[ CAS No. 111141-02-7 ] {[proInfo.proName]}

Name: 111141-02-7|7-(Trifluoromethyl)chroman-4-one|97%
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SKU: A195809
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Quality Control of [ 111141-02-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 111141-02-7 ]

Product Details of [ 111141-02-7 ]

CAS No. :	111141-02-7	MDL No. :	MFCD09998165
Formula :	C₁₀H₇F₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BDGGJAUEQDZWRC-UHFFFAOYSA-N
M.W :	216.16	Pubchem ID :	13953821
Synonyms :

Calculated chemistry of [ 111141-02-7 ] Expand+

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	1
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	46.02
TPSA :	26.3 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) :	-6.01 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.01
Log Po/w (XLOGP3) :	2.26
Log Po/w (WLOGP) :	3.82
Log Po/w (MLOGP) :	2.05
Log Po/w (SILICOS-IT) :	3.36
Consensus Log Po/w :	2.7

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.83
Solubility :	0.317 mg/ml ; 0.00147 mol/l
Class :	Soluble
Log S (Ali) :	-2.45
Solubility :	0.769 mg/ml ; 0.00356 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.75
Solubility :	0.0384 mg/ml ; 0.000178 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.05

Safety of [ 111141-02-7 ]

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

Application In Synthesis of [ 111141-02-7 ]

* 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 [ 111141-02-7 ]
Downstream synthetic route of [ 111141-02-7 ]

[ 111141-02-7 ] Synthesis Path-Upstream 1~7

1
[ 1140496-03-2 ]
[ 111141-02-7 ]

Reference： [1] Patent: US2009/93472, 2009, A1, . Location in patent: Page/Page column 14

2
[ 111140-93-3 ]
[ 111141-06-1 ]
[ 111141-02-7 ]

Reference： [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 1, p. 230 - 243
[2] Patent: US2012/302562, 2012, A1, . Location in patent: Page/Page column 12

3
[ 890839-56-2 ]
[ 111141-06-1 ]
[ 111141-02-7 ]

Reference： [1] Patent: US2006/128689, 2006, A1, . Location in patent: Page/Page column 24

4
[ 111140-93-3 ]
[ 111141-02-7 ]

Reference： [1] Patent: US2008/287428, 2008, A1, . Location in patent: Page/Page column 53-54
[2] Patent: US2008/287428, 2008, A1, . Location in patent: Page/Page column 60
[3] Patent: EP2128157, 2009, A1, . Location in patent: Page/Page column 106-107
[4] Patent: US2007/99954, 2007, A1, . Location in patent: Page/Page column 36
[5] Patent: EP1908753, 2008, A1, . Location in patent: Page/Page column 78
[6] Patent: EP1908753, 2008, A1, . Location in patent: Page/Page column 88

5
[ 145485-43-4 ]
[ 111141-02-7 ]

Reference： [1] Patent: US2006/128689, 2006, A1, . Location in patent: Page/Page column 12

6
[ 98-17-9 ]
[ 111141-02-7 ]

Reference： [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 1, p. 230 - 243

7
[ 98-17-9 ]
[ 111141-06-1 ]
[ 111141-02-7 ]

Reference： [1] Patent: US2012/302562, 2012, A1,

[ 111141-02-7 ] Synthesis Path-Downstream 1~28

1
[ 151-50-8 ]
[ 111141-02-7 ]
[ 111140-56-8 ]

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 230 - 243

2
[ 111140-93-3 ]
[ 111141-06-1 ]
[ 111141-02-7 ]

Yield	Reaction Conditions	Operation in experiment
	With polyphosphoric acid; at 100℃; for 0.333333h;	In a 100 mL round bottom flask, crude acid 27 (7.02 g, 30 mmol) was suspended in polyphosphoric acid (15 mL) and heated at 100 C. for 20 minutes. Then the reaction mixture was cooled to room temp and ice was added while stirring. The resulting solid precipitate was filtered and washed twice with cold water. This crude mixture was purified by silica gel chromatography (ethyl acetate-hexanes) to afford 7-(trifluoromethyl)chroman-4-one 28 (0.899 g, 14.4% yield) and 5-(trifluoromethyl)chroman-4-one 29 (0.214 g, 3.4% yield).

