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[ CAS No. 445303-67-3 ] {[proInfo.proName]}

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Chemical Structure| 445303-67-3
Chemical Structure| 445303-67-3
Structure of 445303-67-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 445303-67-3 ]

CAS No. :445303-67-3 MDL No. :MFCD09878544
Formula : C13H15BF4O2 Boiling Point : -
Linear Structure Formula :- InChI Key :FPCSARGPMNDYAO-UHFFFAOYSA-N
M.W : 290.06 Pubchem ID :46739054
Synonyms :

Calculated chemistry of [ 445303-67-3 ]

Physicochemical Properties

Num. heavy atoms : 20
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.54
Num. rotatable bonds : 2
Num. H-bond acceptors : 6.0
Num. H-bond donors : 0.0
Molar Refractivity : 67.88
TPSA : 18.46 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.31 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 3.89
Log Po/w (WLOGP) : 4.72
Log Po/w (MLOGP) : 3.07
Log Po/w (SILICOS-IT) : 3.3
Consensus Log Po/w : 3.0

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.18
Solubility : 0.0192 mg/ml ; 0.0000662 mol/l
Class : Moderately soluble
Log S (Ali) : -3.98
Solubility : 0.0307 mg/ml ; 0.000106 mol/l
Class : Soluble
Log S (SILICOS-IT) : -5.16
Solubility : 0.00203 mg/ml ; 0.00000698 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.91

Safety of [ 445303-67-3 ]

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 [ 445303-67-3 ]

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

  • Downstream synthetic route of [ 445303-67-3 ]

