Phenylmethyl (4S)-2,5-dioxo-4-oxazolidineacetate

Under a argon atmosphere, 4.5 g of β-aspartic acid benzyl ester was added to a 500 mL flask, Add 300 mL of freshly distilled anhydrous ethyl acetate, Refluxed at 90 ° C for 30 min and then 60 mL of freshly distilled ethyl acetate dissolved in 2.7 g of triphosgene was slowly added dropwise with a constant pressure dropping funnel, Continue to reflux at 90 ° C until the solution becomes clear.After the solution becomes clear, The reaction solution was rapidly cooled (30 min) with an ice-salt bath and then washed 3 times with cold saturated sodium bicarbonate solution, The extract was then washed twice with cold saturated sodium chloride solution, Re-extraction liquid separation, The ethyl acetate solution was finally dried at room temperature with anhydrous sodium sulfate for 30 min.filter, After the filtrate was concentrated, With the new steamed anhydrous petroleum ether precipitation.The resulting white solid was filtered by filtration.Recrystallization from a mixture of ethyl acetate petroleum ether, Finally, white needle-like crystals (83percent yield) were obtained.Under a dry inert gas condition, 10 g of γ-benzyl-L-aspartic acid were added into 100 ml of anhydrous tetrahydrofuran, and reacted with 7 g of triphosgene. Petroleum ether was then added for sedimentating, to obtain a solid. After recrystallization and drying, 7.25 g of γ-benzyl-L-aspartic acid-N-carboxylic acid anhydride (BAS-NCA) monomer were finally obtained. Under an inert gas condition, a solution of n-hexyl amine in dimethyl formamide (DMF) was added into a solution of BAS-NCA in DMF, wherein the molar ratio between n-hexyl amine and γ-benzyl-L-aspartic acid-N-carboxylic acid anhydride (BAS-NCA) was 1:250. After the reaction, diethyl ether was added for sedimentating, to obtain a solid after filtration. After drying, a glutamic acid copolymer having a benzyl protecting group and a polymerization degree of 250 was obtained. After the protecting group was removed, a glutamic acid copolymer having a structure of formula (II) and a polymerization degree of 250 was obtained, denoted as P(Asp)10.0 g (0.04 mol, 250 g / mol) of aspartic acid benzyl ester was added into a dry 500 mL round bottomed flask. Under the protection of N2, about 200 mL of freshly distilled ethyl acetate was added and the mixture was stirred at 90 under reflux.Triphosgene (5.4 g, 0.0182 mol, 296.75 g / mol) was dissolved in about 100 mL of freshly distilled ethyl acetate and slowly added dropwise to a round bottomed flask. The reaction was continued at 90 ° C until the solution became clear.After the reaction was completed, it was cooled well in an ice-salt bath and then rapidly washed twice with cold, saturated, sodium bicarbonate solution and extracted to separate fractions; then with cold, saturated sodium chloride solution Twice, extracted and separated, dried over anhydrous magnesium sulfate, filtered, concentrated, and added to the new steamed precipitated petroleum ether.After the white precipitate was filtered, the mixture was recrystallized from a mixture of ethyl acetate and petroleum ether. After the solution was cooled, the white needle crystals were collected finally to be 7.0 g (0.028 mol, 249.22 g / mol).General procedure: A two-necked, round-bottomed flask was charged with the requisite amino acid (1 eq.) and dried under high vacuum at ∼30–40 mTorr for >36 h to remove as much residual moisture as possible. The reaction flask was equipped with a reflux condenser topped with a dual-connection glass adapter, with one end connected to a nitrogen source and the other vented to the top of the fume hood (to properly exhaust the HCl vapors generated). Depending on the reaction scale, either a magnetic stir bar or mechanical paddle stirrer was inserted. Anhydrous THF was added to give an amino acid concentration of 0.4–0.5 M. To the resulting heavy suspension was added neat diphosgene (0.6–1.0 eq.; see Tables 2 and 4) in one portion. The reaction was carefully warmed to 55 °C with an oil bath or left to stir at ambient temperature. The reaction was considered complete when all the solids in the reaction dissolved and 1H NMR analysis of a vacuum-dried 0.3-mL aliquot indicated complete conversion to the product. Once at ambient temperature, the reaction mixture was transferred to a clean and dry round-bottomed flask, and concentrated on a rotary evaporator with the water bath maintained between 25 and 30 °C. Fresh anhydrous THF (∼6–8 mL/g of amino acid) was added to dissolve the material before reconcentrating. The crude product was