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CAS No. : | 139301-27-2 | MDL No. : | MFCD01074648 |
Formula : | C7H6BF3O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HUOFUOCSQCYFPW-UHFFFAOYSA-N |
M.W : | 205.93 | Pubchem ID : | 2734386 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 42.95 |
TPSA : | 49.69 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.13 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.01 |
Log Po/w (WLOGP) : | 1.53 |
Log Po/w (MLOGP) : | 0.49 |
Log Po/w (SILICOS-IT) : | -0.13 |
Consensus Log Po/w : | 0.78 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.5 |
Solubility : | 0.648 mg/ml ; 0.00315 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.68 |
Solubility : | 0.43 mg/ml ; 0.00209 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.92 |
Solubility : | 2.47 mg/ml ; 0.012 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.9 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
92% | With iron(III) oxide; oxygen In tetrahydrofuranIrradiation | General procedure: In atypical procedure, a flask containing phenylboronic acid (100 mg, 0.82 mmol) was taken and to it were added 10 mol percent of iron(III) oxide photocatalyst(13.1 mg) and tetrahydrofuran (2 ml). The reaction mixture was kept for stirring under diffused sunlight in ordinary open flask until the starting material is consumed on TLC. Quenched with water after completion and the catalyst was filtered off, the filtrate was concentrated in vacuo. The crudeproduct was purified on silica (100–200 mesh) column chromatography (15percentethylacetate/hexane) to offer 73.2 mg (in 95percent yield) of pure crystalline phenol. |
92% | With iron(III) oxide; oxygen In tetrahydrofuran at 20℃; Irradiation | General procedure: In a typical procedure, a flask containing phenylboronic acid (100 mg, 0.82 mmol) was taken and to it were added 10 mol percent of iron(III) oxide photocatalyst(13.1 mg) and tetrahydrofuran (2 ml). The reaction mixture was kept for stirring under diffused sunlight in ordinary open flask until the starting material is consumed on TLC. Quenched with water after completion and the catalyst was filtered off, the filtrate was concentrated in vacuo. The crude product was purified on silica (100–200 mesh) column chromatography (15percentethylacetate/hexane) to offer 73.2 mg (in 95percent yield) of pure crystalline phenol. |
72% | With p-benzoquinone; potassium hydroxide In water for 23 h; Reflux; Green chemistry | General procedure: A mixture of 1,4-benzoquinone (32.4 mg, 0.3 mmol), boronic acid 1 (1 mmol), and KOH (168 mg, 3.0 mmol) in H2O (5 mL) was stirred at reflux temperature under air for 15−45 h. After the full consumption of 1 (monitored by TLC, eluent: PE–EtOAc, 10:1), the reaction was quenched carefully with aq 2 M HCl (15 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H2O (30 mL) and brine (10 mL), and dried (Na2SO4). After the removal of the solvent, the resulting residue was purified by chromatography (silica gel, 20 percent EtOAc in PE) to give the respective products 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium hydride In N,N-dimethyl-formamide at 80 - 100℃; for 14 h; | Step (ii): Synthesis of 2-(4-Trifluoromethoxy-phenyl)-4-(3-trifluoromethyl-pyrazol-l- yl)-quinoline (E 18); Compound 24 (200 mg, 0.62 mmol) was added to a stirred solution of compound 21 (210 mg, 1.55 mmol) and NaH (1.55 mmol) in dry DMF (5.0 mL), EPO <DP n="140"/>under nitrogen. The mixture was stirred at 80-100 0C for about 14 hrs. After this time, the reaction the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2N HCl. The organic layer was collected, washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography to give the desired product (yield 55 percent). Melting range: 108-110 0C1H NMR (400 MHz, CDCl3) δ 8.28-8.23 (m, 3H), 8.02-8.00 (m, 2H), 7.95 (s, IH), 7.86-7.81 (m, IH), 7.65-7.61 (m, IH), 7.39-7.37 (m, 2H), 6.89 (d, J=2.7Hz, IH). IR (Cm"1): 1607, 1505, 1480 MS (m/z): 424 (M+, 100percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.4% | With hydrogenchloride; n-butyllithium; sodium chloride In tetrahydrofuran; n-heptane | EXAMPLE 1E 4-(trifluoromethoxy)phenylboronic Acid A solution of 1-bromo-4-(trifluoromethoxy)benzene (1.69 kg) and triisopropyl borate (1.46 kg) in THF (6.75 L) at -70° C. was treated with 2.25 M butyllithium in hexanes (3.27 L) over 2.3 hours, stirred for 10 minutes, treated with 6M HCl (1.52 L) over 50 minutes, stirred for 18 hours at room temperature, and poured into a mixture of heptane (8.43 L) and 20percent (w/w) sodium chloride (8.44 kg). This mixture was stirred for 10 minutes and separated into an aqueous fraction and an organic fraction. The organic fraction was concentrated to provide a white paste. The paste was dried under vacuum (100 mmHg) at ambient temperature with a nitrogen bleed for 2 days then at 40-50° C. for 18 hours to provide 1.306 kg (90.4percent) of the desired product as a solid. 1H NMR (CDCl3, 300 MHz) δ 7.24-7.19 (m, 2H), 8.14-8.10 (m, 2H) with additional absorptions at 7.19-7.15 (m, 2H) and 8.04-8.00 (m, 2H) corresponding to the cyclic boronic acid trimer. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.1% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 130℃; Sealed tube | 4- (trifluoromethoxy) phenylboronic acid (254mg, 1.24mmol), 3-bromo -N- [6- (2,6- dimethyl - morpholin-4-yl) - pyridine 3-yl] -4-methyl -benzamide 5 (250mg, 0.62mmol), Pd (PPh 3) 4 (36mg, 0.03mmol), Na 2 CO 3 (2.0Maqueous solution, 1.23mL, 2.4mmol) and a mixture of DME (4.5mL) in a sealed tube and heated at130 ° C overnight. The reaction mixture was diluted with EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers were washedwith brine and concentrated to give a crude product, which was then purified bypreparative mass triggered HPLC (C 18 column and eluted with 0.05percent TFA in CH 3CN-H 2 O elution) to give N - (6 - ((2S, 6R) -2,6- dimethyl-morpholino)pyridin-3-yl) -2-methyl-4 '- (trifluoromethoxy) biphenyl-3-carboxylic amide(183.5mg, yield 61.1percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 77℃; for 5h; | 1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole A mixture of <strong>[10075-51-1]1-benzyl-5-bromo-1H-indole</strong> (5.2 g, 18 mmol), 4-trifluoromethoxyphenylboronic acid (4.7 g, 23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.88 g, 1.1 mmol), potassium carbonate (3.8 g, 27 mmol) in dioxane (135 mL) and water (13.5 mL) was heated at 77 C. for 5 hours. The reaction mixture was evaporated to dryness and partitioned in ethyl acetate and 2N hydrochloric acid. The organic phase was washed with water and brine, dried over anhydrous anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using hexane as an eluant to yield the title compound as a light yellow wax/solid (2.8 g, 42%), mp 62-63 C. 1HNMR (300 MHz, DMSO-d6): delta7.85 (s, 1H), 7.75 (d, 2H, J=7.7 Hz), 7.5-7.6 (m, 2H), 7.4 (d, 3H, J=7.7 Hz), 7.2-7.35 (m, 5H), 6.6 (d, 1H, J=3.9 Hz), and 5.45 ppm (s, 2H). |
