Diisopropylethylamine → HCID 11857299, compound

3-(Bromomethyl)-5-methylisoxazole (0.5 mmol) was dissolved in acetonitrile (1.5 mL) and a 0.50 M stock solution of 3-mercapto-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethyl-amino]propionic acid (1.5 mL, 0.75 mmol) in 2.0 M aqueous sodium hydroxide was added. After 2 h, water (2 mL) and acetonitrile (2 mL) were added and the two phase mixture was washed with heptane. The heptane extract was discarded and the aqueous phase was placed in an ice/water bath and the pH was adjusted to 3 with 1.0 M aqueous KHSO4. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was dissolved in acetonitrile (3 mL) and 1-aminocyclopropanecarbonitrile hydrochloride (88 mg, 0.74 mmol), DIPEA (390 μL, 2.2 mmol) and HATU (287 mg, 0.75 mmol) were added. After 2 h, the reaction mixture was diluted with and a 0.50 M aqueous solution of Oxone™ (3.0 mL, 1.5 mmol) was added. After stirring the reaction mixture at 50° for 2 h, water (5 mL) was added and the reaction mixture was concentrated to remove acetonitrile. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with 1.0 M aqueous KHSO4, 1:1 water:saturated NaHCO3, and brine, and dried over anhydrous MgSO4. After concentration, the residue through a plug of silica gel using EtOAc eluent and collected all material with Rf>0.5. After concentration the residue was purified by flash chromatography to give title compound (63 mg) as a white solid mixture of diastereomers, 85% de, (1′S,2R)>(1′R,2R). LC-MS: 489 (M+1), 487 (M−1), 511 (M+23). 1H-NMR (DMSO): 0.74 (m, 1H), 1.01 (m, 1H), 1.36 (m, 2H), 2.44 (s, 3H), 3.36 (m, 1H), 3.68 (m, 2H), 3.75 (m, 1H), 4.41 (m, 1H), 4.77 (q, 2H), 6.33 (s, 1H), 7.25 (t, 2H), 7.47 (dd, 2H), 9.04 (s, 1H).

1. washthe two phase mixture was washed with heptane
2. extractionThe heptane extract
3. customthe aqueous phase was placed in an ice/water bath
4. customThe organic phase was separated
5. extractionthe aqueous phase was extracted with EtOAc
6. washThe combined organic extracts were washed with brine
7. dry with materialdried over anhydrous MgSO4
8. concentrationconcentrated
9. dissolutionThe residue was dissolved in acetonitrile (3 mL)
10. waitAfter 2 h
11. additionwas added
12. concentrationthe reaction mixture was concentrated
13. customto remove acetonitrile
14. extractionThe aqueous layer was extracted with EtOAc
15. washthe combined organic extracts were washed with 1.0 M aqueous KHSO4, 1:1 water
16. dry with materialsaturated NaHCO3, and brine, and dried over anhydrous MgSO4
17. concentrationAfter concentration
18. customcollected all material with Rf>0.5
19. concentrationAfter concentration the residue
20. customwas purified by flash chromatography
21. customto give

ORD record

ord-8e409dc6a8874e5ba7a3e3fdd374fe72

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07893093B2