; for 2.5 h;	Example 1: l-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanoneA solution of 1 ,4-dichlorobenzene (20 g, 136 mmol) in anhydrous THF (200 mL) was cooled to -78 °C. n-BuLi (150 mmol in 60 mL hexane) was added. The mixture was stirred for 1 h, followed by addition of methyl trifluoroacetate (18 mL, 179 mmol) in 30 min. The mixture was allowed to warm up to 0 °C and then stirred for 2 h.Pre-cooled saturated aqueous ammonium chloride solution (100 mL) was added. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (200 mL). The water phase was extracted with ethyl acetate (200 mL). The two ethyl acetate phases were combined and then washed with brine (200 mL). The phases were separated. The organic phase was dried over Na₂S0₄ and then filtrated. The filtrate was concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate / hexane (1/10 v/v) to afford after isolation and dryingl-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone as an orange oil (28.5 g, 86 percent yield).1H NMR (400 MHz, CDC1₃) delta 7.67 (s, 1H), 7.56 to 7.50 (m, 2H).
86%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at 0℃; for 2.5 h;	Example 1: l-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanoneA solution of 1 ,4-dichlorobenzene (20 g, 136 mmol) in anhydrous THF (200 mL) was cooled to -78 °C. n-BuLi (150 mmol in 60 mL hexane) was added. The mixture was stirred for 1 h, followed by addition of methyl trifluoroacetate (18 mL, 179 mmol) in 30 min. The mixture was allowed to warm up to 0 °C and then stirred for 2 h.Pre-cooled saturated aqueous ammonium chloride solution (100 mL) was added. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (200 mL). The water phase was extracted with ethyl acetate (200 mL). The two ethyl acetate phases were combined and then washed with brine (200 mL). The phases were separated. The organic phase was dried over Na₂S0₄ and then filtrated. The filtrate was concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate / hexane (1/10 v/v) to afford after isolation and dryingl-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone as an orange oil (28.5 g, 86 percent yield).1H NMR (400 MHz, CDC1₃) delta 7.67 (s, 1H), 7.56 to 7.50 (m, 2H).

Reference： [1] Patent: WO2012/79235, 2012, A1, . Location in patent: Page/Page column 34
[2] Patent: WO2012/97511, 2012, A1, . Location in patent: Page/Page column 57
[3] Patent: WO2012/97510, 2012, A1, . Location in patent: Page/Page column 56

2
[ 106-46-7 ]
[ 383-63-1 ]
[ 886371-22-8 ]

Yield	Reaction Conditions	Operation in experiment
77.3%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -75 - -70℃; for 1 h; Cooling with liquid nitrogen Stage #2: at -80 - -75℃; for 0.5 h;	General procedure: To a chilled to –75 °C solution of 1,4-dichlorobenzene (10.0 g,68 mmol) in anhydrous THF (150 mL), BuⁿLi (30 mL, 75 mmol,2.5 M solution in hexane) was added dropwise maintaining the reaction temperature below –70 °C. The reaction mixture wasstirred at –75 °C for 1 h, cooled to –80 °C with liquid nitrogenand then a solution of ethyl trifluoroacetate (10.8 g, 76 mmol) in THF (15 mL) was slowly added maintaining the reaction temperature below –75 °C. After 30 min stirring at –75 °C, thereaction mixture was warmed up to –50 °C, and 10percent HCl (20 mL) was added following by warming up to 0 °C and additionof another portion of 10percent HCl (10 mL) until distinct acidity ofthe aqueous layer was achieved. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×40 mL). The combined organics were washed with brine (2×50 mL), dried with Na₂SO, and the drying agent was filtered off. The solvents were distilled off under normal pressure using the Vigreux distillation column. Vacuum distillation of the residue afforded 12.8 g (77.3percent) of compound 2b as light yellow liquid. B.p. 92—100 °C (10 Torr), n_D²⁰ 1.4921.