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 230 - 243
[2]Patent: US2012/302562,2012,A1 .Location in patent: Page/Page column 12

3
[ 105-36-2 ]
[ 111141-02-7 ]
[ 920334-31-2 ]

Yield	Reaction Conditions	Operation in experiment
	With zinc; In tetrahydrofuran; toluene; at 70℃; for 1h;Heating / reflux;	Zinc (300 mg) was suspended in tetrahydrofuran (4 mL). A toluene (8 mL) solution of the compound (500 mg) prepared in <Step 1> of Example 70 and ethyl bromoacetate (590 mg) were added dropwise to the suspension at an outer temperature of 70 C. The reaction mixture was refluxed for 30 minutes, and zinc (300 mg) and ethyl bromoacetate (590 mg) were added thereto. The reaction mixture was refluxed for 30 minutes and left to cool. Subsequently, 1 N hydrochloric acid was added to the reaction mixture. The reaction mixture was separated, and the resulting aqueous layer was then extracted with ethyl acetate. The organic layers were combined and washed with a saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The title compound (700 mg) was obtained as brown oil.
		Zinc (300 mg) was suspended in tetrahydrofuran (4 mL). A toluene (8 mL) solution of the compound (500 mg) prepared in <Step 1> of Example 70 and ethyl bromoacetate (590 mg) were added dropwise to the suspension at an outer temperature of 70C. The reaction mixture was refluxed for 30 minutes, and zinc (300 mg) and ethyl bromoacetate (590 mg) were added thereto. The reaction mixture was refluxed for 30 minutes and left to cool. Subsequently, 1 N hydrochloric acid was added to the reaction mixture. The reaction mixture was separated, and the resulting aqueous layer was then extracted with ethyl acetate. The organic layers were combined and washed with a saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The title compound (700 mg) was obtained as brown oil.

Reference： [1]Patent: US2008/287428,2008,A1 .Location in patent: Page/Page column 60
[2]Patent: EP1908753,2008,A1 .Location in patent: Page/Page column 88

4
[ 111141-02-7 ]
[ 920334-50-5 ]

Yield	Reaction Conditions	Operation in experiment
		Manganese bromide (9.9 g) was added to potassium bis(trimethylsilyl)amide (69.0 mL, 0.5 M toluene solution) at -78 C., and the reaction mixture was stirred at the same temperature for 15 minutes. A tetrahydrofuran (120 mL) solution of the compound (2.49 g) prepared in <Step 2> of Example 6 was added dropwise to the reaction mixture, and the reaction mixture was further stirred at the same temperature for 30 minutes. Subsequently, N-fluorobenzenesulfonimide (14.5 g) was added thereto, and the temperature of the reaction mixture was increased to 0 C. over a period of four hours. The reaction mixture was then neutralized with 1 N hydrochloric acid and extracted with diethyl ether. The organic layer was sequentially washed with water and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 90:10). The title compound (1.0 g) was obtained as pale yellow oil.
		Manganese bromide (9.9 g) was added to potassium bis(trimethylsilyl)amide (69.0 mL, 0.5 M toluene solution) at -78C, and the reaction mixture was stirred at the same temperature for 15 minutes. A tetrahydrofuran (120 mL) solution of the compound (2.49 g) prepared in <Step 2> of Example 6 was added dropwise to the reaction mixture, and the reaction mixture was further stirred at the same temperature for 30 minutes. Subsequently, N-fluorobenzenesulfonimide (14.5 g) was added thereto, and the temperature of the reaction mixture was increased to 0C over a period of four hours. The reaction mixture was then neutralized with 1 N hydrochloric acid and extracted with diethyl ether. The organic layer was sequentially washed with water and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate = 100:0 to 90:10). The title compound (1.0 g) was obtained as pale yellow oil.

Reference： [1]Patent: US2008/287428,2008,A1 .Location in patent: Page/Page column 68
[2]Patent: EP1908753,2008,A1 .Location in patent: Page/Page column 104-105

5
[ 98-17-9 ]
[ 111141-02-7 ]

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 230 - 243

6
[ 593-56-6 ]
[ 111141-02-7 ]
[ 890838-99-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	With pyridine; at 20℃; for 18 - 24h;	Example 4C; <strong>[111141-02-7]7-Trifluoromethyl-chroman-4-one</strong> O-methyl-oxime; A solution of the product of Example 4B (0.84 g, 3.88 mmol) and methoxyl amine hydrochloride (0.65 g, 7.78 mmol, 2eq.) in pyridine (10 mL) was stirred for 18 hrs at ambient temperature and concentrated under vacuum. The residue was dissolved in diethyl ether and washed sequentially with water, 1 N HCl and water. The isolated organic layer was concentrated and the residue chromatographed on silica gel, eluting with 5:95 ethyl acetate: hexanes to afford the title product (0.71 g, 74%).; Example 35D; Example 35C (1.29 g, 6 mmol) was dissolved in 6 ml pyridine. Methoxylamine hydrochloride (1.00 g, 12 mmol) was added and the reaction stirred at ambient temperature for 1 day. The pyridine was removed under reduced pressure, and the residue partitioned between water and diethyl ether. The mixture was extracted with diethyl ether, and the combined organic layers dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography using 5% ethyl acetate in hexanes to give 0.81 g of Example 35D.
74%	With pyridine; at 20℃; for 18h;	EXAMPLE 76C <strong>[111141-02-7]7-Trifluoromethyl-chroman-4-one</strong> O-methyl-oxime; A solution of Example 76B (0.84 g, 3.88 mmol) and methoxyl amine hydrochloride (0.65 g, 7.78 mmol, 2eq.) in pyridine (10 mL) was stirred for 18 hours at ambient temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether and washed sequentially with water, 1N HCl and water. The isolated organic layer was concentrated and the residue chromatographed on silica gel, eluting with 5:95 ethyl acetate: hexanes to afford the title product (0.71 g, 74%). 1H NMR (300 MHz, DMSO-d6) delta 8.60 (d, J 7.5 Hz, 1H, major), 8.00 (d, J 7.5 Hz, 1H, minor), 7.28 (m, 2H), 4.40 (t, J 6.0 Hz, 2H, major), 4.24 (t, J 6.0 Hz, 2H, minor), 3.98 (s, 3H, minor), 3.96 (s, 3H, major), 2.87(t, J 6.0 Hz, 2H, minor), 2.70 (t, J 6.0 Hz, 2H, major). MS (DCI/NH3) m/e 246 (M+H)+.

