[ CAS No. 172023-97-1 ] {[proInfo.proName]}

Name: 172023-97-1|(3-Bromo-5-(trifluoromethyl)phenyl)methanol|97%
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Quality Control of [ 172023-97-1 ]

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SDS Specification

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Product Details of [ 172023-97-1 ]

CAS No. :	172023-97-1	MDL No. :	MFCD09835207
Formula :	C₈H₆BrF₃O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MPYFWGBMAYFJOH-UHFFFAOYSA-N
M.W :	255.03	Pubchem ID :	29919767
Synonyms :

Calculated chemistry of [ 172023-97-1 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	45.27
TPSA :	20.23 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.0 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.11
Log Po/w (XLOGP3) :	2.61
Log Po/w (WLOGP) :	3.96
Log Po/w (MLOGP) :	3.32
Log Po/w (SILICOS-IT) :	3.38
Consensus Log Po/w :	3.07

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.28
Solubility :	0.135 mg/ml ; 0.000531 mol/l
Class :	Soluble
Log S (Ali) :	-2.68
Solubility :	0.527 mg/ml ; 0.00207 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.97
Solubility :	0.0273 mg/ml ; 0.000107 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.73

Safety of [ 172023-97-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 172023-97-1 ]

* 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 [ 172023-97-1 ]
Downstream synthetic route of [ 172023-97-1 ]

[ 172023-97-1 ] Synthesis Path-Upstream 1~5

1
[ 537039-44-4 ]
[ 172023-97-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 65℃; for 0.5 h;	(3-Bromo-5-(trifluoromethyl)phenyl)methanol. (3-Amino-5-(trifluoromethyl)phenyl)methanol (1.6 g, 8.4 mmol) in dry acetonitrile (10 mL) was added dropwise to a solution of copper (II) bromide (2.24 g, 10.0 mmol) and tert-butyl nitrite (1.48 mL, 12.0 mmol) in acetonitrile (20 mL) at 65° C. After stirring for 30 min at 65° C., the reaction mixture was cooled to room temperature, poured into a 1 N hydrochloric acid solution, and extracted with ethyl acetate (2.x.). The organic layers were pooled together, washed with brine (2.x.), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20percent ethyl acetate/hexanes) afforded 1.48 g (69percent). ¹H-NMR (CDCl_3,500 MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 4.75 (s, 2H).

Reference： [1] Patent: US2007/249607, 2007, A1, . Location in patent: Page/Page column 62
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3039 - 3043
[3] Patent: WO2007/88999, 2007, A1, . Location in patent: Page/Page column 164-165
[4] Patent: WO2007/116922, 2007, A1, . Location in patent: Page/Page column 54
[5] Patent: WO2005/100298, 2005, A1, . Location in patent: Page/Page column 65

2
[ 328-67-6 ]
[ 172023-97-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	Stage #1: With borane-THF In tetrahydrofuran at 65℃; for 2 h; Stage #2: With water; sodium hydrogencarbonate In tetrahydrofuran	16). Synthesis of 1-bromomethyl-3-methanesulfonyl-5-trifluoromethyl-benzene; To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (5 mmol, 1.35 g) in THF (8 mL) is added 1M boran in THF (16 mmol, 16 ml_) under nitrogen. The solution is allowed to warm to 65 ⁰C and stirred for 2 hours. The mixture is cooled to room temperature, then poured into saturated aq. NaHCO₃. The mixture is extracted with EtOAc. The combined organic layer is washed with brine, dried over Na₂SO₄, filtrated, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane / EtOAc) to give (3-bromo-5-trifluoromethyl-phenyl)-methanol (418 mg, 69percent).
57%	Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 20 h; Stage #2: With methanol In tetrahydrofuran	Step C: (3-Bromo-5-(trifluoromethyl)phenyl)methanol To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (2.13 gm, 7.92 mmol) in anhydrous THF under nitrogen was added borane dimethylsulfide complex (15.83 mmol, 7.91 mL) and the mixture was stirred at room temperature for 16 hours. A further aliquot of borane dimethylsulfide complex (15.83 mmol, 7.91 mL) was then added and stirring was continued at room temperature for a further 4 hours. LC-MS indicated complete consumption of starting material. Methanol was added cautiously until effervescence ceased then 2N hydrochloric acid (20 mL) was added. The mixture was stirred at room temperature for 20 hours then concentrated to dryness under reduced pressure. The residue was extracted with diethyl ether and the solution washed with water. The organic layer was dried with anhydrous sodium sulfate and the solvent removed under vacuum. The residue was dissolved in a mixture of dichloromethane and methanol, silica gel was added and the solvent removed under vacuum. The solid was placed on a column of silica gel (50 gm) and eluted with hexane-ethyl acetate (85:15) to give the title compound as a yellow oil which crystallized on standing (1.16 gm, 57percent). LC-MS (ES-) Calc: 255, Found: 254 (M-H). ¹H NMR (CDCl₃) δ ppm 7.72 (brs, 1H), 7.69 (brs, 1H), 7.57 (brs, 1H), 4.77 (s, 2H), 1.86 (brs, 1H).

