[ CAS No. 328-90-5 ] {[proInfo.proName]}

Name: 328-90-5|2-Hydroxy-4-(trifluoromethyl)benzoic acid|97%
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Quality Control of [ 328-90-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 328-90-5 ]

Product Details of [ 328-90-5 ]

CAS No. :	328-90-5	MDL No. :
Formula :	C₈H₅F₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XMLFPUBZFSJWCN-UHFFFAOYSA-N
M.W :	206.12	Pubchem ID :	164578
Synonyms :	Desacetyl triflusal	Chemical Name :	2-Hydroxy-4-(trifluoromethyl)benzoic acid

Calculated chemistry of [ 328-90-5 ]

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 :	2.0
Molar Refractivity :	40.43
TPSA :	57.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.07 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.32
Log Po/w (XLOGP3) :	3.51
Log Po/w (WLOGP) :	3.26
Log Po/w (MLOGP) :	2.06
Log Po/w (SILICOS-IT) :	1.79
Consensus Log Po/w :	2.39

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.51
Solubility :	0.0631 mg/ml ; 0.000306 mol/l
Class :	Soluble
Log S (Ali) :	-4.4
Solubility :	0.00817 mg/ml ; 0.0000397 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-2.09
Solubility :	1.68 mg/ml ; 0.00815 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.37

Safety of [ 328-90-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 328-90-5 ]

* 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 [ 328-90-5 ]
Downstream synthetic route of [ 328-90-5 ]

[ 328-90-5 ] Synthesis Path-Upstream 1~14

1
[ 455-24-3 ]
[ 328-90-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With oxygen; potassium acetate; p-benzoquinone In ISOPROPYLAMIDE at 115℃; for 15 h;	III. General procedure for Pd (II) -catalyzedorfcho-hydroxylation with 5 atm 0₂ :A 50 mL high pressure reactor equipped with a magnetic stir bar was charged with Pd(OAc)₂ (11.2 mg, 0.05 mmol), followed by the benzoic acidsubstrate (0.5 mmol), benzoquinone (54.0 mg, 0.5 mmol), KOAc (98.0 mg, 1 mmol) andN, N-dimethylacetamide (1.5 mL) . The reactor was filled with 0₂ (20 atm) , and then evacuated and backed-filled with 0₂ (5 atm, 2 times) . After the reaction mixture was stirred at 115 °C for 15 hours, it was permitted to cool to ambient temperature. The reaction was worked up and the crude product was purified following the procedure described above for hydroxylation with 1 atm O2.

Reference： [1] Journal of the American Chemical Society, 2009, vol. 131, # 41, p. 14654 - 14655
[2] Patent: WO2011/37929, 2011, A2, . Location in patent: Page/Page column 14; 19-20

2
[ 368422-29-1 ]
[ 328-90-5 ]

Reference： [1] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915

3
[ 322-79-2 ]
[ 71-50-1 ]
[ 328-90-5 ]

Reference： [1] Journal of Molecular Liquids, 2015, vol. 206, p. 321 - 327

4
[ 402-45-9 ]
[ 328-90-5 ]

Reference： [1] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915

5
[ 98-17-9 ]
[ 328-90-5 ]

Reference： [1] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915

6
[ 174265-24-8 ]
[ 328-90-5 ]

Reference： [1] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915

7
[ 334018-79-0 ]
[ 328-90-5 ]

Reference： [1] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915

8
[ 322-79-2 ]
[ 328-90-5 ]

Reference： [1] Combinatorial Chemistry and High Throughput Screening, 2010, vol. 13, # 7, p. 569 - 577

9
[ 779-88-4 ]
[ 328-90-5 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1964, vol. 34, p. 3427 - 3430[2] Zhurnal Obshchei Khimii, 1964, vol. 34, p. 3385 - 3389

10
[ 328-93-8 ]
[ 328-90-5 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1964, vol. 34, p. 3427 - 3430[2] Zhurnal Obshchei Khimii, 1964, vol. 34, p. 3385 - 3389

11
[ 124-38-9 ]
[ 98-17-9 ]
[ 328-90-5 ]

Reference：

12
[ 328-90-5 ]
[ 108-24-7 ]
[ 322-79-2 ]

Reference：

13
[ 328-90-5 ]
[ 917-54-4 ]
[ 228572-69-8 ]

Reference： [1] Organic Letters, 2016, vol. 18, # 15, p. 3766 - 3769
[2] Patent: US2008/287428, 2008, A1, . Location in patent: Page/Page column 73
[3] Patent: EP2128157, 2009, A1, . Location in patent: Page/Page column 107
[4] Patent: WO2010/45401, 2010, A1, . Location in patent: Page/Page column 57-58
[5] Patent: WO2010/45402, 2010, A1, . Location in patent: Page/Page column 55-56
[6] Patent: EP1908753, 2008, A1, . Location in patent: Page/Page column 111
[7] Patent: US2013/158067, 2013, A1, . Location in patent: Paragraph 0323

14
[ 328-90-5 ]
[ 58914-34-4 ]

Reference： [1] Patent: WO2014/111457, 2014, A1,

[ 328-90-5 ] Synthesis Path-Downstream 1~88

1
[ 16278-29-8 ]
[ 328-90-5 ]
[ 579-81-7 ]

Reference： [1]Journal of the American Chemical Society,1955,vol. 77,p. 2284,2285

2
[ 328-90-5 ]
[ 636-94-2 ]

Reference： [1]Journal of the American Chemical Society,1954,vol. 76,p. 1051,1054
[2]Photochemistry and Photobiology,2001,vol. 73,p. 463 - 468

3
[ 328-90-5 ]
[ 349-66-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 18h;	To a solution of 600 mg (2.91 mmol) of 2-hydroxy-4-trifluoromethyl-benzoic acid in THF (3 ml) were added dropwise 5.82 ml of a 1 molar solution of BH3-THF complex in THF at 0 C. After the reaction mixture was stirred for 18 h at RT, water was added to destroy excess reducing agent. Then 15 ml of 2N NaOH-solution were added and the mixture was stirred for 30 min. Then ether (10 ml) was added and the aqueous phase was separated. The volatile solvents of the organic phase were removed and the remaining residue was combined with the aqueous phase. The pH of the aqueous phase was then carefully adjusted to 6-7 by addition of dilute acetic acid at 0 C. and the mixture was extracted with ether. The combined extracts were then dried (MgSO4) and concentrated to yield 649 mg (93%) of crude 2-hydroxymethyl-5-trifluoromethyl-phenol (purity 80%) as a light yellow oil. MS (ISP) 191.2 (M-H)-.To a solution of 649 mg of 2-hydroxymethyl-5-trifluoromethyl-phenol (obtained in step a) were added 2 g of manganese dioxide and the mixture was stirred at RT for 16 h. After filtration, the filtrate was concentrated and purified by column chromatography (silica gel; cyclohexane/ethyl acetate 4:1). 2-Hydroxy-4-trifluoromethyl-benzaldehyde was isolated as a light yellow solid (292 mg, 57%). MS (ISP) 189.2 (M-H)-.In analogy to example S6 (steps a to c) 220 mg (1.16 mmol) 2-hydroxy-4-trifluoromethyl-benzaldehyde were converted into 275 mg of [2-(3,4-dichloro-phenyl)-ethyl]-(6-trifluoromethyl-benzofuran-2-ylmethyl)-amine. The compound was obtained as a dark brown oil. MS (ISP) 388.2 (M+H)+.
	With sodium tetrahydroborate; Trimethyl borate; dimethyl sulfate; In tetrahydrofuran; at 20℃; for 0.5h;	Sodium borohydride (3.83 g, 101.31 mmol) and THF (97 mL) were mixed and added dropwise to dimethylsulfate (9.3 mL, 98.08 mmol) at 0C and stirred first for 1 h at this temperature and 4 h at rt until no gas generation was observed. A solution of 4- trifluoromethyl salicylic acid (10 g, 48.52 mmol) and trimethylborate (11.0 mL, 98.98 mmol) in THF (49 mL) was added dropwise to the rm at rt over 30 min. The mixture was stirred at the same temperature for 4.5 h. After the reaction was completed, H20 was added slowly at 0C and the resulting mixture was vigorously stirred for 30 min. Then THF was removed on a rotary evaporator. The residue was extracted with EtOAc (x3) and the combined organic layer was washed with sat. aq. NaHCC sol. (x3) and brine (x3). The organic layer was then dried over Na2S04, filtered, and concentrated in vacuo to give intermediate 137 as a crude, which was used as such in the next reaction (10.12 g, quantitative yield).
		Preparation 12-(HYDROXYMETHYL)-5-(TRIFLUOROMETHYL)PHENOLTo a solution of 2-hydroxy-4-(thfluoromethyl)benzoic acid (5.0 g, 24.3 mmol) in dry DEE (150 ml), under nitrogen atmosphere, lithium aluminium hydride (1.11 g, 29.2 mmol) was added in portions. The reaction mixture was stirred for 12h at ambient25 temperature and then quenched with water and NaOH (5 M). Aqueous HCI (10%) was added and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (isooctane/ EtOAc 1 : 1 ) to give the title compound (2.55 g). MS m/z (rel. intensity, 70 eV) 192 (M+, 32), 174 (45), 146 (bp),30 145 (62), 96 (54).

With sodium tetrahydroborate; Trimethyl borate; dimethyl sulfate; In tetrahydrofuran; at 20℃; for 5h;

Sodium borohydride (3.83 g, 101.31 mmol) and THF (97 mL) were mixed and added dropwise to dimethylsulfate (9.3 mL, 98.08 mmol) at 0 C. and stirred first for 1 h at this temperature and 4 h at rt until no gas generation was observed. A solution of 4-trifluoromethyl salicylic acid (10 g, 48.52 mmol) and trimethylborate (11.0 mL, 98.98 mmol) in THF (49 mL) was added dropwise to the rm at rt over 30 min. The mixture was stirred at the same temperature for 4.5 h. After the reaction was completed, H2O was added slowly at 0 C. and the resulting mixture was vigorously stirred for 30 min. Then THF was removed on a rotary evaporator. The residue was extracted with EtOAc (×3) and the combined organic layer was washed with sat. aq. NaHCO3 sol. (×3) and brine (×3). The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo to give intermediate 137 as a crude, which was used as such in the next reaction (10.12 g, quantitative yield).

Reference： [1]Patent: US2007/185113,2007,A1 .Location in patent: Page/Page column 13
[2]Journal of the American Chemical Society,1954,vol. 76,p. 4476
[3]Patent: WO2014/111457,2014,A1 .Location in patent: Page/Page column 102
[4]Patent: WO2009/133110,2009,A1 .Location in patent: Page/Page column 37
[5]Patent: US2018/319797,2018,A1 .Location in patent: Paragraph 0817-0818
[6]Organic Letters,2019,vol. 21,p. 7258 - 7261

4
[ 779-88-4 ]
[ 328-90-5 ]

Reference： [1]Journal of general chemistry of the USSR,1964,vol. 34,p. 3427 - 3430
Zhurnal Obshchei Khimii,1964,vol. 34,p. 3385 - 3389

5
[ 328-90-5 ]
[ 74-88-4 ]
[ 286441-66-5 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6569 - 6584

6
[ 328-90-5 ]
[ 917-54-4 ]
[ 228572-69-8 ]

Yield	Reaction Conditions	Operation in experiment
75.8%	In tetrahydrofuran; at 20℃; for 4h;	2-Hydroxy-4-(trifluoromethyl)benzoic acid (1.0 g, 4.85 mmol) was dissolved in THF (10 mL), and 1.6 M (10 mL) of methyl lithium was added dropwise at room temperature. Stir under 4 hours.Then quench with distilled water and adjust to pH=7 with dilute HClIt was extracted with ethyl acetate (3 x 50 mL).The collected organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure.Purification by column chromatography (petroleum ether) gave the corresponding product of 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone (750 mg, 75.8%).
		Methyllithium (1.0 M diethyl ether solution, 98.0 mL) was added to a tetrahydrofuran (60.0 mL) solution of <strong>[328-90-5]4-trifluoromethylsalicylic acid</strong> (6.0 g) under ice cooling, and the reaction mixture was stirred at room temperature for two hours. Trimethylsilyl chloride (37.0 mL) and 1 N hydrochloric acid (100 mL) were added to the reaction mixture under ice cooling. The reaction mixture was extracted with ethyl acetate. 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 residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 95:5). The title compound (5.86 g) was obtained as pale yellow oil.
		<Step 1> Synthesis of 2-hydroxy-4-trifluoromethylacetophenone Methyllithium (1.0 M diethyl ether solution, 98.0 mL) was added to a tetrahydrofuran (60.0 mL) solution of <strong>[328-90-5]4-trifluoromethylsalicylic acid</strong> (6.0 g) under ice cooling, and the reaction solution was stirred at room temperature for two hours. Trimethylsilyl chloride (37.0 mL) and 1 N hydrochloric acid (100 mL) were added to the reaction solution under ice cooling. The reaction solution was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elude; n-hexane:ethyl acetate = 100:0 to 95:5). The title compound (5.86 g) was obtained as pale yellow oil.

