457889-46-2|(4'-(Trifluoromethyl)-[1,1'-biphenyl]-4-yl)methanol| Ambeed

Structure of 457889-46-2

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Quality Control of [ 457889-46-2 ] Purity: 97% SDS Specification

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Product Details of [ 457889-46-2 ]

CAS No. :	457889-46-2
Formula :	C₁₄H₁₁F₃O
M.W :	252.23
SMILES Code :	OCC1=CC=C(C2=CC=C(C(F)(F)F)C=C2)C=C1
MDL No. :	MFCD01862515
InChI Key :	YCVFDTRUBSFXSA-UHFFFAOYSA-N
Pubchem ID :	22015014

Safety of [ 457889-46-2 ]

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

Computational Chemistry of [ 457889-46-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	12
Fraction Csp3	0.14
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	63.01
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	20.23 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.59
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	3.55
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.87
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.	3.99
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	4.37
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.87

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.94
Solubility	0.0293 mg/ml ; 0.000116 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.66
Solubility	0.0552 mg/ml ; 0.000219 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	-5.63
Solubility	0.000585 mg/ml ; 0.00000232 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	Yes
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.	-5.32 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	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	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)	1.77

Application In Synthesis of [ 457889-46-2 ]

* 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 [ 457889-46-2 ]

[ 457889-46-2 ] Synthesis Path-Downstream 1~35

1
[ 402-43-7 ]
[ 59016-93-2 ]
[ 457889-46-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;PdCl2[dppf]; In tetrahydrofuran; N,N-dimethyl-formamide;	Step 4. Preparation of (4'-Trifluoromethyl-biphenyl-4-yl)-methanol (compound 36D) 1-Bromo-4-trifluoromethyl-benzene (814 mg, 3.62 mmol), 4-hydroxymethylphenylboronic acid (600 mg, 3.98 mmol), cesium carbonate (2.36 g, 7.24 mmol), and PdCl2(dppf) (132 mg, 0.181 mmol) were added to 10 ml of a 1:1 solution of DMF/THF. The reaction was flushed with nitrogen and heated to 90 C. for 1 h. The reaction was cooled, poured into diethyl ether and washed with water (250 ml), brine (150 ml) and dried over anhydrous sodium sulfate. The crude product was filtered through silica gel, eluted with diethyl ether, and concentrated to provide the title compound. MS m/z 251 (M-1).
	With caesium carbonate;palladium dichloride; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 90℃; for 1h;Heating / reflux;	Step 1.Preparation of (4'-Trifluoromethyl-biphenyl-4-yl)-methanol (Compound 3A) 1-Bromo-4-trifluoromethyl-benzene (814 mg, 3.62 mmol), 4-hydroxymethylphenylboronic acid (600 mg, 3.98 mmol), cesium carbonate (2.36 g, 7.24 mmol), and PdCl2(dppf) (132 mg, 0.181 mmol) were added to 10 ml of a 1:1 solution of DMF/THF. The reaction was flushed with nitrogen and heated to 90 C. for 1 h.The reaction was cooled, poured into diethyl ether and washed with water (250 ml), brine (150 ml) and dried over anhydrous sodium sulfate.The crude product was filtered through silica gel, eluted with diethyl ether, and concentrated to provide the title compound. MS m/z 251 (M-1).
	With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 90℃; for 1h;Inert atmosphere;	A mixture of Compound 33A (450 mg, 2.0 mmol), 4- (hydroxymethyl)phenylboronic acid (334 mg, 2.2 mmol), CS2CO3 (1.30 g, 4.0 mmol), and Pd(PPh3)Cl2 (140 mg, 0.2 mmol) in DMF/THF (10 mL, 1 : 1 in volume) was heated at 90 C under nitrogen for 1 hour. The mixture was cooled down to room temperature, diluted with diethyl ether (50 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified with column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 33B: LC-MS (ESI) m/z: 235 [M-OH]+.

References: [1]Patent: US2004/209936,2004,A1 .
[2]Patent: US2003/225158,2003,A1 .Location in patent: Page 24.
[3]Patent: WO2019/104011,2019,A1 .Location in patent: Paragraph 00470-00472.

