25617-34-9|N-(4-(Trifluoromethyl)phenyl)pivalamide| Ambeed

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Quality Control of [ 25617-34-9 ] Purity: 98% SDS Specification

COA

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Product Details of [ 25617-34-9 ]

CAS No. :	25617-34-9
Formula :	C₁₂H₁₄F₃NO
M.W :	245.24
SMILES Code :	CC(C)(C)C(NC1=CC=C(C(F)(F)F)C=C1)=O
MDL No. :	MFCD03094126
InChI Key :	ZYJDCZQBRUWWOU-UHFFFAOYSA-N
Pubchem ID :	2774289

Safety of [ 25617-34-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 25617-34-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	6
Fraction Csp3	0.42
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	59.92
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	29.1 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.51
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.92
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.65
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	3.39
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.22
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.54

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.83
Solubility	0.0365 mg/ml ; 0.000149 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.23
Solubility	0.0144 mg/ml ; 0.0000589 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.5
Solubility	0.00776 mg/ml ; 0.0000316 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.01 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<2.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.33

Application In Synthesis of [ 25617-34-9 ]

* 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.

Downstream synthetic route of [ 25617-34-9 ]

[ 25617-34-9 ] Synthesis Path-Downstream 1~35

1
[ 455-14-1 ]
[ 3282-30-2 ]
[ 25617-34-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; In dichloromethane;	EXAMPLE 163 STR185 Step 1. Preparation of N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide. A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride (32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0 C. under a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) was added drop-wise over 2 hours, maintaining the temperature below 10 C. After the addition, the contents were allowed to warm to room temperature for 2 hours. The reaction was washed with water (2200 mL), saturated ammonium chloride solution (2200 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford a white solid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g, 98%): mp 157-159 C. 1 H NMR (CDCl3 /300 MHz) 7.61 (ab, 4H, J=8.7, Deltanu=28.6 Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H+, Calc'd 246.1106). Anal. Calc'd for C12 H14 F3 NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.
98%	With triethylamine; In dichloromethane;	Step 1. Preparation of N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride (32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0 C. under a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) was added drop-wise over 2 hours, maintaining the temperature below 10 C. After the addition, the contents were allowed to warm to room temperature for 2 hours. The reaction was washed with water (2200 mL), saturated ammonium chloride solution (2200 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford a white solid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g, 98%): mp 157-159 C. 1 H NMR (CDCl3 /300 MHz) 7.61 (ab, 4H, J=8.7, Deltanu=28.6 Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H+, Calc'd 246.1106). Anal. Calc'd for C12 H14 F3 NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.
97%	With pyridine; In dichloromethane;	EXAMPLE 65 4'-Trifluoromethyl-2,2-dimethylpropionanilide To a stirred solution of 4-trifluoromethylaniline (25 g, 0.155 mol) and pyridine (62 ml, 0.775 mol) in dichloromethane (300 ml) cooled to 0 C. under nitrogen was added dropwise pivaloyl chloride (19 ml, 0.155 mol). The reaction mixture was stirred at room temperature for 3.5 hr, then diluted with dichloromethane (300 ml). The resulting solution was washed sequentially with 1N aqueous hydrochloric acid solution (2*), saturated aqueous sodium bicarbonate solution, water and brine, dried (anhydrous sodium sulfate)and concentrated in vacuo to yield the title compound as a white solid (37 g, 97% yield). 1 H NMR (250 MHz, CDCl3) delta 1.33 (s, 9H); 7.74 (b, 1H); 7.57 (d, 2H); 7.67 (d, 2H).

	With triethylamine; In benzene; at 0 - 20℃;	Synthesis of 5-(trifluoromethyl)-2-(trifluoromethylsulfonamido)benzoic acid Preparation B6, Step 1: To a solution of 4-trifluoromethylaniline (5 g, 0.031 mol) in 50 ml of dry benzene was added triethylamine (6.26 g, 8.63 ml, 0.06 mol) at 0 C. Pivaloyl chloride (4.5 g, 0.04 mol) was added slowly and stirred at RT over night. The RM was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. To the solid was triturated with pet-ether and filtered to give N-(4-(trifluoromethyl)phenyl)-pivalamide (6.7 g) as white solid.
	With triethylamine; In benzene; at 0 - 20℃;	Preparation B6: Synthesis of 5-(trifluoromethyl)-2-(trifluoromethylsulfonamido)benzoic Acid Preparation B6, Step 1: To a solution of 4-trifluoromethylaniline (5 g, 0.031 mol) in 50 ml of dry benzene was added triethylamine (6.26 g, 8.63 ml, 0.06 mol) at 0 C. Pivaloyl chloride (4.5 g, 0.04 mol) was added slowly and stirred at RT over night. The RM was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. To the solid was triturated with pet-ether and filtered to give N-(4-(trifluoromethyl)phenyl)-pivalamide (6.7 g) as white solid.

References: [1]Patent: US6034256,2000,A .
[2]Patent: US6077850,2000,A .
[3]Patent: US5770594,1998,A .
[4]Journal of labelled compounds and radiopharmaceuticals,2010,vol. 53,p. 141 - 147.
[5]Journal of Medicinal Chemistry,1988,vol. 31,p. 1215 - 1220.
[6]Patent: US2005/54627,2005,A1 .Location in patent: Page/Page column 38.
[7]Patent: US2005/54626,2005,A1 .Location in patent: Page/Page column 34.
[8]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2726 - 2732.
[9]Journal of Fluorine Chemistry,2010,vol. 131,p. 800 - 804.
[10]Angewandte Chemie - International Edition,2015,vol. 54,p. 14103 - 14107.
Angew. Chem.,2015,vol. 127,p. 14309 - 14313,5.
[11]Angewandte Chemie - International Edition,2018,vol. 57,p. 9108 - 9112.
Angew. Chem.,2018,vol. 130,p. 9246 - 9250,5.
[12]Chemical Communications,2019,vol. 55,p. 5475 - 5478.

2
[ 25617-34-9 ]
[ 68-12-2 ]
[ 106746-81-0 ]

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1215 - 1220.

4
[ 455-14-1 ]
[ 598-98-1 ]
[ 25617-34-9 ]

References: [1]Synlett,2001,p. 1485 - 1487.
[2]Patent: WO2004/58260,2004,A1 .Location in patent: Page/Page column 14.

5
[ 121-43-7 ]
[ 25617-34-9 ]
C₁₄H₁₉BF₃NO₃ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2561 - 2564.

6
[ 25617-34-9 ]
(3aS,9bR)-8-Trifluoromethyl-1,2,3,3a,5,9b-hexahydro-cyclopenta[c]quinolin-4-one [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2561 - 2564.

7
[ 25617-34-9 ]
[ 237400-20-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2561 - 2564.

8
[ 25617-34-9 ]
8-trifluoromethyl-2,3,3a,9b-tetrahydro-1<i>H</i>-cyclopenta[<i>c</i>]quinolin-4-ylamine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2561 - 2564.

9
[ 25617-34-9 ]
(3aS,9bR)-8-Trifluoromethyl-1,2,3,3a,5,9b-hexahydro-cyclopenta[c]quinoline-4-thione [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2561 - 2564.

10
[ 25617-34-9 ]
2-[2-(2,2-dimethyl-propionylamino)-5-trifluoromethyl-phenyl]-cyclopent-1-enecarboxylic acid methyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2561 - 2564.

11
[ 25617-34-9 ]
[ 106746-82-1 ]

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1215 - 1220.

12
[ 25617-34-9 ]
[ 106746-83-2 ]

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1215 - 1220.

13
[ 51985-43-4 ]
[ 25617-34-9 ]
C₂₁H₂₁ClF₃NO₄ [ No CAS ]

References: [1]Patent: WO2004/58260,2004,A1 .Location in patent: Page/Page column 14.

14
[ 25617-34-9 ]
[ 106746-81-0 ]

Yield	Reaction Conditions	Operation in experiment
65%	With hydrogenchloride; n-butyllithium;	Step 2. Preparation of N-[2-formyl-4-(trifluoromethyl) phenyl]-2,2-dimethyl propanamide. A 1 liter three neck round bottom flask equipped with equalizing addition funnel, magnetic stirer and temperature monitoring device was charged with N-(4-trifluromethylphenyl)-2,2-dimethyl propanamide (10.13 g, 41.4 mmol) and anhydrous tetrahydrafuran (150 mL). The reaction was chilled to -78 C. under nitrogen followed by slow addition of n-butyllithium (50 ml, 2.5 M in hexanes, 124 mmol) over 0.5 hours, such that the temperature of the reaction did not rise above -65 C. The contents were held at -78 C. for one hour, 0 C. for two hours, then chilled back to -78 C. Excess N,N-dimethylformamide (100 mL, 1.37 mol) was added. The contents were warmed to room temperature and stirred for two hours. Aqueous 1 N HCl was added to the reaction until the pH reached 1. The reaction was washed with water (2200 mL), saturated ammonium chloride solution (2200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The product was purified by flash chromatography (silica gel, 10% ethyl acetate, 90% hexanes) to yield, upon concentration of the appropriate fractions, N-(2-formyl-4-trifluoromethylphenyl)-2,2-dimethylpropanamide as a solid (7.36 g, 65%): mp 69-73 C. 1 H NMR (CDCl3 /300 MHz) 11.5 (br s, 1H), 9.99 (s, 1H), 8.67 (d, 1H, J=8.8 Hz), 7.94 (d, 1H, J=1.6 Hz), 7.83 (m, 1H,), 1.37 (s, 9H). ESHRMS m/z 274.1060 (M+H, Calc'd 274.1055). Anal. Calc'd for C13 H14 F3 NO2: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15; H, 5.43; N, 5.01.
	With hydrogenchloride; n-butyllithium;	Step 2. Preparation of N-[2-formyl-4-(trifluoromethyl)phenyl]-2,2-dimethyl Propanamide A 1 liter three neck round bottom flask equipped with equalizing addition funnel, magnetic stirer and temperature monitoring device was charged with N-(4-trifluromethylphenyl)-2,2-dimethyl propanamide (10.13 g, 41.4 mmol) and anhydrous tetrahydrafuran (150 mL). The reaction was chilled to -78 C. under nitrogen followed by slow addition of n-butyllithium (50 ml, 2.5 M in hexanes, 124 mmol) over 0.5 hours, such that the temperature of the reaction did not rise above -65 C. The contents were held at -78 C. for one hour, 0 C. for two hours, then chilled back to -78 C. Excess N,N-dimethylformamide (100 mL, 1.37 mol) was added. The contents were warmed to room temperature and stirred for two hours. Aqueous 1 N HCl was added to the reaction until the pH reached 1. The reaction was washed with water (2200 mL), saturated ammonium chloride solution (2200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The product was purified by flash chromatography (silica gel, 10% ethyl acetate, 90% hexanes) to yield, up(on concentration of the appropriate fractions, N-(2-formyl-4-trifluoromethylphenyl)-2,2-dimethylpropanamide as a solid (7.36 g, 65%): mp 69-73 C. 1 H NMR (CDCl3 /300 MHz) 11.5 (br s, 1H), 9.99 (s, 1H), 8.67 (d, 1H, J=8.8 Hz), 7.94 (d, 1H, J=1.6 Hz), 7.83 (m, 1H,), 1.37 (s, 9H). ESHRMS m/z 274.1060 (M+H+, Calc'd 274.1055). Anal. Calc'd fcr C13 H14 F3 NO2: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15; H, 5.43; N, 5.01.

References: [1]Patent: US6034256,2000,A .
[2]Patent: US6077850,2000,A .

