[ CAS No. 228418-45-9 ] {[proInfo.proName]}

Name: 228418-45-9|Methyl 2-nitro-4-(trifluoromethyl)benzoate|95%
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SKU: A865013
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2D 3D

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Quality Control of [ 228418-45-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 228418-45-9 ]

SDS Specification

Alternatived Products of [ 228418-45-9 ]

Product Details of [ 228418-45-9 ]

CAS No. :	228418-45-9	MDL No. :	MFCD08282772
Formula :	C₉H₆F₃NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WYTRZKAYPKZGCN-UHFFFAOYSA-N
M.W :	249.14	Pubchem ID :	11276727
Synonyms :

Calculated chemistry of [ 228418-45-9 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	4
Num. H-bond acceptors :	7.0
Num. H-bond donors :	0.0
Molar Refractivity :	51.55
TPSA :	72.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.02 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.78
Log Po/w (XLOGP3) :	2.54
Log Po/w (WLOGP) :	3.55
Log Po/w (MLOGP) :	1.88
Log Po/w (SILICOS-IT) :	0.68
Consensus Log Po/w :	2.09

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.98
Solubility :	0.26 mg/ml ; 0.00104 mol/l
Class :	Soluble
Log S (Ali) :	-3.7
Solubility :	0.0495 mg/ml ; 0.000199 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.75
Solubility :	0.447 mg/ml ; 0.00179 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.23

Safety of [ 228418-45-9 ]

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 [ 228418-45-9 ]

* 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 [ 228418-45-9 ]
Downstream synthetic route of [ 228418-45-9 ]

[ 228418-45-9 ] Synthesis Path-Upstream 1~1

1
[ 228418-45-9 ]
[ 61500-87-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogen In ethyl acetate for 3 h;	Step 2; Preparation of Methyl 2-amino-4-trifluoromethylbenzoate; Add a solution of methyl 2-nitro-4-trifluoromethylbenzoate (106 g, 425 mmol) in ethyl. acetate (2.2 L) to a slurry of 10percent palladium on carbon (11.0 g) in ethyl acetate (200 mL)and stir the suspension at room temperature under an atmosphere of hydrogen at 60 psifor 3 h. Filter the suspension through a pad of Celite.(R). and wash the pad with additionalethyl acetate. Remove the solvents under reduced pressure and purify the residue bycolumn chromatography on silica gel, eluting with isohexane/ethyl acetate (9:1), toprovide the title compound as a white crystalline solid (84 g, 95percent).
93%	With hydrogen In ethyl acetate at 20℃; for 18 h;	Step 2. Methyl 2-Amino-4-(trifluoromethyl)benzoate: A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10percent Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H₂ atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite.(R). and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93percent): ¹H-NMR (DMSO-d₆) δ 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
93%	With hydrogen In ethyl acetate at 20℃; for 18 h;	A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10percent Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93percent): 1H-NMR (DMSO-d6) ? 3.79 (s, 3H), 6.75 (dd,J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).

93%	With hydrogen In ethyl acetate at 20℃; for 18 h;	Step 2. Methyl 2-Amino-4-(trifluoromethyl)benzoate; A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10percent Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite.(R). and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93percent): 1H-NMR (DMSO-d6) δ 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
91%	Stage #1: With tin(ll) chloride In dichloromethane; ethyl acetate at 20℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water; ethyl acetate	B. 2-Amino-4-trifluoromethyl-benzoic acid methyl ester. A solution of 2-nitro-4-trifluoromethylbenzoic acid methyl ester (4.3 g, 0.017 mol) was dissolved in a mixture of DCM (20 mL) and EtOAc (20 mL) followed by addition of SnCl₂.2H₂O (19 g, 0.086 mol). The mixture was stirred overnight at room temperature, then was neutralized by shaking with a satd. aq. NaHCO₃ solution. The resulting salts were removed by filtration through a pad of diatomaceous earth. The filtrate was extracted with DCM (3*). The combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo to provide the title compound (3.38 g, 91percent). TLC (silica, 50percent EtOAc/hexanes): R_f=0.60. HPLC (reverse phase): R_T=9.31 min. ¹H NMR (500 MHz, CDCl₃): 7.95 (d, J=8.3 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J=9.3 Hz, 1H), 5.91 (br s, 2H), 3.90 (s, 3H).
67%	With sodium dithionite In ethanol; water at 50℃; for 3 h;	A mixture of methyl 2-nitro-4- (trifluoromethyl) benzoate (2.49 g 0.01 mol), sodium hydrosulfite (8.71 g, 0.05 mol), ethanol (20 ml) and water (20 ml) was heated at 50 ⁰C for 3 h. Water was added and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 5percent ethyl acetate/n-hexane to give 1.46 g(6.67 mmol 67percent) of the title compound as a white powder. ¹H NMR (CDCl₃) δ. 3.90 (s, 3H), 5.50-6,20 (brs, 2H), 6.85 (d, J = 8.48 Hz, IH), 6.90 (s, IH), 7.95 (d, J = 8.48 Hz, IH) . MS Calcd. : 219; Found: 220 (M+H) .

Reference： [1] Patent: WO2006/2342, 2006, A1, . Location in patent: Page/Page column 55-56
[2] Patent: US2004/102636, 2004, A1,
[3] Patent: US2008/269265, 2008, A1, . Location in patent: Page/Page column 10
[4] Patent: EP1449834, 2004, A2, . Location in patent: Page 16
[5] Patent: EP1042305, 2005, B1, . Location in patent: Page/Page column 21
[6] Patent: US2005/38032, 2005, A1, . Location in patent: Page/Page column 27
[7] Patent: WO2006/116412, 2006, A2, . Location in patent: Page/Page column 224
[8] Patent: US2004/224983, 2004, A1, . Location in patent: Page 28
[9] Patent: US2008/287428, 2008, A1, . Location in patent: Page/Page column 65
[10] Patent: EP1908753, 2008, A1, . Location in patent: Page/Page column 99

[ 228418-45-9 ] Synthesis Path-Downstream 1~24

1
[ 228418-45-9 ]
2-hydroxyamino-4-trifluoromethyl-benzoic acid methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4735 - 4739

2
[ 228418-45-9 ]
[ 773851-01-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4735 - 4739

3
[ 228418-45-9 ]
N-(3-oxo-6-trifluoromethyl-3H-benzo[c]isoxazol-1-ylmethyl)-acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4735 - 4739

4
[ 67-56-1 ]
[ 201230-82-2 ]
[ 349-03-1 ]
[ 228418-45-9 ]

Reference： [1]Patent: US6337418,2002,B1 .Location in patent: Example 3
[2]Patent: US6337418,2002,B1 .Location in patent: Example 1-2

5
[ 67-56-1 ]
[ 201230-82-2 ]
[ 121-17-5 ]
[ 228418-45-9 ]

Reference： [1]Patent: US6337418,2002,B1 .Location in patent: Example 5

6
[ 5188-07-8 ]
[ 228418-45-9 ]
[ 192805-69-9 ]

Reference： [1]Patent: US6337418,2002,B1 .Location in patent: Example 6
[2]Patent: US6337418,2002,B1 .Location in patent: Example 7

7
[ 67-56-1 ]
[ 320-94-5 ]
[ 228418-45-9 ]