2
[ 457889-46-2 ]
[ 454464-38-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With thionyl chloride; In chloroform; at 20℃; for 12h;	Example 23A 4-Chloromethyl-4'-trifluoromethylbiphenyl A solution of 5.0 g (19.82 mmol) of (4'-trifluoromethylbiphenyl-4-yl)methanol from Example 22A in 40 ml of chloroform is mixed with 2.89 ml (39.65 mmol) of thionyl chloride dissolved in 10 ml of chloroform, and the mixture is stirred at room temperature for 12 hours. After reaction is complete, the reaction mixture is concentrated to dryness, and the residue is taken up ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is subsequently separated off, dried over sodium sulfate and concentrated after filtration. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.43 mmol, 98% yield) of a colorless solid are obtained. 1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.91 (2H, d), 7.82 (2H, d), 7.78 (2H, d), 7.58 (2H, d), 4.83 (2H, s). MS (EI): 270 (M+).
98%	With thionyl chloride; In chloroform; at 20℃; for 12h;	Example 11A 4-Chloromethyl-4'-trifluoromethylbiphenyl A solution of 5.00 g (19.8 mmol) of (4'-trifluoromethylbiphenyl-4-yl)methanol in 40 ml of chloroform is mixed with 2.89 ml (39.7 mmol) of thionyl chloride dissolved in 10 ml of chloroform, and the mixture is stirred at room temperature over 12 hours. After reaction is complete, the reaction mixture is concentrated to dryness, and the residue is taken up ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is subsequently separated off, dried over sodium sulfate and concentrated after filtration. The resulting crude product is purified by flash chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.4 mmol, 98% of theory) of the title compound are obtained. 1H-NMR (300 MHz, DMSO-d6, delta/ppm): 4.83 (s, 2H), 7.58 (d, 2H), 7.78 (d, 2H), 7.91 (d, 2H), 7.82 (d, 2H). MS (E1): 270 (M+).
98%	With thionyl chloride; In chloroform; at 20℃; for 12h;	Example 16A; 4-Chloromethyl-4'-trifluoromethylbiphenyl 2.89 ml (39.65 mmol) of thionyl chloride dissolved in 10 ml of chloroform are added to a solution of 5.0 g (19.82 mmol) of (4'-trifluoromethylbiphenyl-4-yl)methanol in 40 ml of chloroform, and the mixture is stirred at room temperature for 12 hours. After reaction is complete, the reaction mixture is evaporated to dryness, and the residue is taken up in ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is separated off, dried over sodium sulphate and evaporated after filtration. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.43 mmol, 98% yield) of a colourless solid are obtained.1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.91 (2H, d), 7.82 (2H, d), 7.78 (2H, d), 7.58 (2H, d), 4.83 (2H, s).MS (EI): m/z=270 (M+).