Reference： [1] Russian Chemical Bulletin, 2014, vol. 63, # 10, p. 2264 - 2270[2] Izv. Akad. Nauk, Ser. Khim., 2014, # 10, p. 2264 - 2270,7

[ 886371-22-8 ] Synthesis Path-Downstream 1~15

1
[ 6746-94-7 ]
[ 886371-22-8 ]
(R)-4-cyclopropyl-2-(2,5-dichloro-phenyl)-1,1,1-trifluoro-but-3-yn-2-ol [ No CAS ]
[ 1381993-88-9 ]

Yield	Reaction Conditions	Operation in experiment
78%		Example 2b:(S)-4-Cyclopr o yl-2-(2,5-dichlor o-phenyl)- 1,1,1 -tr ifluor o-but-3-yn-2-olNaphthalene- 1 -sulfonic acid ((R)-2 -hydroxy- 1 -methyl-2,2-diphenyl-ethyl)-amide (130 mg, 0.31 mmol) was charged followed by addition of anhydrous toluene (5 mL) and dimethylzinc (3.1 mmol in 3.1 mL heptane) at RT under inert atmosphere. The reaction mixture was stirred at RT for 0.5 h followed by addition ofethynylcyclopropane (260 mg, 2.8 mmol). The reaction mixture was stirred at RT for 1.5 h. A solution of l-(2,5-dichloro-phenyl)-2,2,2-trifluoro-ethanone (500 mg, 2.1 mmol), prepared according to example 1, in anhydrous toluene (5 mL) was charged at RT over a period of 2 h. The reaction mixture was then stirred at RT for 18 h followed by addition of saturated aqueous ammonium chloride solution (20 mL). The phases were separated. The water phase was extracted with ethyl acetate (2 times with 20 mL). The combined organic phase was washed with brine (20 mL) and dried over Na2S04. The mixture was filtered and concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with dichloromethane / hexane (1/10 v/v) to afford after isolation and drying(S)-4-cyclopropyl-2-(2,5-dichloro-phenyl)- 1,1,1 -trifluoro-but-3-yn-2-ol (500 mg, 78% yield) as a light yellow oil. The ee measured was 46 % (HPLC method description A).1H NMR (400 MHz, CDC13) delta 7.90 (d, J = 2.4 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 8.8, 2.4 Hz, 1 H), 3.52 (s (br), 1 H), 1.39 to 1.36 (m, 1 H), 0.89 to 0.83 (m, 4 H).
		Example 2b: (S)-4-Cyclopro yl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-olNaphthalene- 1 -sulfonic acid ((R)-2-hydroxy-l-methyl-2,2-diphenyl-ethyl)-amide (130 mg, 0.31 mmol) was charged followed by addition of anhydrous toluene (5 mL) and dimethylzinc (3.1 mmol in 3.1 mL heptane) at RT under inert atmosphere. The reaction mixture was stirred at RT for 0.5 h followed by addition of ehtynylcyclopropane (260 mg, 2.8 mmol). The reaction mixture was stirred at RT for 1.5 h. A solution of l-(2,5-dichloro-phenyl)-2,2,2-trifluoro-ethanone (500 mg, 2.1 mmol), prepared according to example 1 , in anhydrous toluene (5 mL) was charged at RT over a period of 2 h. The reaction mixture was then stirred at RT for 18 h followed by addition of saturated aqueous ammonium chloride solution (20 mL). The phases were separated. The water phase was extracted with ethyl acetate (2 times with 20 mL). The combined organic phase was washed with brine (20 mL) and dried over Na2S04. The mixture was filtered and concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with dichloromethane / hexane (1/10 v/v) to afford after isolation and drying (S)-4-cyclopropyl-2-(2,5-dichloro-phenyl)-l,l,l- trifluoro-but-3-yn-2-ol (500 mg, 78% yield) as a light yellow oil. The ee measured was 46 %(HPLC method description A). 1H NMR (400 MHz, CDCI3) delta 7.90 (d, J = 2.4 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 8.8, 2.4 Hz, 1 H), 3.52 (s (br), 1 H), 1.39 to 1.36 (m, 1 H), 0.89 to 0.83 (m, 4 H).

Reference： [1]Patent: WO2012/97510,2012,A1 .Location in patent: Page/Page column 57-58
[2]Patent: WO2012/79235,2012,A1 .Location in patent: Page/Page column 35

2
[ 6746-94-7 ]
[ 886371-22-8 ]
[ 1381993-87-8 ]

Yield	Reaction Conditions	Operation in experiment
84%		Example 2a: 4-Cyclopro yl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-olAnhydrous THF (400 mL) was cooled to -15 C. n-BuLi (175 mmol in 70 mL hexane) was then charged in 20 min. Ethynylcyclopropane (22 mL, 260 mmol) was charged in 30 min to maintain the temperature at -15 to -12 C. The mixture was warmed to 0 C and then stirred at 0 C for 30 min. The reaction mixture was cooled to -45 C and a solution of l-(2,5-dichloro-phenyl)-2,2,2-trifluoro- ethanone (28 g, 115 mmol), prepared according to example 1, in anhydrous THF (40 mL) was charged over a period of 30 min. The reaction mixture was warmed to 0 C and then stirred for 1 h. Pre-cooled saturated aqueous ammonium chloride solution (300 mL) was charged. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (50 mL). The water phase was extracted with ethyl acetate (2 times with 200 mL). The combined organic phase was washed with brine (100 mL) and dried over Na2S04. The mixture was filtered and concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with dichloromethane / hexane (1/10 v/v) to afford after isolation and drying 4-cyclopropyl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-ol (30 g, 84 % yield) as an orange oil. 1H NMR (400 MHz, CDC13) delta 7.90 (d, J = 2.4 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.27 (dd, J = 8.8, 2.4 Hz, 1 H), 4.43 (s (br), 1 H), 1.37 to 1.31 (m, 1 H), 0.87 to 0.77 (m, 4 H).
84%		Example 2a: 4-Cyclopro yl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-ol Anhydrous THF (400 mL) was cooled to -15 C. n-BuLi (175 mmol in 70 mL hexane) was then charged in 20 min. Ethynylcyclopropane (22 mL, 260 mmol) was charged in 30 min to maintain the temperature at -15 to -12 C. The mixture was warmed to 0 C and then stirred at 0 C for 30 min. The reaction mixture was cooled to -45 C and a solution of l-(2,5-dichloro-phenyl)-2,2,2-trifluoro-ethanone (28 g, 115 mmol), prepared according to example 1, in anhydrous THF (40 mL) was charged over a period of 30 min. The reaction mixture was warmed to 0 C and then stirred for 1 h. Pre-cooled saturated aqueous ammonium chloride solution (300 mL) was charged. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (50 mL). The water phase was extracted with ethyl acetate (2 times with 200 mL). The combined organic phase was washed with brine (100 mL) and dried over Na2S04. The mixture was filtered andconcentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with dichloromethane / hexane (1/10 v/v) to afford after isolation and drying4-cyclopropyl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-ol (30 g, 84 % yield) as an orange oil.1H NMR (400 MHz, CDC13) delta 7.90 (d, J = 2.4 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.27 (dd, J = 8.8, 2.4 Hz, 1 H), 4.43 (s (br), 1 H), 1.37 to 1.31 (m, 1 H), 0.87 to 0.77 (m, 4 H).
84%		Example 2a: 4-Cyclopropyl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-ol Anhydrous THF (400 mL) was cooled to -15 C. n-BuLi (175 mmol in 70 mL hexane) was then charged in 20 min. Ethynylcyclopropane (22 mL, 260 mmol) was charged in 30 min to maintain the temperature at -15 to -12 C. The mixture was warmed to 0 C and then stirred at 0 C for 30 min. The reaction mixture was cooled to -45 C and a solution of l-(2,5-dichloro-phenyl)-2,2,2-trifluoro-ethanone (28 g, 115 mmol), prepared according to example 1, in anhydrous THF (40 mL) was charged over a period of 30 min. The reaction mixture was warmed to 0 C and then stirred for 1 h. Pre-cooled saturated aqueous ammonium chloride solution (300 mL) was charged. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (50 mL). The water phase was extracted with ethyl acetate (2 times with 200 mL). The combined organic phase was washed with brine (100 mL) and dried over Na2S04. The mixture was filtered andconcentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with dichloromethane / hexane (1/10 v/v) to afford after isolation and drying4-cyclopropyl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-ol (30 g, 84 % yield) as an orange oil.1H NMR (400 MHz, CDC13) delta 7.90 (d, J = 2.4 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.27 (dd, J = 8.8, 2.4 Hz, 1 H), 4.43 (s (br), 1 H), 1.37 to 1.31 (m, 1 H), 0.87 to 0.77 (m, 4 H).

Reference： [1]Advanced Synthesis and Catalysis,2013,vol. 355,p. 3517 - 3521
[2]Patent: WO2012/79235,2012,A1 .Location in patent: Page/Page column 34-35
[3]Patent: WO2012/97511,2012,A1 .Location in patent: Page/Page column 57-58
[4]Patent: WO2012/97510,2012,A1 .Location in patent: Page/Page column 57

3
[ 106-46-7 ]
[ 431-47-0 ]
[ 886371-22-8 ]

Yield	Reaction Conditions	Operation in experiment
86%		Example 1: l-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone A solution of 1 ,4-dichlorobenzene (20 g, 136 mmol) in anhydrous THF (200 mL) was cooled to -78 C. n-BuLi (150 mmol in 60 mL hexane) was added. The mixture was stirred for 1 h, followed by addition of methyl trifluoroacetate (18 mL, 179 mmol) in 30 min. The mixture was allowed to warm up to 0 C and then stirred for 2 h. Pre-cooled saturated aqueous ammonium chloride solution (100 mL) was added. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (200 mL). The water phase was extracted with ethyl acetate (200 mL). The two ethyl acetate phases were combined and then washed with brine (200 mL). The phases were separated. The organic phase was dried over Na2S04 and then filtrated. The filtrate was concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate / hexane (1/10 v/v) to afford after isolation and drying l-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone as an orange oil (28.5 g, 86 % yield).1H NMR (400 MHz, CDC13) delta 7.67 (s, 1H), 7.56 to 7.50 (m, 2H).
86%		Example 1: l-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanoneA solution of 1 ,4-dichlorobenzene (20 g, 136 mmol) in anhydrous THF (200 mL) was cooled to -78 C. n-BuLi (150 mmol in 60 mL hexane) was added. The mixture was stirred for 1 h, followed by addition of methyl trifluoroacetate (18 mL, 179 mmol) in 30 min. The mixture was allowed to warm up to 0 C and then stirred for 2 h.Pre-cooled saturated aqueous ammonium chloride solution (100 mL) was added. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (200 mL). The water phase was extracted with ethyl acetate (200 mL). The two ethyl acetate phases were combined and then washed with brine (200 mL). The phases were separated. The organic phase was dried over Na2S04 and then filtrated. The filtrate was concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate / hexane (1/10 v/v) to afford after isolation and dryingl-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone as an orange oil (28.5 g, 86 % yield).1H NMR (400 MHz, CDC13) delta 7.67 (s, 1H), 7.56 to 7.50 (m, 2H).
86%		Example 1: l-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanoneA solution of 1 ,4-dichlorobenzene (20 g, 136 mmol) in anhydrous THF (200 mL) was cooled to -78 C. n-BuLi (150 mmol in 60 mL hexane) was added. The mixture was stirred for 1 h, followed by addition of methyl trifluoroacetate (18 mL, 179 mmol) in 30 min. The mixture was allowed to warm up to 0 C and then stirred for 2 h.Pre-cooled saturated aqueous ammonium chloride solution (100 mL) was added. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (200 mL). The water phase was extracted with ethyl acetate (200 mL). The two ethyl acetate phases were combined and then washed with brine (200 mL). The phases were separated. The organic phase was dried over Na2S04 and then filtrated. The filtrate was concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate / hexane (1/10 v/v) to afford after isolation and dryingl-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone as an orange oil (28.5 g, 86 % yield).1H NMR (400 MHz, CDC13) delta 7.67 (s, 1H), 7.56 to 7.50 (m, 2H).

Reference： [1]Patent: WO2012/79235,2012,A1 .Location in patent: Page/Page column 34
[2]Patent: WO2012/97511,2012,A1 .Location in patent: Page/Page column 57
[3]Patent: WO2012/97510,2012,A1 .Location in patent: Page/Page column 56

4
[ 886371-22-8 ]
[ 177530-93-7 ]

Reference： [1]Patent: WO2012/79235,2012,A1
[2]Patent: WO2012/97511,2012,A1
[3]Patent: WO2012/97510,2012,A1

5
[ 886371-22-8 ]
[ 154598-52-4 ]

Reference： [1]Patent: WO2012/79235,2012,A1
[2]Patent: WO2012/97511,2012,A1

6
[ 886371-22-8 ]
[ 1381993-89-0 ]

Reference： [1]Patent: WO2012/79235,2012,A1
[2]Patent: WO2012/97511,2012,A1
[3]Patent: WO2012/97510,2012,A1

7
[ 886371-22-8 ]
[ 1381993-90-3 ]

Reference： [1]Patent: WO2012/79235,2012,A1
[2]Patent: WO2012/97511,2012,A1

8
[ 6746-94-7 ]
[ 886371-22-8 ]
[ 1381993-88-9 ]

Yield	Reaction Conditions	Operation in experiment
46%		Example 2b:(S)-4-Cyclopr o yl-2-(2,5-dichlor o-phenyl)- 1,1,1 -tr ifluor o-but-3-yn-2-olNaphthalene- 1 -sulfonic acid ((R)-2 -hydroxy- 1 -methyl-2,2-diphenyl-ethyl)-amide (130 mg, 0.31 mmol) was charged followed by addition of anhydrous toluene (5 mL) and dimethylzinc (3.1 mmol in 3.1 mL heptane) at RT under inert atmosphere. The reaction mixture was stirred at RT for 0.5 h followed by addition ofethynylcyclopropane (260 mg, 2.8 mmol). The reaction mixture was stirred at RT for 1.5 h. A solution of l-(2,5-dichloro-phenyl)-2,2,2-trifluoro-ethanone (500 mg, 2.1 mmol), prepared according to example 1, in anhydrous toluene (5 mL) was charged at RT over a period of 2 h. The reaction mixture was then stirred at RT for 18 h followed by addition of saturated aqueous ammonium chloride solution (20 mL). The phases were separated. The water phase was extracted with ethyl acetate (2 times with 20 mL). The combined organic phase was washed with brine (20 mL) and dried over Na2S04. The mixture was filtered and concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with dichloromethane / hexane (1/10 v/v) to afford after isolation and drying(S)-4-cyclopropyl-2-(2,5-dichloro-phenyl)- 1,1,1 -trifluoro-but-3-yn-2-ol (500 mg, 78% yield) as a light yellow oil. The ee measured was 46 % (HPLC method description A).1H NMR (400 MHz, CDC13) delta 7.90 (d, J = 2.4 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 8.8, 2.4 Hz, 1 H), 3.52 (s (br), 1 H), 1.39 to 1.36 (m, 1 H), 0.89 to 0.83 (m, 4 H).

Reference： [1]Organic Process Research and Development,2018,vol. 22,p. 103 - 107
[2]Patent: WO2012/97511,2012,A1 .Location in patent: Page/Page column 58-59

9
[ 886371-22-8 ]
[ 154801-74-8 ]
[ 154598-52-4 ]

Reference： [1]Patent: WO2012/97510,2012,A1

10
[ 886371-22-8 ]
[ 1381993-90-3 ]
C₁₄H₁₀Cl₂F₃NO₂ [ No CAS ]

Reference： [1]Patent: WO2012/97510,2012,A1

11
[ 106-46-7 ]
[ 383-63-1 ]
[ 886371-22-8 ]

Yield	Reaction Conditions	Operation in experiment
77.3%		General procedure: To a chilled to -75 C solution of 1,4-dichlorobenzene (10.0 g,68 mmol) in anhydrous THF (150 mL), BunLi (30 mL, 75 mmol,2.5 M solution in hexane) was added dropwise maintaining the reaction temperature below -70 C. The reaction mixture wasstirred at -75 C for 1 h, cooled to -80 C with liquid nitrogenand then a solution of ethyl trifluoroacetate (10.8 g, 76 mmol) in THF (15 mL) was slowly added maintaining the reaction temperature below -75 C. After 30 min stirring at -75 C, thereaction mixture was warmed up to -50 C, and 10% HCl (20 mL) was added following by warming up to 0 C and additionof another portion of 10% HCl (10 mL) until distinct acidity ofthe aqueous layer was achieved. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×40 mL). The combined organics were washed with brine (2×50 mL), dried with Na2SO, and the drying agent was filtered off. The solvents were distilled off under normal pressure using the Vigreux distillation column. Vacuum distillation of the residue afforded 12.8 g (77.3%) of compound 2b as light yellow liquid. B.p. 92-100 C (10 Torr), nD20 1.4921.

Reference： [1]Russian Chemical Bulletin,2014,vol. 63,p. 2264 - 2270
Izv. Akad. Nauk, Ser. Khim.,2014,p. 2264 - 2270,7

12
[ 886371-22-8 ]
5-chloro-3-(trifluoromethyl)-2,1-benzisoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium azide; In N,N-dimethyl-formamide; at 105℃; for 8h;	General procedure: To a stirred suspension of sodium azide (2.08 g, 32 mmol) in DMF (60 mL), 2,2,2-trifluoro-1-(2-fluorophenyl)ethanone 2aF (5.76 g,30 mmol) was added. Heating the suspension to 90 C resulted information of nearly clear solution. During further heating, the formation of a heavy precipitate (NaF) was observed. The reaction course was monitored by 19F NMR spectroscopy. After complete consumption of the starting 2,2,2-trifluoro-1(2-fluorophenyl)ethanone 2aF (complete disappearance of its signals inthe NMR spectrum of the reaction mixture was observed after 4 h),the reaction mixture was cooled to 25 C and poured in coldwater (300 mL). The obtained yellow solution was extractedwith diethyl ether - petroleum ether mixture (1 : 1, 2×100 mL). The combined organics were washed with 2% aqueous citricacid (2×50 mL), brine (50 mL), dried with Na2SO4, and the drying agent was filtered off. The solvents were distilled off undernormal pressure using the Vigreux distillation column. Vacuum distillation of the residue afforded 3.6 g (64%) of compound 1a as light yellow liquid.

Reference： [1]Russian Chemical Bulletin,2014,vol. 63,p. 2264 - 2270
Izv. Akad. Nauk, Ser. Khim.,2014,p. 2264 - 2270,7

13
[ 886371-22-8 ]
[ 154598-53-5 ]

Reference： [1]Russian Chemical Bulletin,2014,vol. 63,p. 2264 - 2270
Izv. Akad. Nauk, Ser. Khim.,2014,p. 2264 - 2270,7

14
[ 886371-22-8 ]
N-(2-chlorobenzyl)-1H-indol-4-amine [ No CAS ]
1-(4-((2-chlorobenzyl)amino)-1H-indol-7-yl)-1-(2,5-dichlorophenyl)-2,2,2-trifluoroethanol [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 3538 - 3542

15
[ 886371-22-8 ]
N-(2-chlorobenzyl)-1H-indol-4-amine [ No CAS ]
(R)-1-(4-((2-chlorobenzyl)amino)-1H-indol-7-yl)-1-(2,5-dichlorophenyl)-2,2,2-trifluoroethanol [ No CAS ]
1-(4-((2-chlorobenzyl)amino)-1H-indol-7-yl)-1-(2,5-dichlorophenyl)-2,2,2-trifluoroethanol [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 3538 - 3542

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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
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P234	Keep only in original container.
P235	Keep cool
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P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
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P273	Avoid release to the environment.
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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:
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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.
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P362	Take off contaminated clothing and wash before reuse.
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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:
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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.
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P411
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P413
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P422
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Disposal
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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
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H226	Flammable liquid and vapour
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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