22227-63-0|Methyl 3-nitro-5-(trifluoromethyl)benzoate| Ambeed

Structure of 22227-63-0

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 22227-63-0 ] Purity: 96% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 22227-63-0 ]

CAS No. :	22227-63-0
Formula :	C₉H₆F₃NO₄
M.W :	249.14
SMILES Code :	O=C(OC)C1=CC(C(F)(F)F)=CC([N+]([O-])=O)=C1
MDL No. :	MFCD06637356
InChI Key :	GMGZRXWZOZSBED-UHFFFAOYSA-N
Pubchem ID :	18942157

Safety of [ 22227-63-0 ]

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

Computational Chemistry of [ 22227-63-0 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	72.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.69
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	2.49
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.55
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.	1.88
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	0.68
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.06

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.95
Solubility	0.279 mg/ml ; 0.00112 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.	-3.65
Solubility	0.0558 mg/ml ; 0.000224 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-2.75
Solubility	0.447 mg/ml ; 0.00179 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	Yes
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.	-6.05 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	2.0 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<1.0
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)	2.16

Application In Synthesis of [ 22227-63-0 ]

* 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 [ 22227-63-0 ]

[ 22227-63-0 ] Synthesis Path-Downstream 1~37

2
[ 67-56-1 ]
[ 328-80-3 ]
[ 22227-63-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	sulfuric acid;Reflux;	3-Nitro-5-(trifluoromethyl)benzoic acid (8) (1.0 g, 4.52 mmol) was dissolved in methanol (30 mL) and a drop of sulfuric acid was added to the solution. The solution was heated at reflux overnight. After cooling to room temperature, the solvent was evaporated and the residue was extracted with ethyl acetate and water. The organic solution was washed with IN aqueous sodium hydroxide (x 2), was dried over magnesium sulfate, was filtered and was concentrated to give methyl 3-nitro-5- (trifluoromethyl)benzoate (1.01 g, 95percent yield) as a yellow solid. XH NMR (400 MHz, CDC13): delta 9.05 (s, 1H), 8.68 (s, 1H), 8.63 (s, 1H), 4.04 (s, 3H).
93%	With acetyl chloride; In methanol; ethyl acetate; at 0℃; for 6.66667h;Reflux;	Reference Example 27Methyl 3-nitro-5-(trifluoromethyl)benzoateTo an ice cooled stirred solution of 3-nitro-5-(trifluoromethyl)benzoic acid (25.00 g, 106.3 mmol) in methanol (500 mL) was added acetyl chloride (22.00 g, 280.2 mmol) dropwise over 20 min.After the addition was complete, the reaction mixture was stirred for 20 min at 0° C., then heated at reflux for 6 h and then cooled to room temperature.The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, filtered through a silica gel and concentrated under reduced pressure to provide methyl 3-nitro-5-(trifluoromethyl)benzoate (24.65 g, 93percent) as a pale yellow oil.1H NMR (500 MHz, CDCl3) delta ppm 4.04 (s, 3H), 8.63 (s, 1H), 8.68 (s, 1H), 9.05 (t, J=1.60 Hz, 1H).
92%	With acetyl chloride; at 20℃; for 18.0h;	AcC1 (19.5 mL) was added dropwise to a solution of 3-nitro-5-(trifluoromethyl)benzoicacid (19.50 g, 83.00 mmol) in MeOH (195 mL) at rt and stirred 18 h. The resultingmixture was concentrated under vacuum, washed with a solution of 10percent of K2C03, extracted twice with DCM, dried over MgSO4, filtrated and concentrated under vacuum to give 19 g of intermediate 267 (92percent yield).

90%	With sulfuric acid; at 0 - 25℃; for 16.0h;	To a mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (20 g, 85 mmol) in MeOH (200 mL) was added H2SO4 (12 mL, 225 mmol) at 0 °C dropwise, then the mixture was stirred for 16 h at 25 °C. Then the solvent was concentrated and was adjusted pH = 9 with NaHC03 solution. The solvent was concentrated to give the residue which was extracted with DCM (200 mL x 2), dried over NaaSOzi, filtered, and concentrated to yield an oil of methyl 3-nitro-5-(trifluoromethyl)benzoate (20 g, 76 mmol, 90percent yield): lH NMR (400 MHz, CD3OD) delta 8.99 (s, 1H), 8.74 (s, 1H), 8.62 (s, 1H), 4.01 (s, 3H); ES-LCMS m/z 250 (M+l).
88%	hydrogenchloride; at 20℃;	Methyl 3-nitro-5-(trifluoromethyl)benzoate. 3-Nitro-5-(trifluoromethyl) benzoic acid (25.0 g, 106.3 mmol) was dissolved in methanol (60 mL) which was bubbled with hydrochloric acid gas for 1 h. The reaction was allowed to stir at room temperature overnight and concentrated. The crude product was dissolved in ethyl acetate, washed with water (2.x.), brine (2.x.) dried over sodium sulfate and concentrated. Flash chromatography on silica gel afforded 23.4 g (88percent) of the desired compound. 1H-NMR (CDCl3, 500 MHz) delta 9.02 (s, H), 8.66 (s, 1H), 8.61 (s, 1H), 4.03 (s, 3H).
87%	With sulfuric acid; for 48.0h;Reflux;	3-Nitro-5-trifluoromethylbenzoic acid (32a) (1 g, 4.25 mmol)was dissolved in methanol (15 mL), and 5 drops of concentratedsulfuric acid were added. The mixture was refluxed for 48 h. Thesolvents were then evaporated under reduced pressure, and theresidue was dissolved in EtOAc (20 mL) and washed with 5percentNa2CO3 (3 x 20 mL) and brine (1 x 20 mL). The organic layer wasdried over anhydrous Na2SO4 and evaporated under reducedpressure. Methyl 3-nitro-5-trifluoromethylbenzoate was usedwithout further purification. Yield: 87percent as a colorless oil. 1H NMR(500 MHz, CDCl3) delta 9.05 (t, J = 1.8 Hz, 1H), 8.68 (t, J = 1.8 Hz, 1H),8.63 (s, 1H), 4.05 (s, 3H). 13C NMR (126 MHz, CDCl3) delta 163.62,148.47,133.16, 132.83 (q, J = 34.7 Hz), 131.87 (q, J = 3.5 Hz), 127.50, 124.42(q, J = 3.8 Hz), 122.37 (q, J = 273.2 Hz), 53.26.
86%	With sulfuric acid; for 20.0h;Heating / reflux;	14). Synthesis of (3-chloromethyl-5-trifluoromethyl-phenyl)-dimethylamine; A solution of 5-nitro-3-(trifluoromethyl)benzoic acid (2.35 g, 10 mmol) and H2SO4 (53 mul_, 1 mmol) in methanol (30 mL) is allowed to warm to reflux and stir for 20 hours. The mixture is cooled to room temperature, then the mixture is concentrated under reduced pressure. The obtained residue is neutralized with saturated aq. NaHCO3. The mixture is extracted with CH2CI2. The combined organic layer is washed with brine, dried over <n="162"/>Na2SO4, filtrated, and concentrated under reduced pressure to give 3-nitro-5-trifluoromethyl- benzoic acid methyl ester (2.15 g, 86percent), which is used in the next step without further purification.
70%	With sulfuric acid; for 3.0h;Inert atmosphere; Reflux;	To a flame dried pressure tube under argon was added 3-nitro-5-(trifluoromethyl)benzoic acid (450 mg, 1.91 mmol) and 20 mL of anhydrous MeOH. Sulfuric acid (0.176 mL) was added and the reaction was heated to reflux and stirred for 3 h. The reaction was cooled to room temperature and slowly poured onto solid NaHCO3, filtered, diluted with 20 mL of deionized H2O, and extracted with EtOAc (x 2). The pooled organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure to give crude material that was purified with column chromatography (75/25 hexanes/EtOAc) to give 11 (332 mg, 1.33 mmol) in 70percent yield as a colorless oil that slowly solidified at 0°C into a white solid.
	With sulfuric acid;Heating / reflux;	Trifluoromethyl-3-nitrobenzoic acid (0.7g, 3.0 mmol) was dissolved in methanol and 10 drops of sulphuric acid (cone.) were added, and the reaction was stirred over night at reflux temperature. Methanol was removed and the residue re-dissolved in dichloromethane and washed with water. The solvent was dried (magnesium sulphate) and removed under vacuum to give 0.71 g of 5- trifluoromethyl-3-nitrobenzoate methyl ester.
	With sulfuric acid;Heating / reflux;	5-Trifluoromethyl-3-nitrobenzoic acid (0.7g, 3.0 mmol) was dissolved in methanol and 10 drops of sulphuric acid (conc.) were added, and the reaction was stirred over night at reflux temperature. Methanol was removed and the residue re-dissolved in dichloromethane and washed with water. The solvent was dried (magnesium sulphate) and removed under vacuum to give 0. 71 g of 5- trifluoromethyl-3-nitrobenzoate methyl ester.
	With thionyl chloride; for 5.0h;Reflux;	Add thionyl chloride (2 mL) dropwise to the solution of 3-nitro-5-(trifluoromethyl) benzoic acid (1.5 g, 6.4 mmol) in methanol (20 mL), reflux for 5 hrs. TLC (PE:EtOAc=l:l) shows the reaction is complete. Concentrate under reduced pressure to give the crude product (1.8 g, 100percent) which is used in next step without further purification.
	With thionyl chloride; for 5.0h;Reflux;	Add thionyl chloride (2 mL) dropwise to the solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.5 g, 6.4 mmol) in methanol (20 mL), reflux for 5 hrs. TLC (PE:EtOAc=1:1) shows the reaction is complete. Concentrate under reduced pressure to give the crude product (1.8 g, 100percent) which is used in next step without further purification.
	With toluene-4-sulfonic acid; for 8.0h;Reflux;	(Reference Example 28) Synthesis of methyl 3-amino-5-(trifluoromethyl)benzoate: A solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.0 g, 4.2 mmol) and p-toluenesulfonic acid (0.05 g) in methanol was stirred while heating under reflux for eight hours. The obtained solution was returned to room temperature and then concentrated under vacuum. The obtained residue was dissolved in methanol, palladium (5.0percent by weight) on carbon (containing 50percent water by weight, 0.2 g) was added thereto, and the obtained solution was stirred at room temperature for three hours under hydrogen atmosphere. The reaction mixture was filtered through Celite® and the filtrate was concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1, Rf = 0.47) to obtain the title compound (0.85 g, 91percent) (hereinafter referred to as the compound of Reference Example 28) as an oily substance. MS(ESI) [M + H]+: 220.

References: [1]Patent: WO2012/37132,2012,A1 .Location in patent: Page/Page column 47.
[2]Patent: US2012/71489,2012,A1 .Location in patent: Page/Page column 59.
[3]Patent: WO2017/125530,2017,A1 .Location in patent: Page/Page column 283.
[4]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.
[5]Patent: WO2014/141187,2014,A1 .Location in patent: Page/Page column 119.
[6]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628.
[7]Patent: US2007/249607,2007,A1 .Location in patent: Page/Page column 71.
[8]European Journal of Medicinal Chemistry,2017,vol. 126,p. 369 - 383.
[9]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 159-160.
[10]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 4933 - 4936.
[11]Patent: WO2005/92316,2005,A1 .Location in patent: Page/Page column 48.
[12]Patent: WO2005/92317,2005,A1 .Location in patent: Page/Page column 65-66.
[13]Patent: WO2014/418,2014,A1 .Location in patent: Page/Page column 45.
[14]Journal of Medicinal Chemistry,2014,vol. 57,p. 9971 - 9982.
[15]Patent: US2015/197511,2015,A1 .Location in patent: Paragraph 0233; 0234.
[16]Patent: EP3345892,2018,A1 .Location in patent: Paragraph 0326; 0327.

3
[ 22227-63-0 ]
[ 22235-25-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With tin(II) chloride dihdyrate; water; In methanol; at 70℃; for 2.0h;	To a mixture of methyl 3-nitro-5- (trifluoromethyl)benzoate (350 mg, 1.40 mmol) and tin(II) chloride dihydrate (1.58 g, 7.02 mmol) in methanol (20 mL) was added water (1 mL) and the resulting mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated and was quenched by the addition of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3X). The combined organic portion was dried over magnesium sulfate, was filtered and was concentrated to give methyl 3-amino-5- (trifluoromethyl)benzoate (300 mg, 98percent yield) as a colorless solid. XH NMR (400 MHz,CDCI3): delta 7.65 (s, 1H), 7.48 (s, 1H), 7.05 (s, 1H), 3.99 (br s, 2H), 3.91 (s, 3H).
96%	With hydrogen;palladium on activated charcoal; In methanol; at 20℃; for 3.0h;	To a solution of methyl 3-nitro-5-(trifluoromethyl) benzoate (1.50 g, 6.02 mmol) in methanol (20 . mL) was added palladium carbon (50percent water-containing product,15 mg) , and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure and dried to give the title compound(1.27 g, 96percent) as a white solid.1H-NMR (DMSO-d6, 300 MHz) delta 3.85 (3H, s) , 5.94 (2H, s) , 7.08 (IH, s), 7.26 (IH, s), 7.42 (IH, s) .
95%	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 2068.65 Torr; for 1.0h;	Reference Example 28Methyl 3-amino-5-(trifluoromethyl)benzoateA solution of methyl 3-nitro-5-(trifluoromethyl)benzoate (Reference Example 27, 24.6 g, 98.9 mmol) in ethanol (1500 mL) was sparged in a Parr bottle with nitrogen for 10 min.After this time, 10 wt percent Pd/C (5.0 g, 5.0 mmol) was added and the reaction mixture was subjected to 40 psi of hydrogen on Parr shaker at room temperature for 1 h.After this time, the reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to provide Methyl 3-amino-5-(trifluoromethyl)benzoate (20.6 g, 95percent) as a light purple oil.1H NMR (500 MHz, CDCl3) delta ppm 3.92 (s, 3H), 4.02 (br s, 2H), 7.05 (s, 1H), 7.48 (s, 1H), 7.64 (s, 1H).

