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With tetraphosphorus decasulfide; In tetrahydrofuran; at 70 - 75℃; for 4h;Inert atmosphere;
Commercially available trifluoroacetamide(39.9842g, 0.353717 mol) powderStir at room temperature with 400 mL THF in a 1000 mL 2-neck-round flask.Then phosphorous pentasulfide (31.4482 g, 0.141486 mol)Add powder and reflux Flow N2 gas while stirring. At this time to maintain 70 ~ 75 for reflux and stirred for 4 hours. After the reaction is finished,After evaporating the solvent with the rotary evaporator, remove the by-product white solid with THF and then distillation.Through yellow liquid form trifluorothioamide(43.38 g, 95.0%) was obtained.
65%
With Lawessons reagent; In tetrahydrofuran; for 2h;Reflux;
A mixture of Trifluoroacetamide (1.2 g, 10.6 mmol), Lawesson's reagent (2.36 g, 5.84 mmol) and THF (10 mL) was heated at reflux for 2 h.The mixture was concentrated and purified by chromatography to give the sub-title compound (0.89 g, 6.9 mmol, 65 %).
With Lawessons reagent;
In brief, thioamides INT-2a,b required for thiazole synthesis can be prepared by reacting the corresponding amides INT-1a,b with Lawesson's reagent.
With Lawessons reagent; In tetrahydrofuran; for 18h;Heating / reflux;
A solution of 2,2,2 -trifluoroacetamide (7.12 g, 63 mmol) and Lawesson's Reagent (15.3 g, 37.8 mmol) in THF (60 ml) was stirred at reflux for 18 h. The reaction mixture was cooled, ethyl bromopyruvate (8 ml, 63 mmol) added and the reaction refluxed for 18 h. The reaction was cooled, evaporated in vacuo, and the resulting crude material extracted into ethyl acetate and washed with water. The organic fraction was dried over MgSO4 and condensed to give a yellow/orange oil. The oil was purified by flash column chromatography on silica eluting with 15 % ethyl acetate in hexane to provide the title compound as a clear oil (3 g, 21 %). 1H NMR (400 MHz, CDCl3) delta 8.39 (1 H, s), 4.47 (2 H, q, J7.1), 1.42 (3 H, t, J7.2).
With Lawessons reagent; In tetrahydrofuran; for 6h;Reflux;
Intermediate 49Ethyl 2-(trifluoromethyl)-1 ,3-thiazole-4-carboxylate To a solution of 2,2,2-trifluoroacetamide (5g) in THF (50ml) was added Lawesson's reagent (9g) and the mixture heated at reflux for 6h. The mixture was cooled to RT overnight. The solvent was concentrated to a volume of 20ml and this was diluted with DCM (60ml). This solution was purified by chromatography on silica gel (3x50g cartridges) eluting with DCM. The clean fractions were combined and the impure product containing fractions combined. The impure fractions were concentrated to a volume of 20ml and purified by chromatography on silica gel (5Og cartridge) eluting with DCM. All the clean product containing fractions were combined and concentrated in vacuo to give 2,2,2- trifluoroethanethioamide as a dark yellow oil. A portion of this oil (1g) was suspended in anhydrous ethanol (20ml) and bromoethylpyruvate (0.97ml) added. This mixture was heated at reflux for 18h. The mixture was cooled and then poured into water (50ml) and the pH adjusted to -8 by the addition of solid sodium bicarbonate. The ethanol was <n="112"/>removed in vacuo and the resultant aqueous solution extracted with ethyl acetate (3x50ml). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. Purification by chromatography on silica gel (2Og cartridge) eluting with DCM gave the title compound (0.358g) as an orange solid. LC/MS Rt2.83min m/z 226 [MH+]. Method A
Step 1 - Preparation of trifluorothioacetamide: To a 1L 4-neck round bottom flask (RBF), equipped with a mechanical stirrer, nitrogen inlet, addition funnel and thermometer, was charged trifluoroacetamide (56.0 grams (g), 1.0 equiv. 0.495 mole) and 100 g of Lawesson's reagent followed by 500 milliliters (mL) of tetrahydrofuran. The reaction mixture was heated to boiling for 2 hours. The solvent was carefully removed by rotary evaporation to yield 86 g of crude product. This material was distilled by kugelrohr distillation under high vacuum (<1 mm Hg) to afford 54 g of light yellow liquid trifluorothioacetamide (84% yield).
Example 4 :2-(trifluoromethyl)pyrimidine-4,6-diol:; 4.11 g of sodium (178.5 mmoles, 1.05 eq.) were added portionwise to 140 mL of EtOH. After completion of the reaction, 31 mL (204 mmoles, 1.20 eq.) of diethylmalonate were added followed by 15 mL (170.0 mmoles, 1.0 eq.) of 2,2,2-trifluoroacetamide. The mixture was EPO <DP n="27"/>refluxed for 3h. Solvents were removed under reduced pressure and the crude mixture was poured into 115 mL of water. The resulting solution was acidified with aqueous HCI 6N. The resulting precipitate was filtered off, triturated with 50 mL of benzene and dried under vacuum at 40C to give 6.5 g of a white solid.Yield : 21 %LC-MS : Tr = 2.82 min. (88 %) (ES-MS: m/z 181.0 (M+H)) [Column : Nucleosil C-18HD, 4x70 mm, 3μm, gradient CH3CN/H2O/TFA 0.05% : 5-100% CH3CN (6 min.), 100% CH3CN (1.5 min.), flow : 1 mL/min]. 1H-NMR (DMSO-D6, 400 MHz) δ : 6.00 (s, 1H).13C-NMR (DMSO-D6, 100 MHz) δ : 90.6 ; 120.0 (q, J = 259.8 Hz) ; 154.8 (q, J = 32.5 Hz) ;172.2.19F-NMR (DMSO-D6, 377 MHz) δ : -48.6.
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