[ 445303-67-3 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 142808-15-9 ]
  • [ 73183-34-3 ]
  • [ 445303-67-3 ]
YieldReaction ConditionsOperation in experiment
67% With potassium acetate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; To a stirred solution of 4-bromo-2-fIuoro-1-(trifluoromethyl)benzene (5 g, 20.57 mmol) in 1,4- dioxane (400 mL), bis(pinacolato)diboron (5.2 g, 20.57 mmol) was added and deoxygenated twice. Potassium acetate (6.05 g, 61.72 mmol), PdCI2(PPh3)2 (0.43 g, 0.61 mmol) were added to it and again deoxygenated. The reaction was heated to 100C for 12 h. The reaction mixture was filtered through celite bed and evaporated to dryness. It was taken in ethyl acetate (200 mL) and was washed with water (2 x 100 mL). The final organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness to afford crude compound, which was purified through column chromatography (silica: 100-20 mesh, eluent: 5% ethyl acetate in hexane) to afford compound (4 g, 67%).
61% With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 10h;microwave irradiation; 4-Bromo-2-fluoro-1-(trifluoromethyl)benzene (5.08 g, 20.91 mmol) was dissolved in DMSO (40 mL), then 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.16 g, 24.25 mmol), PdCl2 (dppf) (0.756 g, 1.05 mmol) and potassium acetate (4.10 g, 41.81 mmol) were added and the mixture was heated in an oil bath at 80 C. for 10 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried with Na2SO4 and evaporated. The residue was purified by automated flash chromatography on a Biotage KP-SIL 340 g column. A gradient from 0% to 20% of EtOAc in heptane over 10 CV was used as mobile phase. 2-(3-Fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (3.72 g, 61%) was isolated.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; N,N-dimethyl-formamide; at 80℃; for 2 - 2.5h;Product distribution / selectivity; a) 6-[3-Fluoro-4-(trifluoromethyl)phenyl]-8-nitro-3,4-dihydro-2(1 H)-quinolinoneTo a stirred solution of <strong>[142808-15-9]4-bromo-2-fluoro-1-(trifluoromethyl)benzene</strong> (1.0 g, 4.1 mmol), bis(pinacolato)diboron (1.1 g, 4.3 mmol) and potassium acetate (1.2 g, 122 mmol) in dimethylformamide (50 mL) was added [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane adduct (81 mg, 0.11 mmol). After purging with nitrogen, the reaction was heated to 80 0C and EPO <DP n="89"/>stirred for 2 h. 6-bromo-8-nitro-3,4-dihydro-2(1 H)-quinolinone (example 77a, 1.0 g, 3.7 mmol), cesium fluoride (1.3 g, 8.4 mmol), and tetrakis(triphenylphosphine)palladium (0) (130 mg, 0.11 mmol) were added and the reaction stirred at 100 0C for 18 h. After cooling to room temperature, the reaction was evaporated to dryness under vacuum. The residue was taken up in ethyl acetate, filtered to remove insolubles, washed with 1 M aq hydrochloric acid, brine, dried (MgSO4), filtered and concentrated under vacuum. Purification by flash chromatography on silica gel (3% ethyl acetate/dichloromethane) gave the title compound (0.77 g, 59%) as a yellow solid. MS (ES) m/e 355.0 (M + H)+.; +/- 6-f3-Fluoro-4-(trifluoromethvnphenyl1-3-hyclroxy-3.4-dihvdro-2(1 H)-quinolinone 4-Bromo-2-fluoro-1-(trifluoromethyl)benzene (0.091 mL, 0.375 mmol), bis(pinacolato)diboror) (0.10 g, 0.394 mmol), potassium acetate (0.11 g, 1.12 mmol), dichloro[1 ,1 '-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.020 g, 0.027 mmol) in DMF (2.0 mL) were heated to 800C under nitrogen for 2.5 hours. After the reaction was cooled, dichloro[1 ,1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.020 g, 0.027 mmol) was added followed by addition of + 6-bromo-3-hydroxy-3,4-dihydro- 2(1 H)-quinolinone (example 85b, 0.095 g, 0.392 mmol) and 2M Na2CO3 in water (0.98 mL). The reaction was heated to 800C. After 12 hours the reaction mixture was cooled and diluted with ethyl acetate, then washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reverse-phase preparative HPLC (10% CH3CN/H2O to 100% CH3CN/H2O with 0.1% TFA) to give the title compound as a solid. 1H NMR (400MHz, D6-DMSO) delta 10.34 (bs, 1 H), 7.79 (m, 2H), 7.69 (m, 2H), 7.59 (d, J = 8.6Hz, 1 H), 6.96 (d, J = 8.3 Hz, 1 H), 5.58 (bs, 1 H), 4.18 (m, 1 H), 3.13 (dd, 1 H), 2.93 (dd, 1 H).
With potassium acetate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 100℃; for 4.5h; PREPARATION 32 2-[3-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A solution of <strong>[142808-15-9]4-bromo-2-fluoro-1-(trifluoromethyl)benzene</strong> (20.57 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (22.62 mmol), potassium acetate (61.70 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.822 mmol) in dioxane (200 mL) was heated at 100 C. for 4.5 h. The reaction mixture was cooled, dissolved into ethyl acetate (500 mL), and washed with water (3*200 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the crude title product.
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane;Inert atmosphere; Example 80A2-[3-Fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A mixture of 25 g (99.8 mmol) of <strong>[142808-15-9]4-bromo-2-fluoro-1-(trifluoromethyl)benzene</strong> in 500 ml of dioxane was admixed under argon at RT with 27.8 g (109.8 mmol) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborolane, 2.91 g (3.99 mmol) of 1,1-bis(diphenylphosphine)-ferrocenedichloropalladium(II) dichlormethane complex and with 29.38 g (299.4 mmol) of potassium acetate. The reaction mixture was stirred below 100 C. for several hours until conversion was substantially complete. The mixture was filtered through Celite and admixed with water. After addition of ethyl acetate and phase separation, the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (silica gel-60, eluent: cyclohexane/ethyl acetate 3:1). This gave 18.22 g of crude product in 73% purity (LC-MS), which was reacted without any further purification steps.1H NMR (400 MHz, DMSO-d6): delta=7.82 (dd, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 1.32 (s, 12H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 0.166667h;Microwave irradiation; General procedure: To 2 mL of 1,4-dioxane in microwave reaction vessel were added bromobenzene (0.20 g, 1.27 mmol), bis(pinacolato)diboron (0.36 g, 1.40 mmol), potassium acetate (0.38 g, 3.8 mmol), and PdCl2(dppf) (0.028 g, 0.038 mmol). The reaction mixture was heated to 110 C by microwave irradiation at power 100 W for 10 min. After solvent was removed under reduced pressure, the residue was purified by dry column vacuum chromatography (DCVC) using dichloromethane (DCM) as eluent provided the 0.16 g in 62 % yield;

  • 2
  • [ 445303-67-3 ]
  • [ 912954-29-1 ]
  • +/-6-[3-fluoro-4-(trifluoromethyl)phenyl]-3-hydroxy-3,4-dihydro-2(1H)-quinolinone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; water; N,N-dimethyl-formamide; at 80.0℃; for 12.0h; +/- 6-f3-Fluoro-4-(trifluoromethvnphenyl1-3-hyclroxy-3.4-dihvdro-2(1 H)-quinolinone 4-Bromo-2-fluoro-1-(trifluoromethyl)benzene (0.091 mL, 0.375 mmol), bis(pinacolato)diboror) (0.10 g, 0.394 mmol), potassium acetate (0.11 g, 1.12 mmol), dichloro[1 ,1 '-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.020 g, 0.027 mmol) in DMF (2.0 mL) were heated to 800C under nitrogen for 2.5 hours. After the reaction was cooled, dichloro[1 ,1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.020 g, 0.027 mmol) was added followed by addition of + 6-bromo-3-hydroxy-3,4-dihydro- 2(1 H)-quinolinone (example 85b, 0.095 g, 0.392 mmol) and 2M Na2CO3 in water (0.98 mL). The reaction was heated to 800C. After 12 hours the reaction mixture was cooled and diluted with ethyl acetate, then washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reverse-phase preparative HPLC (10% CH3CN/H2O to 100% CH3CN/H2O with 0.1% TFA) to give the title compound as a solid. 1H NMR (400MHz, D6-DMSO) delta 10.34 (bs, 1 H), 7.79 (m, 2H), 7.69 (m, 2H), 7.59 (d, J = 8.6Hz, 1 H), 6.96 (d, J = 8.3 Hz, 1 H), 5.58 (bs, 1 H), 4.18 (m, 1 H), 3.13 (dd, 1 H), 2.93 (dd, 1 H).
  • 3
  • [ 445303-67-3 ]
  • [ 6933-10-4 ]
  • [ 1021598-13-9 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 17h; 33 3'-fluoro-2-methyl-4'-(trifluoromethyl)-4-biphenylamine PREPARATION 33 3'-fluoro-2-methyl-4'-(trifluoromethyl)-4-biphenylamine A solution of 4-bromo-3-methylaniline (0.34 mmol), 2-[3-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.52 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.017mmol) in 2M aqueous potassium carbonate solution (1 mL) and N,N-dimethylformamide (1 mL) was heated at 100° C. for 17 h. The reaction mixture was cooled, poured into half-saturated aqueous sodium bicarbonate solution (2 mL), and extracted with (3*5 mL) diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford the crude title product.
  • 4
  • [ 445303-67-3 ]
  • [ 58481-11-1 ]
  • [ 1251844-24-2 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.166667h;microwave irradiation; Methyl 2-chloroisonicotinate (2.86 g, 16.67 mmol), PdCl2 (dppf) (0.278 g, 0.38 mmol) and potassium carbonate (1.161 mL, 19.24 mmol) were distributed equally over 3 microwave reaction vials. 2-(3-Fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (3.72 g, 12.82 mmol) dissolved in methanol (45 mL) was split into 3 equal portions and added to the vials. The vials were capped and heated in a single node microwave reactor at 100° C. for 10 min each. The contents of the vials was combined and the solvent evaporated. The residue was dissolved in DCM and washed with water. The organic phase was filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage.(R). KP-SIL 340 g column. 7:1 of heptane:EtOAc over 10 CV was used as mobile phase. Crude methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)isonicotinate (2.92 g, 76percent) was isolated. MS m/z 300 (M+H)+
  • 5
  • [ 445303-67-3 ]
  • [ 219581-07-4 ]
YieldReaction ConditionsOperation in experiment
With Oxone In water; acetone for 0.25h; 7 A solution of OXONE (1 .50 g, 2.45 mmol) in water (7.8 mL) was added drop-wise over approximately 4 minutes to a solution of 2-[3-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane (710 mg, 2.4 mmol) in acetone (7.8 mL). A precipitate formed during addition of the OXONE. The reaction mixture was stirred vigorously for 15 minutes then quenched with 10% w/v aqueous solution of sodium metabisulfite (20 mL). The aqueous layer was extracted with dichloromethane (x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light yellow oil which was used without purification in the next step.LCMS Rt = 1 .65 min MS m/z 179 [MH]-
