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CAS No. : | 82380-18-5 | MDL No. : | MFCD00192177 |
Formula : | C7H4FNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | REIVHYDACHXPNH-UHFFFAOYSA-N |
M.W : | 137.11 | Pubchem ID : | 2734675 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 33.14 |
TPSA : | 44.02 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) : | -6.15 cm/s |
Log Po/w (iLOGP) : | 1.2 |
Log Po/w (XLOGP3) : | 1.39 |
Log Po/w (WLOGP) : | 1.82 |
Log Po/w (MLOGP) : | 1.22 |
Log Po/w (SILICOS-IT) : | 1.74 |
Consensus Log Po/w : | 1.48 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.01 |
Solubility : | 1.34 mg/ml ; 0.00978 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.92 |
Solubility : | 1.66 mg/ml ; 0.0121 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.16 |
Solubility : | 0.955 mg/ml ; 0.00697 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.35 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P273-P280-P305+P351+P338 | UN#: | 3077 |
Hazard Statements: | H302-H318-H411 | Packing Group: | Ⅲ |
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 |
---|---|---|
82% | With formic acid; oxygen; triethylamine; copper(ll) bromide In acetonitrile at 20℃; for 24 h; UV-irradiation | 4-Bromo-2-fluorobenzonitrile (0.25 mmol), copper bromide (0.03 mmol), triethylamine (0.25 mmol, 1.0 equiv), HCOOH (0.75 mmol, 3.0 equiv) at room temperature,179mmol of the reaction solvent CH3CN was added to the reaction tube, and the mixture was stirred at room temperature for 24 hours under the oxygen atmosphere.After the completion of the reaction was monitored by thin layer chromatography, 20 mL of water and 10 mL of ethyl acetate were added for extraction, followed by drying over anhydrous sodium sulfate, filtering after 5 minutes, washing the filter cake with ethyl acetate (5 mL×3 times), and then swirling off the solvent.The product was isolated by column chromatography (eluent: petroleum ether: ethyl acetate = 6:1), the product was a yellow liquid, yield 82percent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With sodium hydroxide In water for 4 h; Heating / reflux Stage #2: With hydrogenchloride In water at 20℃; |
To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (20.00 g, 145.9 mmol) in 160 mL of water, was added 50percent aqueous sodium hydroxide (40.00 g, 500.0 mmol). The mixture was heated to reflux for 4 hours, cooled to room temperature, poured into iced concentrated hydrochloric acid, and extracted with ether. The product was extracted into saturated aqueous sodium bicarbonate and the ether layer discarded. This aqueous extract was acidified with concentrated hydrochloric acid and extracted with ether. The organic extract was dried over magnesium sulfate, filtered, and evaporated to give a white solid (22.90 g) of 2-fluoro-4-hydroxybenzoic acid in 100percent yield. 1H NMR (300 MHz, CD3COCD3) δ (ppm): 9.80 (b, 1H), 7.87 (t, 1H), 6.77 (dd, 1H), 6.66 (dd, 1H). 19F-NMR (300 MHz, CD3COCD3) δ (ppm): -108.13 (s, decoupled). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With hydroxylamine In methanol; water at 20℃; for 3 h; Heating / reflux | At room temperature, 139 g (2.1 mol) of 50percent hydroxylamine aqueous solution was added dropwise to a methanol solution of 144.0 g (1.05 mol) of 2-fluoro-4-cyanophenol. Temperature of the reaction system was gradually increased and stirred under reflux for 3 hours. After the reaction, this was ice-cooled, and cool water was added to the reaction system to effect precipitation of crystals. The thus obtained crystals were collected by filtration and dried to obtain 139.5 g of (1-A) (yield 82percent).A 8.1 ml (0.1 mol) portion of pyridine was added at room temperature to 300 ml of N,N-dimethylacetamide containing 17 g (0.1 mol) of (1-A), and 6.7 g (33 mmol) of phthaloyl dichloride was added thereto in portions. After the addition, this was stirred at room temperature for 30 minutes and then the reaction temperature was increased to 100°C. This was stirred as such for 3 hours and then spontaneously cooled. Since crystals were precipitated when methanol was added thereto, they were collected by filtration. By drying the thus collected crystals, 36 g (yield 83percent) of (1-B) was obtained.At room temperature, 8.7 ml (50 mmol) of N,N-diisopropylethylamine was added to 300 ml of N,N-dimethylacetamide solution of 8.7 g (20 mmol) of (1-B), and 9.6 g (50 mmol) of octyl chloro formate was added dropwise thereto. A 14 g portion of potassium carbonate was added thereto and stirred as such at room temperature for 3 hours. After adding tetrahydrofuran, separation by filtration was carried out, and methanol was added to the resulting filtrate to effect precipitation of crystals. The crystals were collected by filtration and dried, dispersed in methanol, heated and then filtered to obtain 13.4 g of the illustration compound (1) (yield 90percent).Phase transition temperature of the thus obtained illustration compound (1) was measured by DSC measurement and texture observation under a polarization microscope, thereby obtaining the following results: Cry to SmC at 133 C, SmC to Nb at 159 C and Nb to Iso at 194 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine hydrochloride; | A mixture of 2-fluoro-4-methoxy-benzonitrile (500 mg, 0.246 mmol) and pyridine hydrochloride (2.0 g, 17.2 mmol) is heated at 170 C. for 5 hours. The reaction is partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase is washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 2-fluoro-4-hydroxy-benzonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (20.00 g, 145.9 mmol) in 160 mL of water, was added 50% aqueous sodium hydroxide (40.00 g, 500.0 mmol). The mixture was heated to reflux for 4 hours, cooled to room temperature, poured into iced concentrated hydrochloric acid, and extracted with ether. The product was extracted into saturated aqueous sodium bicarbonate and the ether layer discarded. This aqueous extract was acidified with concentrated hydrochloric acid and extracted with ether. The organic extract was dried over magnesium sulfate, filtered, and evaporated to give a white solid (22.90 g) of 2-fluoro-4-hydroxybenzoic acid in 100% yield. 1H NMR (300 MHz, CD3COCD3) delta (ppm): 9.80 (b, 1H), 7.87 (t, 1H), 6.77 (dd, 1H), 6.66 (dd, 1H). 19F-NMR (300 MHz, CD3COCD3) delta (ppm): -108.13 (s, decoupled). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N-methyl-acetamide; ethyl acetate; | REFERENCE EXAMPLE 36 4-(1,3-Benzodioxol-5-ylmethoxy)-2-fluorobenzonitrile A mixture of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (S. M. Kelly, Helv.Chim.Acta. 1984, Volume 67, P.1572-1579) (30 g), potassium carbonate (45.36 g) and 3,4-methylenedioxybenzyl chloride (42.65 g) in dimethylformamide (500 ml) was stirred at 90 C. for 2 hours. The reaction mixture was filtered and the filtrate evaporated. The residue was stirred with ethyl acetate (500 ml) and filtered affording the title compound (32.1 g) as a cream coloured solid, m.p. 139-140 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Compound 30: To a stirred solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong>, 29 (15.00 g, 0.1094 mol) in DMF (45.0 mL) cooled to 0 C. was added potassium carbonate (37.8 g, 0.274 mol) followed by stifling at 0-5 C. for 30 min. Benzyl bromide (13.7 mL, 0.115 mol) was added to the reaction mixture at EtOAc (150 mL each) to provide 4-(benzyloxy)-2-fluorobenzonitrile, 30 (24.64 g, 0.1084 mol, 99% yield) as white solid. | |
97 - 100% | With potassium carbonate; In acetone; at 50 - 60℃; for 20h; | Benzyl bromide (467 mL, 3.93 mol) and potassium carbonate (1.4 kg, 10.1 mol) were added to a solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (490 g, 3.57 mol) in acetone (3.4 L). The stirred mixture was heated at [60OC] for 20 h, then cooled and filtered. The filtrate was concentrated and the resulting solid was triturated with 10% ethyl acetate-hexane (5 L) and vacuum dried at [350C] to give the desired product (787 g, 97%). A mixture of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (15.0 g, 109 mmol), potassium carbonate (21.0 g, 152 mmol), and benzyl bromide (19.6 g, 115 mmol) in acetone (150 mL) under nitrogen was heated at [50C] overnight. The solid was removed by filtration and the filtrate evaporated to a residue that was mixed with ethyl acetate (500 mL). This solution was washed with brine, dried, and evaporated to give an amorphous solid: (24.9 g, 100%). |
96% | With potassium carbonate; In acetone; | 4-Benzyloxy-2-fluoro-benzonitrile (Compound 7) Following General Procedure F and using <strong>[82380-18-5]2-fluoro-4-hydroxy-benzonitrile</strong> (11.37 g, 83 mmol), acetone (100 mL), potassium carbonate (30 g, 165.8 mmol) followed by benzyl bromide (10.84 mL, 91 mmol) the title product (18 g, 96%) was obtained. 1H-NMR (300 MHz, CDCl3): delta5.10 (s, 2H), 6.75-6.85 (m, 2H), 7.25-7.54 (m, 6H). |
96% | With potassium carbonate; In acetone; | 4-Benzyloxy-2-fluoro-benzonitrile (Compound 7) Following General Procedure F and using <strong>[82380-18-5]2-fluoro-4-hydroxy-benzonitrile</strong> (11.37 g, 83 mmol), acetone (100 mL), potassium carbonate (30 g, 165.8 mmol) followed by benzyl bromide (10.84 mL, 91 mmol) the title product (18 g, 96%) was obtained. 1H-NMR (300 MHz, CDCl3): delta 5.10(s, 2H), 6.75-6.85(m, 2H), 7.25-7.54(m, 6H). |
89% | In N,N-dimethyl-formamide; at 75℃; for 2h; | <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (2 g, 14.6 mmol) in DMF (15 mL) was added potassium carbonate (3 g, 21.7 mmol) and (bromomethyl)benzene (2.7 g, 15.8 mmol). The mixture was heated at 75ºC for 2 hours, poured into water (100 mL), extracted with AcOEt, dried (Na2SO4) and concentrated in vacuo. The resulting solid was filtered and washed with diethyl ether to give the title compound as a white solid (3.7 g, 89%). LRMS (m/z): 228 (M+1)+. |
78% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; | Step 1: Production of 4-benzyloxy-2-fluorobenzonitrile To a solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (20.0 g, 146 mmol) in N,N-dimethylformamide (100 ml) were added potassium carbonate (26.2 g, 190 mmol) and benzyl bromide (19 ml, 160 mmol) and the mixture was stirred at 80C for 2 hr. After allowing to cool to room temperature, water was added to the reaction mixture and the precipitated solid was collected by filtration and washed successively with water and hexane. The obtained solid was washed with a mixed solvent of n-hexane:ethyl acetate=5:1 to give 4-benzyloxy-2-fluorobenzonitrile (25.8 g, yield 78%). 1H-NMR(400MHz, deltappm, DMSO-d6): 7.84(1H, t, J=8.4Hz), 7. 34-7.47(5H, m), 7.25(1H, dd, J=12.0, 2.0Hz), 7.05(1H, dd, J=8.8, 2.8Hz), 5.22 (3H, s). |
With potassium carbonate; In dichloromethane; di-isopropyl ether; acetonitrile; | 1.4. 2-Fluoro-4-(phenylmethoxy)benzonitrile 15.2 ml (0.127 mol) of benzyl bromide and 29.3 g (0.212 mol) of potassium carbonate are added to a solution of 13.3 g (0.106 mol) of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> in 150 ml of acetonitrile. The mixture is stirred at reflux for 1 hour 30 minutes and then filtered, the filtrate is concentrated under reduced pressure, and the oil obtained is diluted in the minimum amount of dichloromethane. After crystallization by addition of diisopropyl ether, filtration and drying, 20.3 g of product are obtained. Melting point: 87 C. | |
With potassium carbonate; In acetonitrile; at 50℃; for 3h; | 2.0 g of potassium carbonate was added to a mixture of 2.0 g of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong>, 2.4 g of benzylbromide and 30 ml of acetonitrile. The obtained mixture was stirred at 50C for 3 hours. Thereafter, the reaction mixture was cooled to a room temperature, and it was then filtrated through Celite (registered trade mark), followed by concentration under reduced pressure. The obtained residue was collected by filtration, and it was then washed with hexane and was then dried, so as to obtain 2.8 g of 4-benzyloxy-2-fluorobenzonitrile.4-benzyloxy-2-fluorobenzonitrile [Show Image] [Show Image] 1H-NMR (CDCl3) delta: 5.11 (2H, s), 6.81 (2H, m), 7.36-7.44 (5H, m), 7.52 (1H, dd, J = 8.6, 7.6 Hz). | |
1.21 g | With potassium carbonate; In N,N-dimethyl-formamide; at 10 - 35℃; | (A) 4-(Benzyloxy)-2-fluorobenzonitrile To a mixture of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (1.00 g) and DMF (30 mL), (bromomethyl)benzene (963 muL) and potassium carbonate (1.50 g) were added at room temperature, and then the reaction mixture was stirred at the same temperature overnight. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with water and brine and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (1.21 g). MS: [M+H]+ 227.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichloroacetonitrile; In N,N-dimethyl-formamide; at 105℃; for 6h;Sealed tube; | PREPARATIVE EXAMPLE 37PREPARATION OF 4-CYANO-3 -FLUOROPHENYL HYDROGEN [({5-[3,4-BIS(3- AZIDOPROPOXY)PHENYL]THIOPHENE^-YL) SULFONYL)AMINO) METHYL)PHOSPHONATE mixture of the phosphonic acid (0.2 g, 0.3S mmol), 2-fluoro-4-hydroxybenzonitriIe (0.077 g, 1.5 quiv), and trichloroacetonitrile (380 uL, 10 equiv) in a solvent mixture of 2.0 mL of anhydrous pyridine md 0.2 mL of DMF in a sealed tube was heated at 1050C for 6h. The reaction mixture was concentrated md used as is in the next step. vIS m/z 623 (M-28). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATIVE EXAMPLE 38 PREPARATION OF 2-[(([(4-CYANO-S-FLUeROPHENOXY)(HYDROXY)PHOSPHORYL]-METHYL} AMINO)SULFONYL]- 1 -BENZOTHIOPHENE-S-CARBOXYLIC ACID A solution of ([(5-formyl-l-bbeta?zothien-2-yl)sulfonyl]amino}methyl)phosphonic acid (0.22 g, 0.66 mmol), trichloroacetonitrile (1.0 niL, 10 mmol) and 2-fluoro-4-hydroxybenzonitriIe (0.18 g, 1.3 mmol) in anhydrous pyridine (10 mL) was heated at 120C for 2.5 h in a pressure bottle. The reaction mixture was then concentrated and the residue triturated with ether and ethyl acetate, and dissolved in 50 % aqueous acetone (25 mL). To this solution were added 2-methyl~2-butene (5 mL), sodium chlorite (0.020 g, 0.22 mmol) and potassium dihydrogen phosphate (0.020 g, 0.15 mmol) in water (1 mL). The mixture was stirred for 30 min then concentrated. The residue was purified by reverse phase HPLC (250 x 21.2 mm Aquasil Cl 8 column, 30% - 70% methanol/water linear gradient, 30 min elution time, elutes ~16 min) to . yield the product as an amorphous white solid.1H NMR (400 MHz, CD3OD) delta (ppm): 8.50 (s, IH); 8.02 (dd, J=8.4, 1.4, IH); 7.92 (d, J=8.8, IH); 7.91 (s, IH); 7.39 (t, J=8.2, IH); 7.04-6.96 (m, 2H). [CH2 peak hidden underneath residual methanol peak at -3.2 ppm]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATIVE EXAMPLE 39 PREPARATION OF 4-CYANO-3 -FLUOROPHENYL [([5,6-BIS(2-AMMONIOETHOXY)-l-BENZOTHIEN-2-YL]SULFONYL} AMINO)METHYL]PHOSPHONATE TRIFLUOROACETATEA mixture consisting of [([5,6-bis(2-azidoethoxy)-l-benzothien-2-yl]suIfonyl}amino)rnethyI]- phosphonic acid (187 mg, 0.39 mmol), the phenol (70 mg, 1.3 equiv), trichloroacetonitrile (0.4 mL, 10 equiv), anhydrous pyridine (3 mL) and 10% of DMF (0.3 mL) was stirred in a sealed tube for 6h at 1050C. After the reaction was complete, pyridine was evaporated in vacuum to give an oily residue. To a solution of the crude adduct in MeOH was added palladium black (19 mg, 10%). The resulting mixture was stirred under 40psi of hydrogen gas overnight. The resulting dark yellow solution was filtered and the organic layer was evaporated to give an oil, which was purified by reverse phase HPLC to afford the diamine.1H NMR (400 MHz, CD3OD) delta (ppm): 7.8 (s, IH), 7.6 (bit, IH), 7.45 (s, IH), 7.4 (s, IH), 7.2 (m, 2H), 4.3 (m, 4H), 3.7 (m, 4H), 3.5 (d, 2H); MS m/z 545 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.8% | With dmap; triethylamine; In dichloromethane;Heating / reflux; | A mixture of <strong>[82380-18-5]2-fluoro-4-hydroxy benzonitrile</strong> (10 g, 0.0729 mol), DMAP (900 mg, 0.00729 mol), triethylamine (30 ml, 0.218 mol) and dimethylthiocarbamoyl chloride (11 g, 0.0875 mol) in dry dichloromethane (200 ml) was stirred at reflux under nitrogen atmosphere overnight. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with pet ether. The product was filtered and dried under vacuum to give the sub-title compound (14 g, 85.8%) as yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride;palladium dihydroxide; In ethanol; | Preparation 49 4-Aminomethyl-3-fluorophenol Hydrochloride A mixture of <strong>[82380-18-5]2-fluoro-4-hydroxy-benzonitrile</strong> (6 g, 43.8 mmol), palladium hydroxide (600 mg), ethanol (60 ml) and 2N hydrochloric acid (6 ml) was hydrogenated (60 psi) for 18 hours. The mixture was filtered through Arbocel and the filter cake was washed with methanol and the filtrates were evaporated in-vacuo. The residue was triturated with diethylether to give 4-aminomethyl-3-fluoro phenol hydrochloride (4.71 g). 1H NMR (400 MHz, DMSO-d6): delta 10.26 (1H, d), 8.30 (1H, s), 7.39 (1H, m), 6.63 (2H, m), 3.94 (2H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The mixture of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (274 mg, 2.1 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 6 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml of dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 1, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethanol and petroleum ether to give 268 mg 4-cyano-3-fluorophenoxyacetic acid as white crystals, mp 150-152 C. The chemical structure analysis was performed by 1HNMR (Acetone-6, 600 MHz): delta 7.75 (m, 1H, Ar-H), 7.00 (m, 2H, Ar-H), 4.93 (s, 2H, OCH2CO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In acetone; for 4h;Heating / reflux; | Example 1; (S)-N-(1-Carbamoyl-ethyl)-2-fluoro-4-(3-fluoro-benzyloxy)-benzamide; a) 2-fluoro-4-(3-fluoro-benzyloxy)-benzonitrile; A mixture of <strong>[82380-18-5]2-fluoro-4-hydroxy-benzonitrile</strong> (15.0 g, 109 mmol), 3-fluorobenzyl bromide (22.7 g, 120 mmol) and potassium carbonate (18.1 g, 131 mmol) in dry acetone (250 mL) was heated under reflux for 4 h. After cooling to room temperature the mixture was filtered and the filtrate was evaporated to leave an off-white solid which was washed with hexane to afford the title compound (26.8 g, 100%) as a white solid. MS: m/e = 245.2 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxygen; triethylamine;copper diacetate; In dichloromethane; at 20℃; for 16h; | 2-Fluoro-4-hydroxybenzonitrile (compound 35c-1; 1.40 g), 2.86 g of 4-fluorophenylboronic acid, 1.86 g of copper (II) acetate, and 7.20 mL of triethylamine were dissolved/suspended in 100 mL of anhydrous CH2Cl2, and 4A molecular sieves were added to this reaction mixture. The reaction mixture was exposed to air through a drying tube and stirred at ambient temperature for 16 hours. The reaction mixture was filtered, and the filtrate was washed with 10% aqueous NaHSO4, 1N aqueous NaOH, and brine, dried over Na2SO4, filtered, and concentrated under vacuum to give 530 mg of compound 36c-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | (a) Synthesis of 4-([4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl]oxy)-2-fluorobenzonitrile To a solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (4.0 g, 29 mmol) in tetrahydrofuran (150 mL) were added cis-2-(4-hydroxycyclohexyl)-lH-isoindole-1,3(2H)-dione (7.2 g, 29 mmol) and triphenylphosphine (9.2 g, 35 mmol), followed by adding dropwise thereto diisopropyl azodicarboxylate (8.3 mL, 35 mmol) under ice-cooling, and the resulting mixture was warmed up to room temperature and then stirred overnight. A saturated aqueous sodium chloride solution and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture, followed by extraction with ethyl acetate (twice), and the organic layer was washed with a saturated aqueous sodium chloride solution. The washed organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel chromatography and then washed with diethyl ether to obtain 4-([4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl]oxy)-2-fluorobenzonitrile (3.4 g, 32%) as white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; at 0 - 20℃; for 2h; | [0106] 2-Fluoro-4-hydroxybenzonitrile (3.55 g, 25.89 mmol) wasdissolved in anhydrous MeOH (100 mL) and the solution was bubbled with anhydroushydrogen chloride at 0 C for 1 h and at room temperature for further 1 h. Afterevaporation of solvent, the solid residue was dried under high vacuum for 2 h to give acrude compound 52, which was directly used in next step reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 3h; | 560 mg of 5-Chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole were dissolved in 10 ml dimethylformamide. 1.2 g of caesiumcarbonate and 395 mg 2-Fluoro-4-hydroxybenzonitrile was added and the mixture was stirred at room temperature for three hours. Then 50 ml of methyl-tert-butylether was added, the mixture washed with brine and dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 153 mg of 2-Fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzonitrile as amorphous lyophilisate. C19H12F4N2OS (392.38), MS(ESI): 393.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In acetonitrile; at 20℃; | EXAMPLE 1: 4-benzyloxy-2-fluorobenzonitrile To a mixture of <strong>[82380-18-5]2-fluoro-4-hydroxy-benzonitrile</strong> (98 g, 0.68 mol) and K2CO3 (94 g, 0.68 mol) in acetonitrile was added benzyl chloride (86.6 g, 0.68 mol). The mixture was stirred overnight at room temperature and the reaction followed by TLC (toluene/AcOEt 8/2). The mixture was filtered, concentrated under vacuum and crystallized from pentane to give 147 g of solid (95 %). 1H-NMR (DMSO d6): 5.25 (s,2H), 7.05 (dd,1H), 7.25 (dd,1H), 7.30-7.60 (m,5H), 7.75 (t,1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium borohydrid;nickel dichloride; In methanol; ethyl acetate; | 2-Fluoro-4-hydroxybenzonitrile (686 mg), nickel chloride (I1) (1.18 g) and Boc2O (2.18 mg) were dissolved in methanol (40 ml) and the solution was cooled to 0 C. To the solution was slowly added sodium borohydride (1.32 g), and the mixture was stirred at 0 C. for 10 minutes and then at room temperature for 24 hours. The resulting mixture was concentrated under reduced pressure and to the concentrate were added ethyl acetate (60 ml) and sodium borohydride (300 mg), followed by filtering. The filtrate was extracted twice with ethyl acetate. The total filtrate was concentrated under reduced pressure, and then purified by column-chromatography (hexane/ethyl acetate=3/1) to yield the compound 20-1a (134 mg, 11 I/o) and 20-1b (710 mg, 42%). |
Yield | Reaction Conditions | Operation in experiment |
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30.2% | With nitric acid; acetic acid; In water; at 40℃; for 24h; | Nitric acid (0.326 ml_, 7.29 mmol) 70% was added dropwise to a stirred solution of 2- fluoro-4-hydroxybenzonitrile (1 g, 7.29 mmol) in acetic acid (20 ml_). The resulting solution was warmed to 40 0C for 24 hr. Solvent removed under reduced pressure to afford a yellow solid. Recrystallisation from EtOH (-15 ml.) afforded 2-fluoro-4-hydroxy-5- nitrobenzonitrile (401 mg, 2.202 mmol, 30.2 % yield) as a yellow solid.1H NMR delta (CDCI3): 7.04 (1 H, d, J = 9.6 Hz), 8.52 (1 H, d, J = 6.4 Hz), 11.10 (1 H, s). |
With nitric acid; acetic acid; at 40℃; | This was prepared from <strong>[82380-18-5]2-fluoro-4-hydroxy-benzonitrile</strong> by nitration (concentrated nitric acid in acetic acid at 40C) followed by hydrogenation in ethanol over 10% palladium/carbon. | |
18.3 g | To a solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (28.9 g) in acetic acid (160 mL) was added conc. sulfuric acid(0.65 mL), and the reaction mixture was stirred at 65C for 10 min. To the reaction mixture was added dropwise a solutionof 69% nitric acid (19.2 g) in acetic acid (50 mL) over 30 min, and the reaction mixture was stirred at 65C for 1.5 hr.The reaction mixture was allowed to cool to room temperature, poured into ice-water (500 mL), and extracted withtoluene. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The obtained crude crystals were recrystallized from IPA/heptaneto give the title compound (18.3 g).1H NMR (300 MHz, CDCl3) delta 7.03 (1H, d, J = 9.4 Hz), 8.52 (1H, d, J = 6.5 Hz), 11.10 (1H, s).B) 7- |
Yield | Reaction Conditions | Operation in experiment |
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In <i>N</i>-methyl-acetamide | 2 3-fluoro-4-cyanoethynyl-1-(4-propylphenyl) carbonyloxybenzene (Compound No. 153) EXAMPLE 2 3-fluoro-4-cyanoethynyl-1-(4-propylphenyl) carbonyloxybenzene (Compound No. 153) To a solution of 100 ml of 3-fluoro-4-cyanophenol in 200 ml of dimethylformamide were added 110 mmol of dimethylbutylsilyl chloride and 110 mmol of imidazole while cooling with an ice bath and stirring, the solution was elevated to room temperature and stirred for 3 hours. The solution was placed into water and extracted with toluene. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a colourless oily product. Distillation of the product under reduced pressure gave 100 mmol of 2-fluoro-4-dimethylbutylsilyloxy benzonitrile. |
Yield | Reaction Conditions | Operation in experiment |
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With triphenylphosphine; In tetrahydrofuran; | REFERENCE EXAMPLE 50 2-Fluoro-4-(thiazol-5-ylmethoxy)benzonitrile Diisopropylazodicarboxylate (4.0 g) was dissolved in a little anhydrous tetrahydrofuran (about 10 ml) and added dropwise to a stirred solution of triphenylphosphine (5.2 g) in anhydrous tetrahydrofuran (150 ml) at 0 C. under nitrogen. After stirring at 0 C. for 15 minutes, during which time a white precipitate formed, a mixture of 2-fluoro-4-hydroxybenzonitrile (S. M. Kelly, Helv.Chim.Acta. 1984, Volume 67, P.1572-1579) (2.0 g) and thiazole-5-methanol (2.3 g) in anhydrous tetrahydrofuran (20 ml) was added dropwise whilst maintaining the temperature at or below 5 C. The reaction mixture was stirred in the cooling bath for a further 2 hours then allowed to warm slowly to room temperature. After standing at room temperature overnight the reaction mixture was partitioned between ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (200 ml). The layers were separated and the organic phase washed with water (100 ml), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluding with a mixture of ethyl acetate and cyclohexane (1:1, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound as a pale yellow solid (2.0 g). | |
With triphenylphosphine; In tetrahydrofuran; | REFERENCE EXAMPLE 50 2-Fluoro-4-(thiazol-5-ylmethoxy)benzonitrile Diisopropylazodicarboxylate (4.0 g) was dissolved in a little anhydrous tetrahydrofuran (about 10 ml) and added dropwise to a stirred solution of triphenylphosphine (5.2 g) in anhydrous tetrahydrofuran (150 ml) at 0 C. under nitrogen. After stirring at 0 C. for 15 minutes, during which time a white precipitate formed, a mixture of 2-fluoro-4-hydroxybenzonitrile (S. M. Kelly, Helv.Chim.Acta. 1984, Volume 67, P.1572-1579) (2.0 g) and thiazole-5-methanol (2.3 g) in anhydrous tetrahydrofuran (20 ml) was added dropwise whilst maintaining the temperature at or below 5 C. The reaction mixture was stirred in the cooling bath for a further 2 hours then allowed to warm slowly to room temperature. After standing at room temperature overnight the reaction mixture was partitioned between ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (200 ml). The layers were separated and the organic phase washed with water (100 ml), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluding with a mixture of ethyl acetate and cyclohexane (1:1, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound as a pale yellow solid (2.0 g). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium iodide; tetrabutylammomium bromide; potassium carbonate; In butanone; | REFERENCE EXAMPLE 32 2-Fluoro-4-(4-pyridylmethoxy)benzonitrile A mixture of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (10.96 g; S. M. Kelly, Helv. Chim. Acta 1984, volume 67, p1572-1579), potassium carbonate (53.2 g), potassium iodide (6.64 g), tetra-n-butylammonium bromide (0.4 g) and 4-picolyl chloride (14.4 g) in methyl ethyl ketone (600 ml) was stirred at reflux for 3 hours. The reaction mixture was filtered and the insoluble material washed with methyl ethyl ketone. The combined filtrate plus washings were evaporated and the residue partitioned between ethyl acetate (300 ml) and water (150 ml). The aqueous phase was extracted twice with ethyl acetate (100 ml) and the combined ethyl acetate solutions washed with brine (100 ml), dried over magnesium sulphate and evaporated. The residue was recrystallized from a mixture of ethyl acetate and pentane to give the title compound (11.5 g) as a plum coloured solid, m.p. 132-133 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium hydroxide; In ethanol; water; ethyl acetate; | (a) Synthesis of 2-fluoro-4-n-octyloxypenylamidine hydrochloride: 60 g of <strong>[82380-18-5]3-fluoro-4-cyanophenol</strong> and 16 g of potassium hydroxide were dissolved in a solvent mixture of 600 ml of ethanol and 60 ml of water. To the resulting solution, was added dropwise 55.8 g of octyl bromide. After the completion of the addition, the obtained mixture was refluxed for six hours and then allowed to cool to room temperature. The solvent was distilled off and 300 ml of ethyl acetate was added to the residue. The organic layer was washed with water until the aqueous layer became neutral. The organic layer was dehydrated over anhydrous sodium sulfate and the solvent was distilled off. After purifying by distillation (main fraction: 0.5 mmHg, 157 to 160 C.), 63 g of 2-fluoro-4-octyloxybenzonitrile was obtained. Yield: 58%. |
Yield | Reaction Conditions | Operation in experiment |
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68% | With hydrogenchloride; sodium hydroxide; In pyridine; toluene; | EXAMPLE 1 4-Fluorobenzoic acid 3'-fluoro-4'-cyanophenyl ester 4-Fluorobenzoyl chloride (2.1 g, 13 mmols) was added with stirring to a solution of <strong>[82380-18-5]3-fluoro-4-cyanophenol</strong> (1.9 g, 14 mmols) dissolved in pyridine (5 ml). After completion of the reaction, the reaction mixture was allowed to stand overnight, followed by adding toluene (50 ml), pouring the resulting mixture into water, separating the toluene layer, washing the toluene layer with 6N hydrochloric acid, 2N NaOH solution and water in this order, finally drying over anhydrous sodium sulfate, distilling off toluene under reduced pressure, and recrystallizing the resulting colorless solids from ethanol to obtain the objective 4-fluorobenzoic acid 3'-fluoro-4'-cyanophenyl ester (2.3 g, 8.9 mmols, yield 68%) which had a melting point of 103.2-104.2 C. A nematic-isotropic phase transition point (hereinafter abbreviated to N-I point) of this compound was found to be 12.1 C. according to extrapolation method where the compound was mixed with a liquid crystal composition of trans-4-alkyl-(4-cyanophenyl)cyclohexanes. Further, its elementary analysis values were as follows: C: 65.08% and H: 2.68% (calculated values: C, 64.87% and H, 2.72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; | EXAMPLE 3 A mixture of 0.04M of p-(5-n-heptalpyrimidin-2-yl)-benzyl bromide [obtainable from the corresponding benzyl alcohol, which is accessible by reaction of 2-n-heptylpropane-1,3-dialdehyde tetraethyl acetal with p-hydroxymethylbenzonitrile or the corresponding amidine by methods described in the literature], 0.04M of 4-cyano-3-fluorophenol, 0.2M of potassium carbonate and 150 ml of 2-butanone is boiled for 48 hours, is cooled down and is worked up in conventional manner. This gives p-(5-n-heptylpyrimidin-2-yl)-benzyl 4-cyano-3-fluorophenyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In pyridine; water; toluene; | EXAMPLE 2 3-Fluoro-4-cyanophenyl 4-(trans-4-methoxymethylcyclohexyl)-benzoate 3-Fluoro-4-cyanophenol (1.5 g, 11 m mol) was dissolved in dry pyridine (5 ml), and to this solution was added a solution of 4-(trans-4-methoxymethylcyclohexyl)benzoyl chloride (2.7 g, 11 m mol), dissolved in toluene (10 ml), followed by reacting the mixture on heating at 60 C. for 3 hours. After completion of the reaction, the reaction mixture was fed into water (100 ml), followed by separating the resulting toluene layer, washing it with 6N--HCl, 2N--NaOH aqueous solution and then water, drying the toluene layer over anhydrous sodium sulfate, distilling off toluene from the toluene layer and recrystallizing the remaining solids from ethanol (8 ml) to obtain the objective 3-fluoro-4-cyanophenyl 4-(trans-4-methoxymethyl)-benzoate (2.7 g, yield 66%) having a C-N point of 109.3 C. and a N-I point of 193.4 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisopropyl (E)-azodicarboxylate; triphenylphosphine In tetrahydrofuran; ethyl acetate | R.40 Reference Example 40 Reference Example 40 A solution of triphenylphosphine (20 g) in tetrahydrofuran (300 mL) cooled at 0° C. is treated dropwise during 5 minutes with diisopropyl azodicarboxylate (15 mL) and stirred for 15 minutes at 0° C. It is then treated, dropwise, with a solution of 2-fluoro-4-hydroxybenzonitrile (7 g) and 3-thienylmethanol (7 g) in tetrahydrofuran (200 mL) during 2 hours, and stirring is continued at ambient temperature for 18 hours. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate (500 mL). This solution is washed with water (200 mL) and aqueous sodium hydroxide solution (1 N), dried over magnesium sulphate and concentrated in vacuo, to give an oil, which is passed through a pad of silica gel (thickness 5 cm) with the aid of dichloromethane. The resulting filtrate is concentrated in vacuo, to give an oil which crystallizes on standing. Recrystallization from isopropyl ether gives 2-fluoro-4-(3-thienyl-methoxy)benzonitrile (6 g), in the form of a white solid, m.p. 63-65° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With hydroxylamine; In methanol; water; at 20℃; for 3h;Heating / reflux; | At room temperature, 139 g (2.1 mol) of 50% hydroxylamine aqueous solution was added dropwise to a methanol solution of 144.0 g (1.05 mol) of 2-fluoro-4-cyanophenol. Temperature of the reaction system was gradually increased and stirred under reflux for 3 hours. After the reaction, this was ice-cooled, and cool water was added to the reaction system to effect precipitation of crystals. The thus obtained crystals were collected by filtration and dried to obtain 139.5 g of (1-A) (yield 82%).A 8.1 ml (0.1 mol) portion of pyridine was added at room temperature to 300 ml of N,N-dimethylacetamide containing 17 g (0.1 mol) of (1-A), and 6.7 g (33 mmol) of phthaloyl dichloride was added thereto in portions. After the addition, this was stirred at room temperature for 30 minutes and then the reaction temperature was increased to 100C. This was stirred as such for 3 hours and then spontaneously cooled. Since crystals were precipitated when methanol was added thereto, they were collected by filtration. By drying the thus collected crystals, 36 g (yield 83%) of (1-B) was obtained.At room temperature, 8.7 ml (50 mmol) of N,N-diisopropylethylamine was added to 300 ml of N,N-dimethylacetamide solution of 8.7 g (20 mmol) of (1-B), and 9.6 g (50 mmol) of octyl chloro formate was added dropwise thereto. A 14 g portion of potassium carbonate was added thereto and stirred as such at room temperature for 3 hours. After adding tetrahydrofuran, separation by filtration was carried out, and methanol was added to the resulting filtrate to effect precipitation of crystals. The crystals were collected by filtration and dried, dispersed in methanol, heated and then filtered to obtain 13.4 g of the illustration compound (1) (yield 90%).Phase transition temperature of the thus obtained illustration compound (1) was measured by DSC measurement and texture observation under a polarization microscope, thereby obtaining the following results: Cry to SmC at 133 C, SmC to Nb at 159 C and Nb to Iso at 194 C. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In butanone; for 6.5h;Heating / reflux; | A 2-butanone (7.6 mL) solution of 1.12 g of tert-butyl=4-(3-bromopropyl)-1-piperidinecarboxylate was added to a 2-butanone (7.0 mL) mixture of 0.50 g of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> and 0.56 g of potassium carbonate, which was then heated to reflux for 6 hours and 30 minutes. After cooling down to room temperature, the reaction mixture was added to a mixture of ethyl acetate and water. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate = 4:1) to provide 0.72 g of tert-butyl=4-[3-(4-cyano-3-fluorophenoxy)propyl]-1-piperidinecarboxylate as colorless oily form. 1H-NMR(CDCl3). delta value: 1.05-1.20(2H,m),1.35-1.45(3H,m),1.46(9H,s),1.65-1.75(2H,m),1.75-1.90(2H,m),2.60-2.75(2H,m),3.99(2H,t,J=6.3Hz),4.00-4.20(2H,m),6.65-6.80(2H,m),7.45-7.54(1H,m). | |
With potassium carbonate; In butanone; for 6.5h;Heating / reflux; | A 2-butanone (7.6 mL) solution of 1.12 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate was added to a 2-butanone (7.0 mL) mixture of 0.50 g of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> and 0.56 g of potassium carbonate, which was then heated to reflux for 6 hours and 30 minutes. After cooling down to room temperature, the reaction mixture was added to a mixture of ethyl acetate and water. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate = 4:1) to provide 0.72 g of tert-butyl 4-[3-(4-cyano-3-fluorophenoxy)propyl]-1-piperidinecarboxylate as colorless oily form. 1H-NMR(CDCl3) delta value: 1.05-1.20(2H,m),1.35-1.45(3H,m), 1.46(9H,s),1.65-1.75(2H,m),1.75-1.90(2H,m), 2.60-2.75(2H,m),3.99(2H,t,J=6.3Hz),4.00-4.20(2H,m), 6.65-6.80(2H,m),7.45-7.54(1H,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
a 4-Benzyloxy-2-fluoro-benzonitrile As described for example 1a, 2-fluoro-4-hydroxy-benzonitrile (9.7 g, 71 mmol) was converted to the title compound (15.0 g, 93%) (using benzyl bromide instead of 3-fluorobenzyl bromide) which was obtained as white crystals after recrystallisation from cyclohexane. MS: m/e=227.2 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ethyl acetate; at 50℃; for 25.5h; | c) (25)-3-(4-Cyano-3-fluorophenoxy)-N-(4-cyano-3-methylphenyl)-2- hydroxy-2-methylpropionamide; 2-Fluoro-4-hydroxy benzonitrile (0.81 g, 5.9 mmol) and (2i?)-2-methyl- oxirane-2-carboxylicacid-(4-cyano-3-methylphenyl)amide (0.905 g, 4.2 mmol) were dissolved in 17.6 ml of EtOAc. Anhydrous K2CO3 (0.29 g; 2.1 mmol) was added and the mixture heated to 5O0C and stirred for 25.5 hours. The mixture was cooled to room temperature, 30 ml of EtOAc added and washed first with 2 x 24 ml of IM Na2CO3 and then 2 x 24 ml of water. Organic layer was dried over Na2SO4, filtered and evaporated to give 1.05 g of crude product.1H NMR (DMSO-d6): 1.43 (3H, s), 2,44 (3H, s), 4.10 (IH, d, J=I 0.0 Hz), 4.36 (IH, d, J=10.0 Hz), 6.29 (IH, bs), 6.96 (IH, dd, J=8.8 Hz5 J=2.3 Hz), 7.18 (IH, dd, J=I 1.9 Hz, J=2.3 Hz), 7.70 (IH, d, J=8.54 Hz), 7.76-7.83 (2H, m), 7.92 (IH, d, J=1.6 Hz), 10.05 (IH, bs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In tetrahydrofuran; at 65℃; for 5h; | d) 2-Cyano-5-[(S)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methyl- propionylaminojbenzoic acid methyl ester; A mixture of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (4.80 g, 35.0 mmol), 5-((R)-3- Bromo-2-hydroxy-2-methylpropionylamino)-2-cyanobenzoic acid methyl ester (8.41 g, 24.7 mmol) and K2CO3 (8.51 g, 61.6 mmol) in THF (150 ml) was heated at 65 0C for 5 hours under nitrogen atmosphere. The mixture was cooled to room temperature and water was added. The product was extracted into ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate 7:3-6:4). <n="13"/>1H NMR (400 MHz, DMSO-tfc): 1.44 (3H, s), 3.91 (3H, s), 4.12 (IH, d, 2Jg6n, = 10.1 Hz), 4.38 (IH, d, %m = 10.1 Hz), 6.33 (IH, s, -OH), 6.96 (IH, dd, 3JH,H = 8.8 Hz, 4JHiotaH = 2.3 Hz), 7.19 (IH, dd, 3JH,F = 11.9 Hz, 4JHlH = 2.3 Hz), 7.80 (IH, t, 3JiW = %,F = 8.4 Hz), 7.95 (IH, d, 3J= 8.5 Hz), 8.17 (IH5 dd, 3J = 8.5 Hz, 4J = 2.2 Hz), 8.73 (IH, d, 4J= 2.1 Hz), 10.47 (IH, s, -NHCO-). |
Yield | Reaction Conditions | Operation in experiment |
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100% | With phosphorus pentasulfide; In ethanol; at 25 - 80℃;Inert atmosphere; | 26.1 Synthesis of 2-fluoro-4-hydroxybenzenecarbothioamide a79.A solution of phosphorus hemipentasulfide (22 g, 49.6 mmol, 2 eq) in ethanol (50 ml), under an argon atmosphere, is treated with <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> a78 (3.4 g, 24.8 mmol, 1 eq) at 25C. The mixture is stirred overnight at 800C, then diluted <n="98"/>with diethyl ether and carefully washed with a saturated aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up in hexane and the precipitate is filtered, taken up in lambda/,lambda/-dimethylformamide and dried to afford 4.24 g of 2-fluoro-4-hydroxybenzenecarbothioamide a79 as an orange solid. Yield: 100 %. LC-MS (MH+): 172. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium iodide; sodium hydroxide In butanone Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloroamine-T; sodium iodide; In acetonitrile; at 20℃; for 1.5h; | To a stirred solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (XCV) (5.15 g, 37.56 mmol) and sodium iodide (6.19 g, 41.32 mmol) in acetonitrile (175 mL) was added Chloramine- T trihydrate (11.64 g, 41.32 mmol). The resulting red-brown mixture was allowed to stir at room temperature. After 1.5 hours, the reaction mixture was concentrated, and the residue partitioned between ethyl acetate and IN hydrochloric acid. The phases were separated, and the organic phase washed with saturated sodium thiosulfate solution and brine. The organic phase was dried (magnesium sulfate), filtered, and concentrated to provide a white solid. Flash chromatography using an Isco Combiflash unit (330 g SiO2 column, 25-50% ethyl acetate/hexanes) afforded 6.65 g (67%) of 2-fluoro-4-hydroxy-5-iodobenzonitrile as a white solid (contaminated with -16% 2- fluoro-4-hydroxybenzonitrile): 1B. NMR (CDCl3) delta 7.92 (d, J= 7.0 Hz, 1H), 6.86 (d, J = 10.0 Hz, 1H), 6.54 (br s, 1H) ppm. Further elution provided 1.28 g (13%) of 2-fluoro-4-hydroxy-3- iodobenzonitrile as a white solid (contaminated with ~12%/?-toluenesulfonamide): 1H NMR (CDCl3) delta 7.51 (dd, J = 7.3, 8.6 Hz, 1H), 6.88 (dd, J= 1.1, 8.6 Hz, 1H), 6.26 (br s, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h; | Reference Example 1 4-(Tert-butyldimethylsilyloxy)-2-fluorobenzonitrile 2-Fluoro-4-hydroxybenzonitrile (30.1 g; manufactured by Wako Pure Chemical Industries, Ltd.) and imidazole (18.3 g; manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in dehydrated DMF (436 mL; manufactured by Kanto Chemical Co., Inc.). After cooling to 0 C., TBDMSCl (48.3 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added and the mixture was stirred for 1 hour while warming to room temperature. Solvent contained in the reaction solution was evaporated under reduced pressure. After adding water, extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, purification was carried out with column chromatography ("COLUMN-A"; n-hexane:ethyl acetate=100:0?94:6) to obtain the title compound (40.3 g). 1H-NMR (300 MHz, CDCl3); delta (ppm) 0.25 (3H, s), 0.25 (3H, s), 0.98 (9H, s), 6.62-6.70 (2H, m), 7.44-7.50 (1H, m) | |
In N,N-dimethyl-formamide; at 0 - 20℃; | Reference Example 1; 4-(Tert-butyldimethylsilyloxy)-2-fluorobenzonitrile 2-Fluoro-4-hydroxybenzonitrile (30.1 g; manufactured by Wako Pure Chemical Industries, Ltd.) and imidazole (18.3 g; manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in dehydrated DMF (436 mL; manufactured by Kanto Chemical Co., Inc.), and the solution was cooled to 0 C. Subsequently, TBDMSCl (48.3 g; manufactured by Tokyo Chemical Industry Co., Ltd.) was added thereto, and the mixture was stirred for one hour while the temperature was raised to room temperature. The solvent was evaporated under reduced pressure from the reaction solution, subsequently water was added thereto, and the mixture was extracted two times with ethyl acetate. The organic layer was washed two times with water and with brine, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by column chromatography (?COLUMN-A.?; n-hexane:ethyl acetate=100:0?94:6). Thus, the title compound (40.3 g) was obtained.1H-NMR (300 MHz, CDCl3); delta (ppm) 0.25 (3H, s),0.25 (3H, s), 0.98(9H, s), 6.62-6.70 (2H, m), 7.44-7.50(1H, m) | |
With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h; | 2-Fluoro-4-hydroxybenzonitrile (30.1 g; made by Wako Pure Chemical Industries Co., Ltd.) and imidazole (18.3 g; made by Tokyo Chemical Industry Co., Ltd.) were dissolved in dehydrated DMF (436 mg; made by Kanto Chemical Co., Inc.). After cooling to 0C, TBDMSCI (48.3 g; made by Tokyo Chemical Industry Co., Ltd.) was added and [the contents] were stirred for one hour while being warmed to room temperature. After distilling off the solvent under reduced pressure, water was added to the reaction solution, and extraction was performed twice using ethyl acetate. The organic layer was washed twice with water and with brine. After drying had been performed using anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, followed by purification by column chromatography ('Column A;' n-hexane: ethyl acetate = 100:0?94:6), and the title compound (40.3 g) was obtained. 1H-NMR (300MHz, CDCl3); delta (ppm) 0.25 (3H, s), 0.25 (3H, s), 0.98 (9H, s), 6.62-6.70 (2H, m), 7.44-7.50 (1H, m) |
With 1H-imidazole; In N,N-dimethyl-formamide; at 0℃; for 0.216667h; | To a mixture of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (5.0 g), imidazole (5.0 g) and DMF (50 mL) was added tert-butylchlorodimethylsilane (8.24 g) in DMF (20 mL) at 0 C. within 13 minutes. The mixture was extracted with PE (200 mL*2). The extracts were concentrated in vacuo to provide 4-((tert-butyldimethylsilyl)oxy)-2-fluorobenzonitrile. MS ESI+: m/z=252 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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99% | Preparation No.23: Synthesis of 2-Fluoro-4-(3-(trifluoromethyl)benzyloxy)benzonitrile; In a 1 L round-bottomed flask, DIAD (14.31 mL, 72.7 mmol) and tnphenylphosphme (19.07 g, 72 7 mmol) m THF (200 mL) were stirred for about 5 mm under nitrogen and cooled to about 0 C. 2-Fluoro-4-hydroxybenzonitrile (6.65 g, 48.5 mmol) was added to give a dark orange solution. The mixture was stirred about an additional 5 mm and then 3-(t?fluoromethyl)benzyl alcohol (7.26 mL, 53 3 mmol) m THF (50 mL) was added. The mixture was stirred overnight at ambient temperature then evapoiated to dryness. The solid was purified on a Combiflash Companion XL system using a 330 g Redi-Sep silica gel column using the following gradient: A: Heptane; B: Ethyl acetate, 10 to 100 %B over 7 column volumes. NMR indicated the presence of t?phenyl phosphme oxide and reduced DIAD. The iesidue was triturated with light petroleum ether (250 mL) for 1 hour, filtered and the solid dried under vacuum overnight. This gave 2-fluoro-4-(3- (t?fluoromethyl)benzyloxy)benzomt?le (9.31 g, 31.2 mmol, 99%). 1H NMR (400 MHz, DMSO- Cl6): delta 7.91 - 7.83 (m, 2H), 7 78 (d, J = 7.7, IH), 7.74 (d, J = 7.8, IH), 7.66 (t, J = 7.7, IH), 7.30 (dd, J = 2.4, 11.9, IH), 7.09 (dd, J = 2.4, 8.8, IH), 5.34 (s, 2H). (Table 2, Method b) Rt = 1.60 mm; MS m/z: 294.04 (M-H) . |
Yield | Reaction Conditions | Operation in experiment |
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Preparative Example 67PREPARATION OF AMMONIUM 4-CYANO-3-FLUOROPHENYL [([5-(AZIDOMETHYL)-THIENO[3,2-b]THIEN-2-YL]SULFONYL}AMINO)METHYL]PHOSPHONATETo the product from the prior Preparative Example (0.0476 g, 0.13 mmol) in anhydrous pyridine/DMF (0.5 mL/0.050 mL) was added <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (0.018 g, 0.13 mmol) followed by trichloroacetonitrile (0.091 mL, 0.90 mmol). The reaction was conducted in a sealed tube and heated to 105 C. for 4.5 h. The reaction was concentrated in vacuo and purified by silica gel plate chromatography (1000 micron, 40/10/1 CHCl3/MeOH/conc. NH4OH). The product was further triturated with CH2Cl2 (3×) and the desired insoluble solid was collected by centrifugation.1H NMR (500 MHz, CD3OD) delta (ppm): 7.84 (s, 1H), 7.50 (t, 1H), 7.39 (s, 1H), 7.14 (dd, 1H), 7.06 (dd, 1H), 4.69 (s, 2H), 3.24 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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Preparation 24: 2-Fluoro-4-hvdroxybenzamideTo a stirred solution of urea hydrogen peroxide (2.1 g, 21.9 mmol) in 6 ml. of water was added solid sodium hydroxide (521 mg, 12.8 mmol). The resulting solution was cooled in an ice bath before a solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (500 mg, 3.65 mmol) in 2 ml. of ethanol was added. The mixture was vigorously stirred for 2 hours at room temperature before it was diluted with water (100 ml.) and ethyl acetate (100 ml_). The mixture was stirred for 5 minutes before 1 M hydrochloric acid was added until pH=4. The aqueous layer was separated and extracted with ethyl acetate (3X50 ml_). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated to give 2-fluoro-4-hydroxybenzamide as a white solid. | ||
With urea hydrogen peroxide adduct; sodium hydroxide; In ethanol; water; at 20℃; for 2h; | To a stirred solution of urea hydrogen peroxide (2.1 g, 21 .9 mmol) in 6 mL of water was added solid sodium hydroxide (521 mg, 12.8 mmol). The resulting solution was cooled in an ice bath before a solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (500 mg, 3.65 mmol) in 2 mL of ethanol was added. The mixture was vigorously stirred for 2 hours at room temperature before it was diluted with water (100 mL) and ethyl acetate (100 mL). The mixture was stirred for 5 minutes before 1 M hydrochloric acid was added until pH=4. The aqueous layer was separated and extracted with ethyl acetate (3X50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated to give 2-fluoro-4-hydroxybenzamide as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25℃; for 2h; | Description for D22 2-Fluoro-4-[([2-(trimethylsilyl)ethyl]oxy}methyl)oxy]benzonitrile (D22) To the solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (2 g) and DIPEA (2.07 mL) in dichloromethane (100 mL) was added SEMCI (2.43 g) at 25 0C dropwise. The reaction solution was sitrred for 2 hours. The reaction solution was washed with water (2x15 mL), dried over sodium sulphate, concentrated to afford 2-fluoro-4-[([2- (trimethylsilyl)ethyl]oxy}methyl)oxy]benzonitrile (D22) (3.90 g) as a clear oil. MS (ES): C14H21NO2Si requires 263; found 264.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
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89% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 20 - 50℃;Inert atmosphere; | (35A) 4-[(3,4-Dichlorobenzyl)oxy]-2-fluorobenzo nitrile 2-Fluoro-4-hydroxybenzonitrile (350 mg, 2.55 mmol) and <strong>[1805-32-9]3,4-dichlorobenzyl alcohol</strong> (542 mg, 3.06 mmol) were dissolved in tetrahydrofuran (7.0 mL), and triphenylphosphine (803 mg, 3.06 mmol) and a 40% diethyl azodicarboxylate toluene solution (1.40 mL, 3.06 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50 C. for 5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 65:35 (v/v)), whereby the objective title compound was obtained as a white solid (676 mg, yield: 89%). 1H NMR (CDCl3, 400 MHz): delta5.06 (2H, s), 6.76-6.85 (2H, m), 7.23-7.28 (1H, m), 7.48-7.59 (3H, m) |
Yield | Reaction Conditions | Operation in experiment |
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0.5 g (23%) | With potassium carbonate; In water; isopropyl alcohol; acetone; | Synthesis of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamide (Compound 2). A mixture of bromoamide ((2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide (2.0 g, 5.70 mmol), anhydrous K2CO3 (2.4 g, 17.1 mmol) in 50 mL of acetone was heated to reflux for 2 h and then concentrated under reduced pressure to give a solid. The resulting solid was treated with <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (1.2 g, 8.5 mmol) and anhydrous K2CO3 (1.6 g, 11.4 mmol) in 50 mL of 2-propanol, was heated to reflux for 3 h, and then concentrated under reduced pressure to give a solid. The residue was treated with 100 mL of H2O and then extracted with EtOAc (2*100 mL). The combined EtOAc extracts were washed with 10% NaOH (4*100 mL) and brine, successively. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to give an oil which was crystallized from CH2Cl2/hexane to give 0.5 g (23%) of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamide as a colorless solid. 1H NMR (CDCl3/TMS) delta 1.63 (s, 3H, CH3), 3.34 (bs, 1H2OH), 4.08 (d, J=9.17 Hz, 1H, CH), 4.50 (d, J=9.17 Hz, 1H, CH), 6.74-6.82 (m, 2H, ArH), 7.50-7.55 (m, 1H, ArH), 7.81 (d, J=8.50 Hz, 1H, ArH), 7.97 (q, J=2.03, 8.50 Hz, 1H, ArH), 8.11 (d, J=2.03 Hz, 1H, ArH), 9.12 (s, 1H, NH). Calculated Mass: 407.1, [M+Na]+430.0. Mp: 124-125 C. |
Yield | Reaction Conditions | Operation in experiment |
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97% | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 6h; | Preparation 104-(2-Benzyloxy-ethoxy)-2-fluoro-benzonitrileScheme 2, Step Jc)A mixture of <strong>[82380-18-5]2-fluoro-4-hydroxy-benzonitrile</strong> (4.57 g, 33.3 mmol), K2C03 (13.8 g, 99.9 mmol) and benzyl 2-bromoethyl ether (5.79 ml, 36.6 mmol) in dry DMF (15 ml) was stirred at 70C for 6h. The reaction mixture was cooled to r.t., poured into 300 ml of water and extracted with EtOAc (2X100 ml). The organic layers were combined, dried over sodium sulfate and evaporated to dryness. The crude residue was purified by chromatography (Biotage SP1 Flash Purification system) on a silica gel cartridge (Biotage SNAP 100 g) eluting with a gradient from hexane / EtOAc 100:0 to 60:40 over 20 CV, affording 8.79 g (yield: 97%) of the title compound as a colourless oil.1H-NMR (400 MHz), delta (ppm, DMSO-de): 7.75 - 7.90 (m, 1 H) 7.26 - 7.38 (m, 5 H) 7.19 (dd, J=11.96, 2.44 Hz, 1 H) 6.99 (dd, J=8.79, 2.32 Hz, 1 H) 4.55 (s, 2 H) 4.22 - 4.34 (m, 2 H) 3.65 - 3.87 (m, 2 H)ESI (+) MS m/z 272 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; oxygen; copper diacetate; In dichloromethane; at 20℃; for 16h;Molecular sieve; | To a suspension of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (270 mg, 1.99 mmol) in CH2Cl2 (20 mL) were added (6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)boronic acid (O; 500 mg, 1.53 mmol), Cu(OAc)2 (276 mg, 1.53 mmol), pyridine (0.6 mL, 7.65 mmol), powdered 4 molecular sieves, and the reaction mixture was stirred at RT for 16 h under an oxygen atmosphere. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of Celite to remove the molecular sieves, and the pad was washed with CH2Cl2 (2×25 mL). The filtrate was washed with H2O (25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 30% EtOAc/hexane afforded compound T (100 mg, crude) as a colorless thick syrup. (Note: All the characteristic protons were seen in the 1H NMR spectrum.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With diisopropyl (E)-azodicarboxylate; In tetrahydrofuran; at 20℃;Inert atmosphere; Cooling with ice; | <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (1.00 g, 7.29 mmol), propan-2-ol (1.24 ml, 16.09 mmol), triphenylphosphine (4.20 g, 16.01 mmol), diisopropylethylamine (5.20 ml, 29.85 mmol) and THF (10 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with nitrogen, the reaction mixture cooled with ice bath and diisopropyl (E)-diazene-1,2-dicarboxylate (3.50 ml, 17.78 mmol) was added dropwise. The reaction mixture was then stirred at room temperature overnight. The solid formed was filtered off and the filtrate concentrated under vacuum. Ethyl acetate and water were added to the crude and the organic layer was washed with brine, dried (Na2SO4) and evaporated to give the desired compound (1.43 g, 99%) as colorless oil. 1H NMR (400 MHz, CDCl3) delta ppm 1.34 (d, J=5.86 Hz, 6 H), 4.51 - 4.61 (m, 1 H), 6.64 (dd, J=11.33, 2.34 Hz, 1 H), 6.69 (dd, J=8.99, 2.34 Hz, 1 H), 7.46 (dd, J=8.60, 7.42 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | A mixture of bromoamide ((2/?)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2- hydroxy-2-methylpropanamide (2.0 g, 5.70 mmol), anhydrous K2CO3 (2.4 g, 17.1 mmol) in 50 mL of acetone was heated to reflux for 2 h and then concentrated under reduced pressure to give a solid. The resulting solid was treated with <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (1.2 g, 8.5 mmol) and anhydrous K2CO3 (1.6 g, 11.4 mmol) in 50 mL of 2-propanol was heated to reflux0 for 3 h and then concentrated under reduced pressure to give a solid. The residue was treated with 100 mL of H20 and then extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were washed with 10% NaOH (4 x 100 mL) and brine, successively. The organic layer was dried over MgS04 and then concentrated under reduced pressure to give an oil which was crystallized from CH2Cl2/hexane to give 0.5 g (23%) of (5)-N-(4-cyano-3-5 (trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamide as a colorless solid. [000352] *H NMR (CDCI3/TMS) delta 1.63 (s, 3H, CH3), 3.34 (bs, 1H,0H), 4.08 (d, J = 9.17 Hz, 1H, CH), 4.50 (d, / = 9.17 Hz, 1H, CH), 6.74 - 6.82 (m, 2Eta, ArH), 7.50-7.55 (m, 1Eta, ArH), 7.81 (d, / = 8.50 Hz, 1H, ArH), 7.97 (q, / = 2.03, 8.50 Hz, 1H, ArH), 8.11 (d, / = 2.03 Hz,0 1H, ArH), 9.12 (s, 1Eta, NH). Calculated Mass: 407.1, [M+Na]+ 430.0. Mp: 124-125 C. | |
23% | A mixture of bromoamide ((2/?)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2- methylpropanamide, R-19 (2.0 g, 5.70 mmol), anhydrous K2CO3 (2.4 g, 17.1 mmol) in 50 mL of acetone was heated to reflux for 2 h and then concentrated under reduced pressure to give a solid. The resulting solid was treated with <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (1.2 g, 8.5 mmol) and anhydrous K2CO3 (1.6 g, 11.4 mmol) in 50 mL of 2-propanol was heated to reflux for 3 h and then concentrated under reduced pressure to give a solid. The residue was treated with 100 mL of 0 and then extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were washed with 10% NaOH (4 x 100 mL) and brine, successively. The organic layer was dried over MgS04 and then concentrated under reduced pressure to give an oil which was crystallized from CH2Cl2/hexane to give 0.5 g (23%) of (5')-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2- hydroxy-2-methylpropanamide as a colorless solid. [000317] FontWeight="Bold" FontSize="10" H NMR (CDCI3/TMS) delta 1.63 (s, 3H, CH3), 3.34 (bs, 1H,0H), 4.08 (d, / = 9.17 Hz, 1H, CH), 4.50 (d, J = 9.17 Hz, 1H, CH), 6.74 - 6.82 (m, 2Eta, ArH), 7.50-7.55 (m, 1Eta, ArH), 7.81 (d, / = 8.50 Hz, 1H, ArH), 7.97 (q, / = 2.03, 8.50 Hz, 1H, ArH), 8.11 (d, J = 2.03 Hz, 1H, ArH), 9.12 (s, 1Eta, NH). Calculated Mass: 407.1, [M+Na]+ 430.0. Mp: 124-125 C. | |
23% | With potassium carbonate; In isopropyl alcohol; acetone; for 3h;Reflux; | Synthesis of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamide (Compound of Formula XIII) A mixture of bromoamide (2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide (2.0 g, 5.70 mmol) and anhydrous K2CO3 (2.4 g, 17.1 mmol) in 50 mL of acetone was heated to reflux for 2 h and then concentrated under reduced pressure to give a solid. The resulting solid was treated with <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (1.2 g, 8.5 mmol) and anhydrous K2CO3 (1.6 g, 11.4 mmol) in 50 mL of 2-propanol and was heated to reflux for 3 h, then concentrated under reduced pressure to give a solid. The residue was treated with 100 mL of H2O and then extracted with EtOAc (2*100 mL). The combined EtOAc extracts were washed with 10% NaOH (4*100 mL) and brine, successively. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to give an oil which was crystallized from CH2Cl2/hexane to give 0.5 g (23%) of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamide as a colorless solid. Calculated Mass: 382.1 [M-H]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; | To a solution of the product of Example 6a (80 mg, 0.52 mmol), 2- fluoro-4-hydroxybenzonitrile (85 mg, 0.62 mmol) and triphenylphosphine (205mg, 0.78 mmol) in tetrahydrofuran (4 ml_) at 0 C was added diethyl azodicarboxylate (137 mg, 0.78 mmol) and then the mixture was warmed to room temperature and stirred at overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted petroleum ether/ethyl acetate =10/1 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by prep-TLC to afford the title compound as a colorless oil (38 mg, Yield: 27%). Rf = 0.3 (100:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCI3) delta 7.51 (t, J = 8.2 Hz, 1 H), 6.82-6.74 (m, 2 H), 4.47 (s, 2 H), 2.06 (t, J = 6.4 Hz, 2 H), 1.69 (s, 3 H), 1.67-1.62 (m, 2 H), 1.52-1.49 (m, 2 H), 1.02 (s, 6 H) ppm; Mass spectrum (ESI +ve) m/z 274 (M + H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Step l:2-Fluoro-4-(2-hydroxy-ethoxy)-benzonitrile (3_44_2) [00360] Anhydrous potassium carbonate (10.0 g, 72.4 mmol) was added to a solution of <strong>[82380-18-5]2-fluoro-4-hydroxy-benzonitrile</strong> 3_44_1 (5.0 g, 36.5 mmol) in N,N- diemthylformamide (50 mL). The resulting mixture was stirred at room temperature for 10 minutes, and 2-bromoethanol (13.5 g, 7.7 mL, 108.0 mmol) was added drop- wise over 15 minutes. The resulting mixture was stirred at room temperature for 3 days. TLC showed the reaction was incomplete. Additional 2-bromoethanol (3 mL) was added and the reaction mixture was stirred for another day, poured into water (300 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate layers were washed with a saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 3_44_2 (5.0 g, 76 % yield) as a white solid. [00361] NMR (CDC13, 400 MHz): delta = 3.99 - 4.01 (m, 2H), 4.02 - 4.14 (m, 2H), 6.73 - 6.81 (m, 2H), 7.51 - 7.55 (m, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; for 16h; | Step 1 : 2-Fluoro-4-(tetrahydro-2H-pyran-2-yloxy)benzonitrile (3_85_2) [00539] 3,4-Dihydro-2H-pyran (DHP, 7.20 mL, 79.12 mmol) was added to a mixture of <strong>[82380-18-5]2-fluoro-4-hydroxy-benzonitrile</strong> (5.42 g, 39.56 mmol) and pyridium p- toluenesulfonate (PPTS, 170 mg, 0.68 mmol) in dry dichloromethane (100 mL) and the mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by column chromatography to give compound 3_85_2 (8.9 g, 100 % yield) as a clear oil. |
89% | With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; | A mixture of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (5.42 g, 39.6 mmol), 3,4-dihydro-2H-pyran (7.20 ml_, 79.1 mmol) and pyridinium p-toluenesulfonate (170 mg, 0.68 mmol) in DCM (100 ml.) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc = 100/1 to 1/1 ) to give title product (7.8 g, 89%) as a white solid. LCMS-C: rt 1.874 min; m/z 221.9 [M+H]+. |
83% | With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃;Inert atmosphere; | To a solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (20 g, 145.9 mmol) and PPTS (733 mg, 2.9 mmol) in DCM (500 ml.) under N2was added 3,4-dihydro-2H-pyran (24.5 g, 292 mmol) and the mixture was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was purified by column chromatography (Pet. ether/EtOAc = 100/0 to 100/2) to give the title compound (27 g, 83%) as a white solid, which was used directly in the next step. |
56% | With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; for 16h; | 6.1.13 2-Fluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzonitrile (29) To a solution of 28 (2 g, 14.6 mmol) and pyridinium 4-toluenesulfonate (73 mg, 0.29 mmol) in dry dichloromethane (25 mL) was added 3,4-dihydro-2H-pyran (9.8 g, 29.2 mmol) slowly. The mixture was stirred at room temperature for 16 h. Then the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane) to give 29 (1.8 g, 56%) as a colourless oil. 1H NMR (400 MHz, CDCl3): delta 7.50 (t, J = 7.8 Hz, 1H), 6.93-6.86 (m, 2H), 5.47 (s, 1H), 3.81-3.62 (m, 2H), 1.90-1.64 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 18h; | To a solution of 5-bromo-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 12, 425 mg, 0.90 mmol) in DMSO (5 mL) was added K2CO3 (372 g, 2.70 mmol) followed by <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (123 g, 0.90 mmol). The reaction mixture was left to stir at room temperature for 18 hours. To the reaction mixture was added water (20 mL) and saturated brine (20 mL) and the product was extracted with EtOAc (50 mL). The organic layer was retained and washed with saturated brine (3*40 mL), dried over MgSO4, and the solvent removed under vacuum. The residue was purified using silica gel column chromatography eluting with 15% EtOAc in heptanes followed by trituration with heptane to afford the title compound as a colourless solid (74 mg, 28%). 1H NMR (400 MHz, CDCl3): delta ppm 3.68 (s, 3H), 3.76 (s, 3H), 5.00 (s, 2H), 6.34-6.38 (m, 2H), 6.82-6.86 (m, 3H), 7.17 (d, 1H), 7.30-7.35 (m, 2H), 7.66 (dd, 1H, 8.12 (d, 1H), 8.17 (d, 1H). 19F NMR (376 MHz, CDCl3) delta ppm -101.9 (m, 1F), -104.1 (m, 1F), -128.5 (m, 1F). |
Yield | Reaction Conditions | Operation in experiment |
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38% | To a solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (1.0 g, 7.3 mmol) in acetonitrile (20 mL) at -30 C was added trifluoromethanesulfonic acid ( 1.2 g, 8.0 mmol) dropwise. The solution was stirred at -30 C for 10 min then N-bromosuccinimide (1.8 g, 10.2 mmol) was added. After stirring at ambient temperature for 18 h, the reaction was quenched by saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude residue was purified by SGC (eluting with petroleum ether/EtOAc = 10/1) to give 5-bromo-<strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (600 mg, 38%) as a white solid. LCMS (ESI) m/z: 214.1 [M-H]+ . 1H-NMR (500 MHz, CDCl3): delta 7.75 (d, J= 6.5 Hz, 1H), 6.90 (d, J= 10.0 Hz, 1H), 6.25 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
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32% | General procedure: To a mixture of NaH (60% in mineral oil, 0.050 g, 1.23 mmol) in anhydrous THF (2 mL) at 0 C under Ar atmosphere was added a solution of the differently substituted phenol or thiophenol (1.11 mmol) in 1 mL of anhydrous THF. This mixture was stirred at r.t. for 20 min. A solution of the different intermediate 17-21 (0.74 mmol) in anhydrous THF (3 mL) was added slowly. The reaction mixture was stirred at r.t. o.n. The mixture was then diluted with ethyl acetate (30 mL), washed with brine (15 mL) and water (30 mL), dried over Na2SO4 and concentrated under vacuum. The crude residue was purified by flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | General procedure: To a mixture of NaH (60% in mineral oil, 0.050 g, 1.23 mmol) in anhydrous THF (2 mL) at 0 C under Ar atmosphere was added a solution of the differently substituted phenol or thiophenol (1.11 mmol) in 1 mL of anhydrous THF. This mixture was stirred at r.t. for 20 min. A solution of the different intermediate 17-21 (0.74 mmol) in anhydrous THF (3 mL) was added slowly. The reaction mixture was stirred at r.t. o.n. The mixture was then diluted with ethyl acetate (30 mL), washed with brine (15 mL) and water (30 mL), dried over Na2SO4 and concentrated under vacuum. The crude residue was purified by flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate; In acetonitrile; at 100℃; for 1.5h;Sealed tube; Inert atmosphere; | 1001891 To a stirred solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (200 mg, 1.46 mmol) and I-(bromomethyl)-4-methylbenzene (270 mg, 1.46 mmol) in anhydrous acetonitrile (3.8 ml) atroom temperature in a sealable pressure tube under nitrogen was added Cs2CO3 (523 mg, 1.6 mmol). The tube was then sealed and the mixture heated to 100C for 1.5 hrs. On completion the reaction was cooled to room temperature and diluted with DCM (10 ml) and washed with water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetonitrile; at 100℃; for 1.5h;Sealed tube; Inert atmosphere; | [00191]To a stirred solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (200 mg, 1.46 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (349 mg, 1.46 mmol) in anhydrous acetonitrile (3.8ml) at room temperature in a sealable pressure tube under nitrogen was added Cs2CO3 (523 mg,1.6 mmol). The tube was then sealed and the mixture heated to 100 oC for 1.5 hr.[00192]The reaction was cooled to rt and diluted with DCM (10 ml) and washed with water(3x 5 ml). The organic layer was dried over MgSO4, filtered and evaporated to dryness to give369mg of the title compound TH NIvIR (500 M}Iz, DMSO-d6) 7.91-7.85 (m, 1H), 7.80 (d, J8.1 Hz, 2H), 7.69 (d, J = 8.0 Hz, 211), 7.30 (dd, J = 11.8, 2.4 Hz, lH), 7.08 (dd, J = 8.8, 2.4 Hz,1 H), 5.36 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39 g | With dmap; diisopropyl-carbodiimide; In dichloromethane; at 15 - 20℃; for 5h; | To the reaction vessel equipped with a stirrer and a thermometer, 30.0 g (0.14 mol) of the compound represented by the formula (A-2), 17.8 g (0.13 mol) of <strong>[82380-18-5]4-cyano-3-fluorophenol</strong>, N, N-dimethylaminopyridine (0.8 g, 6.5 mmol) and dichloromethane (150 mL), and the mixture was stirred with ice. The reaction was carried out while maintaining the temperature of the reaction solution at 15 C or less while dropping N,N'-diisopropylcarbodiimide (19.7 g, 0.16 mol). After completion of the dropwise addition, the reaction was carried out by stirring at room temperature for 5 hours. After the reaction solution was filtered and the precipitate was removed, the solvent was distilled off. The obtained solid was dissolved in methylene chloride and purified by column chromatography (refined solvent: 31 g of silica gel, eluent: dichloromethane 248 mL), and the solvent was evaporated. The resulting solid was subjected to dispersion washing with 124 mL of methanol, and dried to obtain 39.0 g of the compound represented by the formula (H-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With formic acid; oxygen; triethylamine; copper(ll) bromide; In acetonitrile; at 20℃; for 24h;UV-irradiation; | 4-Bromo-2-fluorobenzonitrile (0.25 mmol), copper bromide (0.03 mmol), triethylamine (0.25 mmol, 1.0 equiv), HCOOH (0.75 mmol, 3.0 equiv) at room temperature,179mmol of the reaction solvent CH3CN was added to the reaction tube, and the mixture was stirred at room temperature for 24 hours under the oxygen atmosphere.After the completion of the reaction was monitored by thin layer chromatography, 20 mL of water and 10 mL of ethyl acetate were added for extraction, followed by drying over anhydrous sodium sulfate, filtering after 5 minutes, washing the filter cake with ethyl acetate (5 mL×3 times), and then swirling off the solvent.The product was isolated by column chromatography (eluent: petroleum ether: ethyl acetate = 6:1), the product was a yellow liquid, yield 82%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: acetic acid; sulfuric acid / 0.17 h / 65 °C 1.2: 2 h / 65 °C 2.1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 6.5 h / 10 - 35 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With diethylazodicarboxylate; trimethylphosphane; In tetrahydrofuran; toluene; at 0 - 20℃; | (S)-tert-butyl 3-hydroxy-4-methylenepyrrolidine-1-carboxylate (100 g, 500 mmol) was dissolved in THF (1200 mL) and treated with <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (83 g, 600 mmol) and trimethylphosphine (1 M in THF, 600 mL, 600 mmol). The mixture was cooled to 0 C and DEAD (40 wt% in toluene, 320 mL, 700 mmol) was added dropwise over a period of one hour maintaining the internal temperature below 8 C. The reaction mixture continued to stir at 0 C for 30 minutes and then was allowed to warm to room temperature overnight. The reaction mixture was poured into 1 N NaOH (aq) (1L) and stirred vigorously while a saturated solution of Na2S2O3(aq) (50 mL) was added. The mixture was poured into a 50/50 mixture of ethyl acetate/hexanes and the layers separated. The organic layer was separated, washed with 1 N NaOH (aq) (3 x 1L), water (1 x 1L), and brine (1 x 1L), dried over Na2SO4, filtered and concentrated to an orange oil with a white solid (220 grams). The oil was triturated with hexanes:EtOAc, filtered to remove the white solid, and concentrated to give the title compound as an orange oil (152 g, 95% yield).1H NMR (400 MHz, DMSO-d6) ^: 7.86 (t, J = 8.3 Hz, 1H), 7.31 (dd, J = 11.8, 2.3 Hz, 1H), 7.07 (dd, J = 8.8, 2.3 Hz, 1H), 5.47 (br s, 1H), 5.43 (br s, 1H), 5.34 (s, 1H), 4.03 (m, 1H, partially hidden by solvent peak), 3.89-3.99 (m, 1H), 3.68-3.80 (m, 1H), 3.46 (dd, J = 12.3, 2.3 Hz, 1H), 1.41 (d, J = 7.8 Hz, 9H). MS (m/z) 263.2 (M+H+- t-Bu). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(I) Substitution reaction: adding the reactant 2, 4-difluorobenzonitrile, catalyst and tetrahydrofuran into the reaction vessel, the amount of tetrahydrofuran added is twice the mass of the reactant, the catalyst is a mixture of beta-cyclodextrin and starch in a mass ratio of 3:1, the amount of catalyst added is 2% of the mass of the reactants, keep warm at 10 C, add sodium tert-butoxide in 2 portions, the total amount of sodium tert-butoxide added is 1.1 times the molar amount of 2,4-difluorobenzonitrile, after 3 hours of reaction obtained 2-Fluoro-4-alkoxybenzonitrile. The yield of this step is 95%, the product purity is 85%. (II) Hydrolysis reaction: into the reaction solution containing 2-fluoro-4-alkoxybenzonitrile added 35% hydrochloric acid, the molar ratio of hydrochloric acid and 2-fluoro-4-alkoxybenzonitrile is 1:8, at 30 C slowly added the drops of 2-fluoro-4-alkoxybenzonitrile toluene solution, the molar ratio of 2-fluoro-4-alkylbenzonitrile and toluene is 1:4, after the addition is completed the temperature is kept at 30 C for 3~5 hours. And then Liquid separation extraction, Concentrated, crystallization with methanol at 0 C, and added the mass ratio of methanol and 2-fluoro-4-alkoxybenzonitrile is 3:1, suction filtration, drying and then obtained 3-fluoro-4-cyanophenol. The total yield of the two-step reaction is 74%, the product purity is 99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a stirred solution of substituted phenol (1 mmol) in DMF(4 mL), K2CO3 (3 mmol) was added. Furthermore 2-(chloromethyl)-5-aryl-1,3,4-oxadiazole derivatives (6a-6e) and KI (0.5 mmol) wasadded. The reaction mixture was stirred at RT for 1-2 h. Aftercompletion of the reaction, the reaction mixture was washed withcold water. The solid product was collected by filtration and driedunder the vacuum. It had been further crystallized in ethyl acetate/petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a stirred solution of substituted phenol (1 mmol) in DMF(4 mL), K2CO3 (3 mmol) was added. Furthermore 2-(chloromethyl)-5-aryl-1,3,4-oxadiazole derivatives (6a-6e) and KI (0.5 mmol) wasadded. The reaction mixture was stirred at RT for 1-2 h. Aftercompletion of the reaction, the reaction mixture was washed withcold water. The solid product was collected by filtration and driedunder the vacuum. It had been further crystallized in ethyl acetate/petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a stirred solution of substituted phenol (1 mmol) in DMF(4 mL), K2CO3 (3 mmol) was added. Furthermore 2-(chloromethyl)-5-aryl-1,3,4-oxadiazole derivatives (6a-6e) and KI (0.5 mmol) wasadded. The reaction mixture was stirred at RT for 1-2 h. Aftercompletion of the reaction, the reaction mixture was washed withcold water. The solid product was collected by filtration and driedunder the vacuum. It had been further crystallized in ethyl acetate/petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a stirred solution of substituted phenol (1 mmol) in DMF(4 mL), K2CO3 (3 mmol) was added. Furthermore 2-(chloromethyl)-5-aryl-1,3,4-oxadiazole derivatives (6a-6e) and KI (0.5 mmol) wasadded. The reaction mixture was stirred at RT for 1-2 h. Aftercompletion of the reaction, the reaction mixture was washed withcold water. The solid product was collected by filtration and driedunder the vacuum. It had been further crystallized in ethyl acetate/petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a stirred solution of substituted phenol (1 mmol) in DMF(4 mL), K2CO3 (3 mmol) was added. Furthermore 2-(chloromethyl)-5-aryl-1,3,4-oxadiazole derivatives (6a-6e) and KI (0.5 mmol) wasadded. The reaction mixture was stirred at RT for 1-2 h. Aftercompletion of the reaction, the reaction mixture was washed withcold water. The solid product was collected by filtration and driedunder the vacuum. It had been further crystallized in ethyl acetate/petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | General procedure: To a mixture of NaH (60% in mineral oil, 0.050 g, 1.23 mmol) inanhydrous THF (2 mL) at 0 C under Ar atmosphere was added asolution of the differently substituted phenol or thiophenol(1.11 mmol) in 1mL of anhydrous THF. This mixture was stirred atr.t. for 20 min. A solution of the different intermediate 24e32(0.74 mmol) in anhydrous THF (3 mL) was added slowly. The reactionmixture was stirred at r.t. overnight. The mixture was thendiluted with ethyl acetate (30 mL), washed with brine (15 mL),water (30 mL), and dried over Na2SO4 and concentrated undervacuum. The crude residue was purified by flash column chromatographyor via Biotage Isolera 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | General procedure: To a mixture of NaH (60% in mineral oil, 0.050 g, 1.23 mmol) inanhydrous THF (2 mL) at 0 C under Ar atmosphere was added asolution of the differently substituted phenol or thiophenol(1.11 mmol) in 1mL of anhydrous THF. This mixture was stirred atr.t. for 20 min. A solution of the different intermediate 24e32(0.74 mmol) in anhydrous THF (3 mL) was added slowly. The reactionmixture was stirred at r.t. overnight. The mixture was thendiluted with ethyl acetate (30 mL), washed with brine (15 mL),water (30 mL), and dried over Na2SO4 and concentrated undervacuum. The crude residue was purified by flash column chromatographyor via Biotage Isolera 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | C4-1a (5 g, 36 mmol), DMF (50 mL) was added successively to a 250 mL one-necked flask, and then NaH (1.6 g, 40 mmol) was slowly added in portions. The reaction solution was allowed to react at room temperature for 1 hour. The reaction solution was again placed in an ice bath, and allyl bromide (5.3 g, 44 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 1 h. Ice water was added to the reaction solution to quench the reaction and extracted twice with ethyl acetate (300 mL), and the organic phase washed with brine, dried over sodium sulfate. The mixture was concentrated under reduced pressure, to give compound C4-1b (5.2g, 62% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h; | A solution of <strong>[82380-18-5]2-fluoro-4-hydroxybenzonitrile</strong> (1.087 g, 7.93 mmol) in DMF (26.4 mL) was treated with potassium carbonate (1.644 g, 11.89 mmol) and iodomethane-d3 (0.592 mL, 9.51 mmol) and the reaction mixture heated to 80 C. for 1 hr. The reaction mixture was then quenched with water and extracted with diethyl ether. The organic phase was washed with water and saturated aqueous NaCl solution, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With caesium carbonate In water; dimethyl sulfoxide; isopropyl alcohol at 80℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 0.0833333h; | 15.1 Step 1.2-Fluoro-4-(4-methylphenethoxy)benzonitrile (15-3) 2-fluoro-4-hydroxybenzonitrile (15-1, 155 mg, 1.13 mmol) was dissolved in DCM (10 mL).2-(p- tolyl)ethan-1-ol (15-2, 0.2 mL, 1.43 mmol) was then added via micropipette followed by addition of PPh3 (384 mg, 1.464 mmol). The reaction mixture was stirred at room temperature for 5 min then a solution of DIAD (0.273 mL, 1.32 mmol) in DCM (5 mL) was then added dropwise via addition funnel. After complete addition, the reaction mixture was stirred at room temperature for 5 min (TLC control) and then concentrated to dryness. The resulting residue was purified by silica gel chromatography, eluting with 0- 25% EtOAc/heptane, to afford 15-3 as a white solid (282 mg, 98% yield). 1H NMR (400 MHz, CDCl3) ^ 7.49 (dd, J = 8.8, 7.4 Hz, 1H), 7.17 - 7.12 (m, 4H), 6.74 (dd, J = 8.8, 2.5 Hz, 1H), 6.68 (dd, J = 11.2, 2.4 Hz, 1H), 4.18 (t, J = 6.9 Hz, 2H), 3.07 (t, J = 7.0 Hz, 2H), 2.34 (s, 3H). |
Tags: 82380-18-5 synthesis path| 82380-18-5 SDS| 82380-18-5 COA| 82380-18-5 purity| 82380-18-5 application| 82380-18-5 NMR| 82380-18-5 COA| 82380-18-5 structure
[ 104798-53-0 ]
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