		A solution of <strong>[328-90-5]2-hydroxy-4-(trifluoromethyl)benzoic acid</strong> (10.0 g, 48.5 mmol) andTHF (100 mL) was cooled to <5 0C (internal temperature) and methyllithium (95 mL of a 1.6M solution in Et2O, 152 mmol) was added, keeping the internal temperature <20 0C (slow addition, methane generation). Following methyllithium addition, the solution was warmed to ambient temperature and stirred for 1 h. The solution was then re-cooled to 10 0C and treated carefully with EtOAc (100 mL) and 2N HCl (100 mL). The reaction mixture was further diluted with EtOAc (100 mL) then washed with water (100 mL) and brine (20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give l-(2-hydroxy-4- (trifluoromethyl)phenyl)ethanone (10.3 g) which was used without further purification. The crude l-[2-hydroxy-4-(trifluoromethyl)phenyl]ethanone (9.90 g, 48.5 mmol) from above was dissolved in methanol (100 mL) and acetone (3.56 mL, 48.5 mmol), and pyrrolidine (8.02 mL, 97.0 mmol) were added. The reaction was stirred at ambient temperature for 14 h; LCMS showed reaction completion. The reaction mixture was concentrated and diluted with EtOAc (300 mL), then washed with water (100 mL), 2N HCl (2 x 100 niL), water (50 niL), 2N NaOH (2 x 100 mL), water (50 mL), and brine (20 niL). The organic portion was dried (Na2SO4), filtered, concentrated, and the residue purified by silica gel chromatography (gradient elution, 0-20% EtOAc/hexanes) to give the title compound (8.93 g, 36.6 mmol, 75%) as a white solid. MS (ESI) m/z 245 (M+H)+.
		A solution of <strong>[328-90-5]2-hydroxy-4-(trifluoromethyl)benzoic acid</strong> (10.0 g, 48.5 mmol) andTHF (100 mL) was cooled to <5 0C (internal temperature) and methyllithium (95 mL of a 1.6M solution in Et2O, 152 mmol) was added, keeping the internal temperature <20 0C (slow addition, methane generation). Following methyllithium addition, the solution was warmed to ambient temperature and stirred for 1 h. The solution was then re-cooled to 10 0C and treated carefully with EtOAc (100 mL) and 2N HCl (100 mL). The reaction mixture was further diluted with EtOAc (100 mL) then washed with water (100 mL) and brine (20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give l-(2-hydroxy-4- (trifluoromethyl)phenyl)ethanone (10.3 g) which was used without further purification. The crude l-[2-hydroxy-4-(trifluoromethyl)phenyl]ethanone (9.90 g, 48.5 mmol) from above was dissolved in methanol (100 mL) and acetone (3.56 mL, 48.5 mmol), and pyrrolidine (8.02 mL, 97.0 mmol) were added. The reaction was stirred at ambient temperature for 14 h; LCMS showed reaction completion. The reaction mixture was concentrated and diluted with EtOAc (300 mL), then washed with water (100 mL), 2N HCl (2 x 100 niL), water (50 niL), 2N NaOH (2 x 100 mL), water (50 mL), and brine (20 niL). The organic portion was dried (Na2SO4), filtered, concentrated, and the residue purified by silica gel chromatography (gradient elution, 0-20% EtOAc/hexanes) to give the title compound (8.93 g, 36.6 mmol, 75%) as a white solid. MS (ESI) m/z 245 (M+H)+.
		Methyllithium (1.0 M diethyl ether solution, 98.0 mL) was added to a tetrahydrofuran (60.0 mL) solution of <strong>[328-90-5]4-trifluoromethylsalicylic acid</strong> (6.0 g) under ice cooling, and the reaction mixture was stirred at room temperature for two hours. Trimethylsilyl chloride (37.0 mL) and 1 N hydrochloric acid (100 mL) were added to the reaction mixture under ice cooling. The reaction mixture was extracted with ethyl acetate. 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 residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate = 100:0 to 95:5). The title compound (5.86 g) was obtained as pale yellow oil.
	In tetrahydrofuran; diethyl ether; at 5 - 20℃; for 1h;	A solution of <strong>[328-90-5]2-hydroxy-4-(trifluoromethyl)benzoic acid</strong> (10.0 g, 48.5 mmol) and THF (100 mL) was cooled to <5 C. and methyllithium (95 mL, 1.6M solution in diethyl ether, 152 mmol) was slowly added, keeping the internal temperature <20 C. The resulting solution was warmed to ambient temperature and stirred for 1 hour. The solution was then cooled to 10 C. and treated carefully with EtOAc (100 mL) and 2N HCl (100 mL). The reaction mixture was further diluted with EtOAc (100 mL) then washed with water (100 mL) and brine (20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (10.3 g). This material was used without further purification in the next step.

Reference： [1]Organic Letters,2016,vol. 18,p. 3766 - 3769
[2]Patent: CN110049973,2019,A .Location in patent: Paragraph 0106-0108; 0121-0123
[3]Advanced Synthesis and Catalysis,2019,vol. 361,p. 4448 - 4453
[4]Patent: US2008/287428,2008,A1 .Location in patent: Page/Page column 73
[5]Patent: EP2128157,2009,A1 .Location in patent: Page/Page column 107
[6]Patent: WO2010/45401,2010,A1 .Location in patent: Page/Page column 57-58
[7]Patent: WO2010/45402,2010,A1 .Location in patent: Page/Page column 55-56
[8]Patent: EP1908753,2008,A1 .Location in patent: Page/Page column 111
[9]Patent: US2013/158067,2013,A1 .Location in patent: Paragraph 0323

7
[ 328-90-5 ]
<i>N</i>-(4-bromo-2-fluoro-benzyl)-2-hydroxy-4-trifluoromethyl-benzamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5661 - 5675

8
[ 328-90-5 ]
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-trifluoromethyl-phenoxy]-acetic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5661 - 5675

9
[ 328-90-5 ]
[2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-trifluoromethyl-phenoxy]-acetic acid ethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5661 - 5675

10
[ 402-45-9 ]
[ 328-90-5 ]

