Oxalic Acid → (s)-3-(3-t-Butoxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid t-butyl ester oxalate

In 54.6 cc of acetone was dissolved (2,2-dimethoxyethyl)aminoacetic acid t-butyl ester (6.0 g, 27.7 mmol) and N--Z--Orn(Boc)--OH (10.0 g, 27.7 mmol). To the solution was added, at 15° C. under stirring, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (5.6 g, 29.2 mmol). The mixture was stirred for one hour at room temperature, and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, and washed with a 5% aqueous solution of potassium hydrogen sulfate and a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was concentrated under reduced pressure to give a pale yellow oily substance. This oily substance and p-toluenesulfonic acid 1.0 hydrate (1.04 g, 5.46 mmol) were dissolved in 137 cc of toluene, and the solution was stirred for two hours at 70° C. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and purified by means of silica gel column chromatography (hexane/ethyl acetate=3/2) to give 8.3 g of a pale yellow oily substance. This oily substance (8.3 g, 16.5 mmol) was dissolved in 166 cc of ethyl acetate, to which was added 1.7 g of 10% Pd-C, and then the mixture was stirred for two hours under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was dissolved in 16.6 cc of methanol. To the solution was added oxalic acid 2.0 hydrate (2.1 g, 16.5 mmol), and the mixture was concentrated under reduced pressure. The resulting crystalline product was washed with ethyl acetate to afford 5.1 g (66.8%) of the title compound as white crystals.

1. additionTo the solution was added, at 15° C.
2. stirringThe mixture was stirred for one hour at room temperature
3. concentrationconcentrated under reduced pressure
4. dissolutionThe concentrate was dissolved in ethyl acetate
5. washwashed with a 5% aqueous solution of potassium hydrogen sulfate
6. concentrationThe organic layer was concentrated under reduced pressure
7. customto give a pale yellow oily substance
8. stirringthe solution was stirred for two hours at 70° C
9. extractionextracted with ethyl acetate
10. concentrationThe organic layer was concentrated under reduced pressure
11. custompurified by means of silica gel column chromatography (hexane/ethyl acetate=3/2)
12. customto give 8.3 g of a pale yellow oily substance
13. stirringthe mixture was stirred for two hours under a hydrogen atmosphere
14. filtrationThe catalyst was filtered off
15. dissolutionthe filtrate was dissolved in 16.6 cc of methanol
16. concentrationthe mixture was concentrated under reduced pressure
17. washThe resulting crystalline product was washed with ethyl acetate

ORD record

ord-1667f59929d244b39eb5298938947d12

Source dataset

uspto-grants-1999_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05876756