  • 6
  • [ 445303-67-3 ]
  • [ 350601-39-7 ]
  • methyl 4-amino-3-chloro-6-(3-fluoro-4-(trifluoromethyl)phenyl)picolinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% With bis-triphenylphosphine-palladium(II) chloride; potassium fluoride; In water; acetonitrile; at 115.0℃; for 0.333333h;Microwave irradiation; Example 40 Preparation of methyl 4-amino-3-chloro-6-(3-fluoro-4-(trifluoromethyl)phenyl)picolinate (Compound 29) [0332] <strong>[350601-39-7]Methyl 4-amino-3,6-dichloropicolinate</strong> (630 mg, 2.85 mmol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.06 g, 3.65 mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II) chloride (209 mg, 0.30 mmol, 0.1 equiv), and potassium fluoride (510 mg, 8.8 mmol, 3 equiv) in acetonitrile/ water (8 mL, 3:1) was capped in a 25-mL vial on a Biotage Initiator microwave reactor for 20 min at 115 C., with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude compound was loaded onto a Celite cartridge and dried in vacuum oven. Purification by reverse-phase flash chromatography (0-60, 60, 60-100% acetonitrile/water) afforded the title compound as a white solid (0.57 g, 57%).
  • 7
  • [ 445303-67-3 ]
  • [ 1126320-49-7 ]
  • methyl 6-amino-2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methoxypyrimidine-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
58.9% With bis-triphenylphosphine-palladium(II) chloride; potassium fluoride In water; acetonitrile at 115℃; for 0.333333h; Microwave irradiation; 46 Example 46 PPreparation of methyl 6-amino-2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methoxypyrimidine-4-carboxylate (Compound 26) Example 46 PPreparation of methyl 6-amino-2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-methoxypyrimidine-4-carboxylate (Compound 26) [0364] 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (270 mg, 0.930 mmol), potassium fluoride (128 mg, 2.198 mmol), and bis(triphenylphosphine)palladium(II) chloride (59.3 mg, 0.085 mmol). Subsequently, acetonitrile (2.789 mL) and water (2.79 mL) were added. The reaction vial was then capped and placed in a Biotage Initiator microwave reactor for 20 min at 115° C., with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with H2O. The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via flash chromatography (silica, Hexanes/EtOAc). This yielded the title compound (172 mg, 58.9%) as a white solid.
  • 8
  • [ 392-85-8 ]
  • [ 73183-34-3 ]
  • [ 445303-67-3 ]
  • 2-(4-Fluoro-3-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane [ No CAS ]
  • 2-(2-fluoro-3-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane [ No CAS ]
  • 9
  • [ 445303-67-3 ]
  • [ 142688-28-6 ]
  • C22H14BrF4NO2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 100℃; Microwave irradiation; General Procedure for synthesis of Compound 7 General procedure: To the solution of corresponding compound 6 (0.58 mmol) in dimethoxyethane (2.0 mL) in microwave reaction vessel, were added compound 5 (0.53 mmol), Pd(PPh3)4 (0.018 g, 0.016 mmol) and aqueous 2M Na2CO3 solution (1.3 mL, 2.6 mmol). The reaction mixture was heated to 100 °C by microwave irradiation with power of 100 W. After the completion of reaction was confirmed, solvent was removed in vaccuo. The residue was purified on flash column chromatography using n-hexane (Hex):EA (9:1) as an eluent to obtain compound 7.
  • 10
  • [ 392-85-8 ]
  • [ 73183-34-3 ]
  • [ 445303-67-3 ]
  • 2-(2-fluoro-3-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane [ No CAS ]
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