Sodium Hydroxide → HCID 11857362, compound

2-(Trifluoromethyl)benzyl bromide (0.50 mmol) was dissolved in dioxane (3 mL) and a 0.16 M stock solution of 3-mercapto-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-propionic acid (4.7 mL, 0.75 mmol) in 1.0 M aqueous sodium hydroxide/0.032 M tris(2-carboxyethyl)phosphine hydrochloride was added. After stirring overnight, the reaction mixture was concentrated to half the volume and then diluted with water and washed with heptane. Ethyl acetate (5 mL) was added and the two phase mixture was placed in an ice/water bath and the pH was adjusted to 3 with 3.0 M hydrochloric acid. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The residue was dissolved in DMF (2 mL) and 1-aminocyclopropanecarbonitrile hydrochloride (64 mg, 0.54 mmol), DIPEA (260 μL, 1.5 mmol), HATU (191 mg, 0.50 mmol) were added and the reaction mixture was stirred overnight. After concentrating the residue was dissolved in EtOAc and washed with 1.0 M KHSO4, saturated NaHCO3, and brine and dried over anhydrous MgSO4. Solvent was removed and the residue was dissolved in acetonitrile (3 mL) and a 0.50 M aqueous solution of Oxone™ (1.5 mL, 0.75 mmol) was added. After stirring overnight, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (55 mg) as a white solid mixture of diastereomers in 80% de (1S,2R)>(1R,2R). (compound 35), LC-MS: 552 (M+1), 551 (M−1), 574 (M+23), 1H-NMR (DMSO): 0.80 (m, 1H), 1.05 (m, 1H), 1.38 (m, 2H), 3.38 (m, 1H), 3.68 (m, 2H), 3.80 (m, 1H), 4.40 (m, 1H), 4.88 (q, 2H), 7.25 (t, 2H), 7.47 (dd, 2H), 7.65 (m, 2H), 7.75 (m, 1H), 7.82 (d, 1H), 9.10 (s, 1H).

1. concentrationthe reaction mixture was concentrated to half the volume
2. additiondiluted with water
3. washwashed with heptane
4. additionEthyl acetate (5 mL) was added
5. customthe two phase mixture was placed in an ice/water bath
6. extractionThe aqueous phase was extracted with EtOAc
7. washthe combined organic extracts were washed with brine
8. dry with materialdried over MgSO4
9. concentrationconcentrated
10. dissolutionThe residue was dissolved in DMF (2 mL)
11. stirringthe reaction mixture was stirred overnight
12. concentrationAfter concentrating the residue
13. dissolutionwas dissolved in EtOAc
14. washwashed with 1.0 M KHSO4, saturated NaHCO3, and brine
15. dry with materialdried over anhydrous MgSO4
16. customSolvent was removed
17. dissolutionthe residue was dissolved in acetonitrile (3 mL)
18. additiona 0.50 M aqueous solution of Oxone™ (1.5 mL, 0.75 mmol) was added
19. stirringAfter stirring overnight
20. additionthe reaction mixture was diluted with water
21. extractionextracted with EtOAc
22. washThe combined organic extracts were washed with brine
23. dry with materialdried over anhydrous MgSO4
24. concentrationconcentrated
25. customThe residue was purified by flash chromatography on silica gel
26. customto give

ORD record

ord-31d327e7e71f49cabd96359421c076e1

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07893093B2