98%	With thionyl chloride; In chloroform; at 20℃;	A solution of 5.0 g (19.82 mmol) of (4'-trifluoromethylbiphenyl-4-yl)methanol in 40 ml of chloroform is mixed with 2.89 ml (39.65 mmol) of thionyl chloride dissolved in 10 ml of chloroform, and the mixture is stirred at room temperature for 12 hours. After reaction is complete, the reaction mixture is concentrated to dryness, and the residue is taken up ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is subsequently separated off, dried over sodium sulfate and concentrated after filtration. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.43 mmol, 98% of theory) of a colorless solid are obtained.1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.91 (2H, d), 7.82 (2H, d), 7.78 (2H, d), 7.58 (2H, d), 4.83 (2H, s).MS (EI): 270 (M+).
93%	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 12h;Inert atmosphere;	To a solution of [(4?-(trifluoromethyl)-[1,1?-biphenyl]-4-yl)methanol (4a, 553 mg, 2.19 mmol) in anhydrous CH2Cl2 (20 mL) were added SOCl2 (391 mg, 3.29 mmol) and DMF (32.1 mg, 0.44 mmol) at 0 C. The reaction mixture was then allowed to warm to room tempreature. After stirring the reaction mixture at room temperature for 12 h, the reaction mixture was diluted with water and extracted with ethyl acetate for 3 times. The combined organic layer was dired over MgSO4, filtered, and concentrated. The obtained residue was purified by MPLC using hexane/ethyl acetate as the eluant to give the desired product 5 as a white solid (553 mg, 93%). 1H NMR (400 MHz, CDCl3) delta7.71-7.66 (m, 4H), 7.58 (d, 2H, J=8.2 Hz), 7.50 (d, 2H, J=8.2 Hz),4.55 (s, 2H).
91%	With thionyl chloride; In chloroform; at 20℃; for 12h;	Compound 20' (1 eq, 9.51 mmol) was dissolved in 20 mL of CHC13. SOCl2 (2 eq, 19.0 mmol) was then added and the reaction was stirred at rt during 12h.The reaction mixture was evaporated to dryness and diluted with water (30 mL) and EtOAc (40 mL). The mixture was then extracted three times (3 x 20 mL). The combined organic phases were washed with saturated Na2C03, dried and filtered. After removal of the solvent under reduced pressure, the remaining oil was purified using column chromatography (silica gel, 98/2 Hex/EtOAc) to obtain the desired compound (Rf = 0.2) as an off white solid (2.35 g, 91%) 1H-NMR (CDC13, 600 MHz) delta 7.69 (s, 4H), 7.59 (d, J = 8.1Hz, 2H), 7.49 (d, J = 8.1Hz, 2H), 4.64 (s, 2H); 13C-NMR (CDCI3, 150 MHz) delta: 144.2, 140.0, 137.6, 129.8, 129.4, 127.8, 127.6, 125.9, 120.3, 45.9; ESI-MS m/z for Ci4HnF30 [M + H]+, [M + Na]+;
	With methanesulfonyl chloride; triethylamine; In dichloromethane; for 18h;	The product from Example 3A was dissolved in 10 ml methylene chloride. Triethylamine (468 mg, 4.62 mol) and methanesulfonyl chloride (422 mg, 3.68 mmol) were then added and stirred for 18 h. The reaction was poured into water and extracted with methylene chloride. The organic solution was dried over anhydrous sodium sulfate, decanted and concentrated to provide the title compound that was used without further purification. MS m/z 235 (M-Cl+1).

References: [1]Patent: US2009/227640,2009,A1 .Location in patent: Page/Page column 38.
[2]Patent: US2009/291993,2009,A1 .Location in patent: Page/Page column 24.
[3]Patent: US2010/29772,2010,A1 .Location in patent: Page/Page column 19.
[4]Patent: US2009/215843,2009,A1 .Location in patent: Page/Page column 31.
[5]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 4382 - 4389.
[6]Patent: WO2019/63634,2019,A1 .Location in patent: Page/Page column 44-45.
[7]Patent: EP1216225,2005,B1 .Location in patent: Page/Page column 44.
[8]Patent: US2003/225158,2003,A1 .Location in patent: Page 24.

3
[ 457889-46-2 ]
[ 613241-14-8 ]

Yield	Reaction Conditions	Operation in experiment
65%	With phosphorus tribromide; In diethyl ether; dichloromethane; at 0℃; for 2h;	Step B. 4'-Bromomethyl-4-trifluoromethyl-biphenyl; Phosphorous tribromide (8.67mmol, 1.OM in dichloromethane) is added to a stirred solution of 4'-trifluoromethyl-biphenyl-4-yl)-methanol (2.08g, 8.25mmol) in ethyl ether (40mL) at 0 C under inert atmosphere of nitrogen. The reaction is stirred at 0 C for two hours, quenched at 0 C with water, diluted mixture with ethyl acetate, washed with water, then brine. Organics are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column (silica gel) in 0-40% ethyl acetate/hexane gradient to give 1.68g (5.33mmol, 65%) of title compound.
	With phosphorus tribromide;	The title compound was prepared in the manner analogous to Example 1F using 100F and 1-(bromomethyl)-4-[4-(trifluoromethyl)phenyl]benzene prepared from and phosphorous tribromide and <strong>[457889-46-2](4'-trifluoromethyl-biphenyl-4-yl)-methanol</strong> in a manner analagous to Example 3B. 400 MHz 1H NMR (CDCl3) delta 7.68 (m, 4H), 7.51 (d, 2H), 7.29 (d, 2H), 7.15 (m, 2H), 6.60 (d, 1H), 4.62 (s, 2H), 4.04 (s, 2H), 3.79 (s, 3H), 2.60 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 0.88 (t, 3H).
1.77 g	With phosphorus tribromide; In diethyl ether; at 20℃; for 1.5h;Cooling with ice;	To an ice cold solution of intermediate M10 (2.02g, lequiv) in anhydrous diethyl ether (20ml) protected with a CaCl2 drying tube to insulate moisture was added phosphorus tribromide (0.38ml, 0.5equiv). The mixture was stirred at room temperature for 1.5h to obtain a clear solution. TLC detection showed that the reaction was complete and then the mixture was quenched with saturated sodium bicarbonate solution. The resulting precipitate was filtered off and the filtrate was extracted with dichloromethane twice (40ml), dried over MgSO4, filtered and then evaporated in vacuo to give intermediate M11 (1.77g) as a white solid which could be used in next step without further purification.