42% | With potassium carbonate; In 1,4-dioxane; hexane; dichloromethane; water; | Step 1 1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole 1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole was prepared by coupling of <strong>[10075-51-1]1-benzyl-5-bromo-1H-indole</strong> (5.2 g, 18 mmol) and 4-trifluoromethoxyphenylboronic acid (4.7 g, 23 mmol), using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.88 g, 1.1 mmol), and potassium carbonate (3.8 g, 27 mmol) in dioxane (135 mL) and water (13.5 mL) according to the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using hexane as an eluant yielded the title compound as a light yellow solid (2.8 g, 42%), mp: 62-63 C. 1H-NMR (300 MHz, DMSO-d6): delta7.85 (s, 1H), 7.75 (d, 2H, J=7.7 Hz), 7.5-7.6 (m, 2H), 7.4 (d, 3H, J=7.7 Hz), 7.2-7.35 (m, 5H), 6.6 (d,1H, J=3.9 Hz), and 5.45 ppm (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile;Heating / reflux; | 25 mi (10.0 MMOL) of aqueous 0.4 M sodium carbonate solution and then 303 mg (0.26 MMOL) OF TETRAKIS (TRIPHENYLPHOSPHINE) PALLADIUM (0) are added to a solution of 2.0 g (8.7 MMOL) of methyl 2-BROMO-3-METHYLBENZOATE and 2.16 g (10.5 MMOL) of 4- (trifluoromethoxy) boronic acid in 25 ml of acetonitrile. The mixture is refluxed overnight; after cooling, the reaction medium is diluted with 50 ml of water and extracted with diethyl ether. The combined organic extracts are washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (eluent : 5% of diethyl ether in hexane) to give 2.4 g (89%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Under an argon atmosphere, to 4 ml 1,2-dimethoxyethane are added methyl 6-chloronicotinate (230 mg, 1.06 mmol), [4- (trifluoromethoxy) phenyl] boronic acid (268 mg, 1.31 mmol), 1.28 ml of a 2M aqueous sodium carbonate solution and tetrakis- (triphenylphosphin) palladium (0) (62 mg, 0.05 mmol). The mixture is stirred at 80 °C for 16h, cooled and quenched with water. After threefold extraction with ethyl acetate, the combined organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 7: 1). Yield: 180 mg (57 percent). 'H NMR (400 MHz, DMSO-d6) 8 3.92 (s, 3H), 7.53 (d, 2H), 8.17 (d, 1H), 8.30 (d, 2H), 8.40 (dd, 1H), 9. 18 (d, 1H). MS (ESIF) : 298 [M+H] + HPLC : Retention time 5.01 min (method B) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydrogencarbonate; | EXAMPLE 93D 6-fluoro-4'-(trifluoromethoxy)-1,1'-biphenyl-3-carbonitrile A 100 mL 3-necked flask equipped with a stir bar, a condenser, and a nitrogen inlet was flushed with nitrogen and then charged with <strong>[79630-23-2]3-bromo-4-fluorobenzonitrile</strong> (2.507 g, 1.23*10-2 mol), 4-trifluoromethoxyphenyl boronic acid (2.825 g, 1.23*10-2mol, 1.01 equiv), bis(triphenylphosphine)-palladium(II) chloride (2.0 mg, 2.85*10-6 mol, 0.02 mol%), and sodium bicarbonate (1.577 g, 1.82*10-2 mol, 1.5 equiv). The flask was then evacuated and purged with nitrogen three times, and charged with deoxygenated toluene (6 mL) and deoxygenated water (6 mL). The mixture was heated to 80 C. until HPLC analysis indicated the disappearance of the aryl bromide (less than 16 hours; HPLC conditions: Eclipse XDB-C8 (4.6 mm*150 mm), flow rate: 1.5 mL/min.; mobile phase: 80:20 water(0.1%H3PO4)/CH3CN to 20:80 in 8 minutes, hold to 15 minutes with the column at 35 C. and UV detection: 210 nm. Retention time for the product is 8.88 min, retention time for aryl bromide is 6.47 min, retention time for excess boronic acid is 5.64 min, and retention time for homocoupled product is 10.58 minutes). The reaction was cooled to room temperature and the phases were separated. The organic phase was filtered through a plug of silica (2.5 g) and the silica plug was washed with toluene (25 mL). The filtrate was concentrated to provide the desired product (3.472 g, 92% potency, 93% potency adjusted yield). HRMS (FAB) calcd. for C14H7F4NO (M+H)+; 282.0542, found 282.0536; 1H NMR (CDCl3) delta7.76 (dd, 1H), 7.68 (ddd, 1H), 7.56 (m, 2H), 7.34 (m, 2H), 7.30 (dd, 1H); 13C (CDCl3) delta161.9, 149.5, 134.9, 133.5, 131.9, 130.4, 129.5, 121.2 (2), 120.4, 117.8, 117.7, 109.1; IR(KBr) 2230, 1514, 1490, 1265, 1256, 1223, 1210, 1157; Analytical: Pd 6 ppm, B<30 ppm, Na<1 ppm; mp ~63.5-64.2 C. |
93% | With sodium hydrogencarbonate; | EXAMPLE 93D 6-fluoro-4'-(trifluoromethoxy)-1,1'-biphenyl-3-carbonitrile A 100 mL 3-necked flask equipped with a stir bar, a condenser, and a nitrogen inlet was flushed with nitrogen and then charged with <strong>[79630-23-2]3-bromo-4-fluorobenzonitrile</strong> (2.507 g, 1.23*10-2 mol), 4-trifluoromethoxyphenyl boronic acid (2.825 g, 1.23*102 mol, 1.01 equiv), bis(triphenylphosphine)-palladium(II) chloride (2.0 mg, 2.85*10-6 mol, 0.02 mol %), and sodium bicarbonate (1.577 g, 1.82*10-2 mol, 1.5 equiv). The flask was then evacuated and purged with nitrogen three times, and charged with deoxygenated toluene (6 mL) and deoxygenated water (6 mL). The mixture was heated to 80 C. until HPLC analysis indicated the disappearance of the aryl bromide (less than 16 hours; HPLC conditions: Eclipse XDB-C8 (4.6 mm*150 mm), flow rate: 1.5 mL/min.; mobile phase: 80:20 water(0.1%H3PO4)/CH3CN to 20:80 in 8 minutes, hold to 15 minutes with the column at 35 C. and UV detection: 210 nm. Retention time for the product is 8.88 min, retention time for aryl bromide is 6.47 min, retention time for excess boronic acid is 5.64 min, and retention time for homocoupled product is 10.58 minutes). The reaction was cooled to room temperature and the phases were separated. The organic phase was filtered through a plug of silica (2.5 g) and the silica plug was washed with toluene (25 mL). The filtrate was concentrated to provide the desired product (3.472 g, 92% potency, 93% potency adjusted yield). HRMS (FAB) calcd. for C14H7F4NO (M+H)+: 282.0542, found 282.0536; 1H NMR (CDCl3) delta 7.76 (dd, 1H), 7.68 (ddd, 1H), 7.56 (m, 2H), 7.34 (m, 2H), 7.30 (dd, 1H); 13C (CDCl3) delta 161.9, 149.5, 134.9, 133.5, 131.9, 130.4, 129.5, 121.2 (2), 120.4, 117.8, 117.7, 109.1; IR (KBr) 2230, 1514, 1490, 1265, 1256, 1223, 1210, 1157; Analytical: Pd 6 ppm, B <30 ppm, Na<1 ppm; mp~63.5-64.2 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
122 mg (79%) | With sodium carbonate;Pd(PPh3)4; In ethanol; water; toluene; | b) 6-[(4-Trifluoromethoxy)phenyl]pyridine-2-carboxamide A mixture of <strong>[25194-52-9]6-bromopyridine-2-carboxamide</strong> (110 mg, 0.547 mmol), 4-(trifluoromethoxy)phenylboronic acid (Aldrich; 138 mg, 0.670 mmol), sodium carbonate (185 mg) and Pd(PPh3)4 (32 mg, 5 mol %) in 10 mL of toluene and 2.5 mL each of water and EtOH was heated at reflux overnight. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous layer was washed twice with EtOAc and the pooled organic layers were washed with water (3*), dried (Na2SO4), filtered and concentrated to dryness. Flash chromatography (6:4 hexane/acetone) afforded 122 mg (79%) of the title compound as a white solid, mp 133-135 C. 1H NMR (CDCl3): delta 8.19 (d, J=7.5 Hz, 1H), 8.04 (d, J=9.0 Hz, 2H), 7.96 (t, J=7.8 Hz, 1H), 7.94 (bs, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.1 Hz, 2H), 5.76 (bs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 4h;Combinatorial reaction / High throughput screening (HTS);Product distribution / selectivity; | EXAMPLE 36The Preparation of a series of compounds using multiple parallel synthetic techquires from 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione prepared as in Example 7 Combichem Procedure 1; In a 8 ml screw cap vial was added a solution of 9-Hydroxy-4-iodo-6H-pyrrolo[3,4-c]carbazole-1,3-dione, (0.1 mmol) prepared as in example 7 in dioxane (1 ml), a solution of Reagent 1 (see table) (0.1 mmol) in 1:1 dioxane/2.5 M K2CO3 (1 ml) and [1,1'Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (0.003 g, 0.0037 mmol). The vial was capped and the reaction mixture was shaken for 4 hours at 90 C. After cooling to room temperature, the solution was was removed under vacuum. Purification was carried out via reverse-phase HPLC (3% n-propanol in acetonitrile and 3% n-propanol in water as the eluent; C-18 column). The products were characterised by mass spectral analysis (See Table 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Catalyze; | Example 43; Preparation of 4-[5-(4-trifluoromethoxyphenyl)-pyrimidin-2-yl]-benzaldehyde Step 1. 2-Chloro-5-(4-trifluoromethoxyphenyl)-pyrimidine. The compound was prepared by palladium-catalyzed arylation of <strong>[22536-67-0]2,5-dichloropyrimidine</strong> with 4-trifluoromethoxyphenyl boronic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 150.0℃; for 0.166667h;Microwave irradiation; | Step 2. 4-[6-(4-Trifluoromethoxyphenyl)-pyridin-2-yl]-benzaldehyde. <strong>[588727-65-5]4-(6-Bromo-pyridin-2-yl)-benzaldehyde</strong> (0.31 mmol), 4-trifluoromethoxy boronic acid (0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (0.003 mmol), 2 M potassium carbonate (0.31 mL) and dioxane (2 mL) were combined in a vial and irradiated by microwave for 10 min at 150 C. The reaction mixture was taken up in ether and washed with brine. The organic layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded 80 mg of the product as an off-white solid. 1H NMR (400 MHz, CDCl3) delta 10.11 (s, 1H), 8.32 (d, J=8.5 Hz, 2H), 8.19 (d, J=8.1 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.89 (t, J=7.9 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H); EIMS 343 m/z (M+); mp 109-112 C. | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 150.0℃; for 0.166667h;Microwave irradiation; | 4-(6- Bromo-pyridin-2-yl)-benzaldehyde (0.31 mmol), 4-trifluoromethoxyphenyl boronic acid (0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (0.003 mmol), 2 M potassium carbonate (0.31 mL) and dioxane (2 mL) were combined in a vial and irradiated by microwave for 10 min at 150 0C. The reaction mixture was taken up in ether and washed with brine. The organic layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded the product (80 mg) as an off-white solid: mp 109-112 0C; 1U NMR (400 MHz, CDCl3) delta 10.11 (s, IH), 8.32 (d, J= 8.5 Hz, 2H), 8.19 (d, J= 8.1 Hz, 2H), 8.03 (d, J= 8.4 Hz, 2H), 7.89 (t, J = 7.9 Hz, IH), 7.79 (d, J = 7.7 Hz, IH), 7.74 (d, J = 8.0 Hz, IH), 7.35 (d, J = 8.3 Hz, 2H); EIMS m/z 343 (M+). | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 150.0℃; for 0.166667h;Microwave irradiation; | Step 2. 4-[6-(4-Trifluoromethoxyphenyl)-pyridin-2-yl]-benzaldehyde. 4-(6-Bromo- pyridin-2-yl)-benzaldehyde (0.31 mmol), 4-trifluoromethoxyphenyl boronic acid (0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (0.003 mmol), 2 M potassium carbonate (0.31 mL) and dioxane (2 mL) were combined in a vial and irradiated by microwave for 10 min at 150 0C. The reaction mixture was taken up in ether and washed with brine. The organic layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded the product (80 mg) as an off-white solid: mp 109-112 0C; 1H NMR (400 MHz, CDCl3) delta 10.11 (s, IH), 8.32 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.89 (t, J = 7.9 Hz, IH), 7.79 (d, J = 7.7 Hz, IH), 7.74 (d, J = 8.0 Hz, IH), 7.35 (d, J = 8.3 Hz, 2H); EIMS m/z 343 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With copper diacetate; triethylamine; In dichloromethane; at 20℃; for 2h;Molecular sieve; | (2) Preparation of the intermediate 89(2).; A mixture of the intermediate 89(1) (500 mg, 3.563 mmol), 4-(trifluoromethoxy)phenylboronic acid (1.46 g, 7.136 mmol), copper(II) acetate (648 mg, 3.568 mmol), triethylamine (2.5 ml, 17.84 mmol), molecular sieves 4A and dichloromethane (35 ml) was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite. The residue obtained by concentration of the filtrate under reduced pressure was diluted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane : ethyl acetate = 10 : 1) to give the title compound (132 mg, 12 %) as a yellow oil. 1H-NMR (CDCl3) delta: 6.69 (1H, dd, J = 2.5, 11.5 Hz), 6.82-6.86 (1H, m), 7.11-7.15 (2H, m), 7.30 (2H, d, J = 9.0 Hz), 7.86 (1H, t, J = 8.5 Hz), 10.25 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 150℃; for 0.5h;Inert atmosphere; microwave irradiation; | In a 5 mL vial <strong>[108281-79-4]6-bromo-[1,2,4]triazolo[4,3-a]pyridine</strong> (93 mg), 4-trifluoromethoxyphenylboronie acid (115 mg), and potassium carbonate (187 mg) were suspended in DMF (2 mL) that was previously degassed with