Reference： [1]Patent: US2006/128689,2006,A1 .Location in patent: Page/Page column 12-13; 24
[2]Patent: US2007/99954,2007,A1 .Location in patent: Page/Page column 36
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1338 - 1341

7
[ 145485-43-4 ]
[ 111141-02-7 ]

Yield	Reaction Conditions	Operation in experiment
	With PPA; for 0.5h;	Example 4B; 7-Trifluoromethyl-chroman-4-one; Polyphosphoric acid (10 mL) was heated in water bath and the product of Example 4A (2.5 g) was added. After stirring for 30 min this mixture was poured onto ice and extracted twice with diethyl ether. The combined organic layers were washed with water, aqueous NaHCO3, and water and concentrated. The residue was chromatographed on silica gel, and eluted with 9:1 ethyl acetate: hexanes to afford the title compound (0.84 g, 12% for 2 steps) as a white solid.

Reference： [1]Patent: US2006/128689,2006,A1 .Location in patent: Page/Page column 12

8
[ 890839-56-2 ]
[ 111141-06-1 ]
[ 111141-02-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 20℃; for 0.5h;	Example 35C; Example 35B (0.94 g, 4 mmol) was dissolved in 25 ml of concentrated sulfuric acid. The reaction was stirred at ambient temperature for 30 minutes, then poured onto ice. The mixture was extracted with diethyl ether, and the combined organic layers washed with saturated aqueous sodium bicarbonate, dried with magnesium sulfate and filtered. The solvent was removed under reduced pressure to give 0.73 g of Example 35C containing the 5-trifluoromethyl regioisomer as an impurity.

Reference： [1]Patent: US2006/128689,2006,A1 .Location in patent: Page/Page column 24

9
[ 111140-93-3 ]
[ 111141-02-7 ]

Yield	Reaction Conditions	Operation in experiment
	With PPA; at 100 - 120℃; for 1h;Product distribution / selectivity;	The compound (4.7 g) prepared in <Step 1>of Example 6 was dissolved in polyphosphoric acid (100 g), and the reaction mixture was stirred at an outer temperature in the range of 100 C. to 120 C. for one hour. The reaction mixture was poured into ice water and then extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate =10:1). The title compound (4.2 g) was obtained as colorless crystals.
	With methanesulfonic acid; phosphorus pentoxide; at 70 - 80℃; for 0.666667h;Product distribution / selectivity;	Diphosphorus pentoxide (2.0 g) was added to methanesulfonic acid (18.0 g) little by little, and the mixture was stirred at room temperature for 2.5 hours. The compound (2.0 g) prepared in <Step 1> of Example 6 was added to the mixture over a period of 10 minutes at an outer temperature in the range of 70 C. to 80 C. The reaction mixture was stirred at the same temperature for 30 minutes and was then left to cool. The reaction mixture was poured into ice water (100 mL). The reaction mixture was extracted with ethyl acetate (100 mL and 20 mL). The combined organic layers were washed with water (15 mL), a half-saturated aqueous sodium hydrogencarbonate solution (15 mL), water (10 mL), and a saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate 95:5). The title compound (1.7 g) was obtained as a yellow solid.
	With PPA; at 100 - 120℃;	The compound (4.7 g) prepared in <Step 1> of Example 23 was dissolved in polyphosphoric acid (100 g), and the reaction solution was stirred at an outer temperature in the range of 100C to 120C for one hour. The reaction solution was poured into ice water and then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate = 10:1). The title compound (4.2 g) was obtained as colorless crystals.