15
[ 109-72-8 ]
[ 25617-34-9 ]
[ 74-88-4 ]
2,2-dimethyl-N-(2-methyl-4-trifluoromethylphenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; hexane; water;	EXAMPLE 75 2,2-Dimethyl-N-(2-methyl-4-trifluoromethylphenyl)propanamide To a chilled (28° C.) solution of 4.91 g of <strong>[25617-34-9]2,2-dimethyl-N-(4-trifluoromethylphenyl)propanamide</strong> and 80 ml tetrahydrofuran, was added over two mins, 18.5 ml of a 2.5M solution of N-butyllithium in hexane, with stirring. The reaction mixture was stirred for two hours at 0° C. and added, dropwise over eight minutes, to a solution of 3.19 g of iodomethane and 7 ml of hexane, keeping the temperature between -2° C.+1° C. The solution was stirred for 45 mins (internal temperature reached 18° C.). Water (20 ml) was added and the mixture was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated by preparative HPLC (Waters Associates Prep LC/System 500, silica gel, sample applied in and eluted with methylenechloride, 200 ml/min flow rate). The appropriate fractions were combined, concentrated, and the residue was recrystallized from toluene to give 2.23 g of product, mp 111°-114°

References: [1]Patent: US5292760,1994,A .

16
[ 25617-34-9 ]
[ 66-77-3 ]
[ 180346-13-8 ]

Yield	Reaction Conditions	Operation in experiment
52%	With n-butyllithium; In tetrahydrofuran; hexane;	EXAMPLE 66 2'-[alpha-Hydroxy-(1-naphthyl)methyl]-4'-trifluoromethyl-2,2-dimethylpropionanilide To a stirred solution of 4'-trifluoromethyl-2,2-dimethylpropionanilide (37 g, 0.15 mol) in anhydrous tetrahydrofuran (400 ml) cooled to 0° C. under nitrogen was added slowly a solution of n-butyllithium (160 mL of 2.5M solution in hexane, 0.4 mol). The reaction mixture was stirred at 0° C. for 2 hr, then a solution of 1-naphthaldehyde (40.7 ml, 0.3 mol) in tetrahydrofuran (50 ml) was slowly added. The resulting solution was stirred at room temperature overnight, quenched with water, diluted with ethyl acetate and separated. The aqueous phase was extracted with ethyl acetate (2*) and the combined ethyl acetate extracts were washed with water and brine, dried (anhydrous sodium sulfate) and concentrated. in vacuo to an oil (74 g). The crude product was chromatographed on 2 kg silica gel, eluding with 8:2 hexane/ethyl acetate to yield the title compound as a tan solid (31 g, 52percent yield). 1 H NMR (250 MHz, CDCl3) delta 1.12 (s, 9H); 3.05 (d, 1H); 6.65 (d, 1H); 7.33 (d, 1H); 7.45 (t, 1H); 7.56 (c, 3H); 7.92 (c, 2H); 8.04 (q, 1H); 8.4 (d, 1H); 9.11 (b, 1H).

References: [1]Patent: US5770594,1998,A .

17
[ 25617-34-9 ]
2-(N-pivaloyl)-5-trifluoromethylbenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.8 g (26%)	With n-butyllithium; carbon dioxide; In tetrahydrofuran; hexane; water;	PREPARATION 38 2-(N-Pivaloyl)-5-trifluoromethylbenzoic Acid A solution of 25.0 g (0.102 mol) of 4-trifluoromethyl-N-pivaloylaniline in 140 ml of dry tetrahydrofuran was cooled to 5° C. under a nitrogen atmosphere. This was followed by the dropwise addition of 110 ml (0.22 mol) of 2.0M n-butyllithium in hexane. The addition was carried out over 2 hours while maintaining the temperature below 15° C. When the addition was complete, the temperature was raised to 20° C. and the reaction stirred for 7 hours. The solution was then cooled to -60° C. and dry carbon dioxide gas was bubbled through the reaction at a rapid rate for 15 minutes, during which time the thick suspension was diluted with an additional 150 ml of dry tetrahydrofuran. After stirring for 16 hours, the reaction mixture was treated with 100 ml of saturated aqueous ammonium chloride. The reaction mixture was then concentrated to 150 ml and diluted with 1.0 liter of water. The pH was adjusted to 1.0 with hydrochloric acid, and the resulting solution extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to afford the crude product. This was recrystallized from toluene to give 7.8 g (26percent) of the title compound, m.p. 196°-198° C.

