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With triethylamine; In 1,4-dioxane; water; at 0 - 20℃; for 2.33333h;
[00223] (Boc)2O (44.7 g, 0.21mol) was added portion-wise over 10 min to a 0 0C solution of compound 19.2 (42 g, 0.19 mol), trimethyl amine (51.9 mL, 0.37 mol), dioxane (140 mL) and water (56 mL). After another 10 min, the ice bath was removed and the reaction mixture was stirred while warming to room temperature for another 2 hours. The reaction mixture was diluted in ethyl acetate (150 mL) and washed with 0.5 N HCl (200 mL x 3). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo giving compound 19.3 (52 g, yield 97%) which was used directly in the next step.
[00222] Acetyl chloride (54.6 mL, 0.75 mol) was added drop- wise into ethanol (316 mL) at 0-5 0C. When the addition was completed, the ice bath was removed and the solution allowed to stir while warming to room temperature for another 30 min. D-aspartic acid 19.1 (25 g, 0.188 <n="77"/>mol) was then added. The reaction mixture was refluxed for 2 hours. The reaction solution was then concentrated in vacuo and placed under high vacuum (0.4 mm Hg) overnight. Compound 19.2 was obtained as a white solid (42 g, 99%) and used directly in the next step.
With thionyl chloride; at 20℃; for 25h;Cooling with ice;
General procedure: AAEs were synthesized using a slight modification of an establishedmethod (Furukawa et al., 2016). Briefly, a suspension of 2.0 g of anamino acid in 20 mL of the required alcohol (e.g., methanol for methylester, ethanol for ethyl ester) was stirred vigorously in an ice bath.Then, thionyl chloride (mole ratio of thionyl chloride: aminoacid=1.5:1) was added dropwise to the slurry, and the mixture waskept on ice for 1 h. The resultant solution was stirred thoroughly for24 h at room temperature (Scheme 1a) and then concentrated underreduced pressure after completion of the reaction. The oily residue wasdissolved in alcohol (10 mL) and the solvent was evaporated underreduced pressure to yield the AAE hydrochloride salt. Then, 10 mL ofdistilled water was added to the solution, followed by neutralizationwith ammonia solution (mole ratio of ammonia: AAE salt=2:1). Diethylether (50 mL) was added, and the solution was stirred for 2 h atroom temperature (Scheme 1b). The organic layer was extracted andconcentrated under reduced pressure to yield the AAE. The yields of allthe synthesized compounds were ?72.0% (Table S1). All the synthesizedcompounds were characterized by 1H and 13C nuclear magneticresonance spectroscopy (NMR) and elemental analysis to check theirstructures and purities.
With ammonia; In diethyl ether; water; at 20℃; for 2h;
General procedure: AAEs were synthesized using a slight modification of an establishedmethod (Furukawa et al., 2016). Briefly, a suspension of 2.0 g of anamino acid in 20 mL of the required alcohol (e.g., methanol for methylester, ethanol for ethyl ester) was stirred vigorously in an ice bath.Then, thionyl chloride (mole ratio of thionyl chloride: aminoacid=1.5:1) was added dropwise to the slurry, and the mixture waskept on ice for 1 h. The resultant solution was stirred thoroughly for24 h at room temperature (Scheme 1a) and then concentrated underreduced pressure after completion of the reaction. The oily residue wasdissolved in alcohol (10 mL) and the solvent was evaporated underreduced pressure to yield the AAE hydrochloride salt. Then, 10 mL ofdistilled water was added to the solution, followed by neutralizationwith ammonia solution (mole ratio of ammonia: AAE salt=2:1). Diethylether (50 mL) was added, and the solution was stirred for 2 h atroom temperature (Scheme 1b). The organic layer was extracted andconcentrated under reduced pressure to yield the AAE. The yields of allthe synthesized compounds were ?72.0% (Table S1). All the synthesizedcompounds were characterized by 1H and 13C nuclear magneticresonance spectroscopy (NMR) and elemental analysis to check theirstructures and purities.
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