1.77 g

With phosphorus tribromide; In diethyl ether; at 20℃; for 1.5h;

To an ice cold solution of intermediate Mi0 (2.02 g, 1 equiv) in anhydrous diethyl ether (20 ml) protected with a CaC12 drying tube to insulate moisture was added phosphorus tribromide (0.38 ml, 0.5 equiv). The mixture was stirred at room temperature for 1 .5 h to obtain a clear solution. TLC detection showed that the reaction was complete and then themixture was quenched with saturated sodium bicarbonate solution. The resulting precipitate was filtered off and the filtrate was extracted with dichloromethane twice (40 ml), dried over MgSO4, filtered and then evaporated in vacuo to give intermediate Ml 1 (1.77 g) as a white solid which could be used in next step without further purification.

References: [1]Patent: WO2005/118542,2005,A1 .Location in patent: Page/Page column 119.
[2]Patent: US2003/225158,2003,A1 .Location in patent: Page 81.
[3]Patent: EP2725024,2014,A1 .Location in patent: Paragraph 0138.
[4]Patent: US2014/171431,2014,A1 .Location in patent: Paragraph 0484.

5
[ 90035-34-0 ]
[ 457889-46-2 ]

Yield	Reaction Conditions	Operation in experiment
2.5 g	With sodium tetrahydroborate; ethanol; at 20℃; for 1h;Cooling with ice;	General procedure: To an ice cold solution of intermediate M1 (2.5g, lequiv) in absolute ethanol (20ml) was added NaBH4 (190mg) in batches, and then the mixture was stirred at room temperature for 1h. After the reaction was complete, solvent was evaporated and the residue was diluted with water. Concentrated hydrochloric acid was added dropwise to the solution in an ice bath until no more bubbles were generated. Then, sodium bicarbonate solution was added and the mixture was extracted with dichloromethane three times. The combined organic phase was washed with brine twice, dried over MgSO4, and then filtered. The filtrate was evaporated in vacuo to give intermediate M10 as a white solid (2.5g). 1H-NMR (CDCl3, 300MHz) delta 4.77(s, 2H), 7.48 (d, 2H, J=8.4), 7.61 (d, 2H, J=8.1), 7.70 (s, 4H).
2.5 g	With sodium tetrahydroborate; In ethanol; at 20℃; for 1h;	To an ice cold solution of intermediate Mi (2.5 g, 1 equiv) in absolute ethanol (20 ml) was added NaI3H4 (190 mg) in batches, and then the mixture was stirred at room temperature for 1 h. After the reaction was complete, solvent was evaporated and the residue was diluted with water. Concentrated hydrochloric acid was added dropwise to the solution in an ice bath until no more bubbles were generated. Then, sodium bicarbonate solution was added and the mixture was extracted with dichloromethane three times. The combined organic phase was washed with brine twice, dried over MgSO4, and then filtered. The filtrate was evaporated in vacuo to give intermediate M10 as a white solid (2.5 g). ?H-NMR (CDC13, 300 MHz) oe 4.77 (s, 2H), 7.48 (d, 2H, J8.4), 7.61 (d, 2H, J8.i), 7.70 (s, 4H).

References: [1]Patent: EP1216225,2005,B1 .Location in patent: Page/Page column 43.
[2]Patent: EP2725024,2014,A1 .Location in patent: Paragraph 0137.
[3]Patent: US2014/171431,2014,A1 .Location in patent: Paragraph 0483.

