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Chemical Structure| 90035-34-0
Chemical Structure| 90035-34-0
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Product Details of [ 90035-34-0 ]

CAS No. :90035-34-0 MDL No. :MFCD01862519
Formula : C14H9F3O Boiling Point : -
Linear Structure Formula :- InChI Key :HIMSXOOFWOOYFK-UHFFFAOYSA-N
M.W : 250.22 Pubchem ID :2782712
Synonyms :

Calculated chemistry of [ 90035-34-0 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.07
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 62.27
TPSA : 17.07 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.06 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.29
Log Po/w (XLOGP3) : 3.89
Log Po/w (WLOGP) : 5.34
Log Po/w (MLOGP) : 3.91
Log Po/w (SILICOS-IT) : 4.68
Consensus Log Po/w : 4.02

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.14
Solubility : 0.0182 mg/ml ; 0.0000729 mol/l
Class : Moderately soluble
Log S (Ali) : -3.95
Solubility : 0.0283 mg/ml ; 0.000113 mol/l
Class : Soluble
Log S (SILICOS-IT) : -5.75
Solubility : 0.000441 mg/ml ; 0.00000176 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.65

Safety of [ 90035-34-0 ]

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

Application In Synthesis of [ 90035-34-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 90035-34-0 ]
  • Downstream synthetic route of [ 90035-34-0 ]

[ 90035-34-0 ] Synthesis Path-Upstream   1~14

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YieldReaction ConditionsOperation in experiment
96%
Stage #1: at 70℃; for 0.25 h;
Stage #2: With water; sodium carbonate In propan-1-ol for 1 h; Reflux
Step A:
4'-(trifluoromethyl)biphenyl-4-carbaldehyde
A round bottom flask was charged with 4-bromobenzaldehyde (69.6 g, 376 mmol), 4-(trifluoromethyl)phenylboronic acid (75.0 g, 395 mmol) and 1-propanol (627 mL).
The reaction mixture was stirred for 15 minutes at 70° C. until a clear solution was obtained.
The resulting solution was treated with triphenylphosphine (888 mg, 3.38 mmol), palladium(II) acetate (256 mg, 1.13 mmol), 2M sodium carbonate (226 mL, 451 mmol) and water (138 mL).
The reaction was heated at reflux for 1 hour, open to air.
Water (900 mL) was then added and the reaction was cooled to 7° C. in an ice bath.
The reaction was thoroughly stirred for 30 minutes until the title compound precipitated out.
The mixture was then filtered and the solid washed with cold water (~600 mL).
The solid was then solubilized in diethylether (500 mL) and filtered through a pad of celite and silica, rinsing with diethylether (2*500 mL).
Removal of the solvent under reduced pressure afforded 4'-(trifluoromethyl) biphenyl-4-carbaldehyde (90.0 g, 96percent) as a pure white solid. 1H NMR (400 MHz, CDCl3, δ): 7.75 (s, 4H) 7.76-7.79 (m, 2H) 7.96-8.04 (m, 2H) 10.10 (s, 1H). MS (M+1): 250.3.
94% With tetrabutylammomium bromide; potassium carbonate In 1,4-dioxane; water at 20 - 70℃; for 2 h; Preparation 5; (R,S)-1-(4'-Trifluoromethyl-biphenyl-4-yl)-ethano; Step A. 4'-Trifluoromethyl-biphenyl-4-carbaldehyde; To an ambient temperature solution of 4- (trifluoromethyl)phenylboronic (4.64 g, 24.43 mmol) in dioxane/water (15/15 mL) is added 4-bromo-benzaldehyde (4.42 g, 22.21 mmol), tetrabutylammonium bromide (7.16 g, 22.21 mmol, potassium carbonate (7.67 g, 55.53 mmol) and is degassed for 10 min. Palladium (II) (748 mg, 1.11 mmol) is added and the reaction mixture is heated to 70 °C. After 2 h TLC (20percent EtOAc/hexane) indicates complete consumption of starting material. The reaction is cooled to room temperature diluted with water and extracted with EtOAc (3 x 200 mL). The combined organic extracts are washed with brine, dried (MgS04), filtered, concentrated and chromatographed (330 g Si02, 5percent EtOAc/Hexanes) to yield the title compound (5.54 g, 94percent). 1NMR (400MHz, CDCl3) 8 ppm: 10.09 (s, 1H), 8.01-8.00 (m, 1H), 7.99-7.98 (m, 1H), 7.78-7.75 (m, 2H), 7.74 (s, 4H); Preparation 31 (R,S)-1-(4'-Trifluoromethyl-biphenyl-4-yl)-ethanol Step A. 4'-Trifluoromethyl-biphenyl-4-carbaldehyde To an ambient temperature solution of 4- (trifluoromethyl)phenylboronic (4.64 g, 24.43 mmol) in dioxane/water (15/15 mL) is added 4-bromo-benzaldehyde (4.42 g, 22.21 mmol), tetrabutylammonium bromide (7.16 g, 22.21 mmol, potassium carbonate (7.67 g, 55.53 mmol) and degassed for 10 min. Palladium(II) acetate (748 mg, 1.11 mmol) is added and the reaction mixture is heated to 70 °C. After 2 h TLC (20percent EtOAc/hexane) indicates complete consumption of starting material. The reaction is cooled to room temperature diluted with water and extracted with EtOAc (3 x 200 mL). The combined organic extracts are washed with brine, dried (MgS04), filtered, concentrated and chromatographed (330 g Si02, 5percent EtOAc/Hexanes) to yield the title compound (5.54 g, 94percent). 1NMR (400MHz, CDCl3) No. ppm: 10.09 (s, 1H), 8.01-8.00 (m, 1H), 7.99-7.98 (m, 1H), 7.78-7.75 (m, 2H), 7.74 (s, 4H).
89% With tetrabutylammomium bromide; palladium diacetate; potassium carbonate In 1,4-dioxane; water at 70℃; for 3 h; Inert atmosphere Bromobenzaldehyde (1 eq, 0.95 mmol), 4-(Trifluoromethyl) phenylboronic acid (1.1 eq, 1.05 mmol), palladium (II) acetate, TBAB (1 eq, 0.95 mmol) and K2CO3 (2.5 eq, 2.37 mmol) were dissolved in a water/dioxane mixture (1/1, ν/ν, 1.5/1.5 mL) which was further deoxygenated three times (vacuum/ar). Palladium (II) acetate (0.05 eq, 0.05 mmol) was then added to the solution and the reaction mixture was heated to 70°C under stirring and argon for 3h. Water was added followed by extraction with EtOAc (3 x 10mL). The organic phases were washed with saturated NaCl then dried and filtered. After removal of the solvent, the remaining paste was purified using column chromatography (silica gel, 95/5 Hex/EtOAc) to obtain the desired compound (Rf = 0.35) as a colourless solid (210 mg, 89percent).1H NMR (CDCl3) δ: 10.09 (s, 1H), 7.99 (m, 2H), 7.77 (m, 2H), 7.74 (m, 4H).