nitrogen. Tetrakis(triphenylphosphine) palladium (20 mg) was added and the reaction mixture was heated in a microwave reactor at 150 C. for 30 min, filtered, and concentrated. The residue was subjected to gradient chromatography (MeOH/dichloromethane) to produce white powder, 56.4 mg (43% yield).1H NMR (400 MHz, CDCl3): delta 8.89 (s, 1H), 8.27 (br s, 1H); 7.89 (d, J=9.2 Hz, 1H); 7.59 (d, J=8.4, 2H); 7.52 (d, J=9.6 Hz, 1H); 7.36 (d, J=7.6, 2H).MS (ES+, m/z) 280.0 (base peak, M+H+); 581.0 (2M+Na+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; isopropyl alcohol; toluene; at 90.0℃; for 12h; | Example 807-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (Compound III-1) A mixture of 7-bromophthalazinone (1.09 g, 4.84 mmol), 4-trifluoromethoxyphenyl boronic acid (1.20 g, 5.81 mmol), dppf(Pd)Cl2 (177 mg, 0.242 mmol), potassium carbonate (1.34 g, 9.68 mmol) in degassed toluene (4 mL), degassed water (2 mL) and degassed isopropanol (2 mL) was heated at 90 C. for 12 hours. The layers were separated, the organic layer was concentrated and the residue was purified by trituration with hexanes/ethyl acetate to provide 7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white powder. C15H9F3N2O2. 307.2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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65% | With potassium phosphate; palladium diacetate; In water; N,N-dimethyl-formamide; at 20℃; for 12h; | General procedure: A DMF/water solution (1:1, 2 mL per 1 mmol of 1) of K3 PO4 (1.5 mmol),Pd(OAc)2 (2 mol %), and arylboronic acid 2a-n (0.9 mmol) was stirred atroom temperature for 8-12 h (tlc control). After completion of the reaction, themixture was extracted with CH2Cl2 and the combined organic layers weredried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residuewas purified by column chromatography (silica gel, EtOAc/heptane = 1:4).Starting with 1 (216 mg, 1.00 mmol), K3PO4 (165 mg, 1.50 mmol), Pd(OAc)2(2 mol %), arylboronic acid (149 mg, 0.90 mmol), and a solution ofDMF and water (1:1, 5 mL), 3a-3n was isolated |
Yield | Reaction Conditions | Operation in experiment |
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58% | With potassium phosphate; palladium diacetate; In water; N,N-dimethyl-formamide; at 20℃; | General procedure: A DMF/water solution (1:1, 2 mL per 1 mmol of 1) of K3PO4 (1.5 mmol), Pd(OAc)2(2 mol %), and arylboronic acid 2 (2.2 mmol) was stirred at room temperaturefor 8-12 h (tlc control). After completion of the reaction, the mixture wasextracted with CH2Cl2 and the combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, EtOAc/heptane = 1:4). Starting with 1(216 mg, 1.0 mmol), K3PO4 (345 mg, 2.5 mmol), Pd(OAc)2 (2 mol %), arylboronic acid (334 mg, 2.20 mmol), and solution of DMF andwater (1:1) (2 mL), 4a-f was isolated as a yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13 g | [0200] To the bromide (15 g, 0.04 mol, 1 eq), boronic acid (12.5 g, 0.06 mol, 1.5 eq) and potassium carbonate (22 g, 0.16 mol, 4 eq) in a round bottom flask, solvent (150 mL, toluene/isopropano/water : 2/1/1) was added and stirred under nitrogen for 10 min. To the above solution the palladium catalyst (1 g, 0.012 mol, 0.02 eq) was added and heated at 85 C for 2h. The reaction mixture was diluted with ethyl acetate, separated the organic layer and filtered the organic layer through a plug of celite and silica gel and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided Compound 1 (13 g). |
Yield | Reaction Conditions | Operation in experiment |
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66% | With oxygen; sodium hydroxide; copper dichloride; In methanol; for 15h;Reflux; | General procedure: A mixture of 1.6 mmol of C-nitro-NH-azole (1a-e), 2.6 mmol of arylboronic acid (2a-n), 1.6 mmol of sodium hydroxide, 0.2 mmol of CuCl2 and methanol (15 mL) was refluxed while air was bubbled through the reaction mixture. After completion of the reaction, determined on the basis of TLC analysis, the solvent was removed under reduced pressure using a rotary evaporator. The obtained crude product was purified by silica gel column chromatography with 5:95 v/v MeOH/CHCl3 as an eluent to give corresponding N-aryl-C-nitroazole. The product was crystallized from methanol/water. |
Yield | Reaction Conditions | Operation in experiment |
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12% | With pyridine; pyridine N-oxide; oxygen; copper diacetate; In dichloromethane; at 20.0℃; for 18.0h;Molecular sieve; | General procedure: [0640] To a solution of XII-5 (2.0 g, 10 mmol) in DCM (100 mL), copper (II) acetate (3.6 g, 20 mmol), XII-6 (2.0 g, 12 mmol), pyridine (3 mL), pyridine-N-oxide (1.9 g, 20 mmol) and finely ground, activated 4 molecular sieves (3.0 g) were added. The mixture was stirred at rt. for 18 hrs under O2 atmosphere. The solvent was evaporated and the residue was diluted with AcOEt (150 mL) and filtered. The filtrate was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel with petroleum ether/EtOAc (1:11:2) to yield XII-7 (400 mg, 12% yield) as a yellow solid. MS (ESI) m/z (M+H)+ 386. |
12% | With pyridine; pyridine N-oxide; copper diacetate; In dichloromethane; at 20.0℃; for 18.0h;Molecular sieve; | [0385] To a solution of X-5 (2.0 g, 10 mmol) in DCM (100 mL), copper (II) acetate (3.6 g, 20 mmol), X-6 (2.0 g, 12 mmol), pyridine (3 mL), pyridine-N-oxide (1.9 g, 20 mmol) and finely ground, activated 4A molecular sieves (3.0 g) were added. The mixture was stirred at rt. for 18 hrs under 02 atmosphere. The solvent was evaporated and the residue was diluted with AcOEt (150 mL) and filtered. The filtrate was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel with petroleum ether/EtOAc (1:1 1:2) to yield X-7 (400 mg, 12 % yield) as a yellow solid. MS (ES) m/z (M+H) 386. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In water; N,N-dimethyl-formamide; at 80℃; for 4h; | General procedure: Pd(PPh3)2Cl2 (23 mg, 0.03 mmol), 4-trifluoromethoxyphenylboronic acid (73 mg, 0.35 mmol), compound 15 (100 mg, 0.32 mmol) and TEA (91 mg, 0.90 mmol) were added to a solution of DMF (5 mL) and H2O (0.5 mL). The mixture was stirred at 80 oC for 4 h. Water (10 mL) and EtOAc (30 mL) were added to the reaction. The layers were separated. The aqueous layer was extracted using EtOAc (10 mL). The combined organic extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the resulting residue was purified via silica gel column chromatography using petroleum ether/EtOAc (5/1) to give 16 (67 mg, 48 %) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In water; N,N-dimethyl-formamide; at 80℃; for 4h; | General procedure: Pd(PPh3)2Cl2 (23 mg, 0.03 mmol), 4-trifluoromethoxyphenylboronic acid (73 mg, 0.35 mmol), compound 15 (100 mg, 0.32 mmol) and TEA (91 mg, 0.90 mmol) were added to a solution of DMF (5 mL) and H2O (0.5 mL). The mixture was stirred at 80 oC for 4 h. Water (10 mL) and EtOAc (30 mL) were added to the reaction. The layers were separated. The aqueous layer was extracted using EtOAc (10 mL). The combined organic extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the resulting residue was purified via silica gel column chromatography using petroleum ether/EtOAc (5/1) to give 16 (67 mg, 48 percent) as a yellow solid. |