References: [1]Patent: US4762838,1988,A .

18
[ 455-14-1 ]
[ 3282-30-2 ]
[ 144-55-8 ]
[ 25617-34-9 ]

Yield	Reaction Conditions	Operation in experiment
9.16 g (88%)	In dichloromethane;	PREPARATION 37 4-Trifluoromethyl-N-pivaloylaniline To a solution of 6.87 g (0.043 mol) of 4-trifluoromethylaniline in 110 ml of dichloromethane was added 5.25 ml (0.043 mol) of pivaloylchloride. After stirring for 1.5 hours, 190 ml of a saturated solution of aqueous sodium bicarbonate was added. The reaction proceeded an additional 2 hours and the organic layer was separated and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed to give the title compound, yield 9.16 g (88percent), m.p. 154°-158° C.

References: [1]Patent: US4762838,1988,A .

19
[ 67-56-1 ]
[ 124-38-9 ]
[ 25617-34-9 ]
[ 117324-58-0 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation B6, Step 2: To a solution of N-(4-(trifluoromethyl)phenyl)pivalamide (1 g, 4.08 mmol) in 20 ml of dry THF under nitrogen was added n-butyllithium (0.65 g, 4.1 ml) at 0° C. The reaction mixture was maintained at 0° C. for 3 h and added onto dry ice and stirred at RT over night. The reaction mixture was concentrated and the solid product obtained was dissolved in 25 ml of dry methanol and purged HCl gas for 30 min at 0° C. The mixture was stirred at RT for 2 h and heated at 55° C. over night. The reaction mixture was concentrated, basified with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. The crude product was purified by flash chromatography to give methyl 2-amino-5-(trifluoromethyl)benzoate (0.55 g) as white solid.

References: [1]Patent: US2005/54626,2005,A1 .Location in patent: Page/Page column 34.

20
[ 383-63-1 ]
[ 25617-34-9 ]
[ 1233967-39-9 ]

References: [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2726 - 2732.
[2]Chemistry - A European Journal,2016,vol. 22,p. 13068 - 13071.
[3]Journal of Organic Chemistry,2017,vol. 82,p. 7980 - 7997.
[4]Advanced Synthesis and Catalysis,2019,vol. 361,p. 2129 - 2135.

21
[ 25617-34-9 ]
[ 141-78-6 ]
C₁₄H₁₆F₃NO₂ [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2726 - 2732.

22
[ 25617-34-9 ]
[ 407-25-0 ]
[ 1233967-39-9 ]

References: [1]Journal of Fluorine Chemistry,2010,vol. 131,p. 800 - 804.

23
cesium pivalate [ No CAS ]
[ 1548-13-6 ]
[ 25617-34-9 ]

References: [1]Organic Letters,2011,vol. 13,p. 2256 - 2259.

24
[ 1548-13-6 ]
[ 75-98-9 ]
[ 25617-34-9 ]

References: [1]Organic Letters,2011,vol. 13,p. 2256 - 2259.

25
[ 1240490-43-0 ]
[ 25617-34-9 ]
[ 1240490-44-1 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2010,vol. 53,p. 141 - 147.

26
[ 25617-34-9 ]
[ 1240490-45-2 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2010,vol. 53,p. 141 - 147.

27
[ 25617-34-9 ]
4-(5-chloro-2-methoxymethoxyphenyl)-3-(2-hydroxyethyl)-6-trifluoromethyl-[4-⁽¹⁴⁾C]-quinolin-2(1H)-one [ No CAS ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2010,vol. 53,p. 141 - 147.

28
[ 25617-34-9 ]
4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-[4-⁽¹⁴⁾C]quinolin-2(1H)-one [ No CAS ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2010,vol. 53,p. 141 - 147.

29
[ 62-53-3 ]
[ 25617-34-9 ]
[ 125686-52-4 ]