Yield	Reaction Conditions	Operation in experiment
> 99%	With sulfuric acid; at 20℃; for 48h;Heating / reflux;	Example 3; Synthesis of (S)-(3,5-Bistrifluoromethylbenzyl)-(l-cyclopentylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-lH-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)amine; Step 1; Preparation of Methyl 2-nitro-4-trifluoromethylbenzoate; Add concentrated sulfuric acid (120 mL) dropwise to a solution of <strong>[320-94-5]2-nitro-4-trifluoromethylbenzoic acid</strong> (200 g, 850 mmol) in methanol (2 L) at room temperatureunder nitrogen and heat the mixture at reflux for 48 h. Cool the solution to roomtemperature and remove most of the solvent by evaporation at 45 C under reducedpressure. Pour the turbid residue onto ice/water (2 L) and extract with ethyl acetate (2x1L). Wash the combined organic extracts with brine (1 L), dry over anhydrous magnesiumsulfate, filter and remove the solvent under reduced pressure to provide the titlecompound as a yellow oil (212.2 g, >99%).
98%	sulfuric acid; at 20℃; for 24h;Heating / reflux;	A5. General Method for Aryl Amine Formation Via Carboxylic Acid Esterification Followed by Reduction; Step 1. Methyl 2-Nitro-4-(trifluoromethyl)benzoate: To a solution of <strong>[320-94-5]2-nitro-4-(trifluoromethyl)benzoic acid</strong> (4.0 g, 17.0 mmol) in MeOH (150 mL) at room temp was added cone H2SO4 (2.5 mL). The mixture was heated at the reflux temp for 24 h., cooled to room temp and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4), concentrated in vacuo. The residue was purified by flash chromatography (14% EtOAc/86% hexane) to give the desired ester as a pale yellow oil (4.17 g, 98%); 1H-NMR (DMSO-d6) delta 3.87 (s, 3H), 8.09 (d, J=7.72 Hz, 1H), 8.25 (dd, J=1.11, 8.09 Hz, 1H), 8.48 (d, J=1.11 Hz, 1H).
98%	With sulfuric acid; at 20℃; for 24h;Heating / reflux;	To a solution of <strong>[320-94-5]2-nitro-4-(trifluoromethyl)benzoic acid</strong> (4.0 g, 17.0 mmol) in MeOH (150 mL) at room temp was added conc H2SO4 (2.5 mL). The mixture was heated at the reflux temp for 24 h., cooled to room temp and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4), concentrated in vacuo. The residue was purified by flash chromatography (14% EtOAc/86% hexane) to give the desired ester as a pale yellow oil (4.17 g, 98%): 1H-NMR (DMSO-d6) ? 3.87 (s, 3H), 8.09 (d, J=7.72 Hz, 1H), 8.25 (dd, J=1.11, 8.09 Hz, 1H), 8.48 (d, J=1.11 Hz, 1H).

98%	With sulfuric acid; for 24h;Heating / reflux;	A5. General Method for Aryl Amine Formation via Carboxylic Acid Esterification Followed by Reduction; [] Step 1. Methyl 2-Nitro-4-(trifluoromethyl)benzoate: To a solution of <strong>[320-94-5]2-nitro-4-(trifluoromethyl)benzoic acid</strong> (4.0 g, 17.0 mmol) in MeOH (150 mL) at room temp was added conc H2SO4 (2.5 mL). The mixture was heated at the reflux temp for 24 h., cooled to room temp and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4), concentrated in vacuo. The residue was purified by flash chromatography (14% EtOAc/86% hexane) to give the desired ester as a pale yellow oil (4.17 g, 98%): 1H-NMR (DMSO-d6) delta 3.87 (s, 3H), 8.09 (d, J=7.72 Hz, 1H), 8.25 (dd, J=1.11, 8.09 Hz, 1H), 8.48 (d, J=1.11 Hz, 1H).
	With thionyl chloride; for 27h;Heating / reflux;	Thionyl chloride (19 mL) was added to a methanol (150 mL) solution of <strong>[320-94-5]2-nitro-4-trifluoromethylbenzoic acid</strong> (25.0 g), and the reaction mixture was refluxed for 27 hours. The solvent was distilled off under reduced pressure. Water was added to the residue, and the solution was 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 title compound (24.6 g) was obtained as colorless oil.
	With thionyl chloride; for 27h;Heating / reflux;	Thionyl chloride (19 mL) was added to a methanol (150 mL) solution of <strong>[320-94-5]2-nitro-4-trifluoromethylbenzoic acid</strong> (25.0 g), and the reaction mixture was refluxed for 27 hours. The solvent was distilled off under reduced pressure. Water was added to the residue, and the solution was 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 title compound (24.6 g) was obtained as colorless oil.
	With sulfuric acid; In toluene; at 65℃; for 14h;	100 g of <strong>[320-94-5]2-nitro-4-trifluoromethylbenzoic acid</strong> (0.425 mol, 1 eq), 300 g of methanol and concentrated sulfuric acid were added to a 500 mL four-necked flask, and then the temperature was raised to reflux.The residual amount of <strong>[320-94-5]2-nitro-4-trifluoromethylbenzoic acid</strong> (% of raw material) in the reaction solution was determined by HPLC.The reaction liquid was a crude methyl 2-nitro-4-trifluoromethylbenzoate, and the results are shown in Table 2.