86% With C22H24Cl2N6O2Pd2; potassium carbonate In ethanol; water for 4 h; Reflux General procedure: In a 10 mL glass tube containing a Teflon-coated stir bar was placed p-bromobenzaldehyde 2e (0.05 g, 0.27 mmol, 1 equiv), phenylboronic acid 1a (0.05 g, 0.40 mmol, 1.5 equiv), 2M K2CO3 (0.33 mL, 0.67 mmol, 2.5 equiv), 4-AAP-Pd(II) (0.28 mg, 0.3 mol percent Pd) and EtOH (2 mL). The mixture was stirred at reflux for 4 h. After cooling, the mixture was diluted with ether Et2O (5 mL), washed with sat. aq. NaHCO3 (3 mL), brine (3 mL) and dried over Na2SO4. Evaporation of the solvent and purification of the residue over a silica gel column (Hex: AcOEt 90:10), furnished the biphenyl 3q.
82.7% With C14H8F6O4; nickel trifluoroacetate; potassium carbonate; triphenylphosphine; 1-butyl-3-methylimidazolium trifluoromethanesulfonimide In water at 80℃; for 18 h; Green chemistry General procedure: A 50mL round-bottomed flask was charged with aryl halides (0.5 mmol), arylboronic acid (0.6 mmol), K2CO3 (1.25 mmol), Ni(TFA)2 (0.025 mmol), β-diketone ligand (0.05 mmol), PPh3 (0.05 mmol), 1.5 g of the ionic liquid (IL) and 0.5 g of H2O. Then, the mixture was stirred at 80 open to the atmosphere. The reaction was monitored by TLC and then stopped after the starting material was completely consumed. Next, the mixture was diluted with water (10 mL) and extracted with ether (310 mL). The combined organic layers were washed with brine (310 mL), dried over MgSO4, and concentrated in vacuum. The cross coupling products were not the only product of the reaction. A small amount of homo-coupled products and removal boron product from boric acids were observed. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate, 10:1).
82.9% at 90℃; for 6 h; General procedure: A mixture of compound 1 (3g, 16.21mmol), phenylboronic acid (2.57 g, 21.08 mmol), anhydrous potassium carbonate (K2CO3) (3.36 g, 24.32 mmol), tetrakistriphenylphosphine palladium (Pd(PPh3)4) 93.69 mg, 81.07 μmol) and PEG400 (18 ml) were poured into a 50 mL reaction vial and continued stirring at 90 °C about 6 h, the reaction mixture was added with distilled water, and extracted with ethyl acetate (3 × 150 mL). The organic extracts were dried with anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude residue was purified by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain the pure product as a white solid 2b.
77% With sodium carbonate In 1,2-dimethoxyethane; water at 20℃; for 20 h; Heating / reflux A 3 L 3-neck flask fitted with top stirrer, condenser and argon inlet/outlet was charged with 4-trifluoromethylbenzene boronic acid (90.0 g, 0.474 mol), 4- bromobenzaldehyde (83.29 g, 0.450 mol) and 1,2-dimethoxyethane (1.3 L), followed by 2M aqueous sodium carbonate (474 mL) and palladium acetate (5.32 g, 0.0237 mol). The stirring mixture was heated to reflux for 4 h under argon, then allowed to cool to room temperature over 16 h. The reaction mixture was filtered through hyflo. The filtrate was diluted with saturated brine and extracted 3x with ethyl acetate. The combined extracts were dried over magnesium sulfate and filtered through hyflo, giving a clear orange filtrate which was evaporated to a solid (ca. 120g, crude). Flash chromatography (silica, 10-50percent dichloromethane in pet. ether, 10percent steps) gave a white solid which dissolved in hexane (500mL) on boiling. Crystallisation, finally in ice, gave the title compound as a solid which was filtered off, washed with ice cold hexane and dried, (86.33g, 77percent). 'H-NMR (CDCl3) 6 7.77-8. 03 (8H, m), 10.09 (1H, s).
62% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 110℃; for 24 h; Inert atmosphere The preparation method of the biphenyl compound is:4.625 g (25 mmol) p-bromobenzaldehyde, 9.495 g (50 mmol)P-trifluoromethylbenzeneboronic acid,1.445 g (1.25 mmol) of tetrakis(triphenylphosphine)palladium, 13.8 g (100 mmol) of potassium carbonate,100 mL of ethylene glycol dimethyl ether and 15 mL of water are mixed.Nitrogen was pumped out three times and reacted at 110 degrees for 24 hours.After the reaction is completed, it is extracted with dichloromethane, and the organic phase is washed with water.Washed with saturated saline,Dry over anhydrous magnesium sulfate,The product was isolated by column chromatography (3.878 g).The yield was about 62percent.
55% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 90℃; for 12 h; Inert atmosphere 4-bromobenzaldehyde 1a (1.60 g, 8.8 mmol),4-(trifluoromethyl)phenylboronic acid 1b (2.0 g, 10.5 mmol), fourTriphenylphosphine palladium (508mg, 0.44mmol)And sodium carbonate (2.33g, 22.0mmol)Soluble in a mixed solution of 34mL ethylene glycol dimethyl ether and water (V/V=15/2),The reaction was carried out at 90° C. under argon protection for 12 hours. The reaction solution was concentrated under reduced pressure and 200 mL of water was added.The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A).4'-(trifluoromethyl)-[1,1'-biphenyl]-4-carbaldehyde 1c (1.19 g, white solid) was obtained, yield: 55.0percent.

