1-(4-Methylphenyl)-4,4,4-trifluorobutane-1,3-dione

Pale Yellow Solid

To a 500 mL one-necked flask was added 200 mL of acetonitrile-isopropanol (1: 1), 200 mmol (26.8 mL) of p-methylacetophenone (I), 600 mmol (72 mL) of ethyl trifluoroacetate (II), 360 mmol Diameter of 600nm potassium carbonate, 40 ° C reaction 24h Filtration recovery of potassium carbonate and potassium bicarbonate, high temperature treatment can be reused. Mother liquor distillation, recovery of solvent and unreacted raw materials for the next reaction. Add equal volume of water to the distillation residue, adjust the pH to 6 with 10percent hydrochloric acid, extract with ethyl acetate 4 times, 70mL each time, combine the organic phase, concentrate and freeze to obtain the pale yellow solid product (III) 45.6 G, the yield was 99.08percent.Under nitrogen protection, Separately add methyl tert-butyl ether (3.0 L) and 20 wtpercent sodium ethoxide in ethanol solution (3.55 kg, 10.43 mol), replacing nitrogen 3 times. Control temperature does not exceed 25±5°C, mechanical stirring, Ethyl trifluoroacetate (3) was added in batches (1.27kg, 8.94mol) and p-methylacetophenone (4) (1.0 kg, 7.45 mol). Under nitrogen protection, The control reaction temperature is 25±5°C, mechanical stirring for 24h. TLC detected that the disappearance of the raw materials was completed (developer: petroleum ether/ethyl acetate, volume ratio 1/1). Stop the reaction, the reaction solution was added 5wtpercent hydrochloric acid solution (6.5L) to adjust the pH of 7.0 ~ 8.0, let stand for 15min, Separate the layers and collect the organic phase. The aqueous phase was extracted with ethyl acetate (2.0 L); the organic phases were combined and purified water (8 L) and saturated water were added in order. Wash with brine (5.0 L), dry the organic phase over anhydrous sodium sulfate (1.0 kg), suction filter, and rinse the filter cake with a small amount of ethyl acetate. Concentrate to dryness under reduced pressure at 45 °C to give compound 1 as a red-brown oil. Yield 99.8percent, HPLC purity 98.4percentFollowing the disclosure provided in U. S. Patent No. 5, 760, 068, 4'-Methylacetophenone (5.26 g, 39.2mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried overMgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.Step 1: Preparation of 1- (4-METHYLPHENYL)-4, 4, 4- trifluorobutane-1, 3-dione. [000201] Following the disclosure provided in U. S. Patent No. 5, 760, 068, 4'-Methylacetophenone (5.26 g, 39.2 MMOL) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 MMOL) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 MMOL) ETHYL TRIFLUOROACETATE was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MGS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.Following the disclosure provided in U. S. Patent No. 5, 760, 068, 4'-Methylacetophenone (5.26 g, 39.2 MMOL) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 MMOL) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MGS04, FILTERED and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.Following the disclosure provided in U. S. Patent No. 5, 760, 068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.4'-methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCl was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.4'-methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCl was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.Following the disclosure provided in U. S. Patent No. 5, 760, 068, 4'- Methylacetophenone (5. 26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5. 5 mL (46.2 mmbl) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.Step 1: Step 1: Preparation of 1-(4-methylphenyl)-4, 4, 4-trifluorobutane-1, 3-dione. Following the disclosure provided in U.S. Pat. No. 5, 760, 068, 4'-methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCl was added and the mixture extracted with 4*75 mL ethyl acetate. The extracts were dried over MgSOFollowing the disclosure provided in U. S. Patent No. 5, 760, 068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.(1) To a 100 mL round bottom flask was added 14.9 mmol of 4-methylacetophenone (Compound 3b)Dry THF 30 mL, Cooling to -5 ~ 0 , NaH 0.715 g (29.8 mmol) was added portionwise under nitrogen, Stir at this temperature for 30 min, Was added 3.175 g (22.4 mmol) of ethyl trifluoroacetate, The reaction was stirred at room temperature for 6 h, The solvent was distilled off under reduced pressure, diluted with ice water, The pH of the solution was adjusted to 6 with 1 mol / L HCl, The organic layer was washed with 5 mL of water and dried over anhydrous magnesium sulfate. The solvent was dried and the concentrated product was dried. The organic layer was washed with 5 mL of water, To give compound 4b (4, 4, 4-trifluoro-1- (4-methylphenyl) -1, 3-butanedione) in 89percent yield;25percent sodium methoxide in methanol (51.3 ml, 223.5 mmol) and ethyl trifluoroacetate (24.4 ml, 204.9 mmol) were dissolved in 110 mL methyl tert-butyl ether under N2, at room temperature. 4'-methyl acetophenone (25.0 ml, 186.3 mmol) was added and stirred at room temperature overnight. The reaction was washed with 3M HC1 and dried over magnesium sulfate. The solution was then evaporated and the resulting oil dried under vacuum overnight. The resulting light orange crystalline solid was washed with cold isooctane and dried under vacuum to yield an off white crystalline solid (37.3 g, 87percent yield). LC tWill p-methyl acetophenone (0.67g, 5mmol)Soluble in 20mL dry THF, NaH (0.24 g, 10 mmol) was added at 0°C.Stir for 10 min.Adding ethyl trifluoroacetate under N2 protection(0.9 mL, 7.5 mmol) into the reaction solution, The drop was transferred to room temperature and the reaction was continued for 12 h.After the reaction was completed, it was quenched with saturated aqueous sodium bicarbonate (50 mL).And extracted with ethyl acetate (50 mL x 3).Combine the organic phase, Dry, concentrate.The crude product was purified by column chromatography to give 1 g of a yellow solid.Yield 87.3percent.Intermediate 10: 4, 4, 4-trifluoro-1-(p-tolyl)butane-1, 3-dione To a solution of MeONa prepared from sodium (1.919 g, 83.0 mmol) and methanol (60 mL) was added ethyl 2, 2, 2-trifluoroacetate (ALDRICH, 8.19 ml_, 54.8 mmol) and the reaction was stirred at rt 30 min. Then 1-(p-tolyl)ethanone (ALDRICH, 6.97 mL, 52.2 mmol) was added, the reaction mixture was heated at 60°C overnight. The reaction was checked by LCMS and the end of the reaction was observed. The reaction mixture was concentrated under vacuum and partitioned between sodium carbonate (10percent) 25 mL and DCM (25 mL), the organic layer was separated, dried over NaTo a solution of MeONa prepared from sodium (1.919 g, 83.0 mmol) and methanol (60 mL) was added ethyl 2, 2, 2-trifluoroacetate (ALDRICH, 8.19 mL, 54.8 mmol) and the reaction was stirred at rt 30 min. Then 1-(p-tolyl)ethanone (ALDRICH, 6.97 mL, 52.2 mmol) was added, the reaction mixture was heated at 60° C. overnight. The reaction was checked by LCMS and the end of the reaction was observed. The reaction mixture was concentrated under vacuum and partitioned between sodium carbonate (10percent) 25 mL and DCM (25 mL), the organic layer was separated, dried over NaStep 1: Step 1: Step 1 Step 1 Step 1: Step 1: Sodium metal (6.9g, 0.3mol) and toluene (150 mL) made of an off-white suspension, was added absolute ethanol (20 mL), at 65 ° C for 1 hour, cooled to room temperature. Added p-methylacetophenone (40.2g, 0.3mmol) and ethyl trifluoroacetate (60mL, 0.6mmol), was slowly warmed to 100 ° C for 4 hours. Toluene was evaporated, and the residue was added to a mixture of ice and glacial acetic acid (containing 33percent glacial acetic acid), and extracted four times with ethyl acetate. The combined extracts were washed with water, dried over anhydrous sodium sulfate, the solvent was evaporated to obtain a brown solid 63.5g.To a 0°C coldsolution of 1.01 g (7.53mmol) 4’-methylacetophenon in 20 mL abs. THF 0.36 g (8.94 mmol) sodium hydride (60percent in mineraloil) were added portionwise under argon. After stirring for 30 mintrifluoroacetic acid (1.27 g, 8.94 mmol) was added and stirring was continuedfor 5 h at room temperature. The mixture was added to 50 mL acidified ice-waterand extracted twice with ethyl acetate (50 mL). The combined organic phaseswere washed with water (3 x 50 mL), dried over NaSodium metal (5.76 g, 0.25 mol) was dissolved in methanol (80 ml), then trifluoroacetic acid (22 ml, 0.168 mol) was added at room temperature, followed by dropwise addition of methyl-acetophenone (21.04 g, 0.165 mol). The obtained mixture was stirred at 80 In a 1000 mL three-necked flask, 500 mL of ether was added and 68.0 g (1.0 mol) of sodium ethoxide and 134 g were added with stirring(1.0 mol) p-methylacetophenone, the reaction was heated to 40 ° C, the reaction 6 hours, The solvent was distilled off to give a yellow solid, which was partially dissolved by adding 300 ml of acetonitrile, To the reaction liquid, 230.1 g (1.3 mol)Trifluoroacetyl bromide, and reacted at 50 ° C for 3h. The filtrate was filtered off with suction, and part of the acetonitrile was distilled off to obtain 210g of white solid at -10 ° C, the content was 99.2percent and the yield was 91.2percent.In a 1000 mL three-necked flask, 500 mL of isopropyl ether was added, Under stirring, 81 g (1.5 mol) of sodium methoxide and 134 g (1.0 mol) of p-methylacetophenone were added, The reaction was heated to 30 ° C, reacted for 6 hours, the solvent was distilled off, Add 250ml of m-dichlorobenzene partially dissolved, 127.6g (1.1mol) of trifluoroacetyl fluoride was passed into the reaction solution, and reacted at 40 ° C for 2h. The filtrate was suction filtered to remove some of the m-dichlorobenzene. At 10 ° C, a white solid was obtained 212g, content of 99.0percent, the yield was 92.2percent.In a 1000 mL three-necked flask, 500 mL of isopropyl ether was added and 81 g (1.5 mole) of sodium methoxide and 120.6 g (0.9 mole) of p-methylacetophenone were added with stirring. The reaction was heated to 50 ° C. After 6 hours of reaction, the solvent was distilled off and 250 ml of a toluene portion Dissolved, to the reaction solution was introduced 123g (1mol) trifluoroacetyl chloride, 40 reaction 2h, the filtrate was suction filtered, part of the toluene was distilled off, At -10 ° C, 172 g of a white solid was obtained in an amount of 99.0percent with a yield of 93.0percent.PREPARATIVE General procedure: Step b. A mixture of the 1, 3-diketone from step a (3 mmol, 1 equiv), individual hydrazaine substrates (3.75 mmol, 1.25 equiv), and concentrated HCl (0.4 mL, 1.5 equiv) in ethyl alcohol was refluxed until the reaction completed (monitored with TLC; EtOAc-hexane, 3:7). The resulting mixture was concentrated, diluted with ethyl acetate, and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (EtOAc-hexane, 3:7) to yield pure pyrazole ring derivatives.

A Celecoxib (Celebrex) intermediate

Molecular Weight:230.18
XLogP3:2.9
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:230.05546401
Monoisotopic Mass:230.05546401
Topological Polar Surface Area:34.1
Heavy Atom Count:16
Complexity:275
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes