Chlorotrimethylsilane → HCID 131729734, compound

Methyl N-(tert-butoxycarbonyl)-2-nitro-5-phenoxy-L-phenylalaninate (91) Freshly distilled DMF (45 mL) was added to Zn powder (20.0 g, 306 mmol) under N2. Trimethylsilyl chloride (8.0 mL, ˜0.2 eq.) was added at RT and the resulting suspension was stirred vigorously for 35 min. The resulting pale orange supernatant was removed via syringe. The activated Zn was washed with DMF (2×30 mL). After removal of the DMF, the activated zinc was dried under vacuum using a heat gun. Methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (37.0 g, 112 mmol) was freshly recrystallized from petroleum ether, dried in vacuo, and dissolved in freshly distilled DMF (93 mL), and the solution was added to the activated zinc at 0° C. After 5 min, the cooling bath was removed. The reaction mixture was stirred for 20 min in a RT water bath, at which time TLC analysis indicated disappearance of the starting iodide. The grayish supernatant was transferred via syringe into a dry flask under N2, and the remaining zinc metal was washed with DMF (20 mL). To the flask containing the combined DMF fractions was added sequentially a solution of 2-bromo-1-nitro-4-phenoxybenzene (90) (30.0 g, 102 mmol) in DMF (18 mL), Pd(OAc)2 (1.1 g, 5.1 mmol), then dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (4.9 g, 10.2 mmol). The resulting brown solution was stirred at RT, and the solution turned red within 1 h. The reaction mixture was maintained at RT for 16 h. The reaction mixture was poured into EtOAc (400 mL), and the resulting suspension was filtered through Celite. The filtrate was washed with water (2×400 mL) and saturated aqueous sodium chloride solution (400 mL), and the separated aqueous phase was washed with EtOAc (2×150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (Gradient: 0% to 25% EtOAc in heptane) to provide the title compound as a pale yellow solid (27.9 g, 66%). LCMS m/z 415.1 (M−1). 1H NMR (500 MHz, CDCl3) δ 1.38 (s, 9H), 3.21 (dd, J=13, 9 Hz, 1H), 3.57 (dd, J=13.3, 5.2 Hz, 1H), 3.73 (s, 3H), 4.65-4.72 (m, 1H), 5.17 (br d, J=8 Hz, 1H), 6.87-6.92 (m, 2H), 7.07-7.10 (m, 2H), 7.24-7.27 (m, 1H), 7.44 (dd, J=7.9, 7.9 Hz, 2H), 8.03 (d, J=8.8 Hz, 1H).

1. customThe resulting pale orange supernatant was removed via syringe
2. washThe activated Zn was washed with DMF (2×30 mL)
3. customAfter removal of the DMF
4. dry with materialthe activated zinc was dried under vacuum
5. customdried in vacuo
6. dissolutiondissolved in freshly distilled DMF (93 mL)
7. additionthe solution was added to the activated zinc at 0° C
8. waitAfter 5 min
9. customthe cooling bath was removed
10. stirringThe reaction mixture was stirred for 20 min in a RT water bath
11. customThe grayish supernatant was transferred via syringe into a dry flask under N2
12. washthe remaining zinc metal was washed with DMF (20 mL)
13. additionTo the flask containing the combined DMF fractions
14. stirringThe resulting brown solution was stirred at RT
15. waitthe solution turned red within 1 h
16. filtrationthe resulting suspension was filtered through Celite
17. washThe filtrate was washed with water (2×400 mL) and saturated aqueous sodium chloride solution (400 mL)
18. washthe separated aqueous phase was washed with EtOAc (2×150 mL)
19. dry with materialThe combined organic extracts were dried over Na2SO4
20. filtrationfiltered
21. concentrationconcentrated in vacuo
22. customThe crude residue was purified by silica gel chromatography (Gradient: 0% to 25% EtOAc in heptane)

ORD record

ord-ece3ba581ae84ed19e20a3a7213c046c

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08183238B2