[ CAS No. 346603-63-2 ] {[proInfo.proName]}

Name: 346603-63-2|Methyl 2-methyl-3-(trifluoromethyl)benzoate|95%
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SKU: A351996
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Quality Control of [ 346603-63-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 346603-63-2 ]

SDS Specification

Alternatived Products of [ 346603-63-2 ]

Product Details of [ 346603-63-2 ]

CAS No. :	346603-63-2	MDL No. :	MFCD14698066
Formula :	C₁₀H₉F₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KFJGSNVBDYRBAD-UHFFFAOYSA-N
M.W :	218.17	Pubchem ID :	17837619
Synonyms :

Calculated chemistry of [ 346603-63-2 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	47.69
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) :	-5.49 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.46
Log Po/w (XLOGP3) :	3.02
Log Po/w (WLOGP) :	3.95
Log Po/w (MLOGP) :	3.25
Log Po/w (SILICOS-IT) :	3.23
Consensus Log Po/w :	3.18

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.19
Solubility :	0.14 mg/ml ; 0.000641 mol/l
Class :	Soluble
Log S (Ali) :	-3.24
Solubility :	0.126 mg/ml ; 0.000579 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.75
Solubility :	0.0384 mg/ml ; 0.000176 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.79

Safety of [ 346603-63-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P305+P351+P338	UN#:	N/A
Hazard Statements:	H227-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 346603-63-2 ]

* 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 [ 346603-63-2 ]
Downstream synthetic route of [ 346603-63-2 ]

[ 346603-63-2 ] Synthesis Path-Upstream 1~3

1
[ 67-56-1 ]
[ 62089-35-4 ]
[ 346603-63-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	Reflux	Example 1 (S)-3-Cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide To a solution of 2-methyl-3-trifluoromethyl-benzoic acid (Apollo, 1 g, 4.90 mmol) in methanol (20 mL) was added concentrated sulfuric acid (0.5 mL) and the resulting mixture was heated to reflux overnight. The cooled reaction mixture was concentrated and diluted with water (25 mL) and a saturated sodium bicarbonate solution (25 mL). The mixture was extracted with ethyl acetate (50 mL), the organic phases combined, washed with water and dried over magnesium sulfate. The mixture was filtered and evaporated to give 2-methyl-3-trifluoromethyl-benzoic acid methyl ester (0.95 g, 4.35 mmol, 89percent); ¹H NMR (300 MHz, CDCl₃) δ ppm 2.65 (s, 3H), 3.94 (s, 3H), 7.35 (t, J=7.85 Hz, 1H), 7.72-8.01 (m, 2H).
88%	at 75℃;	To a 500 mL round bottom equipped with an Airflux Condenser and stir bar was added 2- methyl-3-(trifluoromethyl)benzoic acid (30 g, 147 mmol). The solid was taken up in Methanol (101 ml) and to that solution was slowly added sulfuric acid (8.22 ml, 154 mmol). The reaction was then fitted with the condenser and heated to 75 ⁰C overnight. The reaction was cooled back to room temperature, and neutralized by slow addition of IN NaOH (-155 mL). The solution was then extracted with 3 X 300 mL Et₂O, the organic layer dried over magnesium sulfate, and concentrated to an oil, which solidified under vacuum to give off white solid methyl 2-methyl-3-(trifluoromethyl)benzoate (28.25 g, 129 mmol, 88 percent yield) ¹U NMR (400 MHz, DMSO-J₆) δ ppm 2.54 (d, J=I.77 Hz, 3H) 3.89 (s, 3H) 7.53 (t, J=7.83 Hz, IH) 7.89 (d, J=7.83 Hz, IH) 7.97 (d, J=7.83 Hz, IH).

Reference： [1] Patent: US2012/283271, 2012, A1, . Location in patent: Page/Page column 10
[2] Patent: WO2010/135504, 2010, A1, . Location in patent: Page/Page column 101

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[ 52570-33-9 ]
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Reference： [1] Patent: US2003/216571, 2003, A1, . Location in patent: Page/Page column 62-63

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[ 62089-35-4 ]
[ 74-88-4 ]
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Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 360 - 365

[ 346603-63-2 ] Synthesis Path-Downstream 1~88

1
[ 346603-63-2 ]
[ 1256290-47-7 ]

Yield	Reaction Conditions	Operation in experiment
92%		To a 1 L round bottom flask equipped with a stir bar, nitrogen lines, and pressure equalizing addition funnel, was added lithium aluminum deuteride (LAD) (12 g, 286 mmol). The solid material was taken up in anhydrous tetrahydrofuran (THF) (268 ml) and the resulting suspension placed under a nitrogen atmosphere and the temperature lowered to 0 0C. The addition funnel was then charged with a solution of methyl 2-methyl-3- (trifluoromethyl)benzoate (27 g, 124 mmol) in anhydrous tetrahydrofuran (THF) (107 ml), and the substrate was slowly added, drop-wise, to the LAD suspension over approximately 30 minutes. Upon complete addition, the funnel was removed and the inert atmosphere maintained. The reaction temperature was allowed to warm naturally to ambient over 2 hours with vigorous stirring. The reaction was then quenched with a modified Fieser and Fieser workup (adjusting by multiplying normal lithium aluminum hydride reduction workup amount by .8564) by sequential addition of the following: 10.277 mL water, 10.277 mL of 15 wt % NaOH (aq.) solution, and 30.83 mL water. The resulting mixture was stirred at room temperature for 1 hour to allow the precipitate to form and was then filtered, followed by concentration of the solution, in vacuo, to afford a gel. The gel was suspended in dichloromethane and transferred to a 100 mL round bottom flask. The material was concentrated to a gel and then subjected to high vacuum to afford [2-methyl- 3-(trifluoromethyl)phenyl]methanol-d2 (21.883 g, 114 mmol, 92 % yield) as a white solid 1H NMR (400 MHz, DMSO-J6) delta ppm 2.33 (d, J=I.52 Hz, 3H) 5.26 (s, IH) 7.37 (t, J=7.71 Hz, IH) 7.57 (d, J=7.83 Hz, IH) 7.67 (d, J=7.83 Hz, IH).

Reference： [1]Patent: WO2010/135504,2010,A1 .Location in patent: Page/Page column 101-102

2
[ 67-56-1 ]
[ 62089-35-4 ]
[ 346603-63-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	sulfuric acid;Reflux;	Example 1 (S)-3-Cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide To a solution of 2-methyl-3-trifluoromethyl-benzoic acid (Apollo, 1 g, 4.90 mmol) in methanol (20 mL) was added concentrated sulfuric acid (0.5 mL) and the resulting mixture was heated to reflux overnight. The cooled reaction mixture was concentrated and diluted with water (25 mL) and a saturated sodium bicarbonate solution (25 mL). The mixture was extracted with ethyl acetate (50 mL), the organic phases combined, washed with water and dried over magnesium sulfate. The mixture was filtered and evaporated to give 2-methyl-3-trifluoromethyl-benzoic acid methyl ester (0.95 g, 4.35 mmol, 89%); 1H NMR (300 MHz, CDCl3) delta ppm 2.65 (s, 3H), 3.94 (s, 3H), 7.35 (t, J=7.85 Hz, 1H), 7.72-8.01 (m, 2H).
88%	With sulfuric acid; at 75.0℃;	To a 500 mL round bottom equipped with an Airflux Condenser and stir bar was added 2- methyl-3-(trifluoromethyl)benzoic acid (30 g, 147 mmol). The solid was taken up in Methanol (101 ml) and to that solution was slowly added sulfuric acid (8.22 ml, 154 mmol). The reaction was then fitted with the condenser and heated to 75 0C overnight. The reaction was cooled back to room temperature, and neutralized by slow addition of IN NaOH (-155 mL). The solution was then extracted with 3 X 300 mL Et2O, the organic layer dried over magnesium sulfate, and concentrated to an oil, which solidified under vacuum to give off white solid methyl 2-methyl-3-(trifluoromethyl)benzoate (28.25 g, 129 mmol, 88 % yield) 1U NMR (400 MHz, DMSO-J6) delta ppm 2.54 (d, J=I.77 Hz, 3H) 3.89 (s, 3H) 7.53 (t, J=7.83 Hz, IH) 7.89 (d, J=7.83 Hz, IH) 7.97 (d, J=7.83 Hz, IH).

