| 97% |
With sodium methylate In ethanol at 20℃; for 3h; |
General procedure for the synthesis of substituted diketones 3bd(3d as example):
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. 4,4,4-trifluoro-1-phenylbutane-1,3-dione (3b): White crystals;Yield: 97%; m.p. 37e39 C (lit, 38e40 C). 1H NMR (400 MHz,CDCl3): dH 7.96 (m, 2H, ArH), 7.64 (m, 1H, ArH), 7.52 (dd, 3JHH 8.5,3JHH 7.1 Hz, 2H, ArH), 6.58 (s, 1H, C]CH). 13C NMR (101 MHz,Chloroform-d) dC 186.2, 177.4 (q, 2JCF 36.3 Hz), 134.1, 132.9, 129.0(2C), 127.6 (2C), 117.2 (q, 1JCF 283.4 Hz), 92.3 (q, 3JCF 2.1 Hz). |
| 93% |
With potassium <i>tert</i>-butylate In benzene for 15h; Ambient temperature; |
|
| 86% |
Stage #1: acetophenone With sodium hydride In tetrahydrofuran at -5 - 0℃; for 0.5h; Inert atmosphere;
Stage #2: ethyl trifluoroacetate, In tetrahydrofuran at 20℃; for 6h; |
2.1
(1) A 100 mL round bottom flask was charged with 14.9 mmol of acetophenone (Compound 3a)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,Add ice water 30mL dilution,The pH of the solution was adjusted to 6 with 1 mol / L HCl. The extract was extracted three times with 10 mL of ethyl acetate (10 mL x 3). The organic layers were combined and washed with 5 mL of water, dried over anhydrous magnesium sulfate, After the product is dry,Compound 4a (4,4,4- trifluoro-1-phenyl-1,3-butanedione) in 86% yield; |
| 82% |
Stage #1: acetophenone With sodium hydride In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: ethyl trifluoroacetate, In tetrahydrofuran at 0 - 25℃; for 12h; |
|
| 69% |
With potassium <i>tert</i>-butylate In benzene at 10 - 20℃; for 15h; Inert atmosphere; Schlenk technique; |
|
| 60% |
With C2H5O(1-)*HNa In ethanol at 70℃; |
1
General procedure: In a 250 mL round bottom flask the ethyl trifluoroacetate (10.37 g,73.0 mmol) and the suitable ketone (33.0 mmol) were dissolved in a21% solution of EtONa (73.0 mmol) in EtOH. The reaction mixture wasstirred at 70 °C until disappearance (3-4 h) of the ketone spot at TLC(CH2Cl2/MeOH 95/5 v/v). Then the solvent was evaporated, and thesolid residue was dissolved with H2O, acidified with HCl 6 N untilpH 3-4. Then it was extracted with CH2Cl2 (2 × 20 mL), dried overNa2SO4, filtered and evaporated under reduced pressure, to give thecrude reaction product that was purified by chromatography (CH2Cl2/MeOH 95/5 v/v) |
|
With diethyl ether; sodium methylate |
|
|
Stage #1: acetophenone With sodium hydride In N,N-dimethyl-formamide at -5 - 0℃; for 0.5h;
Stage #2: ethyl trifluoroacetate, In N,N-dimethyl-formamide at 20℃; for 5h; |
|
|
With sodium methylate In 1,2-dimethoxyethane at 20℃; |
|
|
With sodium hydride |
|
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With potassium <i>tert</i>-butylate |
|
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With sodium ethanolate In diethyl ether at 20℃; |
|
|
With sodium hydride |
|
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With sodium methylate In tetrahydrofuran; methanol at 0 - 20℃; |
Step a
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. |
|
With sodium methylate In tetrahydrofuran; methanol at 20℃; |
|
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Stage #1: acetophenone With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: ethyl trifluoroacetate, In N,N-dimethyl-formamide at 20℃; |
150.1 Example 150[0507] This example describes the synthesis of 2-(3-(4-chlorophenyl)-5- (trifluoromethyl)- 1H-pyrazol- 1-yl)thiazole-4-carboxylic acid in an embodiment of the invention.
STEP 1: Synthesis of 1 -(3 ,4-difluorophenyl)-4,4,4-trifluorobutane- 1,3 -dione[0508] A stirring solution of 1-(3,4-difluorophenyl)ethanone (3.20 mmol) in DMF (6 ml) was chilled to 0 °C before NaH (3.8 mmol) was added portionwise. The reaction mixture was stirred for 30 minutes at which time ethyl 2,2,2-trifluoroacetate (3.84 mmol) was added and the reaction mixture was allowed to attain rt. Upon completion the reaction was quenched with water the pH was adjusted with 1 N HC1 and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2504, filtered, and concetrated under reduced pressure. The residue was purified directly on silica using gradient elution (5-50 % ethyl acetate in hexanes over 12 CV) to provide a yellow oil. |
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With sodium methylate In methanol for 2h; Reflux; |
General Synthetic Procedure for 4,4,4-Trifluoro-1-phenylbutane-1,3-dione Compounds II
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. |
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With ethanol; sodium Inert atmosphere; Reflux; |
5.2.2 General procedure for the synthesis of 4,4,4-trifluoro-1-arylbutane-1,3-dione
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. |
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With sodium ethanolate In benzene |
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Stage #1: acetophenone With sodium hydride In tetrahydrofuran
Stage #2: ethyl trifluoroacetate, In tetrahydrofuran at 0 - 20℃; for 24h; |
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