4,4,4-TRIFLUORO-1-(4-FLUOROPHENYL)BUTANE-1,3-DIONE

Step 2. Preparation of a) 4, 4, 4-Trifluoro-1-(4-fluoro-phenyl)-butane-1, 3-dione To a solution of ethyl trifluoroacetate (23.9 mL, 199 mmol) in TBME (230 mL) containing sodium methoxide (5.4 M, 39.6 mL, 214 mmol) was added 4-fluoroacetophenone (25 g, 181 mmol) and the resulting mixture stirred at room temperature for 3 h and then poured into ice-water. The mixture was then diluted with HCl (2 N, 200 mL) and then extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulfate and evaporated to afford the title compound (40.9 g, 97%) which was obtained as an orange oil. MS: m/e=232.9 [M-H]-.To a solution of ethyl trifluoroacetate (23.9 mL, 199 mmol) in tertbutylmethylether (230 mL) containing sodium methoxide (5.4 M, 39.6 mL, 214 mmol) was added 4-fluoroacetophenone (25 g, 181 mmol) and the resulting mixture stirred at room temperature for 3 h and then poured into ice-water. The mixture was then diluted with HCl (2 N, 200 mL) and then extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulfate and evaporated to afford the title compound (40.9 g, 97%) which was obtained as an orange oil. MS: m/e=232.9 [M-H]-.General procedure: 40-chloroacetophenone (0.50 mL, 3.86 mmol)was added to a solution of ethyl trifluoroacetate (0.5 mL, 4.20 mmol) containing 5.4M sodium methoxide (0.8 mL, 4.60 mmol) in ethanol (8.0 mL). The reaction mixture was stirred atroom temperature for 3 h, after which the mixturewas diluted withcold water and 2 N HCl (5.0 mL). The resulting mixture was left tostand overnight to obtain a precipitate. The precipitatewas filtered, washed with cold water and air dried to give the pure compound.Add 4.5 g of metallic sodium to 70 ml of anhydrous methanol.After the reaction is completed, it is cooled to room temperature.14 g of p-fluoroacetophenone and 17 g (120 mmol) of ethyl trifluoroacetate were slowly added.After the dropwise addition was completed, the temperature was refluxed for 24 hours, and concentrated to a yellow viscous liquid.Add 2mol/L hydrochloric acid to adjust the pH to 2~3, extract with ethyl acetate.Drying with magnesium sulfate, After distilling off the solvent, a yellow oil was obtained.1-p-fluoro-4, 4, 4-trifluorobutan-1, 3dione 21 g, yield 90%.100 mL of toluene and absolute ethanol (16.56 g, 0.36 mol) were placed in a vessel to give a mixture B; the chopped sodium metal (8.288, 0.36 mmol) was placed in a vessel containing mixture 8 and stirred until the container (41.48, 0.3 mmol) and ethyl trifluoroacetate (51.128, 0.36 mmol) were placed in a vessel to give a mixture C; and the mixture was cooled to & lt; RTI ID = 0.0 & gt; The container is placed in an electric heating device and gradually heated to 60 C within 30 minutes. After 6 hours of reaction, distillation, extraction, washing, organic phase and drying are carried out to obtain mixture D; The extraction was repeated three times with ethyl acetate, and the washing was repeated twice; the drying was carried out using anhydrous sodium sulfate. The mixture D was subjected to distillation under reduced pressure and allowed to stand under cooling condition. A white solid was precipitated, filtered and dried to give intermediate 1-p-fluorophenyl-4, 4, 4-trifluorobutanedione; the product The mass of 1-p-fluorophenyl_4, 4, 4-trifluorobutanedione was 51.245g. Yield: 73.00%.100 ml of toluene and absolute ethanol (16.56 g, 0.36 mol)Placed in a container to give a mixture B; 2.2)The chopped metal will be sodium(8.28 g, 0.36 mol) was placed in a vessel containing mixture B, Stirring to the vesselA white powder appeared, And no sodium surplus, Placing the container under cooling conditions;2.3) A solution of p-fluoroacetophenone (41.48, 0.3andEthyl trifluoroacetate (51.128, 0.36111 O1)Placed in a containerTo obtain a mixture C;2.4) The container is placed in an electrothermal device, In the range of 30 minutesGradually heated to 60 C, 6 hours after the reactionExtracting, washing, combining organic phase and drying process to obtain mixture D;[0042] Said extraction is referred to as extraction with ethyl acetate, and the extraction process is repeated three times; the water washing process is repeated 2; And the drying process is drying using anhydrous sodium sulfate.2.5) The mixture D was subjected to distillation under reduced pressure and allowed to stand under cooling, whereupon a white solid precipitated and was filtered off, driedDried to give intermediate 1-p-fluorophenyl-4, 4, 4-tetrafluorobutanedione;The mass of the product 1-p-fluorophenyl-4, 4, 4-trifluorobutanedione was 51.245 g. Yield: 73.00100 mL of toluene and anhydrous ethanol (16.56 g, 0.36 mol) was placed in a vessel to give a mixture B;The chopped metal sodium (8.288, 0.36 mol) was placed in a vessel containing the mixture 8, After stirring to a white powder in the container and leaving sodium free, place the container under cooling conditions; A mixture of p-fluoroacetophenone (41.48, 0.3 mol) and ethyl trifluoroacetate (51.128, 0.36 mol) was placed in a vessel to give a mixture C; The container was placed in an electric heating device and gradually heated to 60 C in the range of 30 minutes. After 6 hours of reaction, the mixture was subjected to distillation under reduced pressure, extracted, washed with water, and the organic phase was combined to dry the mixture. The extraction is referred to as using ethyl acetate and the extraction process is repeated three times; the washing process is repeated twice; the drying process is carried out using anhydrous sodium sulfate. The mixture D was distilled under reduced pressure and allowed to stand under cooling. The white solid was precipitated and filtered and dried to give intermediate 1-p-fluorophenyl-4, 4, 4-trifluorobutanedione; The mass of the product 1-p-fluorophenyl-4, 4, 4-trifluorobutanedione was 51.245 g. Yield: 73.00%.2.1) 100 mL of toluene and absolute ethanol (16.56 g, 0.36 mol) were placed in a vessel to give mixture B;2.2) The chopped metal sodium (8.28 g, 0.36 mol)Placed in a container containing the mixture B, Stir to the container to appear white powder, And the sodium is left behind, the container is placed under cooling conditions;2.3) A solution of p-fluoroacetophenone (41.4 g, 0.3 mol)And ethyl trifluoroacetate (51.12 g, 0.36 mol) were placed in a vessel, To obtain a mixture C;2.4) Place the container in an electric heating device, In the 30-minute range gradually heated to 60C , After 6 hours of reaction, Vacuum distillation, extraction, washing, The organic phase was combined and the drying was carried out to give the mixture D;The extraction is referred to as using ethyl acetate, And the extraction process was repeated 3 times;The washing process is repeated twiceThe drying process is carried out using anhydrous sodium sulfate.2.5) The mixture D was subjected to distillation under reduced pressure and allowed to stand under cooling conditions, Precipitate the white solid after filtration, dry, To give intermediate 2.1) 100 mL of toluene and absolute ethanol (16.56 g, 0.36 mol) were placed in a vessel to give mixture B;2.2) The chopped metal sodium (8.28 g, 0.36 mol) was placed in a vessel containing the mixture B, stirred to a white powder in the vessel and left without sodium. The vessel was placed under cooling conditions;2.3) A mixture of p-fluoroacetophenone (41.4 g, 0.3 mol) and ethyl trifluoroacetate (51.12 g, 0.36 mol) was placed in a vessel to give a mixture C;2.4) The container was placed in an electric heating device and gradually heated to 60 C over a period of 30 minutes, After 6 hours of reaction, Carrying out vacuum distillation, extracting, washing with water, combining the organic phase and drying to obtain the mixture D; the extraction is referred to as using ethyl acetate, And the extraction process was repeated 3 times;The washing process is repeated twiceThe drying process is carried out using anhydrous sodium sulfate.2.5) The mixture D was subjected to distillation under reduced pressure and allowed to stand under cooling. The white solid was precipitated and filtered, driedTo give the intermediate 1-p-fluorophenyl-4, 4, 4-trifluorobutanedione;The mass of the product 1-p-fluorophenyl-4, 4, 4-trifluorobutanedione was 51.245 g.Yield: 73.00%.2.1) Place 100 mL of toluene and absolute ethanol (16.56 g, 0.36 mol) in a vessel to obtain a mixture B1;2.2) Chopped sodium metal (8.28 g, 0.36 mol) was placed in a vessel filled with mixture B1, stirred into a vesselIn the white powder appears, and no sodium surplus, the container is placed under cooling conditions;2.3) P-fluoroacetophenone (41.4 g, 0.3 mol) and ethyl trifluoroacetate (51.12 g, 0.36 mol) were placed in a vesselTo obtain a mixture C1;2.4) The container is placed in an electric heating device, gradually warmed to 60 C within 30 minutes, and after 6 hours of reactionVacuum distillation, extraction, washed with water, the combined organic phase, the drying process to