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CAS No. : | 168267-99-0 | MDL No. : | MFCD02683115 |
Formula : | C7H8BFO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WPVBHUUZDFUIJA-UHFFFAOYSA-N |
M.W : | 153.95 | Pubchem ID : | 2782674 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 41.19 |
TPSA : | 40.46 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.32 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.29 |
Log Po/w (WLOGP) : | 0.23 |
Log Po/w (MLOGP) : | 1.05 |
Log Po/w (SILICOS-IT) : | 0.12 |
Consensus Log Po/w : | 0.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.94 |
Solubility : | 1.75 mg/ml ; 0.0114 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.74 |
Solubility : | 2.8 mg/ml ; 0.0182 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.94 |
Solubility : | 1.77 mg/ml ; 0.0115 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.7 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: With diisopropopylaminoborane; triethylamine; triphenylphosphine; palladium dichloride In tetrahydrofuran at 65℃; for 12 h; Inert atmosphere Stage #2: With methanol In tetrahydrofuran at 0℃; Inert atmosphere |
General procedure: Triphenylphosphene (0.131 g, 0.5 mmol, 20 mol percent), p-iodoanisol (0.585 g, 2.5 mmol), and triethylamine (1.78 mL, 12.5 mmol) were added to a 50 mL round-bottomed flask equipped with a sidearm, condenser, and stir bar. This solution was then degassed by alternating vacuum and argon three times. Palladium dichloride (0.023 g, 0.13 mmol, 5 mol percent) was then added under positive argon pressure. After stirring at room temperature for 15 min, diisopropylaminoborane (5 mL, 1 M solution in THF, 5 mmol) was added and the reaction mixture was degassed again by alternating vacuum and argon three times. The reaction solution was then heated to reflux. After 12 h of reflux the reaction was cooled to 0 °C and 6 mL of methanol was added through the condenser slowly (Caution: exothermic reaction with evolution of hydrogen). After 15 min of stirring all the solvent was removed under reduced pressure to yield a black solid. This solid was dissolved with sodium hydroxide (3 M, 8 mL) and subsequently washed with hexanes (3.x.10 mL). The aqueous layer was then cooled to 0 °C (ice bath) and acidified to pH <=1 with concentrated HCl, with the boronic acid usually precipitating out as a white solid. The aqueous fraction was then extracted with diethyl ether (3.x.10 mL). The organic fractions were combined, dried with magnesium sulfate and filtered. The solvent was then removed under reduced pressure yielding a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 2h; | A mixture of compound (0.5 g), obtained from step k above, 3-fluoro-4- methylphenylboronic acid (0.314 g), tetrakistriphenylphosphinepalladium (0) (0.057 g) and potassium carbonate (0.414 g) was dried under high vacuum for 10 minutes. The vacuum was released under nitrogen atmosphere and dry dimethylformamide (5 mL) was added at room temperature. The reaction mixture was heated at 120C for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under the reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 30% ethylacetate in hexane as eluant to afford the title compound (0.37 g). Mass (m/z): 527.23 (M+ +1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); water; at 120℃; for 1h; | Example 41; 7- (3-Fluoro-4-Methylphenyl)-5H-dibenzo [c, g] chromene-3, 9-diol [0085]; To a mixture of 7-bromo-H-dibenzo [c, g] chromene-3,9-diol (343 mg, 1 mmol), dimethylformamide (5 mL), 2 M sodium carbonate (1 mL), water (1 mL), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) was added 3-fluoro-4- methylphenylboronic acid (462 mg, 3 mmol). The reaction mixture was heated to 120 C for 1 hr, then cooled and diluted with ethyl acetate (25 mL) and 5% ammonium chloride. The organic layer was washed with water (3 x 10 mL) and brine (10 mL) and dried over anhydrous magnesium sulfate. The solvent was removed and the resulting dark solid was purified by chromatography (2.5% acetonitrile-dichloromethane) to afford a white solid (226 mg, 61%): mp 238-240 C ;'H NMR (DMSO-d6) : 5 4.97 (2H, s), 6.63-6. 65 (2H, m), 6.84 (1H, dd, J=2. 5 Hz, J=8. 5 Hz), 6.91 (1H, dd, J=2. 4 Hz, J=8. 8 Hz), 7.04- 7.13 (2H, m), 7. 38-7. 43 (1H, m), 7.76-7. 84 (2H, m), 8.20 (1H, s), 9.55 (1H, s), 9.72 (1H, s); MS fritz 373 ( [M+H] +). An. HPLC gave purity of 98.2% 280 nm. Anal. for C24H17O3No.0. 3 H20 : Calc'd: C: 76.30 ; H: 4.70 Found: C: 76.04 ; H: 4.60 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.5% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; | Example 1.41; Preparation of (4-Bromo-2-methyl-2H-pyrazol-3-yl)-(3'-fluoro-4'-methyl-biphenyl-4-yl)- amine (Compound 27).A 20-mL scintillation vial was charged with (4-bromo-2-methyl-2H-pyrazol-3-yl)-(4- iodo-phenyl)-amine (80.0 mg, 0.21 mmol), 3-flouro-4-methylphenyl boronic acid (48.9 mg, 0.32 mmol), cesium carbonate (137.9 mg, 0.42 mmol), 1,2-dimethoxyethane (1.5 mL) and water (0.2 mL). The reaction mixture was purged with argon, tetrakis(triphenylphosphine) palladium(O) (24.5 mg, 0.02 mmol) was added then the reaction vessel purged with argon again. The reaction mixture was heated at 800C overnight. Then, it was allowed to cool to ambient temperature, filtered and subjected to a purification by prep EtaPLC (0.05% TFA). The corresponding fractions were collected and lyophilized to afford Compound 27 as a white solid. Yield: 24.8 mg (26.5 %). LCMS m/z (%) = 360 (M+Eta79Br, 100), 362 (M+H81Br, 98). 1H NMR (400MHz, CDCl3): delta 2.30 (s, 3H), 3.75 (s, 3H), 5.31 (s, IH), 6.66 (dd, J=6.8, 1.8 Hz, 2H), 7.22-7.12 (m, 3H), 7.44 (dd, J=9.0, 2.2 Hz, 2H), 7.55 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 20 - 40℃; for 1.75h; | E. Synthesis of l-(3-Methyl-4-flttorophenyl)-3-ethyI-3-azabicyclo[3.1.01hexane Hydrochloride A stirred solution/suspension of 3-brorno-l-ethylmaleiniide (1.0 g, 5mmol) and 3-methyl-4-fluorophenyl boronic acid (830 mg, 5.4mmol) in dioxane(15mL) under nitrogen was degassed with a stream of nitrogen for 10 min, treated with cesium fluoride (1.6g, 10.8mmol) and Cl2Pd(dppf).CH2Cl2 (0.25g, 0.3mmol), then stirred at room temperature for Ih and at 4O0C for 45min. The mixture was then cooled and EPO <DP n="104"/>diluted with methylene chloride (5OmL). The mixture was filtered through Celite (rinse filter cake with methylene chloride) and the brown filtrate concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a column of silica gel (eluted with methylene chloride) to afford a pale yellow solid, which was triturated from cold petroleum ethers to afford arylmaleimide intermediate (982mg, 88%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 20 - 40℃; for 1.75h; | D. Synthesis of l-(3-Fluoro-4-methylphenylV3-ethyl-3-azabicyclof3.1.01hexane Hydrochloride A stirred solution/suspension of 3-bromo-l-ethylmaleimide (1.0 g, 5mmol) and 3-fluoro-4-methylphenyl boronic acid (830 nag, 5.4mmol) in dioxane(15mL) under nitrogen was degassed with a stream of nitrogen for 10 min, treated with cesium fluoride (1.6g, lO.deltammol) and Cl2Pd(dppf). CH2Cl2 (0.25g, 0.3mmol), then stirred at room temperature for Ih and at 4O0C for 45min. The mixture was then cooled and diluted with methylene chloride (5OmL). The mixture was filtered through Celite (rinse filter cake with methylene chloride) and the brown filtrate concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a column of silica gel (eluted with methylene chloride) to afford a pale yellow solid, which was triturated from cold petroleum ethers to afford arylmaleimide intermediate (888 mg, 80%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 20 - 40℃; for 2h; | D. Synthesis of l-(3-FIuoro-4-methylphenyI)-3-(2-propylV3- azabicyclo[3.1.0]hexane Hydrochloride A stirred solution/suspension of 3-bromo-l-(l-methylethyl)maleimide(1.09g, 5mmol) and <strong>[168267-99-0]3-fluoro-4-methylphenylboronic acid</strong> (962mg, 6.25mmol) in dioxane (15mL) under nitrogen was degassed with a stream of nitrogen for 10 min, treated with cesium fluoride (1.8g, l l.deltammol) and Cl2Pd(dppf).CH2Cl2 (0.25g, 0.3mmol), then stirred at room temperature for Ih and at 400C for Ih. The mixture was then cooled and diluted with methylene chloride (5OmL). The mixture was filtered through Celite (rinse filter cake with methylene chloride) and the brown filtrate concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a column of silica gel (eluted with methylene chloride) to afford a yellow solid, which was triturated from petroleum ethers to afford arylmaleimide intermediate (1.1 Ig, 90%) as a pale yellow solid. No MS (M+l) peak. 1H NMR (CDCl3) delta 7.60 (m, 2H), 7.24 (m, IH), 6.62 (s, IH), 4.39 (m, IH), 2.32 (br s, 3H), 1.43 (d, 6H, J=7Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 20 - 40℃; for 3h; | E. Synthesis of l-(3-Fluoro-4-methylphenyl)-3-azabicyclo[3.1.01hexane Hydrochloride A stirred solution of 3-bromo-l-(3,4-dimethoxybenzyl)maleimide (1.31g,4.0mmoi) and <strong>[168267-99-0]3-fluoro-4-methylphenylboronic acid</strong> (770mg, 5.0mmol) in anhydrous dioxane (12mL) under nitrogen was degassed over lOmin with a stream of nitrogen, then treated with cesium fluoride (1.5g, 9.9mmol) and Cl2Pd(dppf).CH2Cl2 (Aldrich, 0.2Og, 0.245mmol), stirred Ih at room temperature, then 2h at 4O0C. The mixture was cooled, diluted with methylene chloride (6OmL), stirred a few minutes, filtered through Celite (rinse with methylene chloride), and the filtrate concentrated in vacuo. The residue was dissolved in methylene chloride and loaded onto a silica gel column and the product EPO <DP n="131"/>eluted with 2% ethyl acetate/methylene chloride to afford the intermediate arylmaleimide (1.12g, 79%) as a yellow solid. MS (M+l) 356.1. 1H NMR (CDCl3) delta 7.63 (m, IH), 7.59 (m, IH), 7.24 (m, IH), 6.94-6.99 (m, 2H), 6.80 (m, IH), 6.68 (s, IH), 4.65 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 2.31 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper diacetate; triethylamine; In dichloromethane; at 20℃; for 20h;Molecular sieve 4A; | A flask is charged with phenol 64 (100 mg, 0.45 mmol, 1 eq), Cu(OAc)2 (83 mg, 1 eq), arylboronic acid 63 (140 mg, 2 eq), and powered molecular sieves (300 mg). The mixture was diluted with DCM (10 mL) followed by the addition OfEt3N (0.32 mL, 5 eq). The reaction mixture was stirred at rt for 20 h. TLC analysis showed desired product. The reaction mixture was filtered through Celite 545, the filtrate was washed with EtOAc. The combined organic layers were concentrated and the crude product was purified by flash chromatography (5% EtOAc in hexanes then 10% EtOAc) to afford partially pure desired product 89 mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; at 90℃; for 46h;Inert atmosphere; | Preparation 2. 4'-Bromomethyl-3'-fluorobiphenyl-2-carboxylic Acid t-Butyl Ester To a solution of 1.0M DCC in DCM (800 mL, 800 mol) cooled at 0 C. was added 2-bromobenzoic acid (2a) (161 g, 800 mmol) followed by DMAP (9.0 g, 740 mmol) and t-butyl alcohol (82.4 mL, 880 mmol). The mixture was stirred at room temperature for 10 minutes, then warmed to room temperature and stirred. After 16 hours, the mixture was then filtered. The organic was washed with saturated NaHCO3 (400 mL), saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure to produce the crude intermediate (2b) as an oil (228.8 g).The crude intermediate (2b) (109.6 g, 426 mmol) and 3-fluoro-4-methylphenyl-boronic acid (72.2 g, 449 mmol) were suspended in isopropyl alcohol (360 mL, 4.7 mmol). A 2.0M solution of sodium carbonate in water (360 mL, 720 mmol) was added and the mixture was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (4.9 g, 4.3 mmol) was then added and the mixture was stirred at 90 C. for 46 hours. The mixture was cooled to room temperature, diluted with EtOAc (800 mL), and the layers were separated. The organic was washed with saturated aqueous NaCl and concentrated under reduced pressure. The recovered oil was purified by silica gel chromatography (3×4-6% EtOAc:hexanes) to yield intermediate (2c) as a clear oil (93.3 g).Intermediate (2c) (89.8 g, 314 mmol, 1.0 eq) was dissolved in CCl4 (620 mL, 6.4 mol) and was degassed under nitrogen. NBS (55.8 g, 314 mmol) was added, followed by benzoyl peroxide (1.5 g, 6.3 mmol) and the mixture was heated at 90 C. under nitrogen for 7 hours. The reaction was cooled in an ice bath, filtered, and concentrated under reduced pressure. The recovered oil was triturated with 150 mL of 3% EtOAc: hexanes. The solution was chilled at -20 C. for 2 hours, then filtered and washed with cold 3% EtOAc:hexanes solution (200 mL) to yield the title compound as an off white solid (88.9 g). 1H-NMR (CDCl3) delta (ppm): 1.3 (m, 9H), 4.6 (s, 2H), 7.0-7.1 (m, 2H), 7.3 (dd, 1H), 7.4 (m, 1H), 7.5 (m, 1H), 7.8 (dd, 1H). | |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; at 90℃; for 46h;Inert atmosphere; | The crude intermediate (2b) (109.6 g, 426 mmol) and 3-fluoro-4-methylphenyl-boronicacid (72.2 g, 449 mmol) were suspended in isopropyl alcohol (360 mL, 4.7 mmol). A 2.0M solution of sodium carbonate in water (360 mL, 720 mmol) was added and the mixture was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (4.9 g, 4.3 mmol) was then added and the mixture was stirred at 90 C. for 46 hours. The mixture was cooled to room temperature, diluted with EtOAc (800 mL), and the layers were separated. The organic was washed with saturated aqueous NaCl and concentrated under reduced pressure. The recovered oil was purified by silica gel chromatography (3×4-6% EtOAc :hexanes) to yield intermediate (2c) as a clear oil (93.3 g). | |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; at 90℃; for 46h;Inert atmosphere; | The crude intermediate (2b) (109.6 g, 426 mmol) and 3-fluoro-4-methylphenyl-boronicacid (72.2 g, 449 mmol) were suspended in isopropyl alcohol (360 mL, 4.7 mmol). A 2.0M solution of sodium carbonate in water (360 mL, 720 mmol) was added and the mixture was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (4.9 g, 4.3 mmol) was then added and the mixture was stirred at 90 C. for 46 hours. The mixture was cooled to room temperature, diluted with EtOAc (800 mL), and the layers were separated. The organic was washed with saturated aqueous NaCl and concentrated under reduced pressure. The recovered oil was purified by silica gel chromatography (3×4-6% EtOAc:hexanes) to yield intermediate (2c) as a clear oil (93.3 g). |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; at 90℃; for 17h;Inert atmosphere; | Compound A (80.0 g, 311 mmol) and <strong>[168267-99-0]3-fluoro-4-methylphenylboronic acid</strong> (52.7 g, 342 mmol) were suspended in isopropyl alcohol (260 mL, 3.5 mol). A solution of sodium carbonate (56.1 g, 529 mmol) in water (260 mL, 15 mol) was added and the mixture was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (3.6 g, 3.1 mmol) was then added and the mixture was stirred at 90 C. for 17 hours. The mixture was concentrated under reduced pressure and suspended in water (200 mL). The aqueous phase was extracted with EtOAc (600 mL) and separated. The organic phase was washed with saturated aqueous NaCl and concentrated under reduced pressure. The recovered oil was purified by silica gel chromatography (4-6% 5*120 g column) to yield compound B as a clear oil (68.2 g). | |
14 g | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; isopropyl alcohol; for 12h;Reflux; | Step 2 tert-butyl 3'-fluoro-4'-methyl-[1,1'-biphenyl]-2-carboxylate Tert-butyl 2-bromobenzoate (10 g, 64.8 mmol), <strong>[168267-99-0](3-fluoro-4-methylphenyl)boronic acid</strong> (14 g, 54 mmol), Pd(PPh3)4(624 mg, 0.54 mmol), and Na2CO3 (11.4 g, 108 mmol) were dissolved in IPA (60 ml) and H2O (60 ml) in a 1 L flask, followed by reflux-stirring for 12 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was separated by using ethyl acetate and brine. The separated organic layer was dried over MgSO4 and filtered. The mixture was separated by column chromatography to give tert-butyl 3'-fluoro-4'-methyl-[1,1'-biphenyl]-2-carboxylate (14 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 90℃; for 16h; | Step A: 2-Chloro-4-(3-fluoro-4-methyl-phenyl)-pyridine To a vial was added 2-chloro-4-bromopyridine (96 mg, 0.5 mmol), Pd(PPh3)4 (30 mg), and toluene/EtOH (4:1, 3 mL). After stirring at room temperature for 5 min, <strong>[168267-99-0]3-fluoro-4-methylphenylboronic acid</strong> (115 mg, 0.75 mmol) and 2 M aqueous K2CO3 (1 mL) were added, and the resulting mixture was heated at 90 C. for 16 h. The resulting mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield 2-chloro-4-(3-fluoro-4-methyl-phenyl)-pyridine as a solid. 1H NMR (CDCl3): 7.58-7.26 (m, 5H), 2.36 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 90℃; | Method BGeneral Procedure for Method BIn a sealable tube, 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (100 mg, 0.157 mmol) in DME (3 mL) was added, followed by boronic acid (100 mg), Cs2CO3 (100 mg), and PdCl2(dppf) (20 mg). The reaction mixture was shaken at 90 C. overnight. The reaction was diluted with EtOAc (5 mL), washed with water (3 mL). The organic layer was separated and concentration under reduced pressure gave an oil, which was used in the next step without further purification. The crude sample was dissolved in EtOH (5 mL), 3N NaOH (0.5 mL) was added and stirred at 60 C. for 3 h. 3N HCl (0.55 mL) was added to neutralize the reactions. Concentration under reduced pressure gave an oil which was purified by preparative HPLC. Example 11 4-{2-(2-Carboxy-ethyl)-3-[6-(3'-fluoro-5-methanesulfonyl-4'-methyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric Acid Title compound was prepared according to general procedure for method B using <strong>[168267-99-0]3-fluoro-4-methylphenylboronic acid</strong>. LC/MS indicated a purity of 100% as measured by UV 214 nM. HR-ES(+):calculated for C33H40FO8S (M+Na)1+ 628.2423, found 628.2418. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
bis(triphenylphosphine)palladium(II)-chloride; In N,N-dimethyl-formamide; | Example 21A 2-Chloro-6-(3-fluoro-4-methylphenyl)-4-(trifluoromethyl)nicotinamide 154 mg (1.00 mmol) of <strong>[168267-99-0]3-fluoro-4-methylphenylboronic acid</strong> and 3.00 ml (6.00 mmol) of a 2 M aqueous potassium carbonate solution are added to 259 mg (1.00 mmol) of 2,6-dichloro-4-(trifluoromethyl)nicotinamide, dissolved in 3.5 ml of DMF. After stirring for 10 min, 140 mg (0.20 mmol) of bis(triphenylphosphine)palladium(II) chloride and 30.4 mg (0.10 mmol) of tri-2-tolylphosphine are added and the reaction mixture is stirred at RT overnight. For workup, the reaction mixture is partitioned between ethyl acetate and water, and acidified to pH 3.5 with 1N hydrochloric acid, the organic phase is removed, the aqueous phase is extracted once more with ethyl acetate, and the combined organic phases are dried over magnesium sulfate and concentrated. The remaining crude product is purified by preparative HPLC (method 8). 200 mg (60% of theory) of the target compound are thus obtained. 1H NMR (400 MHz, DMSO-d6): delta=2.32 (s, 3H), 7.48 (t, 1H), 7.94-7.82 (m, 2H), 8.06 (br. s, 1H), 8.21 (br. s, 1H), 8.39 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
bis(triphenylphosphine)palladium(II)-chloride; In 1,4-dioxane; water; | Example 70A tert-Butyl 2-chloro-6-(3-fluoro-4-methylphenyl)nicotinate 5.10 g (19.7 mmol) of tert-butyl 2,6-dichloronicotinate from Example 30A are initially charged in 106 ml of dioxane and degassed. 3.04 g (19.7 mmol) of <strong>[168267-99-0](3-fluoro-4-methylphenyl)boronic acid</strong> and 59.2 ml (118.4 mmol) of a 2 M aqueous potassium carbonate solution are added and the mixture is stirred at RT for 10 min. Subsequently, 1.385 g (1.97 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.601 g (1.97 mmol) of tri-2-tolylphosphine are added and the reaction mixture is stirred at 60 C. overnight. After cooling, the reaction mixture is filtered through kieselguhr and the filtrate is concentrated to dryness under reduced pressure. The residue is admixed with ethyl acetate/water (1:1), the aqueous phase is removed and the organic phase is washed with water and with saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed under reduced pressure. The residue is chromatographed on silica gel (eluent: 85:15 cyclohexane/ethyl acetate). This affords 5.17 g (77% of theory) of the target compound. 1H NMR (400 MHz, DMSO-d6): delta=1.57 (s, 9H), 2.31 (s, 3H), 4.46 (t, 1H), 7.86-7.90 (m, 2H), 8.11 (d, 1H), 8.25 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 5A 2-Chloro-6-(3-fluoro-4-methylphenyl)nicotinaldehyde The title compound is prepared and purified analogously to Example 1A. The total reaction time is about 5 days. The product fractions are purified further by another HPLC under the same conditions. 200 mg (1.14 mmol) of 2,6-dichloronicotinaldehyde and 175 mg (1.14 mmol) of 3-fluoro-4-methylphenylboronic acid afford 129 mg (45% of theory) of the target compound. 1H NMR (500 MHz, DMSO-d6): delta=2.19 (s, 3H), 7.48 (t, 1H), 7.92 (d, 1H), 7.94 (d, 1H), 8.23 (d, 1H), 8.30 (d, 1H), 10.28 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | General procedure: Triphenylphosphene (0.131 g, 0.5 mmol, 20 mol %), p-iodoanisol (0.585 g, 2.5 mmol), and triethylamine (1.78 mL, 12.5 mmol) were added to a 50 mL round-bottomed flask equipped with a sidearm, condenser, and stir bar. This solution was then degassed by alternating vacuum and argon three times. Palladium dichloride (0.023 g, 0.13 mmol, 5 mol %) was then added under positive argon pressure. After stirring at room temperature for 15 min, diisopropylaminoborane (5 mL, 1 M solution in THF, 5 mmol) was added and the reaction mixture was degassed again by alternating vacuum and argon three times. The reaction solution was then heated to reflux. After 12 h of reflux the reaction was cooled to 0 C and 6 mL of methanol was added through the condenser slowly (Caution: exothermic reaction with evolution of hydrogen). After 15 min of stirring all the solvent was removed under reduced pressure to yield a black solid. This solid was dissolved with sodium hydroxide (3 M, 8 mL) and subsequently washed with hexanes (3×10 mL). The aqueous layer was then cooled to 0 C (ice bath) and acidified to pH ?1 with concentrated HCl, with the boronic acid usually precipitating out as a white solid. The aqueous fraction was then extracted with diethyl ether (3×10 mL). The organic fractions were combined, dried with magnesium sulfate and filtered. The solvent was then removed under reduced pressure yielding a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine;copper diacetate; In tetrahydrofuran; for 12h;Molecular sieve; | Step B. 3-(4-(5-(4-((tert-butoxycarbonyl)amino)phenyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenyl)-2-(1-(3-fluoro-4-methylphenyl)-1H-pyrazole-4-carboxamido)propanoic acid. To a stirred solution of Ethyl 3-(4-(5-(4-((tert-butoxycarbonyl)amino)phenyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenyl)-2-(1H-pyrazole-4-carboxamido)propanoate (65 mg, 0.1 mmol), copper acetate (18 mg) and molecular sieves (500 mg) in THF was added pyridine (0.1 ml) and <strong>[168267-99-0](3-fluoro-4-methylphenyl)boronic acid</strong> (30 mg). After 12 h, the mixture was concentrated and chromatographed over silica gel to give the ethyl ester (14 mg), which hydrolyzed with LiOH as described in Example 1 Step H to give the title compound. EI-MS (m/z): 674 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 150℃; for 4h;Inert atmosphere; microwave irradiation; | A slurry of 2,3-Dichloropyrido[2,3-b]pyrazine (Intermediate F step 2) (500 mg, 2.500 mmol), 3- fluoro-4-methylphenylboronic acid (847 mg, 5.50 mmol),tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.150 mmol) and potassium carbonate (1520 mg, 1 1 .00 mmol) in dioxane (20 ml) was degassed by bubbling nitrogen through (x3). The reaction mixture was heated using microwave radiation under nitrogen at 150 °C for 4h. The resulting mixture was partitioned between EtOAc and water. The organic portion was separated, dried (sodium sulphate), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0-3percent THF in DCM to afford the title compound;LCMS; Rt 1 .28 mins MS m/z 348 [M+H]+ Method 2minl_C_v003 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 150℃; for 0.25h;Microwave irradiation; | Example 485-[(35)-l-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(3,3'-difluoro-4'-methyl-4- biphenylyl)-2,4-dihydro-3H-l -triazol-3-onea) A mixture of 4-(4-bromo-2-fluorophenyl)-5-[(3S)-l-(cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-2,4-dihydro-3H-l,2,4-triazol-3-one (0.244 mmol), (3-fluoro-4- methylphenyl)boronic acid (0.370 mmol), and dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.012 mmol) in dioxane (2.0 mL) and 2M aq potassium carbonate (0.5 mL) was irradiated in the microwave at 150 C for 15 min. The reaction mixture was poured into water (50 mL) and the pH was adjusted to 5 with addition of IN aq HC1. The aqueous layer was extracted with ethyl acetate (3 x 50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (100% ethyl acetate) and then reverse phase HPLC (30-65%acetonitrile/water with 0.1%> NH4OH) provided the title compound as a tan solid (58%). MS(ES)+ m/e 439.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.35 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; cesium fluoride; In 1,4-dioxane; at 90℃; for 3h; | Preparation example 75A mixture of Present compound (T057) 0.35 g, 3- fluoro-4-methylphenylboronic acid 0.28 g, cesium fluoride0.49 g, [1,1? -bis (diphenyiphosphino) ferrocene]palladium(II) dichioride dichloromethane adduct 0.08 g and dioxane 6 mL was stirred at 90C for three hours. After cooling the reaction mixtures, the mixtures were filtered and the filtrates were concentrated under reduced pressure. Theresulting residues were subjected to a silica gel column chromatography to give 2-{ [1- (4, 5-dihydro-4-methyl-5-oxo- 1H-tetrazole--l-yl)-3-methylphenyl-2-yl]methyloxy}-4- (3- fluoro-4-methylphenyl)thiazole (hereinafter, referred to as ??Present compound (T075) ??) 0.35 g.?H NMR (COd3) 6: 2.29(3H, d, J=1.69Hz), 2.58(3H, s), 3.62(3H, s), 5.59(2H, 5), 6.80(1H, s), 7.18(1H, t, J=7.73Hz), 7.29-7.26(1H, rn), 7.39-7.45(4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 10h;Inert atmosphere; | General procedure: A mixture of 1 (2.0mmol), 2b (2.2mmol), Pd(dppf)2Cl2 (5 10mg) and potassium acetate (4.0mmol) were dissolved in anhydrous 1,4-dioxane (10mL) and heated at 90C under nitrogen for 10h. After cooled to room temperature, the mixture was poured into water (20mL) and extracted with dichloromethane. The combined organic layers were dried with anhydrous Na2SO4 and concentrated in vacuum. The crude product was purified by column chromatography with petroleum ether/ethyl acetate (50:1) eluent to afford pure product 3b as a white solid. Yield: 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene; at 200℃; for 0.5h;Microwave irradiation; | Example 398 Synthesis of 4-(3-Fluoro-4-methylphenyl)-N-(4-(furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amine A microwave vial was charged with <strong>[168267-99-0]3-fluoro-4-methylphenylboronic acid</strong> (0.058 g, 0.38 mmol), 4-chloro-N-(4-(2-(trimethylsilyl)furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amine (0.090 g, 0.19 mmol), and sodium carbonate (2.0 M in H2O) (0.38 ml, 0.75 mmol) and dissolved in toluene (1.5 mL) and water (0.2 mL). Pd(Ph3P)4 (0.011 g, 0.0094 mmol) was added and the reaction was microwaved at 200 C. for 30 minutes. The reaction was partitioned between water and DCM. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was redissolved in 2 mL THF and TBAF (0.23 ml, 0.23 mmol) was added. The reaction was stirred at RT overnight. The reaction was concentrated and purified via Gilson HPLC (10-90% ACN:H2O). The clean fractions were partitioned between saturated sodium bicarbonate solution and DCM and the aqueous layer was extracted with DCM. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford 4-(3-fluoro-4-methylphenyl)-N-(4-(furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amine as a light yellow solid. MS: M+H+=479.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.3% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 90℃; for 9h; | 10118] A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimeth- ylpiperidin- 1 -yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy) acetate (0.02 g, 0.044 mmol), (3-fluoro-4-methylphenyl)bo- ronic acid (0.014 g, 0.088 mmol) and 2M Na2CO3 (0.055 ml, 0.110 mmol) in DMF (1 mE) was degassed for 3 mm. Then, Pd(Ph3P)4 (5.07 mg, 4.39 tmol) was degassed for 1 mm and placed in a pre-heated oil bath at 90 C. After 9 h, cooled and purified by prep-RPEC to afford (S)-ethyl 2-(tert-butoxy)-2- (4-(4,4-dimethylpiperidin- 1 -yl)-5-(3-fluoro-4-methylphe- nyl)-2,6-dimethylpyridin-3-yl)acetate (0.0105 g, 0.022 mmol, 49.3% yield) as brown paste. ECMS (M+R)=485.3. |