Reference： [1]Patent: US2012/283271,2012,A1 .Location in patent: Page/Page column 10
[2]Patent: WO2010/135504,2010,A1 .Location in patent: Page/Page column 101

3
[ 346603-63-2 ]
[ 346603-68-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 3.0h;	[0460] To a solution of <strong>[346603-63-2]methyl 2-methyl-3-(trifluoromethyl)benzoate</strong> (0.985 grams, 4.52 mmol) in CCl4 (50 mL) at rt was added NBS (0.884 grams, 7.3 mmol) and AIBN) (350 mg, 2.13 mmol). The suspension was stirred at 80C for 3 hrs. The reaction was cooled to rt and filtered. The filtrate was concentrated under vacuum to afford methyl 2- (bromomethyl)-3-(trifluoromethyl)benzoate (1.17 g, 86% yield) as a yellow oil. The oil (0.463 g, 1.55 mmol) was dissolved in DMF (3 mL) at rt and Et3N (472 mg, 4.67 mmol) and (S)-3-aminoazepan-2-one (218 mg, 1.70 mmol) were added. The mixture was stirred at 60C for 3 hrs, cooled to rt and concentrated under vacuum to afford the crude product, which was triturated with EA and hexanes to afford (S)-2-(2-oxoazepan-3-yl)-4- (trifluoromethyl)isoindolin-1-one (323 mg, 66% yield) as a white solid. MS (ESI) m/z 313.2 [M+H]+.
81%	With N-Bromosuccinimide;dibenzoyl peroxide; In benzene; at 20℃; for 52.0h;Reflux; Inert atmosphere;	To a solution of <strong>[346603-63-2]2-methyl-3-trifluoromethyl-benzoic acid methyl ester</strong> (0.95 g, 4.35 mmol) in benzene (10 mL) was added N-bromosuccinimide (0.77 g, 4.33 g) and benzoyl peroxide (0.052 g, 0.21 mmol) and the resulting mixture heated to reflux for 4 h, cooled and stirred at room temperature for 48 h. The mixture was filtered, the filter cake washed with diethyl ether and the filtrate washed with a 1 N sodium thiosulfate solution (10 mL), brine and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified via automated flash chromatography (Analogix, SF25-80 g column, 5->10% ethyl acetate/hexane gradient) to give 2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (1.04 g, 3.50 mmol, 81%) as an off white solid; 1H NMR (300 MHz, DMSO-d6) delta ppm 3.72-4.16 (m, 3H), 5.03 (s, 2H), 7.47-8.32 (m, 3H).

Reference： [1]Patent: WO2017/201069,2017,A1 .Location in patent: Paragraph 0460
[2]Patent: US2012/283271,2012,A1 .Location in patent: Page/Page column 10
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365

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[ 346603-63-2 ]
C₁₇H₁₇ClF₃NO₂ [ No CAS ]

Reference： [1]Patent: US2012/283271,2012,A1

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[ 346603-63-2 ]
[ 1407232-86-3 ]

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C₁₄H₁₃ClF₃NO₂S [ No CAS ]

Reference： [1]Patent: US2012/283271,2012,A1

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[ 346603-63-2 ]
C₁₅H₁₅ClF₃NO₂ [ No CAS ]

Reference： [1]Patent: US2012/283271,2012,A1

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[ 346603-63-2 ]
[ 1416990-16-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365

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[ 62089-35-4 ]
[ 74-88-4 ]
[ 346603-63-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365

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(S)-2-(2-oxoazepan-3-yl)-4-(trifluoromethyl)isoindolin-1-one [ No CAS ]

Reference： [1]Patent: WO2017/201069,2017,A1

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[ 346603-63-2 ]
(S)-3-(1-oxo-4-(trifluoromethyl)isoindolin-2-yl)azepane-2,7-dione [ No CAS ]

Reference： [1]Patent: WO2017/201069,2017,A1

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[ 346603-63-2 ]
methyl 3-oxo-7-(trifluoromethyl)isoindoline-5-carboxylate [ No CAS ]