Reference： [1] Patent: WO2008/9435, 2008, A1, . Location in patent: Page/Page column 162
[2] Patent: US2007/213371, 2007, A1, . Location in patent: Page/Page column 71
[3] Patent: US2014/171403, 2014, A1, . Location in patent: Page/Page column

3
[ 477535-41-4 ]
[ 172023-97-1 ]

Reference： [1] MedChemComm, 2017, vol. 8, # 5, p. 1121 - 1130

4
[ 328-80-3 ]
[ 172023-97-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3039 - 3043

5
[ 172023-97-1 ]
[ 477535-41-4 ]

Reference： [1] Patent: WO2005/100298, 2005, A1, . Location in patent: Page/Page column 65

[ 172023-97-1 ] Synthesis Path-Downstream 1~27

1
[ 172023-97-1 ]
[ 126747-14-6 ]
[ 954123-16-1 ]

Yield	Reaction Conditions	Operation in experiment
51%	With potassium hydroxide;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 120℃; for 18.1667h;	3'-(hydroxymethyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile. A solution of <strong>[172023-97-1](3-bromo-5-(trifluoromethyl)phenyl)methanol</strong> (3.0 g, 11.8 mmol), 4-cyanophenyl boronic acid (5.2 g, 35 mmol), tetrakis(triphenylphosphine) palladium(0) (2.7 g, 2.4 mmol), and aqueous potassium hydroxide (41 mL, 1N, 41 mmol) in THF (80 mL) was degassed with nitrogen for 10 minutes and then heated at 120 C. for 18 hours. The reaction was cooled to ambient temperature and poured into water (100 mL), then was diluted with ethyl acetate (100 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with a gradient of ethyl acetate/hexanes of 5%-40%. The product 3'-(hydroxymethyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile (1.66 g, 51%) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) delta 7.65-7.80 (m, 7H), 4.85 (s, 2H), 1.90 (bs, 1H). Mass spec.:278.2 (M+H).

Reference： [1]Patent: US2007/249607,2007,A1 .Location in patent: Page/Page column 58

2
[ 172023-97-1 ]
[ 954123-46-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With N-Bromosuccinimide; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h;	1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene. <strong>[172023-97-1](3-Bromo-5-(trifluoromethyl)phenyl)methanol</strong> (1.6 g, 6.3 mmol) and triphenylphosphine (3.3 g, 12.6 mmol) were combined in tetrahydrofuran (30 mL) and cooled to 0 C. N-Bromosuccinimide (2.4 g, 13.2 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (100% hexanes) gave 1.53 g (76%) as a light brown oil. 1H-NMR (CDCl3, 500 MHz) delta 7.73 (s, 1H), 7.70 (s, 1H), 7.58 (s, 1H), 4.44 (s, 2H).

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 15375 - 15386
[2]Patent: US2007/249607,2007,A1 .Location in patent: Page/Page column 62-63
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3039 - 3043

3
[ 172023-97-1 ]
[ 20277-69-4 ]
[ 1003843-94-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	With copper(l) iodide; sodium L-prolinate; In dimethyl sulfoxide; at 95℃; for 20h;	To a solution of <strong>[172023-97-1](3-bromo-5-trifluoromethyl-phenyl)-methanol</strong> (2 mmol, 613 mg), L- proline sodium salt (0.4 mmol, 55 mg), copper iodide (0.2 mmol, 38 mg) in DMSO (4 mL) is added sodium methanesulfinate (2.4 mmol, 245 mg) under nitrogen. The solution is allowed to warm to 95 0C and stirred for 20 hours. The mixture is cooled to room temperature, then added water. The mixture is extracted with dichloromethane. The combined organic layer is washed with brine, dried over Na2SO4, filtrated, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane / EtOAc) to give (3-methanesulfonyl-5-trifluoromethyl-phenyl)-methanol (418 mg, 69%); ESI-MS m/z: 255 [M+1]+, Retention time 1.64 min (condition A).

Reference： [1]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 162

4
[ 172023-97-1 ]
[ 477535-41-4 ]

Yield	Reaction Conditions	Operation in experiment
	With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 1h;	[3-amino-5-(trifluoromethyl)phenyl]methanol (900 mg, 4.71 mmol) (Step A, Example 24) was suspended in CHBr3 (9 mL), and t-butyl nitrite (600 muL, 5.04 mmol) was added dropwise by syringe. The reaction was heated slowly to 80C and was maintained at this temperature for 10 minutes. The reaction was then cooled to room temperature, diluted with hexanes (50 mL), loaded on a silica gel column, and purified with 100% hexanes to 20% EtOAc/hexanes (2 columns) to afford [3-bromo-5- (trifluoromethyl) phenyl] methanol. Rf= 0.31 (25% EtOAc/hexanes). 'H NMR (CDC13, 500 MHz) No. 7.71 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 4.76 (d, J = 5.5 Hz, 2H), 1.86 (t, J = 5.7 Hz, 1H). Step B: 3-Bromo-5-(trifluoromethyl)benzaldehyde A solution of [3-bromo-5-(trifluoromethyl)phenyl]methanol (409 mg, 1.61 mmol) in CH2Cl2 (25 mL) was cooled to 0C and then Dess-Martin periodinane (1.02 g, 2.41 mmol) was added. The reaction was stirred at 0 C for 30 minutes and then warmed to room temperature. After stirring at room temperature for thirty minutes, the reaction was poured into IN NaOH (25 mL). The mixture was extracted with EtOAc (100 mL), and the organic extracts were washed with IN NaOH (25 mL), then brine (25 mL), dried over Na2S04, filtered, and concentrated. Purification by flash chromatography with 25% EtOAc/hexanes afforded 3-bromo-5- (trifluoromethyl)benzaldehyde. 0.60 (25% EtOAc/hexanes). 'H NMR (CDCI3, 500 MHz) 8 10.02 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H).

Reference： [1]Patent: WO2005/100298,2005,A1 .Location in patent: Page/Page column 65

