1-fluoro-3-[(2-methylpropan-2-yl)oxy]propan-2-ol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 2.5 L 4-necked sulfonation flask equipped with mechanical stirrer, dropping funnel, thermometer and an argon in/outlet, was charged with 141 g (938.8 mmol) 1-tert-butoxy-3-fluoro-propan-2-ol, 400 mL dichloromethane, 30.02 g (357.3 mmol) sodium bicarbonate, 400 mL de-ionized water and 10.68 g (89.78 mmol) potassium bromide. The two-phase system was cooled to 0° C. and 712.1 mg (4.56 mmol) 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) were added. To the resulting light orange mixture were added within 2 h 609.1 g (1.072 mol) sodium hypochlorite solution 13.1% while vigorously stirring whereupon the internal temperature transiently rose to 15° C. The reaction mixture was quenched at 0° C. with 9.71 mL (46.8 mmol) sodium bisulfite solution 38-40% leading to disappearance of the orange color. The phases were separated and the aqueous layer was extracted twice with 350 mL dichloromethane. The combined organic phases were washed with 400 mL brine, dried over sodium sulfate, filtered and evaporated to afford 130.02 g (93.5%) crude 1-tert-butoxy-3-fluoro-propan-2-one of 98.9% GC purity. 1H-NMR (CDCl3, 300 MHz): 5.13 (d, JH,F=48, —CH2—F); 4.15 (d, J=1.5, —CH2—O); 1.22 (s, C(CH3)3). A 2.5 L 4-necked sulfonation flask equipped with mechanical stirrer 712.1 mg (4.56 mmol) 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) were added transiently rose to 15° C The phases were separated the aqueous layer was extracted twice with 350 mL dichloromethane The combined organic phases were washed with 400 mL brine dried over sodium sulfate filtered evaporated

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1.5 L 4-necked sulfonation flask equipped with magnetic stirring bar, reflux condenser, thermometer and an argon in/outlet, was charged with 333.3 mL triethylene glycol, 235.2 g (3.012 mol) finely ground potassium hydrogendifluoride and 200 g (1.536 mol) 2-tert-butoxymethyl-oxirane. The suspension was heated under stirring at an internal temperature of 130° C. for 7.5 h. The mixture was allowed to cool to RT over night, treated with 670 mL water and 350 mL tert-butyl methyl ether, the phases were separated and the aqueous phase was extracted with 350 ml tert-butyl methyl ether. The combined organic phases were washed with 350 mL brine, dried over sodium sulfate, filtered and evaporated. The brown oily residue (286 g) was distilled to provide 141 g (61%) 1-tert-butoxy-3-fluoro-propan-2-ol as colorless liquid, b.p. 80-93° C./70-40 mbar. GC composition: 1.1% 2-tert-butoxymethyl-oxirane, 95.1% 1-tert-butoxy-3-fluoro-propan-2-ol and 3.8% of 3-tert-butoxy-2-fluoro-propan-1-ol. 1H-NMR (CDCl3, 300 MHz): 4.45 (dxm, JH,F=46, —CH2—F); 3.93 (m, br, H—C(2); 3.45 (m, —CH2—O); 2.55 (d, br, J=6, OH); 1.20 (s, C(CH3)3). A 1.5 L 4-necked sulfonation flask equipped with magnetic stirring bar reflux condenser The suspension was heated to cool to RT over night the phases were separated the aqueous phase was extracted with 350 ml tert-butyl methyl ether The combined organic phases were washed with 350 mL brine dried over sodium sulfate filtered evaporated The brown oily residue (286 g) was distilled

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Starting from 2-tert-butoxymethyl-oxirane (5), 4-fluoromethyl-5H-furan-2-one can be prepared according to the method described in scheme 2. In the first step, the oxirane ring is opened with potassium hydrogendifluoride to form 1-tert-butoxy-3-fluoro-propan-2-ol (6) which is then oxidized to the corresponding ketone (7). The oxidation can be carried out according to known methods such as e.g. with sodium hypochlorite in the presence of a catalyst such as 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO). In a next step 1-tert-butoxy-3-fluoro-propan-2-one (7) is reacted with tert-butyl acetate in the presence of a strong base such as lithium diisopropylamine (LDA) to form 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (8) which can be cyclizised to 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9) under strong acidic conditions (e.g. by employing trifluoroacetic acid or sulfuric acid 95%). Preferably, the cyclization is carried out with only a small amount of sulfuric acid 95% (e.g. 0.025 mol equivalent in relation to the educt) in a solvent such as 1,2-dimethoxyethane or dioxane. These two last steps can alternatively be carried out in a one-pot procedure, e.g. without isolating 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (8). In a final step 4-fluoromethyl-5H-furan-2-one (III) is obtained by dehydration of 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9). The dehydration can be performed according to known methods, e.g with acetic anhydride in the presence of an amine base such as triethylamine. Alternative dehydration methods include the use of thionyl chloride in the presence of pyridine or mesyl chloride in the presence of triethylamine. In a further alternative dehydration method, 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9) is reacted with acetic anhydride to form the intermediate 4-acetoxy-fluoromethyl-dihydro-furan-2-one which is then reacted with sodium acetate in de-ionized water to obtain the compound of formula III. can be prepared