* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium tetrahydroborate; In ethanol; dimethyl sulfoxide; at 0 - 35℃; for 4h;
Dimethylsulfoxide 30 mL was added to the 100mL reactor, sodium borohydride 0.95 g, stirring dissolved; then 10 mL of absolute ethanol was added, cooled to below 0 C, a solution of intermediate (IV) was added dropwise (1.56 g of intermediate (IV) dissolved in 30 mL of absolute ethanol), add a clear liquid, then stir for 0.5 hours. The temperature was raised to 35 C and stirred for another 2 hours. Then, 0.95 g of sodium borohydride was added, and the mixture was stirred at 30 to 35 C for 1.5 hours. Control the temperature, dropping concentrated hydrochloric acid, adjust the pH = 5.0 or so, stirring until no bubbles released and then with 20% sodium carbonate solution to adjust the pH = 8.0 or so. The turbidity, filter after taking the filtrate, add methanol 200 mL, vacuum distillation, then add methyl tert-butyl ether, precipitation of solid; then solid after methanol recrystallization, filtration, washing, dried to give 1.23 g of a white solid, yield: 78%.
EXAMPLE 7 Production of 4-hydroxy-pyrrolidin-2-on-1-yl-acetamide (Oxiracetam) 3.5 g (18.8 mmol) of 4-hydroxy-pyrrolidin-2-on-1-yl ethyl acetate was dissolved in 35 ml of ethanol and mixed with 14 g of liquid ammonia. The mixture was stirred (pressure 6 bars) in an autoclave at 50 C. for 16 hours. The reaction mixture was cooled to room temperature and the excess ammonia was removed. The obtained suspension was concentrated by evaporation on a rotary evaporator and dried in a high vacuum. 2.95 g of Oxiracetam (99 percent) was obtained. Other data on the product was: HPLC content: 97.1 percent Melting point: 165 to 167 C.
With ammonium hydroxide;
A solution of 7.1 g. ethyl 2-(4-hydroxypyrrolidin-2-on-1-yl)-acetate and 7.1 ml. ammonium hydroxide (d25 0.90) is stirred at ambient temperature for 15 hours. It is then diluted with 140 ml. acetone and stirred at ambient temperature until the gummy precipitate solidifies to form white crystals. By vacuum filtration and drying, there are obtained 5.1 g. 2-(4-hydroxypyrrolidin-2-on-1-yl)-acetamide; m.p. 160-162 C.; Rf 0.32 (silica gel; eluant acetonitrile:water 4:1 v/v).
22 g
With ammonia; In water; at 20℃; for 18h;
The step (4) to obtain the intermediate IV was added concentrated aqueous ammonia 200ml, stirred at room temperature for 18 hours gussets see raw transShould complete, the reaction was stopped, concentrated to remove water and ammonia, to give a yellow oil which was dissolved in acetone was added an oil, a small amount of seed crystals was added with stirring, to precipitate a solid, small amount of acetone wash bottle wall, -10 C crystals 5 hours, filtered to give the class white crude 24g. Purity 99.3%. The crude product was dissolved in 100ml of water, heated to dissolve, decolorized with charcoal for half an hour, the activated carbon was removed by filtration, cooling and crystallization, 5 C allowed to stand overnight, the next day filtered to give a white solid 22g, purity 99.9%, the content of the single hetero ISF3138 less than 0 ? 04%.
To a stirred solution of docosahexaenoic acid (1.0 eq) in DMF (10.0 vol), DIPEA(3.0 eq) and HATU(1.5 eq) were added at room temperature and stirred for 30.0 minutes, then <strong>[68252-28-8]oxiracetam</strong>, compound- 1 (1.2 eq) was added slowly to it and stirred for 2.0 hrs. Reaction was monitored by TLC. On completion of the reaction, the solvent was removed in vacuo and the crude was diluted with water and extract twice with DCM. The organic layer was washed with water followed by brine and dried over anhydrous Na2S04 and evaporated under reduced pressure to obtain the final product, compound-2 (yield: 75%). Mol. Formula: C28H40N2O4 ; Mol. Wt.: 468.63.
With sodium tetrahydroborate; ammonia; In methanol; at -5 - 20℃; for 4h;
Control the temperature of -5 ~ 5 C, the step 3) obtained by the combination2,4-dioxo-1-pyrrolidinecarboxylate 6.858 was dissolved in 15 ml of methanol, and after the addition of 1.518 sodium borohydride, reaction was carried out.After the end of the adjustment to pH to neutral, filter, the filtrate is concentrated directly in 15mL methanol, the control temperature of 20 C, into the ammonia toSaturated, reacted for 4 h, concentrated to remove the solvent,The residue was recrystallized from acetone to give 4.55 g of the compound 4-hydroxy-2-oxo-1-pyrrolidine acetamide in 71.92% yield, m.p. 166-168 (s).
ethyl 4-(N-(2-acetamido)-N-p-toluenesulfonyl)-3-hydroxybutanoate[ No CAS ]
[ 68252-28-8 ]
Yield
Reaction Conditions
Operation in experiment
87.6%
With methanesulfonic acid; trifluoroacetic acid; In tetrahydrofuran; at 25℃; for 4h;
Method one: Taking compound of formula (II)4-(N-(2-acetamido)-N-p-toluenesulfonyl)-3-hydroxybutyrate ethyl ester 20 g,120 ml of tetrahydrofuran was added to the reactor.Then, trifluoroacetic acid / MeSO3H (1:1) was added dropwise at 25 C for 3 h.Mixture. After the dropwise addition, the reaction was carried out at 25 C for 4 h.After the reaction, the solvent is distilled off.Recrystallization from solvent methanol gave 7.73 g of oxiracetam with a yield of 87.6%.
(2) Will be 9.5 g lactone for 5 g methanol dissolved and added to the 40 g 25% (ammonia mass fraction, the same below) in the ammonia water, thermal insulation 20 - 25 C reaction 12 h, bearingpoint, to evaporate the solvent, adding 20 g acetone crystallization product can 8.90 g, methanol recrystallization, drying to obtain the target product 8.2 g: 4 - hydroxy -2 - oxo -1 - pyrrolidine acetamide molar yield 82.6%, HPLC purity 99.9%.
With sodium hydrogencarbonate; In ethanol; at 80℃; for 12h;
145 g (0.95 mol) of methyl 4-chloro-3hydroxybutyrate (B), 71 g (0.95 mol) of glycinamide and 21 g (0.25 mol) of sodium hydrogencarbonate were added to the reaction flask, and 1 L of ethanol was added. The mixture was heated to reflux at 80 C for 12 h, the heating was stopped, and the reaction mixture was filtered. The filtrate was concentrated to dryness under reduced pressure. The reaction solution was suction filtered, and the filter cake was washed with an appropriate amount of ethanol. After draining, the filter cake was placed in an oven and dried to obtain a compound C of 136 g in a molar yield of 90.7%.In summary, the total yield of the target compound 2-(4-hydroxy-2-oxo-1-pyrrolidinyl)acetamide (C) was 90.7%, and the purity was determined by HPLC to be 99.8%.
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