Reference： [1]European Journal of Organic Chemistry,2001,p. 2911 - 2915

11
[ 98-17-9 ]
[ 328-90-5 ]

Reference： [1]European Journal of Organic Chemistry,2001,p. 2911 - 2915

12
[ 174265-24-8 ]
[ 328-90-5 ]

Reference： [1]European Journal of Organic Chemistry,2001,p. 2911 - 2915

13
[ 334018-79-0 ]
[ 328-90-5 ]

Reference： [1]European Journal of Organic Chemistry,2001,p. 2911 - 2915

14
[ 328-90-5 ]
[ 393-46-4 ]

Reference： [1]Journal of the American Chemical Society,1955,vol. 77,p. 2284,2285

15
[ 328-93-8 ]
[ 328-90-5 ]

Reference： [1]Journal of general chemistry of the USSR,1964,vol. 34,p. 3427 - 3430
Zhurnal Obshchei Khimii,1964,vol. 34,p. 3385 - 3389

16
[ 67-56-1 ]
[ 328-90-5 ]
[ 345-28-8 ]

Yield	Reaction Conditions	Operation in experiment
89.1%	With chloro-trimethyl-silane; In toluene; for 12h;Reflux;	(4-1) Preparation of <strong>[328-90-5]2-hydroxy-4-trifluoromethylbenzoic acid</strong> methylester By refluxing <strong>[328-90-5]2-hydroxy-4-trifluoromethylbenzoic acid</strong> and trimethylsilyl chloride (TMSCI) in a toluene solvent for 12 hours, <strong>[328-90-5]2-hydroxy-4-trifluoromethylbenzoic acid</strong> methylester was prepared. Yield: 89.1% Red liquid 1H-NMR (400 MHz, CDCl3) delta 10.88(bs, 1H), 7.95(d, J=8.3 Hz, 1H), 7.25(s, 1H), 7.12(dd, J=8.3, 1.1 Hz, 1H), 3.99(s, 3H)
73%	With hydrogenchloride; sulfuric acid; In water; at 80℃;	2-Hydroxy-4-(trifluoromethyl)benzoic acid (5.0 g, 24.26 mmol), hydrochloric acid (0.2 mL, 2.40 mmol), sulfuric acid (1.5 mL, 28.1 mmol) and methanol (40 mL) were mixed together and the reaction mixture was stirred at 8O0C over night. The mixture was concentrated and reloaded, stirred at 1000C overnight. More H2SO4 was added (heated to 1000C overnight). The mixture was concentrated and ether was added. The organic layer was washed with water twice, saturated solution of bicarbonate then brine, dried over Na2SO4, <n="122"/>filtered and concentrated. The residue was dissolved in 20 ml Et2O and filtered (to remove starting material) and the filtrate was evaporated to afford title compound 58 (3.9 g, 73%) as a clear oil.
73%	With hydrogenchloride; sulfuric acid; at 80 - 100℃;	2-Hydroxy-4-(trifluoromethyl)benzoic acid (5.0 g, 24.26 mmol), hydrochloric acid (0.2 mL, 2.40 mmol), sulfuric acid (1.5 mL, 28.1 mmol) and methanol (40 mL) were mixed together and the reaction mixture was stirred at 80 C. over night. The mixture was concentrated and reloaded, stirred at 100 C. overnight. More H2SO4 was added (heated to 100 C. overnight). The mixture was concentrated and ether was added. The organic layer was washed with water twice, saturated solution of bicarbonate then brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in 20 ml Et2O and filtered (to remove starting material) and the filtrate was evaporated to afford title compound 58 (3.9 g, 73%) as a clear oil.

73%	With hydrogenchloride; sulfuric acid; at 80℃;	2-Hydroxy-4-(trifluoromethyl)benzoic acid (5.0 g, 24.26 mmol), hydrochloric acid (0.2 mL, 2.40 mmol), sulfuric acid (1.5 mL, 28.1 mmol) and methanol (40 mL) were mixed together and the reaction mixture was stirred at 8O0C over night. The mixture was concentrated and reloaded, stirred at 1000C overnight. More H2SO4 was added (heated to 1000C overnight). The mixture was concentrated and ether was added. The organic layer was washed with water twice, saturated solution of bicarbonate then brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in 20 ml Et2O and filtered (to remove starting material) and the filtrate was evaporated to afford title compound 58 (3.9 g, 73%) as a clear oil.
	With sulfuric acid; for 12h;Heating / reflux;	EXAMPLES(Preparation Example 1) 7-Trifluoromethyl-10H-benzo[4,5]furo[3,2-b] indole-1-carboxylic acid (compound 8)2-Carboxymethoxy-4-trifluoromethyl-benzoic acid (product 5a) : An agitated mixture of methanol (80ml), concentrated sulfuric acid (6.7ml), 2-hydroxy-4-trifluoromethyl-benzoic acid (31.2g) was heated at reflux for 12 hrs. After cooling to room temperature, the mixture was worked-up with sodium bicarbonate and ethyl acetate.2-Hydroxy-4~trifluoromethyl-benzoic acid methyl ester from ethyl acetate layer was purified by chromatography (Hexane:EA = 10:1).
	With thionyl chloride; at 0℃; for 8h;Heating / reflux;	Thionyl chloride (11 mL) was added dropwise to methanol (200 mL) under ice cooling. After the dropwise addition, 4-trifluoromethyl-2-hydroxy-benzoic acid (10 g) was added to the solution, and the reaction mixture was then refluxed for eight hours. The solution was cooled to room temperature. The reaction solvent was distilled off under reduced pressure, and the solution was then 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 residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=20:1). The title compound (9.4 g) was obtained as a colorless liquid.
		Thionyl chloride (11 mL) was added dropwise to methanol (200 mL) under ice cooling. After the dropwise addition, 4-trifluoromethyl-2-hydroxy-benzoic acid (10 g) was added to the solution, and the reaction mixture was then refluxed for eight hours. The solution was cooled to room temperature. The reaction solvent was distilled off under reduced pressure, and the solution was then 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 residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate = 20:1). The title compound (9.4 g) was obtained as a colorless liquid.
	With chloride derivative; at 0℃;Reflux;	General procedure: II, IV, and VIII: Thionyl chloride was added dropwise toa solution of benzoic acid derivative (I, III, and VII) in anhydrousmethyl alcohol at 0C. After this addition, the mixture was stirred atreflux for 8?12 hours. The reaction mixture was basified with 10%sodium bicarbonate, and ethyl acetate was added. The organic layerwas dried over anhydrous MgSO4, filtered, and the solvent wasevaporated to give the products II, IV, and VIII.

Reference： [1]Patent: US2015/148550,2015,A1 .Location in patent: Paragraph 0298; 0299; 0300; 0301; 0302
[2]Patent: WO2008/55068,2008,A2 .Location in patent: Page/Page column 120-121
[3]Patent: US2017/749,2017,A1 .Location in patent: Paragraph 0456
[4]Patent: WO2009/137499,2009,A1 .Location in patent: Page/Page column 81
[5]Patent: WO2006/96030,2006,A1 .Location in patent: Page/Page column 11
[6]Patent: US2008/287428,2008,A1 .Location in patent: Page/Page column 54
[7]Journal of the American Chemical Society,2010,vol. 132,p. 3664 - 3665
[8]Patent: EP1908753,2008,A1 .Location in patent: Page/Page column 79
[9]Molecular Pharmacology,2013,vol. 84,p. 726 - 735

17
[ 328-90-5 ]
[ 92-67-1 ]
[ 7719-12-2 ]
[ 220340-69-2 ]

Yield	Reaction Conditions	Operation in experiment
	In chlorobenzene;	EXAMPLE 2 5-Trifluoromethyl-4'-phenylsalicylanilide Phosphorous trichloride (0.70g, 5.1 mmol) was added to a mixture of <strong>[328-90-5]4-trifluoromethylsalicylic acid</strong> and 4-aminobiphenyl in 30 ml of chlorobenzene. The mixture was refluxed for 3.5 hr and a solid collected by filtration of the hot mixture. A second crop was obtained by filtering the cold filtrate. This was triturated with CH2Cl2 and the solid collected by filtration and washed with fresh CH2Cl2. Elemental analysis (C,H,N) was correct for C20H14F3NO2.1/2H2O.

Reference： [1]Patent: US6255298,2001,B1

18
[ 328-90-5 ]
[ 75-03-6 ]
[ 939983-42-3 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium carbonate; In ethanol; for 4h;Heating / reflux;	EXAMPLE 121 rac-(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole To a solution of 2-hydroxy-4-trifluoromethyl-benzoic acid (5 g, 24.258 mmol, Matrix Scientific) in ethanol (50 mL) were added potassium carbonate (8.38 g, 60.645 mmol) and ethyl iodide (7.68 mL, 97.032 mmol). The reaction mixture was heated at gentle reflux for 4 h then concentrated in vacuo. The residue was taken in petroleum ether and water, and the layers were separated. The product was extracted with petroleum ether (1). The organic layers were washed with brine (1), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the crude residue by flash chromatography (40 g of silica gel, eluding with 10% ethyl acetate in hexane) gave 2-ethoxy-4-trifluoromethyl-benzoic acid ethyl ester as colorless oil (4.68 g, 74%).
	With potassium carbonate; In N,N-dimethyl-formamide;	2-Hydroxy-4-trifluoromethyl-benzoic acid (1.20 g, 5.82 mmol) was reacted with ethyliodide (2.2 eq) and K2CO3 (1.69 g) in DMF solution. The reaction mixture was quenched by adding H2O. The mixture was extracted with ethyl acetate (40 ml x 3). A combined organic layer was washed sat NaHCO3 solution (30 ml), H2O (40 ml x 5), and brine, and then dried over MgSO4. The filterate was concentrated in vacuo to yield 2-ethoxy-4-trifluoromethyl benzoic acid ethyl ester. The ester obtained above was reacted with 1 N LiOH (15 ml) in THF and CH3OH cosolvent for 2 hrs as described above to yield title compound(1.2O g, 88%).1H NMR (300MHz, CDCl3): delta 8.32 (d, IH, J = 8.1 Hz), 7.40 (d, IH, J = 8.1 Hz), 7.26 (s, IH), 4.40 (q, 2H, J = 6.9 Hz), 1.62 (t, 3H, J = 6.9 Hz)

Reference： [1]Patent: US2007/129416,2007,A1 .Location in patent: Page/Page column 49/2
[2]Patent: WO2009/96701,2009,A2 .Location in patent: Page/Page column 37-38

19
[ 328-90-5 ]
[ 112921-00-3 ]
C₂₁H₂₁F₃N₆O₈S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 6080 - 6094

20
[ 328-90-5 ]
[ 6638-79-5 ]
[ 925922-75-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;	Reference Example 112 2-hydroxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide WSCD (4.63 g, 24.26 mmol) was added to a solution of 4-(trifluoromethyl) salicylic acid (5.0 g, 24.26 mmol), N,O-dimethylhydroxylamine hydrochloride (2.37 g, 24.26 mmol), HOBt (3.28 g, 24.26 mmol) and diisopropylethylamine (3.14 g, 24.26 mmol) in DMF (50 mL) with ice-cooling, and stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluding solution: ethyl acetate = 1/3) to give the title compound (4.72 g, 78%) as a white crystal. 1H-NMR (300MHz, CDCl3) delta: 3.43 (3H, s), 3.65 (3H, s), 7.08 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 5.4 Hz), 8.09 (1H, d, J = 8.4 Hz), 11.29 (1H, s). Melting point: 69-70C

Reference： [1]Patent: EP1921066,2008,A1 .Location in patent: Page/Page column 73

21
[ 328-90-5 ]
[ 402-15-3 ]

Yield	Reaction Conditions	Operation in experiment
		Thionyl chloride (2.7 mL) and N,N-dimethylformamide (0.1 mL) were added to a toluene (50.0 mL) solution of <strong>[328-90-5]4-trifluoromethylsalicylic acid</strong> (5.0 g), and the reaction mixture was refluxed for 30 minutes. The reaction mixture was left to cool. The reaction mixture was then added dropwise to aqueous ammonia (50.0 mL) under ice cooling, and the reaction mixture was stirred at the same temperature for 10 minutes. The pH of the reaction mixture was adjusted to 3 with concentrated hydrochloric acid, and the reaction mixture was then extracted with ethyl acetate. 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 residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 50:50). The title compound (1.84 g) was obtained as pale beige crystals.

Reference： [1]Patent: US2008/287428,2008,A1 .Location in patent: Page/Page column 72

22
[ 513-48-4 ]
[ 328-90-5 ]
C₁₆H₂₁F₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 48h;	A mixture of 2-hydroxy-4-trifluoromethyl-benzoic acid (300 mg, 1.45 mmol) in DMF was added potassium carbonate (442 mg, 3.20 mmol) followed by 2-iodobutane (589 mg, 3.2 mmol). The mixture was stirred for 48 hours at 110 0C and then diluted with EtOAc. The organic layer was washed with IN HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (2 ml) and then added a solution of 0.5 N-LiOH (2 eq). The mixture was stirred for 2 hours at room temperature and then diluted with EtOAc. The organic layer was washed with IN HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue and N,O- dimethylhydroxylamine hydrochloride (316 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added N-methylmorpholine (0.176 ml, 0.160 mmol). The mixture was stirred for 5 minutes, to which were added N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (316 mg, 0.160 mmol). The mixture was stirred for 2 hours at room temperature and then diluted with EtOAc. The organic layer was washed with IN HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography to give the title compound. (374 mg, 84 %). 1H NMR(300MHz5 CDCl3): delta 7.23 - 7.19 (m, 2H), 7.09 (s, IH), 4.40 - 4.37 (m, IH), 3.42 (s, 3H), 3.34 (s, 3H), 1.77 - 1.67 (m, 2H), 1.30 (d, 3H, J= 3.0 Hz), 0.97 (t, 3H, J= 7.2 Hz).

Reference： [1]Patent: WO2009/96701,2009,A2 .Location in patent: Page/Page column 70-71

23
[ 328-90-5 ]
[ 106-94-5 ]
[ 1175134-10-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃;	2-Hydroxy-4-trifluoromethyl-benzoic acid (673 mg, 3.26 mmol) was reacted with propylbromide (0.85 ml) and K2CO3 (1.42 g) in DMF (15 ml) at 65 0C overnight. The reaction mixture was quenched by adding 10 ml Of H2O. The mixture was extracted with ethylacetate (30 ml x 3). A combined organic layer <n="34"/>was washed with H2O (50 ml x 6) and brine (50 ml), and dried over MgSO4. The filterate was concentrated in vacuo to yield title compound (908 mg, 99%).1H NMR (300MHz, CDCl3): delta 7.83 (d, IH, J = 8.1 Hz), 7.21 (d, IH, J = S.I Hz),7.15 (s, IH), 4.28 (t, 2H, J = 6.9 Hz), 4.03 (t, 2H, J = 63 Hz), 1.88 (m, 2H), 1.82 (m, 2H), 1.07 (m, 6H)

Reference： [1]Patent: WO2009/96701,2009,A2 .Location in patent: Page/Page column 32-33

24
[ 328-90-5 ]
[ 75-26-3 ]
[ 1175134-27-6 ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 48h;	A mixture of 2-hydroxy-4-trifluoromethyl-benzoic acid (500 mg, 2.42 mmol) in DMF (5 mL) was added potassium carbonate (837 mg, 6.06 mmol) and 2-bromopropane (906 mg, 5.33 mmol). The resulting mixture was stirred for 48 hours at 110 C . The reaction mixture was diluted with EtOAc, which was washed with IN HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography^ex/EtOAc^S/l) to give the title compound (200 mg, 28 %). 1H NMR(300MHz, CDCl3): delta 7.73 (d, IH, J = 8.1 Hz), 7.19 (d, IH, J = 8.4 Hz), 7.15 (s, IH), 5.31 - 5.29 (m, IH), 4.68 - 4.60 (m, IH), 1.40 (d, 6H, J= 6.9 Hz), 1.36 (d, 6H, J = 6.6 Hz).

Reference： [1]Patent: WO2009/96701,2009,A2 .Location in patent: Page/Page column 54-55

25
[ 19982-08-2 ]
[ 328-90-5 ]
[ 1185878-11-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	In methanol; at 20℃;	Example 5: Preparation of Memantine-HTB salt. To an assay tube containing 1,3-dimethyl-5-aminoadamantane (100 mg, 0.56 mmol) diluted with methanol (0.4 mL) was added at room temperature Triflusal (138 mg, 0.56 mmol, 1 eq.) resulting in complete dissolution (exothermic reaction). The solvent was evaporated slowly without stirring at room temperature or at 0 C under atmospheric pressure. After complete evaporation, the salt Memantine - HTB 1:1 was obtained as colorless needles (238 mg, quantitative yield). Good quality single crystals were obtained as shown in Fig. 18). The product has been fully characterized by 1HNMR, FTIR, X-Ray diffraction, and melting point (see figures 13 to 17).FT-IR spectrum (see Fig. 13) The FTIR spectra of the crystalline form of Memantine-HTB salt are shown measured as described in Example 7. FTIR spectra were recorded using a Thermo Nicolet Nexus 870 FT-IR, equipped with a beamsplitter KBr system, a 35mW He-Ne laser as the excitation source and a DTGS KBr detector. The spectra were acquired in 32 scans at a resolution of 4 cm-1. The sample (KBr pellets) shows a Fourier Transform Infra Red spectrum with absorption bands at 3178 (w, br), 2948.9 (m), 2919.2 (m), 2848.8 (m), 1592.5 (s), 1501.2 (m), 1453.7 (m), 1438.1 (s), 1389 (s), 1240 (s), 1175.2 (s), 1152 (m), 1122.4 (s), 921.3 (m) cm-1 (see figure 13).1H-NMR spectrum (see Fig. 14) Proton nuclear magnetic resonance analyses were recorded in deuterated chloroform (CDCl3) in a Varian Mercury 400 spectrometer, equipped with a broadband probe ATB 1H/19F/X of 5 mm. Spectra were acquired dissolving 5-10 mg of sample in 0.6 mL of deuterated solvent. 1H NMR spectrum (see figure 14) in D-chloroform at 400 MHz shows peaks at 7.92 (d, J = 8.2 Hz, 1 H) ; 7.22 (s, 1H); 7.07 (d, J = 8.2Hz, 1 H) ; 2.19-2.12 (m, 1 H) ; 1.66 (s, 2H) ; 1.47 (d, J = 11.5 Hz, 2H ; 1.40 (d, J = 11.5 Hz, 2H ) ; 1.29 (d, J = 12.6 Hz, 2H) ; 1.19 (d, J = 12.6 Hz, 2H) ; 1.13 (d, J = 12.7 Hz, 1 H) ; 0.95 (d, J = 12.7 Hz, 1 H) ; 0.78 (s, 6H).DSC analysis (see Fig. 15) DSC analyses were recorded with a Mettler DSC822e. A sample of 3.5690 mg was weighed into 40 muL aluminium crucible with a pinhole lid and was heated, under nitrogen (50 mL/min), at 10C/min from 30 to 300 C. The novel type of crystal of the present invention is characterized in that the endothermic sharp peak corresponding to the melting point has an onset at 205.73 C (fusion enthalpy - 67.1 J/g), measured by DSC analysis (10 C/min) (see figure 15).TG analysis (see Fig. 16) Thermogravimetric analyses were recorded in a thermogravimetric analyzer Mettler TGA/SDTA851e. A sample of 8.6156 mg was weighed into a 70 muL alumina crucible with a pinhole lid and was heated at 10 C/min from 30 to 300 C, under nitrogen (50 mL/min). The TG analysis of the crystalline form according to the invention shows 3.94% weight loss between 30 and 200 C corresponding to the presence of impurities derived from the preparation method (no purification) (see figure 16).Powder X-Ray diffraction pattern (see Fig. 17A) XRPD analysis was performed using a Philips X'Pert diffractometer with Cu Kalpha radiation in Bragg-Brentano geometry. The system is equipped with a proportional detector. The measurement parameters were as follows: the range of 2theta was 3 to 40 at a scan rate of 1.8 per minute (see figure 17A). List of selected peaks: 2theta ()d (A)I (%) 6.71 13.18 26 8.57 10.32 53 10.23 8.65 4 11.39 7.77 6 13.31 6.65 100 14.15 6.26 6 14.98 5.91 34 15.51 5.72 25 16.56 5.35 14 17.07 5.20 3 17.61 5.04 25 17.90 4.96 14 18.34 4.84 15 18.95 4.68 35 19.84 4.48 2 20.82 4.27 7 22.10 4.02 5 22.54 3.94 3 22.76 3.91 3 24.50 3.63 2 25.30 3.52 7 25.76 3.46 5 26.68 3.34 3 27.15 3.28 2 29.29 3.05 2 32.80 2.73 2 39.46 2.28 1 In addition the Powder X-Ray diffraction pattern of the starting products memantine base and HTBwere compared to the XRPD above (Fig. 17B), proving the formation of the salt.

