Acetic Acid → Sodium (3R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate

A solution of Nα-(tert-butyloxycarbonyl)-D-aspartic anhydride (J. Med. Chem. 1996; 3842) (19 g, 88 mmol) in tetrahydrofuran (150 ml) was added dropwise to an ice-cooled suspension of sodium borohydride (3.4 g, 88 mmol) in tetrahydrofuran (75 ml), and once addition was complete, the mixture was stirred for a further 2 hours. Acetic acid (30 ml) was added dropwise and the mixture then evaporated under reduced pressure. The residue was partitioned between water (150 ml) and ether (150 ml) and 2N hydrochloric acid (20 ml) carefully added. The layers were separated, the aqueous phase further extracted with ether (2×150 ml), and the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. The product was dissolved in 2N sodium hydroxide (50 ml), and the solution stirred for 1 hour. The mixture was washed with ether (2×50 ml), acidified with 2N hydrochloric acid (50 ml) and extracted with dichloromethane (4×100 ml). The combined dichloromethane extracts were dried (MgSO4) and evaporated under reduced pressure. The acid product (7.8 g, 35.6 mmol) was dissolved in methanol (100 ml) sodium hydroxide (1.42 g, 35.6 mmol) added, and the reaction stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure the residue azeotroped with toluene and then triturated with diisopropyl ether to afford the title compound as a white solid, 8.6 g; 1H NMR (DMSOd6, 400 MHz) δ: 1.38 (s, 9H), 2.17 (m, 2H), 3.21–3.50 (m, 3H), 6.74 (d, 1H).

1. temperaturecooled
2. customthe mixture then evaporated under reduced pressure
3. customThe residue was partitioned between water (150 ml) and ether (150 ml) and 2N hydrochloric acid (20 ml)
4. additioncarefully added
5. customThe layers were separated
6. extractionthe aqueous phase further extracted with ether (2×150 ml)
7. dry with materialthe combined organic solutions dried (MgSO4)
8. customevaporated under reduced pressure
9. dissolutionThe product was dissolved in 2N sodium hydroxide (50 ml)
10. stirringthe solution stirred for 1 hour
11. washThe mixture was washed with ether (2×50 ml)
12. extractionextracted with dichloromethane (4×100 ml)
13. dry with materialThe combined dichloromethane extracts were dried (MgSO4)
14. customevaporated under reduced pressure
15. additionadded
16. stirringthe reaction stirred at room temperature for 1 hour
17. customThe mixture was evaporated under reduced pressure the residue
18. customazeotroped with toluene
19. customtriturated with diisopropyl ether

ORD record

ord-f8149d0ad05e4253a70dcc29ad919d01

Source dataset

uspto-grants-2006_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07045653B2