Benzyl Bromide → 5-Amino-2-(2-aminopropionylamino)-2-difluoromethylpentanoic acid

To a solution of 3.2 g of 2-amino-5-benzyloxycarbonylamino-2-difluoromethylpentanoic acid in 10 ml of 1 M aqueous sodium hydroxide is added at 0° C. simultaneously a solution of tert-butoxycarbonylazide, prepared from 3 g of tert-butoxycarbonylhydrazine, and a solution of 5.5 ml of 2 M aqueous sodium hydroxide. The reaction mixture is stirred overnight then extracted twice with 50 ml of ether. The alkaline aqueous solution is then adjusted to a pH of 2 with hydrochloric acid and extracted with ethylacetate. Usual work-up gives a solid residue which is dissolved in 15 ml of dry dimethylformamide and treated at room temperature with 1.6 g of benzylbromide in the presence of 2 ml of dicyclohexylamine. The reaction mixture is stirred for 14 hours and then the precipitate is filtered off. The filtrate is evaporated under reduced pressure. The resulting residue is partitioned between 100 ml of ethylacetate and water. The organic phase is washed successively with 20 ml of 1 normal aqueous hydrochloric acid, 20 ml of water, 20 ml of 5% aqueous sodium bicarbonate, 20 ml of water and 50 ml of brine then dried over magnesium sulfate. The solvent is evaporated and the residue taken up in 10 ml of trifluoroacetic acid. After 1 hour at room temperature the excess trifluoroacetic acid is stripped off under reduced pressure and the residue is taken up in a saturated solution of sodium bicarbonate and extracted with 50 ml of ether. The ether phase is dried over magnesium sulfate and then added at 0° C. to a solution of N-benzyloxycarbonyl-O-ethoxycarbonylalanine (2 g) in 20 ml of ether. Stirring is continued overnight at room temperature. The solvent is evaporated and the resulting syrupy residue is taken up in glacial acetic acid (20 ml) and hydrogenated over Pd/C 10% (200 mg). After completion of the hydrogen uptake the catalyst is filtered off. The filtrate is concentrated under reduced pressure with toluene and the residue purified by ion exchange chromatography on an acidic resin to give 5-amino-2-(2-aminopropionylamino)-2-difluoromethylpentanoic acid.

1. extractionthen extracted twice with 50 ml of ether
2. extractionextracted with ethylacetate
3. customUsual work-up gives a solid residue which
4. stirringThe reaction mixture is stirred for 14 hours
5. filtrationthe precipitate is filtered off
6. customThe filtrate is evaporated under reduced pressure
7. customThe resulting residue is partitioned between 100 ml of ethylacetate and water
8. washThe organic phase is washed successively with 20 ml of 1 normal aqueous hydrochloric acid, 20 ml of water, 20 ml of 5% aqueous sodium bicarbonate, 20 ml of water and 50 ml of brine
9. dry with materialthen dried over magnesium sulfate
10. customThe solvent is evaporated
11. waitAfter 1 hour at room temperature the excess trifluoroacetic acid is stripped off under reduced pressure
12. extractionextracted with 50 ml of ether
13. dry with materialThe ether phase is dried over magnesium sulfate
14. additionadded at 0° C. to a solution of N-benzyloxycarbonyl-O-ethoxycarbonylalanine (2 g) in 20 ml of ether
15. stirringStirring
16. waitis continued overnight at room temperature
17. customThe solvent is evaporated
18. filtrationAfter completion of the hydrogen uptake the catalyst is filtered off
19. concentrationThe filtrate is concentrated under reduced pressure with toluene
20. customthe residue purified by ion exchange chromatography on an acidic resin

ORDレコード

ord-b44e61b9ce194081a44d7b7036c8e969

出典データセット

uspto-grants-1982_05

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US04330559