5
[ 537039-44-4 ]
[ 172023-97-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 65℃; for 0.5h;	(3-Bromo-5-(trifluoromethyl)phenyl)methanol. (3-Amino-5-(trifluoromethyl)phenyl)methanol (1.6 g, 8.4 mmol) in dry acetonitrile (10 mL) was added dropwise to a solution of copper (II) bromide (2.24 g, 10.0 mmol) and tert-butyl nitrite (1.48 mL, 12.0 mmol) in acetonitrile (20 mL) at 65 C. After stirring for 30 min at 65 C., the reaction mixture was cooled to room temperature, poured into a 1 N hydrochloric acid solution, and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) afforded 1.48 g (69%). 1H-NMR (CDCl3, 500 MHz) delta 7.71 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 4.75 (s, 2H).
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃;	(1) 3-Nitro-5-(trifluoromethyl)benzoic acid (5Og) is dissolved in tetrahydrofuran (300ml) and thereto is added dropwise a l.OM-borane tetrahydrofuran complex/ tetrahydrofuran (300ml) at 0C under nitrogen atmosphere over 2 hours and the mixture is stirred at 75C for 1 hour and a half. The reaction solution is allowed cool to room temperature and concentrated under reduced pressure, and thereto is added a IN- hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude (3-nitro-5-trifluoromethyl-phenyl)-methanol. The obtained crude product is dissolved in methanol (50OmL) and thereto is added 10% palladium-carbon (5g) and the mixture is stirred under hydrogen atmosphere at room temperature overnight. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give crude (3-amino-5-trifluoromethyl-phenyl)-methanol. To copper (II) bromide (53.6g) is added acetonitrile (500ml), followed by an addition dropwise of tert-butyl nitrite (35.7ml) under ice-cooling and the mixture is stirred under nitrogen atmosphere for 5 minutes. To reaction mixture is added dropwise a solution of the above crude (3-amino-5-trifluoromethyl-phenyl)- methanol in acetonitrile (200ml) under ice-cooling over 1 hour and 15 minutes and the mixture is stirred at room temperature under nitrogen atmosphere overnight. To reaction mixture is added a lN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a lN-hydrochloric acid, water and a saturated <n="166"/>brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 7:1?4:1) to give (3-bromo-5- trifluoromethyl-phenyl)-methanol (40.7g). NMR (CDCl3): 1.90 (lH,t), 4.76 (2H,d), 7.56 (IH, s), 7.68 (IH, s), 7.72 (lH,s)
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃;	To copper (II) bromide (53.6 g) is added acetonitrile (500 ml), followed by an addition dropwise of tert-butyl nitrite (35.7 ml) under ice-cooling and the mixture is stirred under nitrogen atmosphere for 5 minutes. To reaction mixture is added dropwise a solution of the above crude (3-amino-5-trifluorornethyl- phenyl)-methanol in acetonitrile (200 ml) under ice-cooling over 1 hour and 15 minutes and the mixture is stirred at room temperature under nitrogen atmosphere overnight. To reaction mixture is added a lN-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a lN-hydrochloric acid, water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 7: 1- >4: 1) to give (3-bromo-5-trifluoromethyl- phenyl)-methanol (40.7 g). NMR (CDCl3): 1.90 (lH,t), 4.76 (2H,d), 7.56 (IH, s), 7.68 (IH, s), 7.72 (lH,s).

With tert.-butylnitrite; Bromoform; at 80℃; for 0.166667h;

[3-amino-5-(trifluoromethyl)phenyl]methanol (900 mg, 4.71 mmol) (Step A, Example 24) was suspended in CHBr3 (9 mL), and t-butyl nitrite (600 muL, 5.04 mmol) was added dropwise by syringe. The reaction was heated slowly to 80C and was maintained at this temperature for 10 minutes. The reaction was then cooled to room temperature, diluted with hexanes (50 mL), loaded on a silica gel column, and purified with 100% hexanes to 20% EtOAc/hexanes (2 columns) to afford [3-bromo-5- (trifluoromethyl) phenyl] methanol. Rf= 0.31 (25% EtOAc/hexanes). 'H NMR (CDC13, 500 MHz) No. 7.71 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 4.76 (d, J = 5.5 Hz, 2H), 1.86 (t, J = 5.7 Hz, 1H). Step B: 3-Bromo-5-(trifluoromethyl)benzaldehyde A solution of [3-bromo-5-(trifluoromethyl)phenyl]methanol (409 mg, 1.61 mmol) in CH2Cl2 (25 mL) was cooled to 0C and then Dess-Martin periodinane (1.02 g, 2.41 mmol) was added. The reaction was stirred at 0 C for 30 minutes and then warmed to room temperature. After stirring at room temperature for thirty minutes, the reaction was poured into IN NaOH (25 mL). The mixture was extracted with EtOAc (100 mL), and the organic extracts were washed with IN NaOH (25 mL), then brine (25 mL), dried over Na2S04, filtered, and concentrated. Purification by flash chromatography with 25% EtOAc/hexanes afforded 3-bromo-5- (trifluoromethyl)benzaldehyde. 0.60 (25% EtOAc/hexanes). 'H NMR (CDCI3, 500 MHz) 8 10.02 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H).