49.3% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 90℃; for 9h;Inert atmosphere; | (S)-Ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5-(3-fluoro-4-m 2,6-dimethylpyridin-3-yl)acetate: A mixture of (S)-ethyl 2-(5-bromo-4-(4,4- dimethylpiperidin-l-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.02 g, 0.044 mmol), <strong>[168267-99-0](3-fluoro-4-methylphenyl)boronic acid</strong> (0.014 g, 0.088 mmol) and 2M Na2C03 (0.055 ml, 0.110 mmol) in DMF (1 mL) was degassed for 3 min. Then, Pd(Ph3P)4 (5.07 mg, 4.39 mupiiotaomicron) was degassed for 1 min and placed in a pre-heated oil bath at 90 C. After 9 h, cooled and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-5-(3-fluoro-4-methylphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0105 g, 0.022 mmol, 49.3 % yield) as brown paste. LCMS (M+H) = 485.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 3h; | Under an argon atmosphere, to a suspension of 3-fluoro-4-methylphenylboronic acid (0.43 g, 2.8 mmol), <strong>[3638-04-8]2,4-dichloro-6-methoxy-1,3,5-triazine</strong> (1.0 g, 5.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) in toluene (8 ml) was added 2M aqueous tripotassium phosphate solution (4.0 ml) at room temperature, and the mixture was stirred at 100 C. for 3 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water, partitioned, washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/chloroform=2/3-1/2) to give the title compound (0.58 g, yield 81%). (0720) 1H-NMR (CDCl3) delta: 2.37 (3H, d, J=2.1 Hz), 4.17 (3H, s), 7.32 (1H, t, J=7.9 Hz), 8.12 (1H, dd, J=10.7, 1.7 Hz), 8.19 (1H, dd, J=7.9, 1.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.5% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); caesium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; at 50℃; for 1.5h;Inert atmosphere; | A RBF was charged with (P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.65 g, 2.78 mmol), <strong>[168267-99-0](3-fluoro-4-methylphenyl)boronic acid</strong> (1.282 g, 8.33 mmol), copper (i) chloride (0.234 ml, 8.33 mmol), cesium carbonate (0.889 ml, 11.11 mmol), and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.393 g, 0.555 mmol) The flask was flushed with Ar (g) and DMF (13.88 ml) was added. The flask was then lowered into a 50 C. heating bath for 1.5 h. The mixture was cooled and filtered through celite with the aid of EtOAc. The filtrate was partitioned between EtOAc and water which led to an emulsion. The layers were separated, and the aq. layer was extracted with EtOAc (2*). The organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (100-g SNAP Ultra column, 25-g silica gel loading column, 10-60% EtOAc/Heptane) to give (P)-perfluorophenyl 1-(2,3'-difluoro-5-methoxy-4'-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydroquilioline-6-sulfonate (1.22 g, 1.957 mmol, 70.5% yield) as an off-white solid. m/z (ESI) 624.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro(2-dicyclohexylphosphino-2?,6?-dimethoxy-1,1?-biphenyl)(2?-amino-1,1?-biphenyl-2-yl) palladium(II); potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 16h; | Step 1 : 3 -Fluoro-4-methyl- 1 , 1 '-biphenyl In a 2 dram vial, phenyl iodide (800 mg, 3.92 mmol) and <strong>[168267-99-0](3-fluoro-4-methylphenyl)boronic acid</strong> (604 mg, 3.92 mmol) were dissolved in DMF (19.6 mL). An aquoues solution of K2CO3 (2.17 g in 1.9 mL H20) and Sphos Palladacycle G2 (28.3 mg, 39.0 muetaiotaomicron) was added, and the resulting suspension was stirred vigorously at 80 C for 16 h. After cooling to room temperature, DCM (15 mL) was added, and the organic layer was washed with water (10 mL), 10% LiCl (aq., 3 x 10 mL), and dried over Na2S04. The residue obtained after removal of the solvent in vacuo was subjected to purification by flash chromatography (Si02, heptane to 20% EtOAc in heptane). 3-Fluoro-4-methyl-l,l'-biphenyl was obtained as colorless oil (746 mg, 3.61 mmol, 91%, 90% purity). 1H NMR (400 MHz, DMSO-d6) delta 7.69 - 7.66 (2H, m), 7.48 - 7.36 (6H, m), 2.27 (3H, d, J= 1.68 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | A mixture of 3-iodo-N-tert-pentyl-5-(1H-tetrazol-1-yl)benzamide (intermediate 3) (96.3 mg, 0.25 mmol) and commercially available <strong>[168267-99-0]3-fluoro-4-methylphenylboronic acid</strong> (50.0 mg, 325 tmol) in 1,2-dimethoxyethane (1.67 ml) and 2 M Na2CO3 solution (416 tl, 832 tmol) was purged with argon in an ultrasonic bath for 5 mi triphenylphosphine (13.1 mg, 50.0 tmol) and palladium(II)acetate (5.61 mg, 25.0 tmol) were added at room temperature, and afterwards the reaction mixture was stirred for 3h under reflux conditions. The reaction mixture was cooled to room temperature and purified by flash chromatography on silica gel [heptane/ethyl acetate (10- 50%)j and crystallization from dichloromethane/heptane to yield the title compound (63 mg, 69%) as a white solid, MS (ISP) mz = 368.2 [(M+H)j, mp 161C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium carbonate; tris-(o-tolyl)phosphine; palladium dichloride; In 1,2-dimethoxyethane; water; at 80℃; for 4h; | 264 mg N-(3-bromobenzoyl)-azepane (0.92 mmol), 217 mg 3-fluoro-4-tolylboronic (1.36 mmol), 194 mg Na2CO3 (1.84 mmol), 10.4 mg PdCI2 (0.046 mmol), 29.5 mg tris(2- methylphenyl)-phosphine (0.092 mmol) were given in a screw-cap reactor, DME (5.5 mL) and H2O (1.0 mL) were added, the reactor was closed tightly and heated to 80C under stirring. After 4 h the mixture was cooled to room temperature, diluted with H2O (10 mL) and extracted with AcOEt (2x20 mL), the pooled organic extracts were washed with 5 % NaHCO3 (2x10 mL) and brine (10 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product was purified by preparative-HPLC. 205 mg of the compound IV-a were obtained (71 % yield). LR-MS: m/z 312.3 ([M+H]+, clc 312.18). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; at 110℃; for 0.5h;Inert atmosphere; | A reaction vessel was sealed with potassium carbonate (83 mg, 0.597 mmol), PdC (dppf) (21 .85 mg, 0.030 mmol), (2R)-4-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-methyl-2- (methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide (Intermediate 3) (150 mg, 0.299 mmol) and <strong>[168267-99-0](3-fluoro-4-methylphenyl)boronic acid</strong> (59.8 mg, 0.388 mmol) and heated in Emrys Optimiser to 1 10 C for 30 min. The organic phase was diluted with DCM (20 mL) and extracted with DCM (3 x10ml) and then washed with water 20 mL, saturated brine 30 mL, dried over sodium sulphate and evaporated in vacuo. The residue was purified with combiflash silical chromatography (eluted with DCM/EtOAc from 10-100% over 20 min). The product (2R)-4-(7-(3-fluoro-4-methylphenyl)-4-oxoquinazolin-3(4H)-yl)- 2-methyl-2-(methylsulfonyl)-N- ((tetrahydro-2H-pyran-2-yl)oxy)butanamide (142 mg, 0.254 mmol, 85 % yield) and was obtained as a colorless oil. LCMS: (M+1) 532.3 at 1 .12 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetonitrile; at 80℃; for 0.5h;Inert atmosphere; | PdCI2(dppf) (0.361 g, 0.493 mmol) was added to a solution of (3-fluoro-4- methylphenyl)boronic acid (0.910 g, 5.91 mmol), (2R)-4-(5-bromo-4-fluoro-1 - oxoisoindolin-2-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2- yl)oxy)butanamide (Intermediate 16) (2.5g, 4.93 mmol) and K2C03 (1 .362 g, 9.85 mmol) in acetonitrile (15 ml_) and water (2 ml_) under a nitrogen atmosphere. The resulting solution was stirred at 80 C for 30 min. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (EtOH/DCM: 1 :50) to give (2R)-4-(4- fluoro-5-(3-fluoro-4-methylphenyl)-1 -oxoisoindolin-2-yl)-2-methyl-2-(methylsulfonyl)-N- (tetrahydro-2H-pyran-2-yl)oxy)butanamide (2.2 g, 3.61 mmol, 73 % yield) as a brown solid. LCMS: [M+H] 559.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In methanol; water; at 80℃; for 16h; | To a solution of rnethyl-2-brorno-5-furanocarboxylate (1.11 g,542 mmol, 1.0 eq) in 22 ml. toluene were added 3-fluoro-4-methyihenzeneboronic acid (1.0 g, 6.50 rnmol, 1.2 eq) in 1.9 mL methanolfollowed by Pd(PPh3)4 (220 mg, 0.19 mmoi, 0035 eq) and K2C03 (2 M in water,3.34 mL, 6.67 mrnol, 1.23 eq) at room temperature. The reaction mixture was heated to 80 C for 16 h before it was diluted with water and the product was extracted with ethyl acetate (3x 15 mL). The combined organic extracts were dried over Na2 S04. the solvent was removed under reduced pressure and the product was purified by flash chromatography (434% EtOAc linear gradient in hexanes) to give 5 (1.06 g, 83%) as a white solid. ?H NMR (400 MHz, CDCI3) 3 7.48 7.38 (m, 2H), 7.25 718(m, 2H), 6.69 (d, .1=3.6 Hz, IH), 3.91 (s, 3H), 2.29 (d, J=2.0 Hz, 3H.?3C NrvIR (101 MHz, CDCI3) 3 = 161.58 (d, J244.9 Hz), 159.23,156.61 (d, .J=30 Hz), 14371, 132.01 (d, J=5.5 Hz), 129.07 (d, J=8.5 Hz).125.96 (d,J17.5 Hz), 120.37 (d,J3.3 Hz), 120.12, 111.52 (d,J24.7Hz),107.15, 52.02, 14.66 (d, J:::35 Hz). MS (ESI) for CI3H11FO3 [M+H] 235.09. |
Tags: 168267-99-0 synthesis path| 168267-99-0 SDS| 168267-99-0 COA| 168267-99-0 purity| 168267-99-0 application| 168267-99-0 NMR| 168267-99-0 COA| 168267-99-0 structure
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P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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