Reference： [1]Patent: EP2098500,2009,A1 .Location in patent: Page/Page column 16-18

26
[ 328-90-5 ]
[ 75-65-0 ]
[ 1042972-97-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide;dmap; In tetrahydrofuran; at 20℃; for 64h;	<Step 1> Synthesis of <strong>[328-90-5]2-hydroxy-4-trifluoromethylbenzoic acid</strong> tert-butyl ester A solution of tetrahydrofuran (50 mL) of N,N'-dicyclohexylcarbodiimide (11.0 g) was added dropwise to a tetrahydrofuran (50 mL) suspension of <strong>[328-90-5]2-hydroxy-4-trifluoromethylbenzoic acid</strong> (10.0 g), tert-butanol (92.8 mL) and 4-(N,N-dimethylamino)pyridine (0.24 g), and stirred at room temperature for 64 hours. The precipitate was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elude; n-hexane:ethyl acetate = 100: 0 to 95:5). The title compound (8.18 g) was obtained as colorless oil. <Step 2> Synthesis of tert-butyl 2-(2-(tert-butoxycarbonyl)-5-trifluoromethylphenoxy)ethylcarbamete

Reference： [1]Patent: EP2128157,2009,A1 .Location in patent: Page/Page column 109

27
[ 455-24-3 ]
[ 328-90-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With oxygen; potassium acetate; p-benzoquinone;palladium diacetate; In ISOPROPYLAMIDE; at 115℃; under 3800.26 Torr; for 15h;Product distribution / selectivity;	III. General procedure for Pd (II) -catalyzedorfcho-hydroxylation with 5 atm 02 :A 50 mL high pressure reactor equipped with a magnetic stir bar was charged with Pd(OAc)2 (11.2 mg, 0.05 mmol), followed by the benzoic acidsubstrate (0.5 mmol), benzoquinone (54.0 mg, 0.5 mmol), KOAc (98.0 mg, 1 mmol) andN, N-dimethylacetamide (1.5 mL) . The reactor was filled with 02 (20 atm) , and then evacuated and backed-filled with 02 (5 atm, 2 times) . After the reaction mixture was stirred at 115 C for 15 hours, it was permitted to cool to ambient temperature. The reaction was worked up and the crude product was purified following the procedure described above for hydroxylation with 1 atm O2.

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 14654 - 14655
[2]Patent: WO2011/37929,2011,A2 .Location in patent: Page/Page column 14; 19-20

28
[ 322-79-2 ]
[ 328-90-5 ]

Reference： [1]Combinatorial Chemistry and High Throughput Screening,2010,vol. 13,p. 569 - 577

29
[ 328-90-5 ]
[ 67-63-0 ]
[ 1175134-69-6 ]

Yield	Reaction Conditions	Operation in experiment
79%		To a solution of p-(trifluoromethyl)salicylic acid (CAS 345-28-8) (500 mg, 2.271 mmol), 2-propanol (0.209 ml, 2.725 mmol) and triphenylphosphine (706.2 mg, 2.612 mmol) in 6.5 ml tetrahydrofurane under nitrogen at 0 C., was added dropwise a solution of di-tert-butyl azodicarboxylate (575.2 mg, 2.498 mmol) in 1 ml tetrahydrofurane. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. 8 ml 2N NaOH (15.9 mmol) was added and the reaction mixture was heated in an 80 C. oil bath for 5 hours. The reaction mixture was allowed to cool to room temperature and extracted twice with 5 ml ether. The aqueous layer was acidified under ice bath cooling with a 5N HCl solution to pH 1. The resulting precipitate was filtered and dried in vacuo to provide 444 mg (79%) of the title compound as a white solid. MS (m/e): 247.0 (M+H+).
79%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 1.5h;Inert atmosphere;	AF: 2-Isopropoxy-4-trifluoromethyl-benzoic acidTo a solution of p-(trifluoromethyl)salicylic acid (CAS 345-28-8) (500 mg , 2.271 mmol), 2- propanol (0.209 ml, 2.725 mmol) and triphenylphosphine (706.2 mg, 2.612 mmol) in 6.5 ml tetrahydrofurane under nitrogen at 0 0C, was added dropwise a solution of di-tert-butyl azodicarboxylate (575.2 mg, 2.498 mmol) in 1 ml tetrahydrofurane. The reaction mixture was allowed to warm to room temperature and stirred for 1,5 hours. 8 ml 2N NaOH (15.9 mmol) was added and the reaction mixture was heated in an 800C oil bath for 5 hours. The reaction mixture was allowed to cool to room temperature and extracted twice with 5 ml ether. The aqueous layer was acidified under ice bath cooling with a 5N HCl solution to pH 1. The resulting precipitate was filtered and dried in vacuo to provide 444 mg (79 %) of the title compound as a white solid. MS(nVe): 247.0 (M+H+).

Reference： [1]Patent: US2011/53904,2011,A1 .Location in patent: Page/Page column 20-21
[2]Patent: WO2011/23667,2011,A1 .Location in patent: Page/Page column 37

30
[ 328-90-5 ]
[ 167558-54-5 ]
[ 1359997-24-2 ]

Reference： [1]Organic and Biomolecular Chemistry,2012,vol. 10,p. 1602 - 1611

31
[ 328-90-5 ]
[ 167558-54-5 ]
[ 1359997-45-7 ]

Reference： [1]Organic and Biomolecular Chemistry,2012,vol. 10,p. 1602 - 1611

32
[ 328-90-5 ]
[ 100-39-0 ]
benzyl 2-hydroxy-4-(trifluoromethyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 2h;	BnBr (1.20 mL, 8.325 mmol) was added to a solution of <strong>[328-90-5]2-hydroxy-4-(trifluoromethyl)benzoic acid</strong> (1.50 g, 7.277 mmol) in TBAF (10 mL, 1 M solution in THF) and the mixture was stirred at r.t. for 2 h. The reaction mixture was poured into NaHCO3 (saturated aqueous solution, 100 mL) and extracted with EtOAc (100 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5?30% EtOAc/hexanes) to furnish 2.18 g of benzyl 2-hydroxy-4-(trifluoromethyl)benzoate (colourless oil, yield: quantitative).1H NMR (CDCl3, 250 MHz) delta ppm: 10.89 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.44 (m, 6H), 7.10 (d, J=8.5 Hz, 1H), 5.42 (s, 2H).
100%	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 2h;	Step 1 : Benzyl 2-hydroxy-4-(trifluoromethyl)benzoate BnBr (1.20 mL. 8.325 mmol) was added to a solution of 2-hydroxy-4- (trifluoromethyl)benzoic acid (1.50 g, 7.277 mmol) in TBAF (10 mL, 1 M solution in THF) and the mixture was stirred at r.t. for 2 h. The reaction mixture was poured into ail CO 3 (saturated aqueous solution, 100 mL) and extracted with EtOAc (100 mL). It was dried over Na2S04 (anhydrous), filtered and concentrated. The crude residue was flash chromato graphed on Si02 ( 5-3()% EtOAc/hexanes) to furnish 2.18 g of benzyl 2-hydroxy-4- (trifiuoromethyl)benzoate (colourless oil. yield: quantitative). lH NMR (CDC13, 250 MHz) delta ppm: 10.89 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.44 (m, 6H), 7.10 (d, J = 8.5 Hz, 1H), 5.42 (s, 2H

Reference： [1]Patent: US2012/149769,2012,A1 .Location in patent: Page/Page column 29
[2]Patent: WO2013/37985,2013,A1 .Location in patent: Page/Page column 95

33
[ 328-90-5 ]
[ 1042972-91-7 ]

Reference： [1]Patent: US2013/158067,2013,A1

34
[ 328-90-5 ]
[ 106-95-6 ]
[ 1447710-59-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 80℃; for 3h;	In a 25 mL round-bottomed flask, <strong>[328-90-5]2-hydroxy-4-(trifluoromethyl)benzoic acid</strong> (300 mg, 1.46 mmol, Eq: 1.00) was combined with acetonitrile (3.00 mL). K2CO3 (503 mg, 3.64 mmol, Eq: 2.50) and 3-bromoprop-l-ene (454 mg, 325 mu, 3.64 mmol, Eq: 2.50) were added. The reaction mixture was heated to 80 C and stirred for 3 h. The solvent was evaporated. The crude reaction mixture was poured into water and extracted with DCM (2x). The organic layers were dried over Na2S04 and concentrated in vacuo. 2-Allyloxy-4- trifluoromethyl-benzoic acid allyl ester (433 mg) was recovered. The crude bisalkylated product was combined with ethanol (2.5 mL) and water (0.5 mL) and sodium hydroxide (116 mg, 2.91 mmol, Eq: 2.00) was added. The reaction mixture was heated to 80 C and stirred for 16 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was treated with aqueous 1 M HCl solution until pH=l-2 was reached. After that, the mixture was extracted with DCM (3x). The organic layers were dried over Na2S04 and concentrated in vacuo to yield a light yellow solid (296 mg; 83% two steps), m/z = 245.2 [M-H]
433 mg	With potassium carbonate; In acetonitrile; at 80℃; for 3h;	In a 25 ml round-bottomed flask, 2-hydroxy-4-(trifluorom- ethyl)benzoic acid (300 mg, 1.46 mmol, Eq: 1.00) was combined with acetonitrile (3.00 ml). K2C03 (503 mg, 3.64 mmol, Eq: 2.50) and 3-bromoprop-1-ene (454 mg, 325 muL, 3.64 mmol, Eq: 2.50) were added. The reaction mixture was heated to 80 C. and stirred for 3 h. The solvent was evaporated. The crude reaction mixture was poured into water and extracted with DCM (2x). The organic layers were dried over Na2SO4 and concentrated in vacuo. 2-Allyloxy-4-trifluorom- ethyl-benzoic acid allyl ester (433 mg) was recovered. The crude bisalkylated product was combined with ethanol (2.5 ml) and water (0.5 ml) and sodium hydroxide (116mg, 2.91 mmol, Eq: 2.00) was added. The reaction mixture was heated to 80 C. and stirred for 16 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was treated with aqueous 1 M HCl solution until pH=1-2 was reached. After that, the mixture was extracted with DCM (3x). The organiclayers were dried over Na2SO4 and concentrated in vacuo to yield a light yellow solid (296 mg; 83% two steps). m/z245.2 [M-H].

Reference： [1]Patent: WO2013/104613,2013,A1 .Location in patent: Page/Page column 47
[2]Patent: US2013/196965,2013,A1 .Location in patent: Paragraph 0234

35
[ 328-90-5 ]
[ 1447710-57-7 ]

Reference： [1]Patent: WO2013/104613,2013,A1
[2]Patent: US2013/196965,2013,A1

36
[ 328-90-5 ]
[ 1578179-21-1 ]