86%	With hydrogen;palladium 10% on activated carbon; In methanol;	Methyl 3-amino-5-(trifluoromethyl)benzoate. Methyl 3-nitro-5-(trifluoromethyl)benzoate (9.0 g, 36.1 mmol) in methanol (30 mL) was flushed with nitrogen, and treated with palladium (10percent on charcoal, 0.90 g). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Flash chromatography on silica gel (30percent ethyl acetate/hexanes) afforded 6.8 g (86percent). 1H-NMR (CDCl3, 500 MHz) delta 7.64 (s, H), 7.49 (s, 1H), 7.05 (s, 1H), 3.91 (s, 3H). Mass spec.: 220.05 (MH)+.
74%		A solution of 3-nitro-5-trifluoromethyl-benzoic acid methyl ester (8.6 mmol, 2.15 g) and tin chloride dihydrate (25.8 mmol, 5.82 in ethanol (40 ml) is allowed to warm to 60 0C and stir for 4 hours. The mixture is cooled to room temperature, then concentrated under reduced pressure. The obtained residue is neutralized with saturated aq. NaHCO3. The mixture is filtered and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: hexane / EtOAc) to give 3-amino-5- trifluoromethyl-benzoic acid methyl ester (74percent, 1.4 g); ESI-MS m/z: 220 [M+1]\\ Retention time 1.81 min (condition A).
0.85 g	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 3.0h;	(Reference Example 28) Synthesis of methyl 3-amino-5-(trifluoromethyl)benzoate: A solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.0 g, 4.2 mmol) and p-toluenesulfonic acid (0.05 g) in methanol was stirred while heating under reflux for eight hours. The obtained solution was returned to room temperature and then concentrated under vacuum. The obtained residue was dissolved in methanol, palladium (5.0percent by weight) on carbon (containing 50percent water by weight, 0.2 g) was added thereto, and the obtained solution was stirred at room temperature for three hours under hydrogen atmosphere. The reaction mixture was filtered through Celite® and the filtrate was concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1, Rf = 0.47) to obtain the title compound (0.85 g, 91percent) (hereinafter referred to as the compound of Reference Example 28) as an oily substance. MS(ESI) [M + H]+: 220.

References: [1]Patent: WO2012/37132,2012,A1 .Location in patent: Page/Page column 47.
[2]Patent: WO2007/4749,2007,A1 .Location in patent: Page/Page column 125.
[3]Patent: US2012/71489,2012,A1 .Location in patent: Page/Page column 59.
[4]Patent: US2007/249607,2007,A1 .Location in patent: Page/Page column 72.
[5]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 159; 160.
[6]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.
[7]Journal of Medicinal Chemistry,2014,vol. 57,p. 9971 - 9982.
[8]Patent: EP3345892,2018,A1 .Location in patent: Paragraph 0326; 0327.

4
[ 22227-63-0 ]
[ 334792-91-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9971 - 9982.

5
[ 22227-63-0 ]
[ 334792-87-9 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9971 - 9982.

6
[ 22227-63-0 ]
[ 334792-88-0 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

7
[ 22227-63-0 ]
[ 334792-90-4 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

8
[ 22227-63-0 ]
[ 334792-89-1 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

9
[ 22227-63-0 ]
[ 334792-92-6 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9971 - 9982.

10
[ 22227-63-0 ]
[ 334792-93-7 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9971 - 9982.

11
[ 22227-63-0 ]
[ 334792-95-9 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

12
[ 22227-63-0 ]
[ 334792-94-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

13
[ 22227-63-0 ]
WA₄₃₆ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9971 - 9982.

14
[ 22227-63-0 ]
[ 180146-66-1 ]

Yield	Reaction Conditions	Operation in experiment
55%		To lithium aluminium hydride (0.32 g, 8.7 mmol) in tetrahydrofuran (8 mL) was carefully, and drop wise, added a solution of <strong>[22227-63-0]5-trifluoromethyl-3-nitrobenzoate methyl ester</strong> in tetrahydrofuran (2 mL) and stirred at room temperature over night. The reaction was quenched with careful addition of water (20 mL) then acidified using hydrochloric acid (3 M) and finally extracted with diethylether (3 x 50mL). The combined organic phases were dried (magnesium sulphate) and the solvent was removed under vacuum. The residue was purified on silica gel column (diethyl ether/heptane 1 : 3) to provide 0.35 g, (55percent) of 5-trifluoromethyl-3-nitrobenzylalcohol.
55%		To lithium aluminium hydride (0.32 g, 8.7 mmol) in tetrahydrofuran (8 mL) was carefully, and drop wise, added a solution of <strong>[22227-63-0]5-trifluoromethyl-3-nitrobenzoate methyl ester</strong> in tetrahydrofuran (2 mL) and stirred at room temperature over night. The reaction was quenched with careful addition of water (20 mL) then acidified using hydrochloric acid (3 M) and finally extracted with diethylether (3 x 50mL). The combined organic phases were dried (magnesium sulphate) and the solvent was removed under vacuum. The residue was purified on silica gel column (diethylether/heptane 1 : 3) to provide 0. 35 g, (55percent) of 5-trifluoromethyl-3-nitrobenzylalcohol.

References: [1]Patent: WO2005/92316,2005,A1 .Location in patent: Page/Page column 48.
[2]Patent: WO2005/92317,2005,A1 .Location in patent: Page/Page column 66.

15
[ 328-80-3 ]
[ 22227-63-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sulfuric acid; In methanol; water;	Intermediate 46: Methyl 3-nitro-5-(trifluoromethyl)-benzoate Methanol (20 ml) was added to 3-nitro-5-(trifluoromethyl)benzoic acid (5.1 g, 22 mmol) to preapre a solution, and 2.0 ml of concentrated sulfuric acid was added to the solution. The mixture was heated under reflux for 1.5 hr. The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was then slowly poured into sodium hydrogencarbonate. The insolubles were filtered, 300 ml of water was then added thereto, and the mixture was extracted twice with 200 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (development system: hexane: ethyl acetate = 6: 1) to give the title compound (5.0 g, 91percent). Physicochemical properties of intermediate 46

References: [1]Patent: EP1229024,2002,A1 .

16
[ 328-80-3 ]
[ 74-88-4 ]
[ 22227-63-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15.0h;	To a solution of 3-nitro-5- (trifluoromethyl) benzoic acid(3.00 g, 12.8 irimol) in N,N-dimethylformamide (100 mL) were added potassium carbonate (5.29 g, 38.3 mmol) and iodomethane(1.19 mL, 19.1 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (chi3) . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was' concentrated under reduced pressure, and the residue, was collected by filtration and washed with ethyl acetate-hexane to give the title compound (2.90 g, 92percent) as a yellow solid.1H-NMR (DMSO-de, 300 MHz) delta'3.95 (3H, s) , 8.55 (IH, s), 8.75(IH, s) , 8.81 (IH, s) .

References: [1]Patent: WO2007/4749,2007,A1 .Location in patent: Page/Page column 125.

17
[ 22227-63-0 ]
[ 1214361-12-2 ]

References: [1]Patent: US2012/71489,2012,A1 .

18
[ 22227-63-0 ]
[ 886496-87-3 ]

References: [1]Patent: US2012/71489,2012,A1 .

19
[ 22227-63-0 ]
[ 477535-43-6 ]

References: [1]Patent: US2012/71489,2012,A1 .

20
[ 22227-63-0 ]
[ 1252657-92-3 ]

References: [1]Patent: US2012/71489,2012,A1 .

