Imidazole → (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-6-phenyl-2-(4-pyridin-2-ylbenzyl)hexanoic acid

Temperature

40 °C

A solution of the product of Example 111-8 (250 g, 529 mmol) in N-methylpyrrolidinone (2L) under N2 was treated with milled lithium hydroxide monohydrate (33.3 g, 793.5 mmol, 1.5equivalents) and N,N-(dimethylamino)pyridine (6.5 g, 53 mmol, 0.1 equivalent) and stirred at 40° C. for 10 hrs. The reaction mixture was cooled to about 22° C., treated with imidazole (827.5 g, 12.2 mol, 23 equivalents) over 15 minutes, stirred at 22° C. for 30minutes, cooled to 6° C., and treated with t-butyldimethylsilyl chloride (876.94 g, 5.819 mol, 11 equivalents) over 45 minutes. This mixture was warmed to 22° C., stirred at 20° C. for 1.5 hours, and stirred at 40° C. overnight. The reaction mixture was cooled to 22° C., charged with 1.25 L of distilled water over 10 minutes and mixed for 2 hrs. The reaction mixture was charged with 1.25 L of brine, 1.25 L of ethyl acetate and 1.25 L of heptanes. The aqueous layer was extracted with 1.25 L of ethyl acetate and 1.25 L of heptanes. The combined organic layer was washed with brine (2×1.2 L), concentrated and chased with heptanes (1.4 L). The resulting oil was dissolved in N,N-dimethylformamide (812 mL), partitioned between heptanes (5.25 L) and 10% aqueous K2CO3 (1.25 L). The heptane layer was extracted with 10% K2CO3 (2×400 mL) and N,N-dimethylformamide (260 mL). The combined aqueous layer (DMF/K2CO3) was washed with 4×5L heptanes. The aqueous layer was cooled to 5° C., charged with 2.5L of toluene, adjusted to pH 5 with 5% HCl, and extracted with 1.6 L of toluene. The combined toluene layer was washed with brine (2×1.75 L), and water (2×1.75 L), concentrated to oil and chased with toluene (2×800 mL) to give the title compound. 1H NMR (CDCl3): δ 8.50(m, 1H), 7.5-7.8(m, 4H), 7.0-7.2 (m, 8H), 4.6 (m, 1H), 3.6-4.0(m, 2H), 2.5-2.9(m, 4H), 2.25(s, residual toluene), 1.5-2.0(m, 2H), 1.0-1.3 (s+d, boc), 0.85(s, t-butyl), 0 (m, 6H).

1. temperatureThe reaction mixture was cooled to about 22° C.
2. stirringstirred at 22° C. for 30minutes
3. temperaturecooled to 6° C.
4. temperatureThis mixture was warmed to 22° C.
5. stirringstirred at 20° C. for 1.5 hours
6. stirringstirred at 40° C. overnight
7. temperatureThe reaction mixture was cooled to 22° C.
8. additionmixed for 2 hrs
9. extractionThe aqueous layer was extracted with 1.25 L of ethyl acetate and 1.25 L of heptanes
10. washThe combined organic layer was washed with brine (2×1.2 L)
11. concentrationconcentrated and chased with heptanes (1.4 L)
12. dissolutionThe resulting oil was dissolved in N,N-dimethylformamide (812 mL)
13. custompartitioned between heptanes (5.25 L) and 10% aqueous K2CO3 (1.25 L)
14. extractionThe heptane layer was extracted with 10% K2CO3 (2×400 mL) and N,N-dimethylformamide (260 mL)
15. washThe combined aqueous layer (DMF/K2CO3) was washed with 4×5L heptanes
16. temperatureThe aqueous layer was cooled to 5° C.
17. additioncharged with 2.5L of toluene
18. extractionextracted with 1.6 L of toluene
19. washThe combined toluene layer was washed with brine (2×1.75 L), and water (2×1.75 L)
20. concentrationconcentrated to oil and chased with toluene (2×800 mL)

ORD record

ord-0b592ff13e5a4a35a569c9255092bd34

Source dataset

uspto-grants-2010_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07834043B2