67515-55-3|4-Fluoro-3-(trifluoromethyl)benzoic acid| Ambeed

Structure of 67515-55-3

*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 [ 67515-55-3 ] Purity: 98% 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 [ 67515-55-3 ]

CAS No. :	67515-55-3
Formula :	C₈H₄F₄O₂
M.W :	208.11
SMILES Code :	O=C(O)C1=CC=C(F)C(C(F)(F)F)=C1
MDL No. :	MFCD00061294
Boiling Point :	No data available
InChI Key :	WZBPZYCJUADXRS-UHFFFAOYSA-N
Pubchem ID :	522268

Safety of [ 67515-55-3 ]

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

Computational Chemistry of [ 67515-55-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	6.0
Num. H-bond donors	1.0
Molar Refractivity	38.36
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	37.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.39
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	2.43
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.12
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.	3.09
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	2.69
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.74

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.85
Solubility	0.296 mg/ml ; 0.00142 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.	-2.86
Solubility	0.29 mg/ml ; 0.00139 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	-2.94
Solubility	0.237 mg/ml ; 0.00114 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	No
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.	-5.84 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.	0.56

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<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)	1.61

Application In Synthesis of [ 67515-55-3 ]

* 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 [ 67515-55-3 ]

[ 67515-55-3 ] Synthesis Path-Downstream 1~35

Yield	Reaction Conditions	Operation in experiment
		Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 3-fluoro-4-nitrobenzoic acid; 4-fluoro-3-nitrobenzoic acid; 5-fluoro-2-nitrobenzoic acid; 2-fluoro-3-(trifluoromethyl)benzoic acid; 4-fluoro-3-(trifluoromethyl)benzoic acid; 5-fluoro-2-(trifluoromethyl)benzoic acid; 2-hydroxy-3-isopropyl-benzoic acid; 3-iodobenzoic acid; ...

2
[ 67515-55-3 ]
[ 381229-48-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of 2.03 ml of sec-BuLi (1.3M in cyclohexane, 2.64 mmol) and 0.4 ml of TMEDA under argon at -90 C. was added a solution of 0.25 g of <strong>[67515-55-3]4-fluoro-3-trifluoromethyl-benzoic acid</strong> (1.2 mmol) in 8 ml THF over 20 min (temperature kept between -92 C. and -88 C.). After 30 min stirring at the same temperature, the initially light orange suspension turned brown. A solution of 1.14 g of hexachloroethane (4.82 mmol) in 10 ml THF was then added within 2 min (temperature raised to -62 C.). The reaction mixture was then left to warm slowly to RT (1 hour) and treated carefully with 2 ml water. The reaction mixture was then concentrated in vacuo, diluted with water and extracted with diethylether. The aqueous phase was then acidified with concentrated HCl and extrated twice with ethylacetate. The combined ethylacetate phases were subsequently washed with water (3) and brine (1), dried over magnesium sulfate, filtered and concentrated in vacuo to yield 0.28 g of a residue which was purified by silicagel chromatography (eluent heptane/AcOEt 90:10 to 75:25) to yield 22 mg of 3-chloro-4-fluoro-5-trifluoromethyl-benzoic acid as a light yellow solid. MS: 241.1 (M-H)-.

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 4393 - 4403.
[2]Patent: US2007/185058,2007,A1 .Location in patent: Page/Page column 17.

3
[ 67515-55-3 ]
[ 1002105-80-7 ]
4-(<i>tert</i>-butyl-dimethyl-silanyloxy)-2-(4-fluoro-3-trifluoromethyl-benzoylamino)-butyric acid methyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3112 - 3129.

4
[ 67515-55-3 ]
4-fluoro-3-(trifluoromethyl)benzoic acid hydrazide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 528 - 542.

5
[ 67515-55-3 ]
[ 1006040-73-8 ]

Yield	Reaction Conditions	Operation in experiment
> 95 - ~ 100%		Scheme 2General Approach for Synthesis of Carboxylate 11To a solution of the desired alcohol (1.0 equiv) in anhydrous THF was added potassium t-butyloxide (2.5 equiv, IM solution in THF). The mixture was heated at 70 0C for 15 min then cooled down to room temperature. 4-Fluoro-3-trifluoromethylbenzoid acid (10) (1.0 equiv) in THF was added and the resultant was heated at 75 0C overnight. After cooling down to room temperature, the reaction was diluted with ethyl acetate and washed with water. The water layer was acidified to pH = 3 with HCl (2M) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and <n="71"/>concentrated in vacuo to afford the title compound which was used for next reaction without further purification.4-(2-(Pentyloxy)ethoxy)-3-(triflupromethyl)benzoic acid (Ha)The title compound was prepared based on the general protocol for synthesis of carboxylate 11 in > 95% yield. HPLC retention time on a C8(2) column (3O x 3.00 mm, 3 mu) is 2.97 min with gradient 20-98% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase.; Description 1 Alternative Method (DlA) 4-(2-(Pentyloxy)ethoxy)-3-(trifluoromethyl)benzoic acid (Dl)A 5 L round bottom flask was inerted and charged with a solution of «-pentyloxyethanol (82.5 g, 0.62 mol, 1.1 equiv), THF (1.2 L), and 1.0 M potassium t-butoxide in THF (1417 mL, 1.4 mol, 2.5 equiv) at room temperature (18 to 23 0C). The mixture was heated to 65 0C. After 15 minutes, a solution of 4-fluoro-3 (trifluromethyl) benzoic acid (118 g, 0.56 mol) in THF (1256 rnL) was charged slowly over 30 minutes. No frothing was observed. After 2.5 hours, the reaction was found to be complete by HPLC. The reaction mixture was cooled to ambient temperature (18 to 23 C) and stirred overnight. The reaction mixture was quenched with water (1400 mL), concentrated to remove THF5 then adjusted to a pH of 2 with 6 N HCl. The mixture was extracted twice with MTBE (750 mL, 150 mL), the organics were combined, dried with magnesium sulfate, filtered, and concentrated under vacuum to afford the title product (188 g, 104% yield, 92.8% AUC by HPLC).
		Description 1 4-(2-(Pe?tyloxy)ethoxy)-3-(trifluoromethyl)benzoic acid (Dl)2-(pentyloxy)ethanol (318 mg, 2.4 mmol, 1 equiv) was stirred with potassium t- butyloxide (6 mL, IM solution in THF, 6.0 mmol, 2.5 equiv), THF (10 mL) at 750C for -10 minutes. 4-Fluoro-3-trifluoromethylbenzoic acid was added and the mixture heated at 75C overnight. The mixture was then condensed , diluted in water, acidified, extracted with ethyl acetate and dried over Na2SO4- The organic layers were condensed to provide the title product.

References: [1]Patent: WO2008/16674,2008,A1 .Location in patent: Page/Page column 69-70; 123.
[2]Patent: WO2008/16674,2008,A1 .Location in patent: Page/Page column 122.

6
[ 67515-55-3 ]
[ 445026-27-7 ]

Yield	Reaction Conditions	Operation in experiment
> 99%		General protocol for synthesis of substituted 4-(allyloxy)benzoic acid (2)To a solution, of the desired alcohol (1.05 equiv) in anhydrous THF was added potassium r-butyloxide (2.05 equiv). The mixture was heated at 65 0C for 10 minutes then added substituted 4-fluorobenzoic acid (1) (1.00 equiv) in THF. The resultant solution was heated at 65 0C 1 to 3 hours. After cooling down to room, temperature, the reaction was diluted with ethyl acetate and washed with 10% KHSO4 or IN HCl (Ix), and saturated NaCl (Ix). The organic layer was dried over MgSO4, filtered, and the solvent was removed in vacuo to afford intermediate 2.4-(Allyloxy)-3-(trifluoromethyl)benzoic acid (2a)The title compound was prepared from <strong>[67515-55-3]4-fluoro-3-(trifluoromethyl)benzoic acid</strong> (Ia) in >99% (5.65 g) yield. HPLC retention time on a C8(2) column (30 x 3.00 mm, 3 mu) was 2.53 min with gradient 20-98% acetonitrile-H2O (0.1% TFA) in 4.0 min as mobile phase. 1H NMR (400 MHz, DMSOd6) delta 13.10 (br s, IH), 8.15 (dd, IH, J= 8.8 Hz, J= 2.4 Hz ), 8.08 (d, IH, J= 2.4 Hz), 7.35 (d, IH, J= 8.8 Hz), 5.95-6.80 (m, IH), 5.38-5.45 (m, IH), 5.26-5.32 (m, IH), 4.77-4.82 (m, 2H).
> 99%		General protocol for synthesis of substituted 4-(allyloxy)benzoic acid (2)To a solution of the desired alcohol (1.05 equiv) in anhydrous THF was added potassium t-butyloxide (2.05 equiv). The mixture was heated at 650C for 10 minutes then added substituted 4-fluorobenzoic acid (1) (1.00 equiv) in THF. The resultant solution was heated at 65 0C 1 to 3 hours. After cooling down to room temperature, the reaction was diluted with ethyl acetate and washed with 10% KHSO4 or IN HCl (Ix), and saturated NaCl (Ix). The organic layer was dried over MgSO4, filtered, and the solvent was removed in vacuo to afford intermediate 2.; 4-(Allyloxy)-3-(trifluoromethyl)benzoic acid (2a)The title compound was prepared from <strong>[67515-55-3]4-fluoro-3-(trifiuoromethyl)benzoic acid</strong>(Ia) in >99% (5.65 g) yield. HPLC retention time on a C8(2) column (30 x 3.00 mm, 3 mu) was 2.53 min with gradient 20-98% acetonitrile-H2O (0.1% TFA) in 4.0 min as mobile phase. 1H NMR (400 MHz, DMSO-d6) delta 13.10 (br S5 IH), 8.15 (dd, IH, J= 8.8 Hz, J= 2.4 Hz ), 8.08 (d, IH, J= 2.4 Hz), 7.35 (d, IH, J= 8.8 Hz)5 5.95-6.80 (m, IH), 5.38-5.45 (m, IH)1 5.26-5.32 (m, IH), 4.77-4.82 (m, 2H).

References: [1]Patent: WO2008/16674,2008,A1 .Location in patent: Page/Page column 82.
[2]Patent: WO2008/16692,2008,A2 .Location in patent: Page/Page column 94.

7
[ 67515-55-3 ]
[ 1005407-63-5 ]

Yield	Reaction Conditions	Operation in experiment
100%		Scheme 24-(Octyloxy)-3-(trifluoromethyl)benzoic acid (Ha)To a solution of 1-octanol (315 muL, 2.0 ?raiol) in anhydrous THF (5 mL) was added potassium ^-butoxide (5 mL, IM solution in THF). The mixture was heated at 70 0C for 15 min then cooled down to room temperature. 4-Fluoro-3- trifluoromethylbenzoid acid (10) (417 mg, 2.0 mmol) in THF (5 mL) was added and the resultant was heated at 75 0C overnight. After cooling down to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The water layer was acidified to a pH of approximately 3 with HCl (2M) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (632 mg, HPLC purity > 95%), which was used for next reaction without further purification. HPLC retention time on a C8(2) column (30 x 3.00 mm, 3 mu) was 3.28 min with gradient 50-98% acetonitrile-H2O (0.1% trifluoroacetic acid (TFA)) in 3.5 min as mobile phase.; Description 5 Alternative Method A (D5A) 4-(OctyIoxy)-3-(trifluoromethyl)benzoic acid (D5)A 12 L round bottom flask was inerted and charged with 1-octanol (103 g, 0.793 mol, 1 equiv), THF (2 L), 1 M potassium er-butoxide (2 L, 2.5 equiv) and heated to 65 0C and held for 45 minutes. The reaction was charged over 1 hour with 4-fluoro-3- trifluoromethyl benzoic acid (165 g, 0.793 mol) while maintaining the temperature at 64 to 67 0C. After 2 hours, the reaction mixture was sampled. The sample was concentrated, quenched into 1 N HCl, extracted with ethyl acetate, removed the ethyl acetate, diluted with acetonitrile and injected in to the HPLC. The reaction was complete. The reaction mixture was stirred overnight at 18 to 23 0C. The mixture was cooled to 5 to 10 0C and cautiously quenched with water (1.6 L). The quench was exothermic and the temperature was maintained at T<10 0C. The resulting mixture was concentrated under vacuum until no noticeable THF was coming off. The resulting aqueous mixture was acidified to pH 1 to 2 using 6 N HCl (400 mL). The mixture was extracted with MTBE (2 x 2.5 L). The MTBE phases were combined, washed with brine (2 L), dried with magnesium sulfate, filtered over Celite, concentrated to afford the title product (279 g, 111% yield, 95.6% AUC by HPLC) as a tan solid.

References: [1]Patent: WO2008/16692,2008,A2 .Location in patent: Page/Page column 79; 150.

8
[ 67515-55-3 ]
[ 18107-18-1 ]
[ 176694-36-3 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; diethyl ether; dichloromethane; at 0℃; for 0.333333h;	To a solution of <strong>[67515-55-3]4-fluoro-3-(trifluoromethyl)benzoic acid</strong> Ia (1.04 g, 5 mmol) in DCM/MeOH (4: 1, 10 mL) at 0 0C was added drop-wise a solution OfTMSCHN2 (2.0 M <n="119"/>in ether, 2.6 mL, 5.1 mmol). The reaction mixture was stirred at 00C until the colorless solution started to turn light yellow and maintained its light yellow color. The reaction was stirred for an additional 20 minutes then a few drops of acetic acid was added to quench the last few drops OfTMS-CHN2 (the solution turns colorless from light yellow). The solvent was removed in vacuo to give a crude product which was used directly for next step. MS (ESI, M-HH+) = 223.0
		A solution of <strong>[67515-55-3]4-fluoro-3-(trifluoromethyl)benzoic acid</strong> (260 mg, 1.25 mmol, 1 eq) in MeOH (0.5 ml_) and CH2CI2 (2 ml_) was treated with TMSCHN2 (2M in hexanes, 0.85 ml_, 1.70 mmol, 1.4 eq) dropwise with stirring at room temperature. After the reaction was stirred for 10 min, acetic acid was added until the yellow color disappeared. The mixture was concentrated to afford methyl 4-fluoro-3- (trifluoromethyl)benzoate, which was used in the next step without further purification.

References: [1]Patent: WO2008/16692,2008,A2 .Location in patent: Page/Page column 117-118.
[2]Patent: WO2009/140342,2009,A1 .Location in patent: Page/Page column 130.

9
[ 111-87-5 ]
[ 67515-55-3 ]
[ 1005407-63-5 ]

Yield	Reaction Conditions	Operation in experiment
96%		Description 14-(octyloxy)-3-(trifluoromethyl)benzoic acid (D1)A 1.5M solution of NaHM with THF (4.5 vol) and n- octanol (1.52 vol; 2eq) is charged and heated to 55-600C. A solution of 4-fluoro-3- (trifluoromethyl)benzoic acid (1 wt, 1eq) in THF (2 vol) is charged, washing through with further THF (1 vol). The reaction mixture is stirred at 57+/-3 0C until deemed <n="12"/>complete by HPLC (ca. 24h, <4% area <strong>[67515-55-3]4-fluoro-3-(trifluoromethyl)benzoic acid</strong> remaining). The reaction is then cooled to 20-250C and solvent swapped into water (10vol) by vacuum distillation (remove ca. 15vol distillate) to afford a tan slurry which is extracted into TBME (10vol). Water (10vol) is charged to the organic layer, and the product is extracted into the aqueous layer. The aqueous layer is washed with TBME (4 x 5vol), then acidified with 5N HCI (3 vol) and extracted into TBME (2x5vol). The combined organic extracts are washed with water (3x5vol) and 15% brine solution (4vol), then dried over magnesium sulphate (0.2 wt) and filtered, washing through with further TBME (2 vol). The volatiles are removed under vacuum to afford a tan solid of D1 (1.02 kg; 96%th.; 146% w/w).
	With potassium tert-butylate; In tetrahydrofuran; at 75℃; for 3 - 4h;Product distribution / selectivity;	1-octanol (315 muL, 2.0 mmol), THF (5 mL), potassium -butoxide (5 mL, IM solution in THF), 4-Fluoro-3-trifluoromethylbenzoic acid (417 mg, 2.0 mmol) were mixed and heated at 75 0C for 3-4hrs. The reaction mixture was then diluted with ethyl acetate and washed with water. The water layer was acidified and extracted with ethyl acetate. The <n="151"/>organic layer was washed with brine and dried OVCrNa2SO4 and concentrated to afford the title compound (632 mg, HPLC purity > 95%), which was used for next reaction without further purification. HPLC retention time on a C8(2) column (30 x 3.00 mm, 3 mu) was 3.28 min with gradient 50-98% acetonitrile-H2O (0.1% trifluoroacetic acid (TFA)) in 3.5 min as mobile phase.

References: [1]Patent: WO2009/98193,2009,A1 .Location in patent: Page/Page column 10-11.
[2]Organic process research and development,2011,vol. 15,p. 649 - 659.
[3]Patent: WO2008/16692,2008,A2 .Location in patent: Page/Page column 149-150.
[4]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 942 - 947.

10
[ 67515-55-3 ]
[ 100-51-6 ]
[ 536975-35-6 ]

Yield	Reaction Conditions	Operation in experiment
72%		4-Benzyloxy-3-trifluoromethyl-benzoic Acid (CAB03046) Sodium hydride (60%, 1.80 g, 45 mmol) was added to a solution of <strong>[67515-55-3]4-fluoro-3-trifluoromethyl benzoic acid</strong> (4.162 g, 20 mmol) and benzyl alcohol (3.25 g, 30 mmol) in DMSO (50 mL). The mixture was stirred overnight at room temperature, poured into water (50 mL) and acidified with concentrated hydrochloric acid. The white precipitate was filtered off, dissolved in ethyl acetate (ca. 50 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane. Yield: 4.252 g (72%). 1H-NMR (400 MHz, CDCl3) delta=5.37 (s, 2H), 7.32-7.48 (m, 6H), 8.12 (d, J=2.0 Hz, 1H), 8.18 (dd, J=8.6, 2.0 Hz, 1H), 13.16 (br s, 1H, -COOH). LRMS (FAB+): 91.1 (100), 297.1(18, [M+H]+).
		(93-1) Synthesis of 4-benzyloxy-3-trifluoromethylbenzoic acid (compound 93-1) To a solution of potassium t-butoxide (27.5 g) in N,N-dimethylformamide (120 ml) was added dropwise a solution of benzyl alcohol (15.9 ml) in N,N-dimethylformamide (60 ml) over 10 min. The mixture was stirred for 30 min, and a solution of <strong>[67515-55-3]4-fluoro-3-trifluoromethylbenzoic acid</strong> (20.0 g) in N,N-dimethylformamide (90 ml) was added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and further at 50C for 1 hr. The reaction mixture was added to ice water, and acidified with 1M hydrochloric acid (300 ml). The precipitated solid was collected by filtration, and washed with water and then hexane to give the object product (28.2 g) as a white powder. 1H-NMR(CDCl3) delta (ppm): 5.29(2H, s), 7.10(1H, d, J=8.7Hz), 7.33-7.37(1H, m), 7.39-7.45(4H, m), 8.22(1H, dd, J=2.0, 8.7Hz), 8.36(1H, d, J=2.0Hz).

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3540 - 3560.
[2]Patent: US2004/19016,2004,A1 .Location in patent: Page/Page column 62.
[3]Patent: EP2168944,2010,A1 .Location in patent: Page/Page column 177.

11
[ 67515-55-3 ]
[ 536975-36-7 ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3540 - 3560.

12
[ 67515-55-3 ]
[ 536975-37-8 ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3540 - 3560.

13
[ 67515-55-3 ]
[ 537683-42-4 ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3540 - 3560.

14
[ 67515-55-3 ]
4-[(4-Hydroxy-3-trifluoromethyl-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3540 - 3560.

15
[ 67515-55-3 ]
[ 220381-29-3 ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 528 - 542.

16
[ 67515-55-3 ]
[ 202822-73-9 ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 528 - 542.

17
[ 67515-55-3 ]
3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-(3H)-one [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 528 - 542.

18
[ 67515-55-3 ]
3-[(5-chloro-2-methoxyphenyl)methyl]-5-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-(3H)-one [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 528 - 542.

19
[ 67515-55-3 ]
3-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 528 - 542.

20
[ 67515-55-3 ]
[ 710287-62-0 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3112 - 3129.

21
[ 67515-55-3 ]
2-(4-fluoro-3-trifluoromethyl-phenyl)-5,6-dihydro-4<i>H</i>-[1,3]oxazine-4-carboxylic acid hydroxyamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3112 - 3129.

22
[ 67515-55-3 ]
[ 134099-29-9 ]