obtain a mixture D1;The extraction was referred to as extraction with ethyl acetate, and the extraction process was repeated 3 times; the washing process was repeated 2Times; the drying process is drying with anhydrous sodium sulfate.2.5) After the mixture D1 was distilled under reduced pressure and allowed to stand under cooling, the white solid was precipitated, filtered, driedDrying to give the intermediate 1-p-fluorophenyl-4, 4, 4-trifluorobutane dione;The mass of 1-p-fluorophenyl-4, 4, 4-trifluorobuten dione was 51.245 g. Yield: 73.00%.2.1) 100 mL of toluene and absolute ethanol (16.56 g, 0.36 mol) were placed in a vessel to obtain a mixture B;2.2) Chopped sodium metal (8.28 g, 0.36 mol) was placed in a vessel with mixture B and stirred into the vesselAfter a white powder appears and there is no sodium remaining, the container is placed under cooling conditions;2.3) P-fluoroacetophenone (41.4 g, 0.3 mol) and ethyl trifluoroacetate (51.12 g, 0.36 mol) were placed in a vesselTo obtain a mixture C;2.4) The container is placed in an electric heating device, gradually warmed to 60 C within 30 minutes, and after 6 hours of reactionLine vacuum distillation, extraction, washing, combined organic phase, the drying process, to obtain a mixture D;The extraction was referred to as extraction with ethyl acetate, and the extraction process was repeated 3 times; the washing process was repeated 2Times; the drying process is drying with anhydrous sodium sulfate.2.5) After the mixture D was distilled under reduced pressure and allowed to stand under cooling, the white solid precipitated, filtered and driedDrying to give the intermediate 1-p-fluorophenyl-4, 4, 4-trifluorobutane dione;The mass of 1-p-fluorophenyl-4, 4, 4-trifluorobuten dione was 51.245 g. Yield: 73.00%.General procedure: 4-Methoxyacetophenone (3.0 g, 20 mmol) and sodium methoxide (2.16 g, 40 mmol) were added into 80 ml dry benzene, and the mixture was stirred for 15 min. To this mixture ethyl trifluoroacetate (5 ml, 42 mmol) was added dropwise, and then stirred at 50 C for 8 h. The resulting mixture was cooled to the room temperature and acidified with dilute hydrochloric acid. The organic layer was collected, washed with a saturated NaHCO3 solution and dried over anhydrous MgSO4. The organic solvent was removed by rotary evaporation. The residuewas recrystallized with ethanol to give the light yellow crystal TMPD in yield 70%.Ethyl trifluoroacetate (2.35 g, 1.66 mmol) was placed in a 50 mL round bottom flask, and dissolved in methyl tert-butyl ether (7.5 mL). To the stirred solution was added 25 weight % sodium methoxide (4.0 mL, 17.7 mmol) via an addition funnel over a 2 minute period. Next, 4'-fluoroacetophenone (2.1 g, 15 mmol) was dissolved in methyl tert-butyl ether (2 mL), and added to the reaction dropwise over 5 minutes. After stirring overnight (15.75 hours), 3N HCl (7.0 mL) was added. The organic layer was collected, washed with brine (7.5 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 3.2 g of pale-orange solid. The solid was recrystallized from iso-octane to give 2.05 g of the dione.General procedure: To a freshly prepared sodium methylate solution in methanol and THF ethyl trifluoroacetate (1.2 equiv) was added under stirring at 0 followed by addition of ketone 2 (1.0 equiv). The reaction mixture was allowed to stir for additional 3-24 h until the starting materials were consumed, as determined by thin-layer chromatography (TLC). Then the solvent was removed under reduced pressure and the residue was acidified with hydrochloric acid (1 N), followed by extracted with acetic ether. The combined organic layers were dried (MgSO4), Fitered and the filtrate was concentrated under reduced pressure. The crude product was puried by column chromatography. Yield: 40-90%. For some cases, the crude products can be straight used for step c without the column chromatography procedure.General procedure: Referring to Scheme 1, to the appropriate acetophenone derivative (0.05 mol) and ethyltrifluoroacetate (0.075 mol) in methanol (20 mL), sodium methoxide solution (0.1 mol of Na + 15 mL ofCH3OH) was added dropwise at room temperature, and the mixture was refluxed for 2 h. After themethanol was evaporated under vacuum, the residue was dissolved in ethyl acetate (50 mL), washedwith 5% HCl (25 mL) and water (25 mL), and dried over sodium sulfate. After the solvent wasevaporated under vacuum, the corresponding compound II was obtained.General procedure: Sodium (1.5equiv) was dissolved under inert conditions in 3-5ml absolute ethanol, and ethyl trifluoroacetate (2equiv) (diluted in absolute ethanol) was added. Afterwards, a suitable acetophenone (1equiv), dissolved in absolute ethanol, was added. The reaction mixture was heated under reflux conditions overnight and cooled to room temperature. Quenching was performed using hydrochloride acid (1N), and the mixture was stirred for 15min. After extraction with ethyl acetate, the combined organic phases were washed with brine. The organic layer was dried over MgSO4, filtrated and the solvent was removed under reduced pressure. The greasy residue was used without any further purification.To a stirred solution of 4-fluoroacetophenone (1.02 g, 7.38 mmol) in anhydrous THF (10 mL) was added sodium hydride (60% w/w, 886 mg, 22.15 mmol) portion wise at RT. The mixture was stirred for 30 min, to it was added ethyl acetate (3.0 mL, 29.5 mmol) and it was further stirred at 40 C for 3 h. The mixture was cooled to RT, quenched with IN HC1 and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound obtained was purified by silica gel column chromatography to yield 813 mg of the desired product; 1H NMR (300 MHz, CDC13) delta 2.19 (s, 3H), 6.13 (s, 1H), 7.12 (t, = 8.4 Hz, 2H), 7.89 (t, = 5.4 Hz, 2H), 16.16 (br s, 1H).General procedure: P-fluoroacetophenone (0.69 g, 5 mmol) or p-bromoacetophenone (0.99 g, 5 mmol) and ethyl trifluoroacetate (1.42 g, 10 mmol) were placed in a 50 mL round bottom flask and placed in an ice bath. 30 mL of anhydrous tetrahydrofuran was added, followed by taking (0.69 g, 30 mmol) of sodium, and cutting into fine sodium scraps, slowly adding them to a round bottom flask, and stirring, overnight. Check for residual sodium and, if any, pour the reaction into absolute ethanol to completely remove residual sodium. If there is no residual sodium beads, dilute all the solvent under reduced pressure, add 20mL of water, then add hydrochloric acid solution to acidify to pH = 2 ~ 3, then add 50mL CH2Cl2, wash with water (30mL × 3), saturated brine (30mL × 2) The organic layer was dried over anhydrous Na2SO4 . The CH2Cl 2 was distilled off, and column chromatography was carried out using petroleum ether: ethyl acetate = 10:1, 10:1 (Rf = 0.3) as eluent, respectively, to obtain red solid 4 and white solid 7 respectively, yield 80%.General procedure: To a tetrahydrofuran solution of acetophenones (100mmol) was added NaH (200mmol), and the mixture was stirred for 5min. Ethyl trifluoroacetate (250mmol) was then added. The reaction mixture was stirred at room temperature for 4h and neutralized with 2N HCl. The precipitate formed was collected, washed with methanol and dried, which was directly used for the next step without further purification.General procedure: A mixture of 1, 3-dione adducts (0.05mol) with selected substituted phenylhydrazines (0.06mol) in ethanol or N, N-Dimethylformamide (DMF) (200ml) was refluxed for 8h. Water was then added after the reaction mixture was cooled down to room temperature. The resulting precipitate was collected and recrystallized from methanol to give target compounds.General procedure: 1-(40-Chlorophenyl)-4, 4, 4-trifluorobutane-1, 3-dione (150.0 mg, 0.60 mmol), 40-methoxybenzaldehyde (73.0 mL, 0.60 mmol) andurea (108.0 mg, 1.80 mmol) were added to ethanol (2.0 mL), followedby the addition of CeCl37H2O (25 mol%). The reactionmixture was refluxed at 65 C for 3 h. The mixture was allowed tocool to room temperature and poured into crushed ice, stirred for10 min, filtered, washed with cold water and air dried. The solidobtained was recrystallized from hot ethanol to obtain the pureproduct.General procedure: 1-(40-Chlorophenyl)-4, 4, 4-trifluorobutane-1, 3-dione (150.0 mg, 0.60 mmol), 40-methoxybenzaldehyde (73.0 mL, 0.60 mmol) andurea (108.0 mg, 1.80 mmol) were added to ethanol (2.0 mL), followedby the addition of CeCl37H2O (25 mol%). The reactionmixture was refluxed at 65 C for 3 h. The mixture was allowed tocool to room temperature and poured into crushed ice, stirred for10 min, filtered, washed with cold water and air dried. The solidobtained was recrystallized from hot ethanol to obtain the pureproduct.

Molecular Weight:234.15
XLogP3:2.7
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:3
Exact Mass:234.03039208
Monoisotopic Mass:234.03039208
Topological Polar Surface Area:34.1
Heavy Atom Count:16
Complexity:277
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes