benzyl N-[(3S)-2,5-dioxooxolan-3-yl]carbamate

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The above illustrated starting compound which is commercially available N-CBZ aspartic acid (205.7 g, 0.77 mol) was added to acetic anhydride (300 ml). This mixture was stirred at 75° C. for 4 hours. The excess acetic anhydride and acetic acid byproduct were distilled from the mixture under reduced pressure and the residue was recrystallised from hot dichloromethane. The product was collected by filtration, washed with hexane and dried at ambient temperature under reduced pressure to give a white fluffy solid. The excess acetic anhydride and acetic acid byproduct were distilled from the mixture under reduced pressure the residue was recrystallised from hot dichloromethane The product was collected by filtration washed with hexane dried at ambient temperature under reduced pressure to give a white fluffy solid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Carbobenzyloxy-L-aspartic anhydride (1 mmol) was dissolved in 50 mL methylene chloride, followed by the addition of 1.05 eq of dodecylamine and 1.1 eq of triethylamine. The reaction was capped to prevent evaporation, and stirred for 12 hours. When no trace of starting material could be detected by thin layer chromatography (TLC) (CH2Cl2, 5% MeOH), the reaction was quenched with 20 mL 1N hydrochloric acid followed by extraction with chloroform (5×). The organic layer was dried over magnesium sulfate, and 7 was obtained as a white solid (yield 97%). The reaction was capped evaporation the reaction was quenched with 20 mL 1N hydrochloric acid followed by extraction with chloroform (5×) The organic layer was dried over magnesium sulfate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Carbobenzyloxy-L-aspartic anhydride (1 mmol) was dissolved in 50 mL methylene chloride, followed by the addition of 1.05 eq of dodecylamine and 1.1 eq of triethylamine. The reaction was capped to prevent evaporation, and stirred for 12 hours. When no trace of starting material could be detected by thin layer chromatography (TLC) (CH2Cl2, 5% MeOH), the reaction was quenched with 20 mL 1N hydrochloric acid followed by extraction with chloroform (5×). The organic layer was dried over magnesium sulfate, and 7 was obtained as a white solid (yield 97%). The reaction was capped evaporation the reaction was quenched with 20 mL 1N hydrochloric acid followed by extraction with chloroform (5×) The organic layer was dried over magnesium sulfate

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The above illustrated starting compound which is commercially available N-CBZ aspartic acid (205.7 g, 0.77 mol) was added to acetic anhydride (300 ml). This mixture was stirred at 75° C. for 4 hours. The excess acetic anhydride and acetic acid byproduct were distilled from the mixture under reduced pressure and the residue was recrystallised from hot dichloromethane. The product was collected by filtration, washed with hexane and dried at ambient temperature under reduced pressure to give a white fluffy solid. The excess acetic anhydride and acetic acid byproduct were distilled from the mixture under reduced pressure the residue was recrystallised from hot dichloromethane The product was collected by filtration washed with hexane dried at ambient temperature under reduced pressure to give a white fluffy solid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 16.0 g N-benzyloxycarbonyl-L-aspartic acid (Z-Asp) in 24 ml toluene, was added 7.7 g of acetic anhydride, and the reaction was continued at room temperature for six hours to form N-benzyloxycarbonyl-L-aspartic anhydride (Z-Asp O).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Carbobenzyloxy-L-aspartic anhydride (1 mmol) was dissolved in 50 mL methylene chloride, followed by the addition of 1.05 eq of dodecylamine and 1.1 eq of triethylamine. The reaction was capped to prevent evaporation, and stirred for 12 hours. When no trace of starting material could be detected by thin layer chromatography (TLC) (CH2Cl2, 5% MeOH), the reaction was quenched with 20 mL 1N hydrochloric acid followed by extraction with chloroform (5×). The organic layer was dried over magnesium sulfate, and 7 was obtained as a white solid (yield 97%). The reaction was capped evaporation the reaction was quenched with 20 mL 1N hydrochloric acid followed by extraction with chloroform (5×) The organic layer was dried over magnesium sulfate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Carbobenzyloxy-L-aspartic anhydride (1 mmol) was dissolved in 50 mL methylene chloride, followed by the addition of 1.05 eq of dodecylamine and 1.1 eq of triethylamine. The reaction was capped to prevent evaporation, and stirred for 12 hours. When no trace of starting material could be detected by thin layer chromatography (TLC) (CH2Cl2, 5% MeOH), the reaction was quenched with 20 mL 1N hydrochloric acid followed by extraction with chloroform (5×). The organic layer was dried over magnesium sulfate, and 7 was obtained as a white solid (yield 97%). The reaction was capped evaporation the reaction was quenched with 20 mL 1N hydrochloric acid followed by extraction with chloroform (5×) The organic layer was dried over magnesium sulfate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-carbobenzyloxy-L-aspartic anhydride (236) (546 mg, 2.19 mmol) and 4-(aminomethyl)benzoic acid hydrochloride (237) (383 mg, 2.53 mmol) was suspended in pyridine (8 mL) and treated with triethylamine (1 mL). The white suspension was stirred at room temperature for 9 h then concentrated under reduced pressure. The residue was dissolved in acetic acid and stirred at 83° C. for 24 h, concentrated, diluted with DCM, washed with an aqueous solution of KHSO4 and H2O then concentrated. The residue was diluted once again with benzene, concentrated and the remaining yellow solid was triturated with MeOH/H2O (1:1) to give title compound 238 (471 mg, 56% yield). then concentrated under reduced pressure The residue was dissolved in acetic acid stirred at 83° C. for 24 h concentrated diluted with DCM washed with an aqueous solution of KHSO4 and H2O then concentrated The residue was diluted once again with benzene concentrated the remaining yellow solid was triturated with MeOH/H2O (1:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 15 mL of ethyl acetate was suspended 5.0 g (18.73 mmol) of N-benzyloxycarbonyl-L-aspartic acid (compound B′). This solution was stirred at room temperature in a nitrogen atmosphere. Thereto was added dropwise 1.76 g of acetyl chloride (98%, 22.48 mmol). The mixture was stirred at 60° C. for 2 hours. After completion of the reaction, 50 mL of toluene and 6 mL of dimethylformamide were added to the reaction mixture. The resultant mixture was heated to 90 to 103° C. to remove 20 mL of volatile ingredients including the ethyl acetate and the excess acetyl chloride by azeotropic distillation. The N-benzyloxycarbonyl-L-aspartic anhydride (compound 1) thus yielded was subjected to the subsequent step without being taken out. To the reaction mixture was added dropwise 2.0 g (18.69 mmol) of benzylamine at 44 to 54° C. Thereafter, a Dean Stark condenser was attached to the reactor, and the reaction mixture was heated with refluxing and stirring for 30 minutes. After the reaction mixture was cooled, 0.36 g (18.95 mmol) of p-toluenesulfonic acid monohydrate was added thereto and this mixture was heated at 110° C. with refluxing for 8 hours to conduct azeotropic dehydration (reaction yield, 80%; optical purity, 94%ee). The resultant reaction mixture was cooled and then, while being kept at 70° C., subjected twice to washing with 10 mL of saturated aqueous sodium hydrogen carbonate solution and then once to washing with 10 mL of saturated aqueous sodium chloride solution, followed by liquid separation each time. Subsequently, the organic layer obtained was heated with refluxing for 30 minutes to conduct azeotropic dehydration and then cooled to cause crystallization. Crystals began to separate out at 65° C. The organic layer was stirred for 1 hour with cooling to 20° C. and then further stirred at 10° C. or lower for 30 minutes. The crystals formed were isolated by filtration, washed with 20 mL of toluene, and then vacuum-dried to obtain 4.64 g of white crystals (13.73 mmol; isolation yield, 71.1%). The solid obtained was ascertained to be (3S)-1-benzyl-3-benzyloxycarbonylaminopyrrolidine-2,5-dione (compound 2′) by 1H-NMR spectroscopy. Analysis by HPLC revealed that this reaction product had a chemical purity of 100% and an optical purity of 100%ee. The mixture was stirred at 60° C. for 2 hours were added to the reaction mixture to remove 20 mL of volatile ingredients the excess acetyl chloride by azeotropic distillation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 24.9 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic acid anhydride in 100.4 g of ethyl acetate were added 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride and 7.6 g (0.055 mole) of potassium carbonate dissolved in 9.3 g of water. The reaction was carried out for 3 hours with stirring at 15°-20 C. Thereafter, 100.4 g of acetic acid and 75.3 g of water was added to the concentrate and the mixture was stirred for one hour at 15°-20.C. Precipitated crystals were filtered, washed and dried to obtain crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester. concentrate the mixture was stirred for one hour at 15°-20.C Precipitated crystals were filtered washed dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 24.9 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic acid anhydride in 100.4 g of acetic acid were added 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride and 7.6 g (0.055 mole) of potassium carbonate. The reaction was carried out for 3 hours with stirring at 15°-20.C. Thereafter 75.3 g of water was added and the mixture was stirred for one hour at 15°-20.C. The precipitated crystals were filtered, washed and dried to obtain crystals of N-benzyloxycarbonyl-α-L-aspartyl-phenylalanine methyl ester. Analysis of HPLC revealed that the crystals had an α-isomer:β-isomer ratio of 99.6:0.4. The yield of the α-isomer was 28.6 g. In the filtrate, 7.2 g of the α-isomer and 6.2 g of the β-isomer were present. The precipitated crystals were filtered washed dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Suitable amount of sample was withdrawn from the uniform reaction mixture thus obtained and dissolved in a methanol solution containing 5% by weight of triethylamine. α- and β-Isomers of N-benzyloxycarbonylcarbobenzoxy-L-aspartic acid methyl ester formed by the reaction of N-benzyloxycarbonyl-L-aspartic anhydride with methanol and residual N-benzyloxycarbonyl-L aspartic acid were determined by high performance liquid chromatography. The content and yield of N-benzyloxycarbonyl-L-aspartic anhydride were calculated from measured values. Results are shown in Table 7. Suitable amount of sample was withdrawn from the uniform reaction mixture thus obtained