6
[ 127783-73-7 ]
[ 457889-46-2 ]

Yield	Reaction Conditions	Operation in experiment
93%		Example 107; 3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-ylmethyl)-propoxy]-benzoylamino}- propionic acid; Step A. (4'-Trifluoromethyl-biphenyl-4-yl)-methanol; To a solution of 4'-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (3.71g, 13.3mmol) in tetrahydro-furan (30mL) is added lithium aluminum hydride (14.6 mmol, 1.0 M in tetrahydro-furan) at 0 C under inert atmosphere of nitrogen. After the reaction is stirred at 0 C for 10 minutes following completion of hydride addition, it is quenched with ethyl acetate (lOmL) followed by potassium hydrogen sulfate (1.0 M, 15mmol) slowly at 0 C, diluted mixture with ethyl ether and filtered. Organic layers are washed with brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. Column chromatography (silica gel) with 20-80% ethyl acetate/hexane gradient gives 3.1g (12.3mmol, 93%) of title compound.

References: [1]Patent: WO2005/118542,2005,A1 .Location in patent: Page/Page column 118-119.

7
[ 195457-71-7 ]
[ 457889-46-2 ]

Yield	Reaction Conditions	Operation in experiment
79%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h;Inert atmosphere;	Under nitrogen atmosphere, at 0 C, to a stirring mixture of LiAlH4 (2.0 M THF solution, 3.0 mL, 6.00 mmol) in dry THF (10 mL), commercially available 4-[4- (trifluoromethyl)-phenyl]-benzoic acid (0.4 g, 1.5 mmol) in dry THF (10 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0 C H20 (0.23 mL), 3.0 M KOH solution (0.23 mL) and H20 (0.77 mL) were very slowly added. The mixture was stirred for 1 h at 0 C, filtered to remove the solid residue, and the organic phase dried over Na2S04. The organic solution was again filtered, concentrated to dryness and the resulting crude product purified by column chromatography using a Teledyne ISCO apparatus, eluting with CyrEtOAc (from 100:0 to 70:30) to afford the title compound (0.3 g, 79%), as white solid. 1H NMR (DMSO-d6): delta 4.56 (d, J= 5.7 Hz, 2H), 5.25 (t, J= 5.7 Hz, 1H), 7.45 (d, J= 8.1 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.81 (d, J= 8.1 Hz, 2H), 7.89 (d, J= 8.1 Hz, 2H).
79%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h;Inert atmosphere;	Step 1. Preparation of [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methanol Under nitrogen atmosphere, at 0 C., to a stirring mixture of LiAlH4 (2.0 M THF solution, 3.0 mL, 6.00 mmol) in dry THF (10 mL), commercially available 4-[4-(trifluoromethyl)-phenyl]-benzoic acid (0.4 g, 1.5 mmol) in dry THF (10 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0 C. H2O (0.23 mL), 3.0 M KOH solution (0.23 mL) and H2O (0.77 mL) were very slowly added. The mixture was stirred for 1 h at 0 C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered, concentrated to dryness and the resulting crude product purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:EtOAc (from 100:0 to 70:30) to afford the title compound (0.3 g, 79%), as white solid. 1H NMR (DMSO-d6): delta 4.56 (d, J=5.7 Hz, 2H), 5.25 (t, J=5.7 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.89 (d, J=8.1 Hz, 2H).
66.8%		Description 8a: 4-(4-trifluoromethylphenyl)-benzyl alcohol (D8a); To a solution of 4-(4-trifluoromethylphenyl)-benzoic acid (Apollo, 3g, 11.27mmol) in THF (100ml) was added dropwise a solution of LiAIH4 1 M in THF (1 1.3ml, 11.27mmol) and the mixture was stirred at room temperature for 30 minutes. Water (50ml) was then added dropwise. The insoluble material was filtered on a Celite pad and washed with CH2CI2.The filtrate was washed with CH2CI2 and the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a white solid (1.9g, yield= 66.8%); 1H NMR (300MHz, DMSO d6, ppm): 7.9 (d, 2H), 7.85 (d, 2H), 7.7 (d,2H), 7.45 (d, 2H), 5.3 (t, 1 H), 4.55 (d, 2H).

66.8%

Description 5a: 4-(4-trifluoromethylphenyl)-benzyl alcohol (D5a); To a solution of 4-(4-trifluoromethylphenyl)-benzoic acid (Apollo, 3g, 11.27mmol) in THF (100ml) was added dropwise a solution of LiAIH4 1 M in THF (11.3ml, 11.27mmol) and the mixture was stirred at room temperature for 30 minutes. Water (50ml) was then added dropwise. The insoluble material was filtered on a Celite pad and washed with CH2CI2. The filtrate was washed with CH2CI2 and the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a white solid (1.9g, yield= 66.8%). H1 NMR (300MHz, DMSO d6, ppm): 7.9 (d, 2H), 7.85 (d, 2H), 7.7 (d, 2H), 7.45 (d, 2H), 5.3 (t, 1 H), 4.55 (d, 2H).

References: [1]Patent: WO2013/78430,2013,A1 .Location in patent: Paragraph 0353.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 10101 - 10111.
[3]Patent: US9353075,2016,B2 .Location in patent: Page/Page column 122.
[4]Patent: WO2009/71504,2009,A1 .Location in patent: Page/Page column 65.
[5]Patent: WO2010/15653,2010,A1 .Location in patent: Page/Page column 39.

8
[ 647842-34-0 ]
[ 457889-46-2 ]

Yield	Reaction Conditions	Operation in experiment
95%		Example 22A (4'-Trifluoromethylbiphenyl-4-yl)methanol 12.73 ml (12.73 mmol) of a 1 M solution of lithium aluminum hydride in THF are added dropwise to a solution of 6.24 g (21.21 mmol) of ethyl 4'-trifluoromethylbiphenyl-4-carboxylate from Example 21A in 60 ml of dry THF at 0 C. After the reaction is complete, the mixture is mixed with saturated ammonium chloride solution and taken up in ethyl acetate, and the organic phase is separated off and dried over sodium sulfate. After filtration, the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). 5.1 g (20.21 mmol, 95% yield) of a colorless solid are obtained. 1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.88 (2H, d), 7.82 (2H, d), 7.71 (2H, d), 7.46 (2H, d), 5.23 (1H, t), 4.58 (2H, d). MS (EI): 252 (M+).
95%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃;	Example 10A (4'-Trifluoromethylbiphenyl-4-yl)methanol 12.7 ml (12.7 mmol) of a 1 M lithium aluminum hydride solution in THF are slowly added to a solution of 6.24 g (21.2 mmol) of ethyl 4'-trifluoromethylbiphenyl-4-carboxylate in 60 ml of dry THF at 0 C. After the reaction is complete, the mixture is hydrolyzed with saturated ammonium chloride solution and taken up in ethyl acetate, and the organic phase is separated off and dried over sodium sulfate. After filtration, the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 5:1). 5.10 g (20.2 mmol, 95% of theory) of the title compound are obtained. 1H-NMR (300 MHz, DMSO-d6, delta/ppm): 4.58 (d, 2H), 5.23 (t, 2H), 7.46 (d, 2H), 7.71 (d, 2H), 7.82 (d, 2H), 7.88 (d, 2H). MS (EI): 252 (M+).
95%		Example 15A; (4'-Trifluoromethylbiphenyl-4-yl)methanol 12.73 ml (12.73 mmol) of a 1 M solution of lithium aluminium hydride in THF are added dropwise to a solution of 6.24 g (21.21 mmol) of ethyl 4'-trifluoromethylbiphenyl-4-carboxylate in 60 ml of dry THF at 0 C. After reaction is complete, saturated ammonium chloride solution is added to the mixture, which is taken up in ethyl acetate, and the organic phase is separated off and dried over sodium sulphate. After filtration, the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). 5.1 g (20.21 mmol, 95% yield) of a colourless solid are obtained.1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.88 (2H, d), 7.82 (2H, d), 7.71 (2H, d), 7.46 (2H, d), 5.23 (1H, t), 4.58 (2H, d).MS (EI): m/z=252 (M+).

95%

With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃;

12.73 ml (12.73 mmol) of a 1 M solution of lithium aluminum hydride in THF are added dropwise to a solution of 6.24 g (21.21 mmol) of ethyl 4'-trifluoromethylbiphenyl-4-carboxylate in 60 ml of dry THF at 0 C. After the reaction is complete, the mixture is mixed with saturated ammonium chloride solution and taken up in ethyl acetate, and the organic phase is separated off and dried over sodium sulfate. After filtration, the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). 5.1 g (20.21 mmol, 95% of theory) of a colorless solid are obtained.1H-NMR (300 MHz, DMSO-d6, delta/ppm): 7.88 (2H, d), 7.82 (2H, d), 7.71 (2H, d), 7.46 (2H, d), 5.23 (1H, t), 4.58 (2H, d).MS (EI): 252 (M+).