Reference： [1]Patent: WO2006/2342,2006,A1 .Location in patent: Page/Page column 55
[2]Patent: US2008/269265,2008,A1 .Location in patent: Page/Page column 10
[3]Patent: EP1449834,2004,A2 .Location in patent: Page 16
[4]Patent: EP1042305,2005,B1 .Location in patent: Page/Page column 21
[5]Patent: US2008/287428,2008,A1 .Location in patent: Page/Page column 65
[6]Patent: EP1908753,2008,A1 .Location in patent: Page/Page column 99
[7]Patent: CN109824560,2019,A .Location in patent: Paragraph 0062-0066; 0068-0072

8
[ 228418-45-9 ]
[ 61500-87-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 3102.97 Torr; for 3h;	Step 2; Preparation of Methyl 2-amino-4-trifluoromethylbenzoate; Add a solution of methyl 2-nitro-4-trifluoromethylbenzoate (106 g, 425 mmol) in ethyl. acetate (2.2 L) to a slurry of 10% palladium on carbon (11.0 g) in ethyl acetate (200 mL)and stir the suspension at room temperature under an atmosphere of hydrogen at 60 psifor 3 h. Filter the suspension through a pad of Celite and wash the pad with additionalethyl acetate. Remove the solvents under reduced pressure and purify the residue bycolumn chromatography on silica gel, eluting with isohexane/ethyl acetate (9:1), toprovide the title compound as a white crystalline solid (84 g, 95%).
93%	palladium-carbon; In ethyl acetate;	Step 2 Methyl 2-Amino-4-(trifluoromethyl)benzoate A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93%): 1H-NMR (DMSO-d6) delta 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
93%	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 20℃; for 18h;	Step 2. Methyl 2-Amino-4-(trifluoromethyl)benzoate: A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93%): 1H-NMR (DMSO-d6) delta 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).

93%	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 20℃; for 18h;	A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93%): 1H-NMR (DMSO-d6) ? 3.79 (s, 3H), 6.75 (dd,J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
93%	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 20℃; for 18h;	Step 2. Methyl 2-Amino-4-(trifluoromethyl)benzoate; A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93%): 1H-NMR (DMSO-d6) delta 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
91%		B. 2-Amino-4-trifluoromethyl-benzoic acid methyl ester. A solution of 2-nitro-4-trifluoromethylbenzoic acid methyl ester (4.3 g, 0.017 mol) was dissolved in a mixture of DCM (20 mL) and EtOAc (20 mL) followed by addition of SnCl2.2H2O (19 g, 0.086 mol). The mixture was stirred overnight at room temperature, then was neutralized by shaking with a satd. aq. NaHCO3 solution. The resulting salts were removed by filtration through a pad of diatomaceous earth. The filtrate was extracted with DCM (3*). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (3.38 g, 91%). TLC (silica, 50% EtOAc/hexanes): Rf=0.60. HPLC (reverse phase): RT=9.31 min. 1H NMR (500 MHz, CDCl3): 7.95 (d, J=8.3 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J=9.3 Hz, 1H), 5.91 (br s, 2H), 3.90 (s, 3H).
67%	With sodium dithionite; In ethanol; water; at 50℃; for 3h;	A mixture of methyl 2-nitro-4- (trifluoromethyl) benzoate (2.49 g 0.01 mol), sodium hydrosulfite (8.71 g, 0.05 mol), ethanol (20 ml) and water (20 ml) was heated at 50 0C for 3 h. Water was added and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 5% ethyl acetate/n-hexane to give 1.46 g(6.67 mmol 67%) of the title compound as a white powder. 1H NMR (CDCl3) delta. 3.90 (s, 3H), 5.50-6,20 (brs, 2H), 6.85 (d, J = 8.48 Hz, IH), 6.90 (s, IH), 7.95 (d, J = 8.48 Hz, IH) . MS Calcd. : 219; Found: 220 (M+H) .
	With tin(ll) chloride; In dichloromethane; ethyl acetate; at 20℃; for 16h;	D. 2-Amino-4-trifluoromethylbenzoic acid methyl ester. To a stirred solution of 2-nitro-4-trifluoromethylbenzoic acid (6.0 g, 25 mmol) in dry DMF (30 mL) at 0 C. was added DBU (35 mL, 25 mmol) followed in 15 min by iodomethane (16 mL, 25 mmol). The reaction mixture was allowed to warm to ambient temperature and stir overnight, then was partitioned between water and EtOAc. The organic layer was washed with water and dried (MgSO4), and the resulting crude product was purified on silica gel (MPLC, hexanes/EtOAc) to provide the methyl ester as a yellow oil (5.7 g, 91%). This material was immediately dissolved in 3:1 EtOAc/DCM (50 mL), and SnCl2.2H2O (26 g, 110 mmol) was added with stirring. The mixture was held at ambient temperature for 16 h, then 5% aqueous NaHCO3 was added cautiously. The aqueous phase was extracted with DCM (3×), and the combined organic layers were dried (MgSO4). Filtration and concentration provided the aniline as a light yellow solid (4.5 g, 21 mmol, 84% for two steps). HPLC (reversed-phase): RT=9.38 min. 1H NMR (400 MHz, CDCl3): 7.95 (d, J=8.3 Hz, 1H), 6.91 (s, 1H), 6.85 (dd, J=8.6, 1.3 Hz, 1H), 6.2-5.5 (bs, 2H), 3.90 (s, 3H).
	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 20h;	First, 10% Pd-C (2.5 g) was added to a methanol (490 mL) solution of the compound (24.6 g) prepared in <Step 1> of Example 190, and the mixture was stirred in a hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was subjected to Celite filtration. The solvent was then distilled off under reduced pressure. The title compound (21.3 g) was obtained as gray-white crystals.
	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 20h;	First, 10%Pd-C (2.5 g) was added to a methanol (490 mL) solution of the compound (24.6 g) prepared in <Step 1> of Example 190, and the mixture was stirred in a hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was subjected to Celite filtration. The solvent was then distilled off under reduced pressure. The title compound (21.3 g) was obtained as gray-white crystals.

Reference： [1]Patent: WO2006/2342,2006,A1 .Location in patent: Page/Page column 55-56
[2]Patent: US2004/102636,2004,A1
[3]Patent: US2008/269265,2008,A1 .Location in patent: Page/Page column 10
[4]Patent: EP1449834,2004,A2 .Location in patent: Page 16
[5]Patent: EP1042305,2005,B1 .Location in patent: Page/Page column 21
[6]Patent: US2005/38032,2005,A1 .Location in patent: Page/Page column 27
[7]Patent: WO2006/116412,2006,A2 .Location in patent: Page/Page column 224
[8]Patent: US2004/224983,2004,A1 .Location in patent: Page 28
[9]Patent: US2008/287428,2008,A1 .Location in patent: Page/Page column 65
[10]Patent: EP1908753,2008,A1 .Location in patent: Page/Page column 99

9
[ 74-88-4 ]
[ 228418-45-9 ]

