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In N,N-dimethyl-formamide; at 0 - 15℃; for 6h;Inert atmosphere;
To a solution of <strong>[13613-65-5][(3R)-3-hydroxybutanoyl]oxysodium</strong> (3 g, 23.79 mmol, 1 equiv.) in DMF (40 mL) was added bromomethylbenzene (4.48 g, 26.17 mmol, 3.11 mL, 1 .1 equiv.) drop-wise at 0°C under N2.The reaction mixture was warmed to 15°C and stirred at 15°C for 6 h, at which time the residue was poured into water (80 mL). The aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (80 mL), dried over anhydrous Na2504, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate1 :0, 5/1) to afford benzyl (3R)-3-hydroxybutanoate (3.82 g, 19.65 mmol, 82.60percent yield) as white oil.
With water; sodium hydroxide; In methanol; at 15℃; for 12h;Inert atmosphere;
To a mixture of methyl (3R)-3-hydroxybutanoate (20 g) in methanol (133 mL) and H20 (67mL) was added NaOH (8.13 g) in one portion at 15°C under N2. The mixture was stirred at 15 °C for 12 h.The reaction mixture was concentrated under reduced pressure to give [(3R)-3- hydroxybutanoyl]oxysodium (20 g, 93.69percent yield) was obtained as a white solid.
85%
With sodium hydroxide; In water; at 10 - 30℃; for 6h;
In a 500ml three-vial bottle,Methyl (R)-3-hydroxybutyrate (76.0 g) obtained in Example 1 was added and 300 ml of water was added.Control temperature is less than 30 °C,Sodium hydroxide (25.8 g) was slowly added in batches over 3 hours.Control temperature is not higher than 10 °C,After the addition, continue to react for 3 hours.Until the reaction is completed.Add 0.3g of activated carbon,Continue stirring for 0.5 hours,filter,The filtrate was concentrated to 100 ml,At this point, a large amount of solids precipitated.To room temperature,Stir and crystallize for 1 hour,Centrifugation,Vacuum dryingObtained 68.9 g of (R)-3-hydroxybutyrate as a white solid,Yield 85.0percent,The ee value is 91.5percent.
As shown in Scheme 4, sodium [beta] -hydroxybutyrate (1 mol equivalent) was suspended in dry dimethylformamide at a concentration of 0.2 moles. 1-Bromohexane (0.7 mol equivalent) was added, and the reaction vessel was sealed, and It was heated to 60 for 18 hours with stirring, and During that time, the reaction mixture became transparent. Then, it was cooled, and fed to a separatory funnel, and diluted with 1.5 volumes of ethyl acetate (based on reaction volume). This was then washed five times with 0.5 volume of saturated aqueoussodium bicarbonate solution and once with brine. The ethyl acetate layer was then dried over magnesium sulfate, filtered and the solvent was removed by rotary evaporation. The crude product was analyzed by 1 H NMR and GC-MS. Pure (> 95%) of the product was observed, and The major contaminant was 1-bromohexane, and which was further removed by vacuum pumping.
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