Reference： [1]Patent: US2007/249607,2007,A1 .Location in patent: Page/Page column 62
[2]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3039 - 3043
[3]Patent: WO2007/88999,2007,A1 .Location in patent: Page/Page column 164-165
[4]Patent: WO2007/116922,2007,A1 .Location in patent: Page/Page column 54
[5]Patent: WO2005/100298,2005,A1 .Location in patent: Page/Page column 65

6
[ 172023-97-1 ]
[ 557-21-1 ]
[ 569370-38-3 ]

Yield	Reaction Conditions	Operation in experiment
33%	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 20 - 90℃; for 1h;	3-(Hydroxymethyl)-5-(trifluoromethyl)benzonitrile. <strong>[172023-97-1](3-Bromo-5-(trifluoromethyl)phenyl)methanol</strong> (1.4 g, 5.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.64, 0.55 mmol) and zinc cyanide (388 mg, 3.31 mmol) were combined in dimethylformamide (6 mL). The reaction mixture degassed repeatedly using the freeze-thaw method. After warming to room temperature, the reaction was heated at 90 C. for 1 h, cooled to room temperature and concentrated. The crude product was dissolved in ethyl acetate, washed with water (2×), 1 N hydrochloric acid (2×), brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography on silica gel gave 0.37 g (33%). LC/MS (HPLC method 3): tR=2.06 min, 202.02(MH)+.
	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 2h;	(2) (3-Bromo-5-trifluoromethyl-phenyl)-methanol (33.9g) is dissolved in N,N-dimethylformamide (40OmL) and thereto are added zinc(II) cyanide (16.39g) and tetrakis(triphenylphosphine)palladium (7.68g) and the mixture is heated under nitrogen atmosphere at 120C for 2 hours. The reaction solution is allowed cool to room temperature, and filtered through Celite, and the filtrate is concentrated under reduced pressure. Thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2: 1) to give 3- hydroxymethyl-5-trifluoromethyl-benzonitrile (23.4g). NMR (CDCl3): 2.09 (lH,t), 4.85 (2H,d), 7.83 (lH,s), 7.87 (2H,s)
	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 2h;	(2) (3-Bromo-5-trifluoromethyl-phenyl)-methanol (33.9 g) is dissolved in N3N- dimethylformamide (40OmL) and thereto are added zinc(II) cyanide (16.39g) and tetrakis(triphenylphosphine)palladium (7.68 g) and the mixture is heated under nitrogen atmosphere at 12O0C for 2 hours. The reaction solution is allowed cool to room temperature, and filtered through Celite, and the filtrate is concentrated under reduced <n="56"/>.55pressure. Thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 2:1) to give 3-hydroxymethyl~5- trifluoromethyl-benzonitrile (23.4g). NMR (CDCl3): 2.09 (lH,t), 4.85 (2H,d), 7.83 (lH,s), 7.87 (2H,s).

Reference： [1]Patent: US2007/249607,2007,A1 .Location in patent: Page/Page column 70
[2]Patent: WO2007/88999,2007,A1 .Location in patent: Page/Page column 165
[3]Patent: WO2007/116922,2007,A1 .Location in patent: Page/Page column 54-55

7
[ 172023-97-1 ]
[ 73963-98-1 ]
[ 569370-38-3 ]

Yield	Reaction Conditions	Operation in experiment
61%	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 160℃; for 0.333333h;Microwave irradition;	STEP A: Preparation of 3-hydroxymethyl-5-trifluoromethyl-benzonitrile A mixture of <strong>[172023-97-1](3-bromo-5-trifluoromethyl-phenyl)-methanol</strong> (500 mg, 1.96 mmol), zinc cyanide (230 mg, 1.96 mmol) and tetrakis(triphenylphosphine) palladium (68 mg, 0.059 mmol) in DMF (2 ml) was heated by microwave at 160 C. for 20 minutes. The mixture was partitioned between ethyl ether (20 ml) and water (10 ml). The aqueous layer was extracted with ether and combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The product was purified on Biotage column (12+M), eluding with 2% ethyl acetate in heptane (1 CV), 2-20% (10 CV), 20% (2CV) to yield the title compound (240 mg, 61%) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta ppm 2.05 (s, 1H) 4.8 (s, 2H) 7.82 (s, 1H) 7.86 (s, 2H).

Reference： [1]Patent: US2007/213371,2007,A1 .Location in patent: Page/Page column 71

8
[ 328-67-6 ]
[ 172023-97-1 ]

Yield	Reaction Conditions	Operation in experiment
69%		16). Synthesis of 1-bromomethyl-3-methanesulfonyl-5-trifluoromethyl-benzene; To a solution of <strong>[328-67-6]3-bromo-5-(trifluoromethyl)benzoic acid</strong> (5 mmol, 1.35 g) in THF (8 mL) is added 1M boran in THF (16 mmol, 16 ml_) under nitrogen. The solution is allowed to warm to 65 0C and stirred for 2 hours. The mixture is cooled to room temperature, then poured into saturated aq. NaHCO3. The mixture is extracted with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtrated, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane / EtOAc) to give (3-bromo-5-trifluoromethyl-phenyl)-methanol (418 mg, 69%).
57%		Step C: (3-Bromo-5-(trifluoromethyl)phenyl)methanol To a solution of <strong>[328-67-6]3-bromo-5-(trifluoromethyl)benzoic acid</strong> (2.13 gm, 7.92 mmol) in anhydrous THF under nitrogen was added borane dimethylsulfide complex (15.83 mmol, 7.91 mL) and the mixture was stirred at room temperature for 16 hours. A further aliquot of borane dimethylsulfide complex (15.83 mmol, 7.91 mL) was then added and stirring was continued at room temperature for a further 4 hours. LC-MS indicated complete consumption of starting material. Methanol was added cautiously until effervescence ceased then 2N hydrochloric acid (20 mL) was added. The mixture was stirred at room temperature for 20 hours then concentrated to dryness under reduced pressure. The residue was extracted with diethyl ether and the solution washed with water. The organic layer was dried with anhydrous sodium sulfate and the solvent removed under vacuum. The residue was dissolved in a mixture of dichloromethane and methanol, silica gel was added and the solvent removed under vacuum. The solid was placed on a column of silica gel (50 gm) and eluted with hexane-ethyl acetate (85:15) to give the title compound as a yellow oil which crystallized on standing (1.16 gm, 57%). LC-MS (ES-) Calc: 255, Found: 254 (M-H). 1H NMR (CDCl3) delta ppm 7.72 (brs, 1H), 7.69 (brs, 1H), 7.57 (brs, 1H), 4.77 (s, 2H), 1.86 (brs, 1H).
	With hydrogenchloride; In tetrahydrofuran; water; ethyl acetate;	Step 1: (3-bromo-5-(trifluoromethyl)phenyl)methanol To a stirred solution of <strong>[328-67-6]3-bromo-5-(trifluoromethyl)benzoic acid</strong> (1 g, 3.72 mmol) in THF (5 ml) at -78 C. with stirring under nitrogen was added dropwise over 10 mins borane tetrahydrofuran complex 1M in THF (18.59 ml, 18.59 mmol) and then the reaction mixture was warmed to RT over 20 hours. The reaction mixture was cooled in an ice/water bath and quenched dropwise with MeOH (10 ml) followed by 1M HCl until effervescence ceased. Water was added and stirred at RT for 30 mins. THF was removed under reduced pressure, and the compound extracted into EtOAc. The organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-50% EtOAc in Hexanes as eluent to afford the title product. 1H NMR (400 MHz, d6-DMSO): delta 7.83 (s, 1H), 7.83 (s, 1H) 7.69 (s, 1H), 5.54-5.51 (t, 1H), 4.60-4.59 (d, 2H)

Reference： [1]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 162
[2]Patent: US2007/213371,2007,A1 .Location in patent: Page/Page column 71
[3]Patent: US2014/171403,2014,A1 .Location in patent: Page/Page column

10
[ 172023-97-1 ]
[ 75-03-6 ]
C₁₀H₁₀BrF₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 1h;	a) Preparation of intermedia Ethyl iodide (0.5 mL, 6.12 mmol) was added to a mixture of 3-bromo-5-(trifluoro- methyl)benzyl alcohol (1.3 g, 5.10 mmol), sodium hydride (60% in mineral oil, 0.23 g, 5.61 mmol) in DMF (15 mL) at 0 C .The mixture was stirred at r.t. for 1 h, then diluted with sat. NaHCC"3 and extracted with EtO Ac. The organic layer was washed with NaHCC"3 solution, dried (MgS04), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash chromatography (silica; EtO Ac/heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo, to yield intermediate 100 (1 g, 69%).