Yield	Reaction Conditions	Operation in experiment
96%		A. 2-Nitro-4-trifluoromethylbenzoic acid methyl ester. To a stirred solution of 2-nitro-4-trifluoromethylbenzoic acid (4.3 g, 0.018 mol) in DMF (10 mL) was added DBU (5.4 mL, 0.036 mol) under a nitrogen atmosphere. The reaction mixture was stirred for 15 min after which iodomethane (2.2 mL, 0.036 mol) was added at 0 C. The mixture was warmed to room temperature and stirred overnight. The mixture was diluted with EtOAc (60 mL) and washed with H2O (3*). The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (hexanes/EtOAc) to provide the title compound (4.30 g, 96%). TLC (silica, 50% EtOAc/hexanes): Rf=0.55. 1H NMR (500 MHz, CDCl3): 8.22 (s, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 3.97 (s, 3H).
91%		D. 2-Amino-4-trifluoromethylbenzoic acid methyl ester. To a stirred solution of 2-nitro-4-trifluoromethylbenzoic acid (6.0 g, 25 mmol) in dry DMF (30 mL) at 0 C. was added DBU (35 mL, 25 mmol) followed in 15 min by iodomethane (16 mL, 25 mmol). The reaction mixture was allowed to warm to ambient temperature and stir overnight, then was partitioned between water and EtOAc. The organic layer was washed with water and dried (MgSO4), and the resulting crude product was purified on silica gel (MPLC, hexanes/EtOAc) to provide the methyl ester as a yellow oil (5.7 g, 91%). This material was immediately dissolved in 3:1 EtOAc/DCM (50 mL), and SnCl2.2H2O (26 g, 110 mmol) was added with stirring. The mixture was held at ambient temperature for 16 h, then 5% aqueous NaHCO3 was added cautiously. The aqueous phase was extracted with DCM (3×), and the combined organic layers were dried (MgSO4). Filtration and concentration provided the aniline as a light yellow solid (4.5 g, 21 mmol, 84% for two steps). HPLC (reversed-phase): RT=9.38 min. 1H NMR (400 MHz, CDCl3): 7.95 (d, J=8.3 Hz, 1H), 6.91 (s, 1H), 6.85 (dd, J=8.6, 1.3 Hz, 1H), 6.2-5.5 (bs, 2H), 3.90 (s, 3H).

Reference： [1]Patent: US2005/38032,2005,A1 .Location in patent: Page/Page column 27
[2]Patent: US2004/224983,2004,A1 .Location in patent: Page 28

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[ 1445-45-0 ]
[ 320-94-5 ]
[ 228418-45-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	In toluene; at 80℃; for 16h;	A mixture of <strong>[320-94-5]2-nitro-4-trifluoromethylbenzoic acid</strong> (23.5 g, 0.10 mol) , trimethyl orthoacetate (60.1 g, 0.50 ralphaol) and toluene (60 ml) was heated at 80 0C for 16 h. The EPO <DP n="225"/>reaction mixture was concentrated in vacuo. Toluene was added and concentrated again to remove excess reagent. The residue was purified by column chromatography on silica gel with a 1-10% ethyl acetate/n-hexane gradient mixture to give 24.9g (0.50 mol 100%) of the title compound as a colorless oil.1H NMR (CDCl3) delta.:3.97 (s, 3H), 7.87-7.90 (m, IH), 7.95- 7.97 (m, IH) , 8.22 (s, IH) .

Reference： [1]Patent: WO2006/116412,2006,A2 .Location in patent: Page/Page column 223; 224

11
[ 320-94-5 ]
[ 228418-45-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With conc H2SO4; In methanol;	Step 1 Methyl 2-Nitro-4-(trifluoromethyl)benzoate To a solution of <strong>[320-94-5]2-nitro-4-(trifluoromethyl)benzoic acid</strong> (4.0 g, 17.0 mmol) in MeOH (150 mL) at room temp was added conc H2SO4 (2.5 mL). The mixture was heated at the reflux temp for 24 h., cooled to room temp and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4), concentrated in vacuo. The residue was purified by flash chromatography (14% EtOAc/86% hexane) to give the desired ester as a pale yellow oil (4.17 g, 98%): 1H-NMR (DMSO-d6) delta 3.87 (s, 3H), 8.09 (d, J=7.72 Hz, 1H), 8.25 (dd, J=1.11, 8.09 Hz, 1H), 8.48 (d,J=1.11 Hz, 1H).

Reference： [1]Patent: US2004/102636,2004,A1

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[ 67-56-1 ]
[ 22227-55-0 ]
[ 228418-45-9 ]