73% | With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In water; N,N-dimethyl-formamide; at 85℃; | General procedure: Weigh 2,4-dichloro-7H-pyrrolopyrimidine (372 mg, 1 eq),P-trifluoromethoxyphenylboronic acid (1000 mg, 1.1 eq), triethylamine (1.2 eq),Bis(triphenylphosphine)palladium(II) chloride (0.1eq), N,N-dimethylformamide(28.5 ml), water (0.5 ml) was added to the flask and the temperature was raised to 85°C for 4 hours.After stopping the reaction, add water to the reaction solution100ml, stirring, ethyl acetate (20ml*4) extraction,The ester layer was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography.(petroleum ether:ethyl acetate=20:1)Obtained solid (680 mg, 41percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.1% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 130℃;Sealed tube; | 4- (trifluoromethoxy) phenylboronic acid (254mg, 1.24mmol), 3-bromo -N- [6- (2,6- dimethyl - morpholin-4-yl) - pyridine 3-yl] -4-methyl -benzamide 5 (250mg, 0.62mmol), Pd (PPh 3) 4 (36mg, 0.03mmol), Na 2 CO 3 (2.0Maqueous solution, 1.23mL, 2.4mmol) and a mixture of DME (4.5mL) in a sealed tube and heated at130 C overnight. The reaction mixture was diluted with EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers were washedwith brine and concentrated to give a crude product, which was then purified bypreparative mass triggered HPLC (C 18 column and eluted with 0.05% TFA in CH 3CN-H 2 O elution) to give N - (6 - ((2S, 6R) -2,6- dimethyl-morpholino)pyridin-3-yl) -2-methyl-4 '- (trifluoromethoxy) biphenyl-3-carboxylic amide(183.5mg, yield 61.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; isopropyl alcohol; toluene; at 85℃; for 2h;Inert atmosphere; | To the bromide (15 g, 0.04 mol, 1 eq), boronic acid (12.5 g, 0.06 mol, 1.5 eq) and potassium carbonate (22 g, 0.16 mol, 4 eq) in a round bottom flask, solvent (150 mL, toluene/isopropanol/water: 2/1/1) was added and stirred under nitrogen for 10 min. To the above solution the palladium catalyst (1 g, 0.012 mol, 0.02 eq) was added and heated at 85 C. for 2 h. The reaction mixture was diluted with ethyl acetate, separated the organic layer and filtered the organic layer through a plug of celite and silica gel and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided Compound I (13 g). |
13 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; isopropyl alcohol; toluene; at 20 - 85℃; for 2h;Inert atmosphere; | To the bromide (15 g, 0.04 mol, 1 eq), boronic acid (12.5 g, 0.06 mol, 1.5 eq) and potassium carbonate (22 g, 0.16 mol, 4 eq) in a round bottom flask, solvent (150 mL, toluene/isopropanol/water: 2/1/1) was added and stirred under nitrogen for 10 min. To the above solution the palladium catalyst (1 g, 0.012 mol, 0.02 eq) was added and heated at 85 C. for 2 h. The reaction mixture was diluted with ethyl acetate, separated the organic layer and filtered the organic layer through a plug of celite and silica gel and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided Compound 1 (13 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium fluoride; tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 22h;Inert atmosphere; Sealed tube; | 4.4.7 3,5-Dichloro-2,6-bis(4-(trifluoromethoxy)phenyl)pyridine (4g) Starting with <strong>[2402-79-1]2,3,5,6-<strong>[2402-79-1]tetrachloropyridine</strong></strong> 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 5.0 mol %), 4-(trifluoro-methoxy)phenylboronic acid (257 mg, 1.25 mmol), KF (174 mg, 3.0 mmol) and toluene (8.0 mL), 4g was isolated as a colorless solid (159 mg, 68%); mp=60-62 C. 1H NMR (300 MHz, CDCl3): delta=7.28-7.31 (m, 4H, CH), 7.79-7.85 (m, 4H, CH), 7.95 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): delta=120.3 (q, 1JC-F=259.5 Hz, CF3), 120.4 (CH), 128.7 (C), 131.1 (CH), 135.5 (C), 139.7 (CH), 149.8 (q, 3JC-F=1.8 Hz, C), 152.9 (C). 19F NMR (282.4 MHz, CDCl3): delta=-57.3 (CF3). IR (ATR, cm-1): ?=3055 (w), 1901 (w), 1608 (m), 1503 (m), 1403 (m), 1301 (m), 1205 (s), 1168 (s), 1109 (s), 1046 (m), 1029 (w), 1014 (m), 923 (m), 899 (m), 875 (m), 808 (m), 767 (m), 754 (m), 668 (m), 603 (m), 532 (m), 389 (w). GC-MS (EI, 70 eV): m/z (%): 468 (M+, 23), 467 (100), 434 (23), 433 (14), 432 (65), 400 (2), 397 (6), 384 (5), 382 (8), 335 (7), 311 (6), 300 (6), 210 (4), 202 (4), 123 (3), 113 (5), 87 (3), 69 (22). HRMS (ESI, 70 eV): calcd for C19H10Cl2F6NO2 ([M+H]+): 467.9987, found 467.9997. Anal. Calcd for C19H9Cl2F6NO2 (468.18): C, 48.74; H, 1.94; N, 2.99. Found: C, 48.66; H, 1.861; N, 2.949. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; isopropyl alcohol; toluene; at 100℃; for 3.6h;Sealed tube; | Example 147 5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine A (0.575 g, 2.70 mmol), B (0.834 g, 4.05 mmol), Pd(dppf)Cl2 (0.200 g, 0.27 mmol), Potassium carbonate (0.746 g, 5.40 mmol) were mixed. Toluene (4 mL), 2-isopropanol (2 mL), water (4 mL) were added. The vial was then capped tight, stirred at 100 C. for 3.6 h. The mixture was diluted with EtOAc, washed with brine, dried with MgSO4, concentrated and purified by silica gel column (Rf=0.13 in 20% EtOAc/hexane) to afford the title compound (0.523 g, 66%). 1H NMR (400 MHz, DMSO-d6) delta 8.17-8.12 (m, 1H), 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.80-7.74 (m, 2H), 7.56-7.50 (m, 1H), 7.50-7.44 (m, 2H), 6.45 (s, 2H). m/z: 295 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
509mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; lithium chloride; In 1,4-dioxane; water; at 100℃; for 3.5h; | 12184] A mixture of 500 mg of methyl 6-bromobenzo[b] thiophene-2-carboxylate, 494 mg of 4-(trifluoromethoxy) phenylboronic acid, 407 mg of lithium chloride, 352 mg of sodium carbonate, 107 mg of tetrakis(triphenylphosphine) palladium (0), 20 ml of 1 ,4-dioxane, and 10 ml of water was stirred for 3.5 hours a: 1000 C. Afier being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform was added to the residues, and insoluble matter was separated by filtration. Afier water was added to the filtrate, extraction was performed using chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 509mg of methyl 6-(4-trifluoromethoxyphenyl)benzo[b]thiophene-2-car- boxylate (hereinafier, described as a ?compound 45 of the present invention?)12185] Compound 45 of the Present Invention 12186] ?H-NMR (CDC13) oe: 8.09 (s, 1H), 8.03 (s, 1H),7.96-7.94 (n, 1H), 7.68-7.66 (m, 2H), 7.62-7.60 (m, 1H),7.34-7.32 (m, 2H), 3.97 (s, 3H) |
509 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; lithium chloride; In 1,4-dioxane; water; at 100℃; for 3.5h; | A mixture of 500 mg of <strong>[360576-01-8]methyl 6-bromobenzo[b]thiophene-2-carboxylate</strong>, 494 mg of 4-(trifluoromethoxy)phenylboronicacid, 407 mg of lithium chloride, 352 mg of sodium carbonate, 107 mg of tetrakis(triphenylphosphine)palladium(0), 20 ml of 1,4-dioxane, and 10 ml of water was stirred for 3.5 hours at 100C. After being cooled to room temperature,the reaction mixture was concentrated under reduced pressure. Chloroform was added to the residues, and insolublematter was separated by filtration. After water was added to the filtrate, extraction was performed using chloroform. Theorganic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reducedpressure. The residues were subjected to silica gel column chromatography, thereby obtaining 509 mg of methyl 6-(4-trifluoromethoxyphenyl)benzo[b]thiophene-2-caboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; pyridine N-oxide; copper diacetate; In dichloromethane;Molecular sieve; | XXV-10 was prepared following the similar procedure for obtaining Compound40. ?HNMR (CDC13, 400MHz) oe 7.50-7.42 (m, 2H), 7.40-7.31 (m, 4H), 7.26-7.20 (m, 1H), 7.10-7.03 (m, 3H), 3.73 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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55% | To a solution of 7-bromo-4-(pyrimidin-2-ylm- ethyl)-2,3,4,5-tetrahydro-1 ,4-benzoxaze-pin-5-one [Example 1, Step 3] (277 mg, 0.83 mmol, 1.00 equiv) in Toluene/iPrOH/H20 (2:1:1, 4 mE) was added potassium carbonate (459 mg, 3.32 mmol, 4.00 equiv) and [4-(trifluo- romethoxy)phenyl]boronic acid (257 mg, 1.25 mmol, 1.50 equiv). The mixture was stirred for 10 mm at room temperature. Then Pd(dppf)C12 (12 mg, 0.02 equiv) was added to the solution. The mixture was stirred at 85 C. for 2 h. After cooling the reaction mixture, ethyl acetate (30 mE) was added, and the organic layer was separated. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPEC with the following conditions: Column,)(l3ridge Prep Cl 8 013D Column, 5 um, 19* 150 mm; mobile phase, Water (10 mmol/E NH4HCO3) and CH3CN (50.0% CH3CN up to 52.0% in 7 mm); Detector, UV 254, 220 nm to afford 190mg (55%) of 4-(pyrimi- din-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3,4,5-tet- rahydro-1,4-benzoxazepin-5-one as a white solid. EC-MS:mlz=416 [M+H] ?H NMR (400 MHz, Chioroform-d) oe 8.75-8.74 (m, 2H), 8.20-8.19 (m, 1H), 7.66-7.61 (m, 3H), 7.29-7.28 (m, 1H), 7.27-7.26 (m, 1H), 7.24-7.23 (m, 1H), 7.13-7.11 (m, 1H), 5.12 (s, 2H), 4.60-4.57 (m, 2H), 3.81-3.78 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With pyridine; copper diacetate; In dichloromethane; at 20 - 24℃;Sealed tube; Inert atmosphere; | To a reaction flask were added <strong>[4928-88-5]methyl 1H-1,2,4-triazole-3-carboxylate</strong> (5.00 g, 39.3 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (8.10 g, 39.3 mmol), and copper(II) acetate (7.15 g, 39.3 mmol). The flask was sealed, and evacuated/backfilled with nitrogen (3x). Dichloromethane ( 157 mL) was added, followed by pyridine (4.77 mL, 59.0 mmol). The reaction mixture was allowed to stir at room temperature overnight. Water was added, and the reaction mixture was filtered through Celite®. The filtrate was transferred to a separatory funnel, and the layers were separated. The organic layers were further washed with water (3x), combined, dried over sodium sulfate, filtered, and concentrated . The crude product was triturated with a small amount of ethyl acetate/hexanes and filtered. The title compound was obtained as a white solid (2.17 g, 19percent): mp 156-158 °C; 1H NMR (300 MHz, CDCI3) delta 8.65 (s, 1H), 7.86 - 7.75 (m, 2H), 7.48 - 7.32 (m, 2H), 4.06 (s, 3H); 19F NMR (471 MHz, CDCI3) delta -58.00 ; 13C NMR (126 M Hz, CDCI3) delta 159.89, 149.29, 134.81, 122.44, 122.07, 121.35, 119.29, 53.06; EIMS m/z 288 ([M ]+). |
19% | With pyridine; copper diacetate; In dichloromethane; at 20℃;Inert atmosphere; Sealed tube; | Example 7 Preparation of methyl 1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole-3-carboxylate (C28) (0430) (0431) To a reaction flask was added <strong>[4928-88-5]methyl 1H-1,2,4-triazole-3-carboxylate</strong> (5.00 g, 39.3 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (8.10 g, 39.3 mmol), and copper(II) acetate (7.15 g, 39.3 mmol). The flask was sealed, and evacuated/backfilled with nitrogen (3×). Dichloromethane (157 mL) was added, followed by pyridine (4.77 mL, 59.0 mmol). The reaction mixture was allowed to stir at room temperature overnight. Water was added, and the reaction mixture was filtered through Celite®. The filtrate was transferred to a separatory funnel, and the layers were separated. The organic layers were further washed with water (3×), combined, dried over sodium sulfate, filtered, and concentrated. The crude product was triturated with a small amount of ethyl acetate/hexanes and filtered to provide the title compound as a white solid (2.17 g, 19percent): mp 156-158° C.; 1H NMR (300 MHz, CDCl3) delta 8.65 (s, 1H), 7.86-7.75 (m, 2H), 7.48-7.32 (m, 2H), 4.06 (s, 3H); 19F NMR (471 MHz, CDCl3) delta ?58.00; 13C NMR (126 MHz, CDCl3) delta 159.89, 149.29, 134.81, 122.44, 122.07, 121.35, 119.29, 53.06; EIMS m/z 288 ([M]+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 2h; | a) 8-(4-(Trifluoromethoxy)phenyl)-|T ,2,41triazolo|T ,5-alpyridin-2-amine In a 500 ml round-bottomed flask were combined 8-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (CAS 1124382-72-4, 6.00 g, 28.2 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (11.6 g, 56.3 mmol) and cesium carbonate (18.4 g, 56.3 mmol) in dioxane (300 ml) and water (30 ml) to give a light brown solution. l, -Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (2.06 g, 2.82 mmol) was added. The reaction mixture was stirred for 2 hours at 100C. Chromatography (silica gel, 330 g, ethyl acetate/heptane = 40:60 to 100:0) yielded the title compound as light brown solid (7.64 g, 92% ). MS: m/z = 295.