Reference： [1]Patent: WO2013/171712,2013,A1 .Location in patent: Page/Page column 110

11
[ 172023-97-1 ]
C₁₁H₁₁F₃O₃ [ No CAS ]

Reference： [1]Patent: WO2013/171712,2013,A1

12
[ 172023-97-1 ]
[ 1539643-17-8 ]
[ 1613514-12-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In ethyl acetate; N,N-dimethyl-formamide;	Step 2: 3-bromo-5-(trifluoromethyl)benzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate To a stirred solution of <strong>[172023-97-1](3-bromo-5-(trifluoromethyl)phenyl)methanol</strong> (567 mg, 2.223 mmol) in DMF (5 mL) at RT under nitrogen was added CU (360 mg, 2.223 mmol) and the reaction mixture heated at 50 C. for 20 hours. Tert-butyl piperidin-4-yl carbamate (445 mg, 2.223 mmol) was added and the reaction mixture stirred at 50 C. for 3 hours. On cooling to RT the mixture was diluted with DCM and washed with a saturated solution of sodium bicarbonate, a saturated solution of brine, and the organic portion was dried over MgSO4 filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-100% EtOAc in Hexanes as eluent to afford the title product; LC-MS: Rt 1.59 mins; MS m/z 427.2 [M-tBu]+; Method 2minLowPHv03

Reference： [1]Patent: US2014/171403,2014,A1 .Location in patent: Page/Page column

13
[ 172023-97-1 ]
[ 1613577-15-3 ]

Reference： [1]Patent: US2014/171403,2014,A1

14
[ 172023-97-1 ]
[ 1613514-21-8 ]

Reference： [1]Patent: US2014/171403,2014,A1

15
[ 172023-97-1 ]
[ 1613577-17-5 ]

Reference： [1]Patent: US2014/171403,2014,A1

16
[ 172023-97-1 ]
[ 258331-10-1 ]
tert-butyl 2-(2-((3-bromo-5-(trifluoromethyl)benzyl)oxy)phenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere; Cooling with ice;	A solution of (3-bromo-5-(trifluoromethyl)phenyl)methanol (CAS 172023-97-1 ) (0.525 g, 2.06 mmol) and ferf-butyl 2-(2-hydroxyphenyl)acetate (Intermediate 21 ) (0.557 g, 2.67 mmol) and PPh3 (0.702 g, 2.67 mmol) in THF (20.6 mL) was cooled to 0 C in an ice/water bath under nitrogen. DIAD (0.520 mL, 2.67 mmol) was added dropwise. The reaction was allowed to warm to room temperature and then stirred overnight. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried with MgS04, filtered and concentrated. This was purified by flash chromatography (0-40% EtOAc: Heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-c/6) delta ppm 7.97 (s, 1 H) 7.93 (s, 1 H) 7.84 (s, 1 H) 7.16 - 7.31 (m, 2 H) 7.01 (d, J=7.58 Hz, 1 H) 6.88 - 6.97 (m, 1 H) 5.23 (s, 2 H) 3.56 (s, 2 H) 1.31 (s, 9 H).

Reference： [1]Patent: WO2015/9977,2015,A1 .Location in patent: Page/Page column 132; 133

17
[ 328-80-3 ]
[ 172023-97-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3039 - 3043

18
[ 172023-97-1 ]
[ 954123-48-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3039 - 3043

19
[ 172023-97-1 ]
[ 68-12-2 ]
3-(hydroxymethyl)-5-(trifluoromethyl)benzaldehyde [ No CAS ]

Reference： [1]MedChemComm,2017,vol. 8,p. 1121 - 1130

20
[ 477535-41-4 ]
[ 172023-97-1 ]

Reference： [1]MedChemComm,2017,vol. 8,p. 1121 - 1130

21
[ 172023-97-1 ]
2-(3-(hydroxymethyl)-5-(trifluoromethyl)benzyl)-3-(phenylamino)-acrylonitrile [ No CAS ]

Reference： [1]MedChemComm,2017,vol. 8,p. 1121 - 1130

22
[ 172023-97-1 ]
(3-((4-amino-2-methylpyrimidin-5-yl)methyl)-5-(trifluoromethyl)phenyl)methanol [ No CAS ]

Reference： [1]MedChemComm,2017,vol. 8,p. 1121 - 1130

23
[ 172023-97-1 ]
C₃₆H₂₉F₉IrN₇O [ No CAS ]