Reference: [1] Patent: US2012/165343, 2012, A1, . Location in patent: Page/Page column 15
[2] Applied Organometallic Chemistry, 2012, vol. 26, # 9, p. 478 - 482
[3] Patent: WO2005/118542, 2005, A1, . Location in patent: Page/Page column 43; 55-56
[4] Green Chemistry, 2011, vol. 13, # 1, p. 169 - 177
[5] ChemMedChem, 2016, p. 2194 - 2204
[6] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 4, p. 787 - 792
[7] Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 2821 - 2826
[8] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 2975 - 2990
[9] Catalysis Communications, 2014, vol. 58, p. 154 - 157
[10] Tetrahedron Letters, 2018, p. 681 - 686
[11] Patent: WO2003/87088, 2003, A2, . Location in patent: Page/Page column 18
[12] Patent: CN108484412, 2018, A, . Location in patent: Paragraph 0116; 0117; 0118; 0119
[13] Patent: CN107759522, 2018, A, . Location in patent: Paragraph 0147; 0152; 0153-0155
[14] Patent: EP2725024, 2014, A1, . Location in patent: Paragraph 0125; 0126
[15] Patent: US2014/171431, 2014, A1, . Location in patent: Paragraph 0471; 0472
[16] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 453 - 462
[17] Angewandte Chemie - International Edition, 2018, vol. 57, # 17, p. 4622 - 4626[18] Angew. Chem., 2018, vol. 130, # 17, p. 4712 - 4716,5
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YieldReaction ConditionsOperation in experiment
12.1 g With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 85℃; for 2 h; Reference Example 6-2
4'-(Trifluoromethyl)biphenyl-4-carbaldehyde
A mixture of 4-bromobenazotrifluoride (10.0 g), 4-formylphenylboronic acid (7.33 g), tetrakis(triphenylphosphine)palladium(0) (308 mg), potassium carbonate (30.7 g), tetrahydrofuran (300 mL) and water (100 mL) was stirred at 85°C for 2 hours.
After cooling the reaction mixture to room temperature, water was added to it, which was then extracted with ethyl acetate twice and the combined organic layers were washed with saturated brine.
After adding anhydrous magnesium sulfate to the organic layers, the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure.
The resulting residue was dissolved in n-hexane (60 mL) with heating and thereafter cooled to 0°C.
The resulting precipitate was recovered by filtration to give the titled compound as a gray solid (12.1 g).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.71 - 7.80 (m, 6 H) 7.96 - 8.03 (m, 2 H) 10.09 (s, 1 H).
MS EI posi: 250[M]+.
Reference: [1] Patent: WO2005/3118, 2005, A1, . Location in patent: Page/Page column 34
[2] Patent: WO2006/63791, 2006, A1, . Location in patent: Page/Page column 27
[3] Patent: WO2006/63811, 2006, A2, . Location in patent: Page/Page column 30
[4] Patent: WO2006/63812, 2006, A1, . Location in patent: Page/Page column 24
[5] Journal of the American Chemical Society, 2009, vol. 131, p. 8163 - 8172
[6] Chemical Communications, 2015, vol. 51, # 40, p. 8439 - 8441
[7] Patent: EP2881384, 2015, A1, . Location in patent: Paragraph 0295; 0296
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YieldReaction ConditionsOperation in experiment
90.1% With potassium carbonate In tolueneInert atmosphere; Reflux 4'-trifiuoromethy.biphenyi-4-carbaldehyde (Compound 25}Pd(PPh3)4 (6 g) was added to a mixture of 4-fbrmyiphenylboronic acid plnacoS cyclic ester (53 g, 0,22 mol), 4-trifluoromethylbromobenzene(50 g, 0.22 mol), and potassium carbonate (63 g, 0.46 mol) In toluene (2 L) under nitrogen protection. The mixture was refiuxed overnight. After cooling to room temperature, the solvent was removed under vacuum. To the residue were added water (l L) and ethyl acetate (1 L), The organic phase was collected, and the water phase was extracted with ethyl acetate (1 L x2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPFC (PE: EA = 50: 1) to afford the title compound (50.2 g, 90.1percent). LC- S: 251.2 (M+l).
Reference: [1] Patent: WO2012/130299, 2012, A1, . Location in patent: Page/Page column 113
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Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5813 - 5816
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Reference: [1] New Journal of Chemistry, 2016, vol. 41, # 1, p. 372 - 376
[2] Organic Process Research and Development, 2012, vol. 16, # 1, p. 117 - 122
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Reference: [1] Patent: EP1216225, 2005, B1, . Location in patent: Page/Page column 43
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Reference: [1] Organometallics, 2011, vol. 30, # 6, p. 1299 - 1302
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Reference: [1] Patent: US2004/63753, 2004, A1,
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Reference: [1] Patent: US4520007, 1985, A,
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Reference: [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 24, p. 6959 - 6963[2] Angew. Chem., 2016, vol. 128, # 24, p. 7073 - 7077,5
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Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 20, p. 3909 - 3912
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Reference: [1] Organometallics, 2011, vol. 30, # 6, p. 1299 - 1302
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Reference: [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 24, p. 6959 - 6963[2] Angew. Chem., 2016, vol. 128, # 24, p. 7073 - 7077,5
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YieldReaction ConditionsOperation in experiment
2.5 g at 20℃; for 1 h; 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) δ 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 1 h; 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) ö 4.77 (s, 2H), 7.48 (d, 2H, J8.4), 7.61 (d, 2H, J8.i), 7.70 (s, 4H).
Reference: [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
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