Tetrahydrofuran → (3S,4R)-3-benzyl-7-bromo-chroman-4-ol

Temperatur

60 °C

A 1M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (6.55 L, 6.55 mol) was added over 20 minutes to a solution of (1R, 2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (1975 g, 5.82 mol) in dimethyl sulfoxide (9.88 L) at ambient temperature. The mixture was slowly heated to 60° C. under aspirator vacuum to displace the tetrahydrofuran from the reaction mixture, and then heated at 60 to 65° C. for 5 hours under aspirator vacuum at which point the reaction was judged to be complete according to thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction mixture was cooled to ambient temperature and quenched by adding water (10 L) followed by 1N aqueous hydrochloric acid (10 L). The resulting tan suspension was filtered, washed with water (2 L), and dissolved in ethyl acetate (12 L). This solution was washed with water (two times 12 L), concentrated to a low volume, dissolved in isopropyl ether (4 L), and concentrated under atmospheric pressure at 50 to 60° C. to 1.0 L, at which point solids began to precipitate. The resulting suspension was cooled to ambient temperature, stirred for 12 hours, concentrated to one-half its volume, cooled to 0 to 5° C., and filtered giving 916 g (49%) of (3S, 4R)-3-benzyl-7-bromo-chroman-4-ol as a white solid. The filtrate was concentrated to a dark oil (906 g), dissolved in isopropyl ether (1.5 L) at reflux, cooled to ambient temperature, stirred, and filtered yielding an additional 82 g of solid. The filtrate was concentrated and chromatographed on silica gel (60-230 mesh) eluting with 3:1 hexanes/ethyl acetate. Product-rich fractions were concentrated and recrystallized from isopropyl etheryielding an additional 82 g of solid. The total yield of (3S, 4R)-3-benzyl-7-bromo-chroman-4-ol was 1080 g (58%): 1H NMR (400 MHz, CDCl3) δ 7.29-7.33 (m, 2H), 7.21-7.25 (m, 1H), 7.15-7.19(m, 3H), 7.06-7.09 (m, 2H), 4.44 (bs, 1H), 4.21 (dd, J=2.6, 11.3 Hz, 1H), 3.97(dd, J=4.5, 11.3 Hz, 1H), 2.68(dd, J=6.5, 13.8 Hz, 1H), 2.51 (dd, J=9.1, 13.8 Hz, 1H), 2.18-2.23 (m, 1H), 1.85 (d, J=4.3 Hz, 1H); IR 3274 (br), 3181 (br), 1598, 1573, 1493, 1480, 1410, 1219, 1070, 1052, 1023, 859, 700 cm−1; mp 143.5-144.0° C.

1. temperatureheated at 60 to 65° C. for 5 hours under aspirator vacuum at which
2. temperatureThe reaction mixture was cooled to ambient temperature
3. customquenched
4. additionby adding water (10 L)
5. filtrationThe resulting tan suspension was filtered
6. washwashed with water (2 L)
7. dissolutiondissolved in ethyl acetate (12 L)
8. washThis solution was washed with water (two times 12 L)
9. concentrationconcentrated to a low volume
10. dissolutiondissolved in isopropyl ether (4 L)
11. concentrationconcentrated under atmospheric pressure at 50 to 60° C. to 1.0 L, at which point solids
12. customto precipitate
13. temperatureThe resulting suspension was cooled to ambient temperature
14. concentrationconcentrated to one-half its volume
15. temperaturecooled to 0 to 5° C.
16. filtrationfiltered

ORD-Eintrag

ord-418d34baa6a54695b1412b651569b3a8

Quelldatensatz

uspto-grants-2001_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06288242B1