21
[ 22227-63-0 ]
[ 1529769-29-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine; In ethanol;Reflux;	Mix <strong>[22227-63-0]methyl 3-nitro-5-(trifluoromethyl)benzoate</strong> (1.8 g, 12 mmol), ethanol (6 mL) and 80percent (w/w) hydrazine (10 mL), reflux overnight. Concentrate the mixture, partition the resulting residue between ethyl acetate and water, collect the organic layer, wash with sodium bicarbonate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product (1.23 g, 77percent) which is used in next step without further purification.
	With hydrazine; In ethanol;Reflux;	Mix <strong>[22227-63-0]methyl 3-nitro-5-(trifluoromethyl)benzoate</strong> (1.8 g, 12 mmol), ethanol (6 mL) and 80percent (w/w) hydrazine (10 mL), reflux overnight. Concentrate the mixture, partition the resulting residue between ethyl acetate and water, collect the organic layer, wash with sodium bicarbonate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product (1.23 g, 77percent) which is used in next step without further purification.

References: [1]Patent: WO2014/418,2014,A1 .Location in patent: Page/Page column 45; 46.
[2]Patent: US2015/197511,2015,A1 .Location in patent: Paragraph 0235; 0236.

22
[ 22227-63-0 ]
[ 1529769-30-9 ]

References: [1]Patent: WO2014/418,2014,A1 .

23
[ 22227-63-0 ]
[ 22227-34-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrazine hydrate; In methanol; at 25℃; for 16.0h;	A mixture of <strong>[22227-63-0]methyl 3-nitro-5-(trifluoromethyl)benzoate</strong> (20 g, 80 mmol) and hydrazine hydrate (5.56 mL, 96 mmol) in MeOH (100 mL) was stirred for 16 h at 25 °C. Then the solvent was concentrated to yield an off white solid of 3 -nitro-5 -(trifluoromethyl)benzohydrazide (20 g, 72.2 mmol, 90percent yield): lH NMR (400 MHz, CD3OD) delta 8.89 (s, 1H), 8.65 (s, 1H), 8.50 (s, 1H); ES- LCMS m/z 250 (M+H).
43%	With hydrazine hydrate; In ethanol; for 2.0h;Reflux;	Hydrazine hydrate (2 mL, 20.06 mmol) was added into a solutionof <strong>[22227-63-0]methyl 3-nitro-5-(trifluoromethyl)benzoate</strong> (32b) (1 g,4.01 mmol) in ethanol (20 mL). The mixture was refluxed for 2 h.The solventwas evaporated, and the residuewas dissolved in CHCl3(20 mL) and washed with water (3 20 mL) and brine (1 x 20 mL).The organic layerwas dried over anhydrous Na2SO4 and evaporatedunder reduced pressure. The product was purified using columnchromatography (mobile phase: CHCl3/MeOH, 20:1). Yield: 43percent as ayellowish solid; mp 120-122 °C. 1H NMR (500 MHz, acetone) delta 9.94(s, 1H), 8.96 (s, 1H), 8.66 (s, 1H), 8.63 (s, 1H). 13C NMR (126 MHz,CD3OD) delta 165.45, 150.03, 137.44, 133.36 (q, J = 34.3 Hz), 130.72 (q,J 3.6 Hz), 126.67, 124.20 (q, J = 272.3 Hz), 123.99 (q, J = 3.9 Hz).

References: [1]Patent: WO2014/141187,2014,A1 .Location in patent: Page/Page column 119.
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628.
[3]European Journal of Medicinal Chemistry,2017,vol. 126,p. 369 - 383.

24
[ 22227-63-0 ]
2-methyl-5-(3-nitro-5 -(trifluoromethyl)phenyl)-1,3,4-oxadiazole [ No CAS ]

References: [1]Patent: WO2014/141187,2014,A1 .

25
[ 22227-63-0 ]
3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)aniline [ No CAS ]

References: [1]Patent: WO2014/141187,2014,A1 .
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628.

26
[ 22227-63-0 ]
2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide [ No CAS ]

References: [1]Patent: WO2014/141187,2014,A1 .

27
[ 22227-63-0 ]
2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide [ No CAS ]

References: [1]Patent: WO2014/141187,2014,A1 .

28
[ 22227-63-0 ]
(S)-methyl 2-(4-((2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)carbamoyl)phenylsulfonamido)-3-(3-(4-(pyrimidin-2-ylamino)piperidin-1-yl)-5-(trifluoromethyl)benzamido)propanoate [ No CAS ]