9
[ 457889-46-2 ]
[ 1128269-51-1 ]
C₃₁H₂₂F₆N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step B. 5-(Trifluoromethyl)-1-(2'-[4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-2,3'-bipyridin-6-yl)-1H-pyrazole-4-carboxylic acid; To a vial were added successively KOtBu (15.0 mg, 0.13 mmol), <strong>[457889-46-2][4'-(trifluoromethyl)biphenyl-4-yl]methanol</strong> (US Patent 2004209936) (36.0 mg, 0.14 mmol) and DMF (0.3 mL). After 5 min, the title compound from Example 237 Step A (20.0 mg, 0.05 mmol) was added. After 30 min, the reaction mixture was treated with NaOH (0.1 mL, 3 N aqueous, 0.3 mmol), MeOH (0.1 mL) and 1,4-dioxane (0.1 mL) at 50 C. for 20 min. Reverse phase HPLC using a YMC C-18 column (65 to 100% acetonitrile in water, each with 0.1% v/v TFA) gave the title compound: LCMS m/z 584.9 [M+H]+; 1H NMR (400 MHz, CDCl3) delta 8.44 (dd, J=7.6, 1.9 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 8.27 (dd, J=4.9, 2.0 Hz, 1H), 8.20 (s, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.69 (s, 4H), 7.62-7.53 (m, 5H), 7.10 (dd, J=7.5, 4.9 Hz, 1H), 5.63 (s, 2H).

References: [1]Patent: US2009/209556,2009,A1 .Location in patent: Page/Page column 58.

10
[ 457889-46-2 ]
[ 1439366-95-6 ]

References: [1]Patent: WO2013/78430,2013,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 10101 - 10111.
[3]Patent: US9353075,2016,B2 .

11
[ 457889-46-2 ]
[ 1659-31-0 ]
[ 632-20-2 ]
[ 1439368-11-2 ]

Yield	Reaction Conditions	Operation in experiment
100%		Under nitrogen atmosphere, to a stirred mixture of <strong>[457889-46-2][4-[4-(trifluoromethyl)-phenyl]-phenyl]-methanol</strong> (0.3 g, 1.19 mmol) in dry CH2Cl2 (2.0 mL), DMAP (0.015 g, 0.12 mmol) and di-2-pyridyl-carbonate (0.309 g, 1.43 mmol) were added. The reaction mixture was left to react at rt for 15 h, then diluted with CH2Cl2 and washed first with a saturated NH4Cl solution (3.0 mL) and subsequently with a saturated NaHCO3 solution (3×3 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford a colorless oil (0.3 g, 68%), as a mixture (ratio 1.8:1) of 2-pyridyl-[4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2-oxopyridine-1-carboxylate. The mixture of isomers was not separated and used in the next step without any further purification. To a stirred mixture of D-threonine (0.063 g, 0.53 mmol) and NaHCO3 (0.067 g, 0.8 mmol) in H2O (3.0 mL), the crude mixture containing 2-pyridyl-[4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2-oxopyridine-1-carboxylate (0.3 g, 0.8 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound as transparent oil (0.21 g, quant.), which was used in the next step without further purification. MS (ESI) m/z: 415 [M-NH4]+; (ESI) m/z: 396 [M-H]-. 1H NMR (DMSO-d6): delta 1.11 (d, J=6.4 Hz, 3H), 3.97 (dd, J=3.5, 8.9 Hz, 1H), 4.05-4.12 (dq, J=3.5, 6.4 Hz, 1H), 5.13 (s, 2H), 7.00 (d, J=8.9 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.1 Hz, 2H), 7.91 (d, J=8.1 Hz, 2H), 12.59 (s, 1H).
0.21 g		To a stirred mixture of D-threonine (0.063 g, 0.53 mmol) and NaHC03 (0.067 g, 0.8 mmol) in H20 (3.0 mL), the crude mixture containing 2-pyridyl-[4-[4-(trifluoromethyl)- phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2- oxopyridine-l-carboxylate (0.3 g, 0.8 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et20 (3x5 mL). The aqueous phase was acidified with 2.0 M HC1 solution to pH 2-3 and subsequently extracted with EtOAc (3x10 mL). The organic fraction was dried over Na2S04, filtered and concentrated to dryness to afford the title compound as transparent oil (0.21 g, quant.), which was used in the next step without further purification. MS (ESI) m/z: 415 [M- NH4]+; (ESI) m/z: 396 [M-H]-. 1H NMR (DMSO-d6): delta 1.1 1 (d, J= 6.4 Hz, 3H), 3.97 (dd, J= 3.5, 8.9 Hz, 1H), 4.05 - 4.12 (dq, J= 3.5, 6.4 Hz, 1H), 5.13 (s, 2H), 7.00 (d, J= 8.9 Hz, 1H), 7.51 (d, J= 8.1 Hz, 2H), 7.75 (d, J= 8.1 Hz, 2H), 7.82 (d, J= 8.1 Hz, 2H), 7.91 (d, J= 8.1 Hz, 2H), 12.59 (s, 1H).