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.7% | With pyridine; oxygen; copper diacetate; In dichloromethane; at 20℃; | To a solution of 93 (1g. 1i.9rnmol) and 23(3.67g, 17.8mmol) in DCM( Onil) was addedCu(OAc)2 (4.32g. 23. Smmoi) and pyridine(2 .82g. 35. 7mmoi) at room temperature under 02, Themixture was stirred at room temperature overnight, The suspension was filtered through a pad ofCelite and filter cake was washed with DCM(30m1). The combined organic layers were washedwith water and diied over Na2 04. The crude product was purified by silica gel chromatographyto give product 94 (50mg, yield: 1.7%).LCNIS: rn/z, 245.i(M±F1)t |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; for 8h;Inert atmosphere; Reflux; | 3,6-dibromo-thieno [3,2-b] thiophene11.3 g (0.038 mol) of(4-trifluoromethoxy) phenylboronic acid 16.0 g(0.078 mol),Tetrakis (triphenylphosphine) palladium(0), 114 ml of 2M potassium carbonate,TetrahydrofuranMixed with 360 ml,And the mixture was refluxed under nitrogen for 8 hours.After cooling, the reaction mixture was extracted with water and dichloromethane, and further separated by a silica gel column (developing solvent: ethyl acetate / hexane = 10/1) to obtain 14.8 g (84.6%) of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 24h;Inert atmosphere; | General procedure: 4-Bromothiazole-2-carboxylic acid (compound 1, 1 eq) and boronic acid derivatives (compound 2a-g, 1.5 eq) were suspended in dimethoxy ethane (DME)/H2O (16 volume, 3:1). Then, Pd(PPh3)4 (0.05 eq) and K2CO3 (1.5 eq) were added to the suspension. The obtained mixture was heated to about 100 C and stirred for about 24 h under nitrogen atmosphere. The solution was cooled to room temperature and acidified with concentrated hydrochloric acid. Then, the precipitate was filtered and washed with water. The obtained wet cake was redissolved in dichloromethane. The organic phase was washed with saturated sodium bicarbonate (NaHCO3) aqueous solution for 30 min. Then, the aqueous phase was acidified again with concentrated hydrochloric acid, and the precipitate was filtered to obtained compounds 3a-g. |
75% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 98℃; for 24h;Inert atmosphere; | Step A:<strong>[88982-82-5]4-bromothiazole-2-carboxylic acid</strong> (1,1.0 g, 4.8 mmol)Dissolved in ethylene glycol dimethyl ether (12mL)And water (4mL),Add 4-trifluoromethoxybenzeneboronic acid (13, 1.5 g, 7.2 mmol)And anhydrous potassium carbonate (994 mg, 7.2 mmol),Then tetrakis(triphenylphosphine)palladium (277 mg, 0.24 mmol) was added.The resulting mixture was heated to 98 C under nitrogen for 24 hours.TLC analysis indicated the end of the reaction.The reaction solution is cooled to room temperature, then add water (40mL),The pH was adjusted to 2-3 with 6M hydrochloric acid.Filter and filter the cake into 15 mL of dichloromethane.The dichloromethane layer was washed with 10% sodium carbonate.Divide the water phase,Adjust the pH of the aqueous phase to 2-3 with 6M hydrochloric acid.Filter the precipitated solids,Purify the filter cake with purified water until the washing solution is neutral.Drying gave compound 14 (1.03 g), yield: 75%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; bis[tris( 1,1-dimethylethyl)phosphine]-palladium; In 1,4-dioxane; water; at 80℃; for 16.0h;Inert atmosphere; | A mixture of A-14 (300.00 mg, 1.52 mmol), [4-(trifluoromethoxy)phenyllboronic acid (344.31 mg, 1.67 mmol), K3P04 (645.30 mg, 3.04 mmol) and Pd(t-Bu3P)2 (155.36 mg, 304.00 jimol) in dioxane (20.00 mL) and H20 (2.0 mL) was stirredunder N2 at 80 °C for 16 hours. The mixture was diluted with EtOAc (20 mL), filtered through silica gel, and eluted with EtOAc (10 mL), and the filtrate was concentrated to give the crude product which was purified by Prep-HPLC to give Compound 12 as a solid. ?H NMR (400 MHz, CDC13) oe11 8.54 (d, 1H), 8.08 - 7.90 (m, 1H), 7.78 - 7.62 (m, 3H), 7.34 (d, 2H), 6.99 (dd, 1H), 6.69 - 6.50 (m, 1H). LCMS R = 1.209 mm in 2.0 mm chromatography, MS ESI calcd. forC,4H,0F3N20 [M+H1 279.1, found 278.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.55 mg | With potassium phosphate; bis[tris( 1,1-dimethylethyl)phosphine]-palladium; In 1,4-dioxane; water; at 80℃; for 16h; | A mixture of [4-(trifluoromethoxy)phenyllboronic acid (202.45 mg, 983.08 pmol), A-2 (100.0mg, 655.39 pmol), Pd(t-Bu3P)2 (33.49 mg, 65.54 pmol) and K3P04 (278.24 mg, 1.31 mmol) indioxane (10 mL) and H20 (1 mL) was stirred at 80 C for 16 hours, at which point the desiredproduct was observed by LCMS. The mixture was then concentrated to give the crude product,which was purified by Prep-HPLC to afford Compound 6 (38.55 mg) as a solid. 1H NMR (400MHz, CDCl3) oe11 8.30 (s, 1H), 7.74 - 7.63 (m, 3H), 7.58 (d, 2H), 7.39 (br d, 1H), 7.33 (br d, 2H).LCMS R = 0.98 1 mm in 2.0 mm chromatography, MS ESI calcd. for C,4H,0F3N20 [M+H1 279.1, found 278.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium phosphate; bis[tris( 1,1-dimethylethyl)phosphine]-palladium; In 1,4-dioxane; water; at 75℃; for 16h;Inert atmosphere; | A-50A mixture of <strong>[1837-55-4]3,5-dichloropyridazine</strong> (1.38 g, 9.26 mmol), [4-(trifluoromethoxy)phenyllboronic acid (1.53 g, 7.41 mmol), Pd(t-Bu3P)2 (378.71 mg, 0.74 mmol) and K3P04 (3.93 g, 18.53 mmol) in 1,4-Dioxane (80 mL) and water (20 mL) was stirredat 75 C for 16 hours under N2. After cooling to r.t., the mixture was concentrated. The residue was diluted with H20 (100 mL), and the mixture was extracted with EtOAc (150 mL x 2). The combined organic phase was washed with water (50 mL) and brine (50 mL), dried over Na2504, filtered and concentrated to give the crude product. The crude product was purified by silica gel column (EtOAc in PE = 0% to 10% to 20%) to give 3-chloro-5-[4-(trifluoromethoxy)phenyllpyridazine (1800 mg, 5.3 116 mmol, 57% yield) as a solid. LCMS Rt = 0.800 mm in 1.5 mm chromatography, MS ESI calcd. for C,,H7C1F3N2O [M+H1 275.0, found274.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
520 mg | With potassium phosphate; bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere; | A mixture of A-5 (500.00 mg, 3.58 mmol), [4- (trifluoromethoxy)phenyl]boronic acid (1.11 g, 5.37 mmol), Pd(i-Bu3P)2 (146.36 mg, 286.40 muiotaetaomicron) and K3P04 (1.52 g, 7.16 mmol) in dioxane (20 mL) and H20 (4 mL) was stirred at 80 C for 16 hours under N2. The mixture was concentrated to a residue, which was diluted with H20 (30 mL) and extracted with EtOAc (150 mL x 2). The combined organic phase was washed with water (50 mL x 2) and brine (50 mL), dried over Na2S04, filtered and concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE = 5% to 10% to 15%) to give A-6 (520.00 mg, 1.96 mmol) as a solid. 1H NMR (400MHz, CDC13) = 9.14 (d, 1H), 8.96 (d, 1H), 8.16 (d, 2H), 7.41 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.05 g | With potassium phosphate; bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 80℃; for 12h;Inert atmosphere; | A mixture of A-9 (800 mg, 4.35 mmol), [4- (trifluoromethoxy)phenyl]boronic acid (1.25 g, 6.09 mmol), Pd(i-Bu3P)2 (111.15 mg, 217.50 muiotaetaomicron) and K3P04 (1.66 g, 7.83 mmol) in dioxane (40 mL) and H20 (8 mL) was stirred at 80 C for 12 hours under N2. The mixture was concentrated to a residue that was diluted with H20 (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic phase was washed with water (50 mL x 2) and brine (50 mL), dried over Na2S04, filtered and concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 10% to 15%) to afford A-10 (1.05 g, 3.96 mmol) as a solid. 1H NMR (400MHz, CDC13) = 9.04 (s, 2H), 7.67 (d, 2H), 7.44 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
170 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | A mixture of A-63 (1 g, 6.71mmol), [4-(trifluoromethoxy)phenyl]- boronic acid (1.52 g, 7.38 mmol), Pd(dppf)Cl2.CH2Cl2 (822.23 mg, 1.01 mmol) and Cs2C03 (4373.74 mg, 13.42 mmol) in 1,4-dioxane (20 mL) and water (4 mL) under N2 was stirred at 90 C for 16 hours. After cooling, the reaction mixture was diluted with EtOAc (20 mL), and filtered through a Celite pad, eluted with EtOAc (20 mL), and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE = 0percent to 3percent to 8percent) to afford A-108 (250 mg, 0.91 mmol) as a solid. 1H NMR (400MHz, CDC13) _ = 8.79 (d, 1H), 8.65 (d, 1H), 8.05 (d, 2H), 7.37 (d, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.4% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 98℃; for 24h;Inert atmosphere; | Step A:<strong>[37131-87-6]5-bromopyrimidine-2-carboxylic acid</strong> (41, 1.0 g, 5.0 mmol)Dissolved in ethylene glycol dimethyl ether (12 mL) and water (4 mL),Add 4-trifluoromethoxybenzeneboronic acid (13, 1.5 g, 7.5 mmol)And anhydrous potassium carbonate (1.0 g, 7.5 mmol),Then tetrakis(triphenylphosphine)palladium (289 mg, 0.25 mmol) was added.The resulting mixture was stirred at 98 C for 24 hours under a nitrogen atmosphere.TLC analysis indicates the end of the reactionThe reaction solution is cooled to room temperature.Then add water (40 mL),The pH was adjusted to 2-3 with 6M hydrochloric acid.Filtered, the filter cake is dissolved in dichloromethane,The organic layer was washed with 20 mL of saturated sodium bicarbonate solution.Divide the water layer,The aqueous layer was adjusted to pH 2-3 with a 6M hydrochloric acid solution.The solid was filtered and the filter cake was washed with water until neutral.The filter cake was dried to give compound 45 (1.2 mg).Yield: 85.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 20℃;Inert atmosphere; | General procedure: A mixture of (4-iodophenyl)(methyl)sulfane (Compound 4A) (500 mg, 2 mmol), 4-bromophenylboronic acid (400 mg, 2 mmol), Na2CCh (636 mg, 6 mmol), and Pd(PPh3)4 (115 mg, 0.1 mmol) in toluene/EtOH/H20 (20/10/4 mL) was stirred at 80 C under nitrogen overnight The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. - NMR (CDCb, 500 MHz): d (ppm) 2.52 (s, 3H), 7.32 (d, J= 8.5 Hz, 2H), 7.43 (d, J= 8.5 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 7.55 (d, J= 8.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; at 90℃; for 4h;Inert atmosphere; | General procedure: To asolution of bromotetrahydroquinoline or bromoquinoline2, 3, 5 or 6 (1.0 equiv.) in 1,4-dioxane (30 mL) in atwo-necked flask was added aq K2CO3 (3.0 M, 15 mL)and the mixture was stirred for 10 min at room temperature under an N2 atmosphere. Pd(PPh3)4 (0.05 equiv.)and the unsubstituted or 4-substituted phenylboronicacid (1.3 equiv. for monobromides, 2.6 equiv. for dibromides)were added. The mixture was refluxed for 4 h at90 C. The progress of the reaction was monitored byTLC. After completion of the reaction, the mixture wasdiluted with H2O and extracted with CHCl3 (3 × 20 mL).The combined organic layers were dried over anhydrousNa2SO4, filtered, and the filtrate was concentrated underreduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane/EtOAc) toafford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.97 g | With pyridine; oxygen; copper diacetate; In toluene; at 80 - 90℃; for 6h;Molecular sieve; | A mixture of compound j (5.00 g, 22.0 mmol, 1.00 eq), compound i (5.45 g, 26.5 mmol, 1.20 eq), Cu(OAc)2 (6.00 g, 33.1 mmol, 1.50 eq), Py (5.23 g, 66.1 mmol, 5.34 mL, 3.00 eq) and 4A MS (3.00 g, 22.0 mmol, 1.00 eq) in toluene (75 mL) was degassed and purged with O2 for 3 times, and then the mixture was stirred at 90C for 6 hr under O2 atmosphere. The resulting mixture was cooled, then filtered with celite, washed with ethyl acetate (50 mL), then the solution was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 5: 1). Compound k (4.97g, 97.15% purity) was obtained as a yellow oil and confirmed by LCMS (EW12195-115-P1C), HNMR. LC-MS (ESI): m/z (M+H) 387.7; NMR (400MHz, CDCb) d = 7.65 - 7.60 (m, 2H), 7.41-7.37 (m, 2H). |
Tags: 139301-27-2 synthesis path| 139301-27-2 SDS| 139301-27-2 COA| 139301-27-2 purity| 139301-27-2 application| 139301-27-2 NMR| 139301-27-2 COA| 139301-27-2 structure
A993265[ 2396699-94-6 ]
4-(Trifluoromethoxy)phenylboronic acid mida ester
Reason: Derivatives
[ 179113-90-7 ]
(3-(Trifluoromethoxy)phenyl)boronic acid
Similarity: 0.98
[ 958457-41-5 ]
(4-(4-(Trifluoromethoxy)phenoxy)phenyl)boronic acid
Similarity: 0.98
[ 870822-70-1 ]
(6-(Trifluoromethoxy)naphthalen-2-yl)boronic acid
Similarity: 0.95
[ 1256345-88-6 ]
(3-Methoxy-5-(trifluoromethoxy)phenyl)boronic acid
Similarity: 0.95
[ 957120-22-8 ]
(3-Hydroxy-5-(trifluoromethoxy)phenyl)boronic acid
Similarity: 0.95
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