	With polyphosphoric acid; In water; for 0.5h;	EXAMPLE 76B 7-Trifluoromethyl-chroman-4-one; Polyphosphoric acid (10 mL) was heated in water bath and Example 76A (2.5 g) was added. After stirring for 30 minutes this mixture was poured onto ice and extracted twice with diethyl ether. The combined organic layers were washed with water, aqueous NaHCO3, and water and concentrated. The residue was chromatographed on silica gel, and eluted with 9:1 ethyl acetate: hexanes to afford the title compound (0.84 g, 12% for 2 steps) as a solid. 1H NMR (300 MHz, DMSO-d6) delta 7.96 (d, J 7.5 Hz, 1H), 7.40 (m, 2H), 4.62 (t, J 6.0 Hz, 2H), 2.88 (t, J 6.0 Hz, 2H). MS (DCI/NH3) m/e 234 (M+NH4)+.
	With polyphosphoric acid; at 100 - 120℃; for 1h;Product distribution / selectivity;	The compound (4.7 g) prepared in <Step 1> of Example 6 was dissolved in polyphosphoric acid (100 g), and the reaction mixture was stirred at an outer temperature in the range of 100C to 120C for one hour. The reaction mixture was poured into ice water and then extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate = 10:1). The title compound (4.2 g) was obtained as colorless crystals.
	With methanesulfonic acid; phosphorus pentoxide; at 20 - 80℃; for 3.16667h;Product distribution / selectivity;	Diphosphorus pentoxide (2.0 g) was added to methanesulfonic acid (18.0 g) little by little, and the mixture was stirred at room temperature for 2.5 hours. The compound (2.0 g) prepared in <Step 1> of Example 6 was added to the mixture over a period of 10 minutes at an outer temperature in the range of 70C to 80C. The reaction mixture was stirred at the same temperature for 30 minutes and was then left to cool. The reaction mixture was poured into ice water (100 mL). The reaction mixture was extracted with ethyl acetate (100 mL and 20 mL). The combined organic layers were washed with water (15 mL), a half-saturated aqueous sodium hydrogencarbonate solution (15 mL), water (10 mL), and a saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate = 95:5). The title compound (1.7 g) was obtained as a yellow solid.

Reference： [1]Patent: US2008/287428,2008,A1 .Location in patent: Page/Page column 53-54
[2]Patent: US2008/287428,2008,A1 .Location in patent: Page/Page column 60
[3]Patent: EP2128157,2009,A1 .Location in patent: Page/Page column 106-107
[4]Patent: US2007/99954,2007,A1 .Location in patent: Page/Page column 36
[5]Patent: EP1908753,2008,A1 .Location in patent: Page/Page column 78
[6]Patent: EP1908753,2008,A1 .Location in patent: Page/Page column 88

10
[ 111141-02-7 ]
C₁₀H₈F₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; sodium acetate; In ethanol; for 4h;Heating / reflux;	Step C:; A solution of the product from Step B (2 g, 9.26 mmol), NH2OH.HCl (960 mg, 13.9 mmol, 1.5 eq) and NaOAc (1.14 g, 13.9 mmol, 1.5 eq.) in 50 mL of EtOH was heated under reflux for 4 h. Then the reaction mixture was concentrated, washed with water and brine, extracted with EtOAc, dried with MgSO4 and concentrated to give 1.8 g of product.

Reference： [1]Patent: US2009/93472,2009,A1 .Location in patent: Page/Page column 14

11
[ 1140496-03-2 ]
[ 111141-02-7 ]

Yield	Reaction Conditions	Operation in experiment
	With aluminum (III) chloride; In dichloromethane; at 0 - 20℃;	Step B:; To a solution of the product of step A (6 g, 0.0256 mol) in 30 mL of dry DCM was added drop-wise 7.48 mL of SOCl2 (4 eq.). The reaction mixture was heated to reflux, at which time two drops of DMF were added. Refluxing of the reaction was continued for 1 h. The mixture was cooled to room temperature. The solvent and the excess of SOCl2 were removed at reduced pressure to give corresponding crude propionyl chloride, which was used in the next step. The solution of this crude propionyl chloride in 40 mL of dry DCM was firstly cooled in an ice-water bath, followed slowly by addition of solid aluminum chloride (3.75 g, 0.02816 mol, 1.1 eq.). The reaction mixture was stirred overnight at room temperature, and then poured into 100 mL of crushed ice. The organic layer was recovered and the aqueous layer was extracted 3 times with DCM. All of the organic extracts were combined, washed with brine and water, concentrated, and the residue was purified by HPLC to give 4.14 g of product.

Reference： [1]Patent: US2009/93472,2009,A1 .Location in patent: Page/Page column 14

12
[ 867-13-0 ]
[ 111141-02-7 ]
[ 920334-14-1 ]