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 10101 - 10111.
[2]Patent: US9353075,2016,B2 .Location in patent: Page/Page column 123.
[3]Patent: WO2013/78430,2013,A1 .Location in patent: Paragraph 0354; 0355.

12
[ 457889-46-2 ]
[ 1659-31-0 ]
[ 1439368-08-7 ]
[ 1439368-10-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In dichloromethane; at 20℃; for 15h;Inert atmosphere;	Under nitrogen atmosphere, to a stirred mixture of [4-[4-(trifluoromethyl)-phenyl]- phenylj-methanol (0.3 g, 1.19 mmol) in dry CH2C12 (2.0 mL), DMAP (0.015 g, 0.12 mmol) and di-2-pyridyl-carbonate (0.309 g, 1.43 mmol) were added. The reaction mixture was left to react at rt for 15 h, then diluted with CH2C1 and washed first with a saturated NH4CI solution (3.0 mL) and subsequently with a saturated NaHC03 solution (3X3 mL). The organic fraction was dried over Na2S0 , filtered and concentrated to dryness to afford a colorless oil (0.3 g, 68%), as a mixture (ratio 1.8: 1) of 2-pyridyl-[4-[4-(trifluoromethyl)- phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2- oxopyridine-l-carboxylate. The mixture of isomers was not separated and used in the next step without any further purification. MS (ESI) m/z : 396 [M-Na]+, 412 [M-K]+.
	With dmap; In dichloromethane; at 20℃; for 15h;Inert atmosphere;	Under nitrogen atmosphere, to a stirred mixture of <strong>[457889-46-2][4-[4-(trifluoromethyl)-phenyl]-phenyl]-methanol</strong> (0.3 g, 1.19 mmol) in dry CH2Cl2 (2.0 mL), DMAP (0.015 g, 0.12 mmol) and di-2-pyridyl-carbonate (0.309 g, 1.43 mmol) were added. The reaction mixture was left to react at rt for 15 h, then diluted with CH2Cl2 and washed first with a saturated NH4Cl solution (3.0 mL) and subsequently with a saturated NaHCO3 solution (3×3 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford a colorless oil (0.3 g, 68%), as a mixture (ratio 1.8:1) of 2-pyridyl-[4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl carbonate and [4-[4-(trifluoromethyl)-phenyl]-phenyl]-methyl-2-oxopyridine-1-carboxylate. The mixture of isomers was not separated and used in the next step without any further purification. MS (ESI) m/z: 396 [M-Na]+, 412 [M-K]+.

References: [1]Patent: WO2013/78430,2013,A1 .Location in patent: Paragraph 0354.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 10101 - 10111.
[3]Patent: US9353075,2016,B2 .Location in patent: Page/Page column 122; 123.

13
[ 128796-39-4 ]
[ 457889-46-2 ]

References: [1]Patent: EP2725024,2014,A1 .
[2]Patent: US2014/171431,2014,A1 .
[3]Patent: US2009/215843,2009,A1 .

14
[ 1122-91-4 ]
[ 457889-46-2 ]

References: [1]Patent: EP2725024,2014,A1 .
[2]Patent: US2014/171431,2014,A1 .
[3]Patent: WO2019/63634,2019,A1 .

15
[ 457889-46-2 ]
[ 1417526-27-2 ]