oxepane-2,7-dione

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The adipate/acetate of amylopectin potato starch was prepared using a 1:20 mixture. 810 gram dry starch was suspended in water to 39% suspension. The pH was adjusted to 8.5 with a 4.4% (w/w) sodium hydroxide solution and 1.3 ml of 30% of H2O2 solution were added. Then 6 g of 1:20 adipic anhydride reagent was added drop wise keeping the pH at 8.5 with a 4.4% (w/w) sodium hydroxide solution. Afterwards 41 grams of acetic anhydride was added drop wise to a pH 8.5. The acetic anhydride reaction was performed in approx. 1.5 hours. After the acetic anhydride dosage the suspension was stirred for 10 minutes at pH 8.5. Then the suspension was neutralised with sulphuric acid to pH 5.5 and the final product was dewatered, washed and dried using methods known to the art. were added washed dried

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

Procedure: A mixture of 403 mg (3.15 mmol) adipic acid anhydride, 604 mg (2.5 mmol) D-proline-benzyl-ester hydrochloride and 274 ml (2.5 mmol) N-methyl-morpholin in 10 ml dichloromethane was stirred at room temperature for 1 hour. Then 0.5 g polymer bound primary amine (2 meq/g) were added and stirring was continued for 1 hour. After filtration 823 ml (7.5 mmol) N-methyl-morpholin, 338 mg (2.5 mmol) 1-hydroxybenzotriazole, 479 mg (2.5 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 450 mg (2.5 mmol) D-proline-ethyl-ester were added and the mixture was stirred for another 48 hours. Removal of the solvent and chromatography on silicagel with ethylacetate gave 135 mg (12%) (R)-1-[6-[(R)-2-ethoxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid benzyl ester as a light yellow oil, MS m/e (%): 459 (M+H+, 100). stirring was continued for 1 hour were added the mixture was stirred for another 48 hours Removal of the solvent and chromatography on silicagel with ethylacetate

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

Procedure: 100 g adipinic acid and 100 ml acetanhydride were refluxed for 5 hours. The solvent was removed at a rotovap and 100 ml acetonitrile were added to the residue and the mixture was kept in a freezer over night. Then the mixture was fritted and the resulting residue was washed with 50 ml acetonitrile and dried. The solvent was removed at a rotovap and 100 ml acetonitrile were added to the residue the mixture was kept in a freezer over night the resulting residue was washed with 50 ml acetonitrile dried

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

Procedure: The adipate/acetate of amylopectin potato starch was prepared using a 1:20 mixture. 810 gram dry starch was suspended in water to 39% suspension. The pH was adjusted to 8.5 with a 4.4% (w/w) sodium hydroxide solution and 1.3 ml of 30% of H2O2 solution were added. Then 6 g of 1:20 adipic anhydride reagent was added drop wise keeping the pH at 8.5 with a 4.4% (w/w) sodium hydroxide solution. Afterwards 41 grams of acetic anhydride was added drop wise to a pH 8.5. The acetic anhydride reaction was performed in approx. 1.5 hours. After the acetic anhydride dosage the suspension was stirred for 10 minutes at pH 8.5. Then the suspension was neutralised with sulphuric acid to pH 5.5 and the final product was dewatered, washed and dried using methods known to the art. were added washed dried

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

Procedure: The adipate/acetate of amylopectin potato starch was prepared using a 1:20 mixture. 810 gram dry starch was suspended in water to 39% suspension. The pH was adjusted to 8.5 with a 4.4% (w/w) sodium hydroxide solution and 1.3 ml of 30% of H2O2 solution were added. Then 6 g of 1:20 adipic anhydride reagent was added drop wise keeping the pH at 8.5 with a 4.4% (w/w) sodium hydroxide solution. Afterwards 41 grams of acetic anhydride was added drop wise to a pH 8.5. The acetic anhydride reaction was performed in approx. 1.5 hours. After the acetic anhydride dosage the suspension was stirred for 10 minutes at pH 8.5. Then the suspension was neutralised with sulphuric acid to pH 5.5 and the final product was dewatered, washed and dried using methods known to the art. were added washed dried

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Rapamycin 42-ester with adipic acid was prepared by a variation of the method of Example 2. Adipic anhydride was prepared by combining 146 mg adipic acid in 1.0 mL dimethylformamide with 200 μL dicyclohexylcarbodiimide and incubating at room temperature 2 h. 300 μL of the supernatant of this reaction was added to 90 mg rapamycin and 45 mg dimethylaminopyridine dissolved in 200 μL methylene chloride. After 5 min the mixture was centrifuged to sediment precipitated material. The supernatant was partitioned between 3 mL water with 100 μL acetic acid and 2×1 mL methylene chloride. The organic layers were combined, dried with anhydrous sodium sulfate and the solvent evaporated. The residue was dissolved in 1.0 mL methanol and 0.5 mL ethanol, cooled in ice, and precipitated by adding 5 mL water. This was centrifuged, the supernatant discarded and the residue dried in a vacuum desiccator, yielding 78 mg white powder. After 5 min the mixture was centrifuged to sediment precipitated material The supernatant was partitioned between 3 mL water with 100 μL acetic acid and 2×1 mL methylene chloride dried with anhydrous sodium sulfate the solvent evaporated The residue was dissolved in 1.0 mL methanol 0.5 mL ethanol, cooled in ice precipitated by adding 5 mL water the residue dried in a vacuum desiccator