dissolved in a minimal amount of THF (∼4–6 mL/g of amino acid) and transferred to a large precipitation container. Under a blanket of nitrogen, with vigorous mechanical stirring, heptane (6–8 crude volume) was added over 10–30 min to precipitate. The resulting solid was collected by vacuum filtration, washed with additional heptane (1–2 crude volume), and dried in a vacuum oven at room temperature overnight. Anhydrous DCM (∼8–10 mL/g NCA) was added to the material and stirred for 15–30 min under nitrogen in order to dissolve as much of the crude material as possible. Oven-dried celite with a bed height of 2–4 cm was prepared in a sintered glass Buchner funnel, topped with a Whatman glass microfiber filter, and rinsed with anhydrous DCM before use (taking care to avoid cracks in the bed). The DCM-NCA suspension was filtered through the celite bed and then rinsed through with additional anhydrous DCM (3–5 mL/g of NCA). The clear filtrate was concentrated on a rotary evaporator with the water bath maintained at 25–30 °C. Anhydrous THF (∼6–8 mL/g of NCA) was added to dissolve the product before reconcentrating. The material was dissolved in a minimal amount of THF (∼4–6 mL/g of NCA), precipitated with heptane (6–8 crude volume), and collected/dried using the same method as described for the first precipitation. The final product was packaged under either nitrogen or argon in a container that was then sealed in a FoodSaver heat-seal vacuum bag and stored at 78 °C until use.beta-Benzyl-L-aspartate-N-carboxylic anhydride (BLA-NCA) was dissolved in a mixed solvent of N, N-dimethylformamide (DMF) and dichloromethane, and was then subjected to polymerization reaction with use of butylamine as an initiator, at 40C for two days. After N terminal was acetylated with acetic anhydride, the resultant mixture was subjected to reprecipitation, and then to drying to give poly(beta-benzyl-L-aspartate) (PBLA) polymer. PBLA was dissolved in DMF, and, then, diethylenetriamine in an amount of 50-fold equivalent with regard to benzyl ester was added. The resultant mixture was made to react at 40C for one day. The resultant reaction liquid was added dropwise to an aqueous solution of acetic acid. The resultant solution was put in a dialysis tube, and, thus, dialysis was conducted with use of 0.01 N hydrochloric acid as an outer liquid. After evaporation, freeze drying was conducted to give white powders of poly(N-(2-aminoethyl)-aminoethylaspartamide. Thus obtained polymer (hereinafter referred to also as DET) was a hydrochloride of polymer of the following structural formula wherein n was 98.Polyethylene glycol whose one terminal was methoxy and the other terminal was aminopropyl, and whose average molecular weight was 12, 000 was dissolved in dichloromethane. To the resultant solution, there was added a solution which had been prepared by dissolving BLA-NCA in a mixed solvent of DMF and dichloromethane. The resultant solution was made to react at 40C for two days. Furthermore, N terminal was acetylated with acetic anhydride, and, thus, polyethylene glycol-block-poly(beta-benzyl-L-aspartate) (PEG-PBLA) was obtained. From analysis with NMR, the polymerization degree of PBLA portion was known to be 68. In the following, a block copolymer wherein PEG has a molecular weight of 12, 000, and wherein PBLA portion has a polymerization degree of 68 may be referred to as PEG-PBLA (12-68) (parenthetically mentioned figure 12 stands for molecular weight of 12, 000, and 68 stands for polymerization degree). Thus obtained PEG-PBLA (12-68) was dissolved in benzene, and was then subjected to freeze drying. The freeze-dried product was dissolved in DMF in an atmosphere of argon. To the resultant solution, there was added diethylenetriamine, which had been purified by distillation drying, in an amount of 50-fold equivalent with regard to benzyl ester. The resultant mixture was stirred in argon atmosphere at 40C for 24 hours. The resultant reaction solution was added dropwise to 10 % acetic acid. The resultant solution was dialyzed against 0.1 N hydrochloric acid with use of dialysis membrane having a molecular weight cut off of 3500. The resultant inner liquid was recovered, and was then freeze dried to give white solid of PEG-DET block copolymer in the form of hydrochloride having structural formula (V) below:

Molecular Weight:249.22
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:5
Exact Mass:249.06372245
Monoisotopic Mass:249.06372245
Topological Polar Surface Area:81.7
Heavy Atom Count:18
Complexity:348
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes