tert-Butyl hydroperoxide → [(1S,3S,5S)-3-(Tritylamino)-6-oxabicyclo[3.1.0]hexan-1-yl]methanol

Temperature

-35 °C

A reactor was charged with (+)-diethyl-L-tartrate (2.23 L, 13.0 mol) and methylene chloride (10.5 L). Stirring was started and the mixture was cooled to −30 to −40° C. Titanium (IV) isopropoxide (3.93 L, 13.4 mol) was slowly added while maintaining the internal temperature between −30 to −40° C. A solution of [(4S)-4-(tritylamino)cyclopent-1-en-1-yl]methanol (4.2 kg, 11.8 mol) in methylene chloride (19 L) was slowly added to the reaction mixture, while maintaining the temperature between −30 to −40° C. After stirring for 20 minutes, t-butyl hydroperoxide (5-6 M in decane, 3.3 L, 16.3 mol) was slowly added while maintaining the temperature between −30 to −40° C. Upon completion of the addition, the reaction mixture was analyzed by HPLC, which confirmed the formation of the product and presence of 3% (AUC) of the starting material. The reaction mixture was carefully quenched into a 100-L reactor containing a cold aqueous solution (0 to 5° C.) of iron (II) sulfate heptahydrate (10.5 kg) and tartaric acid (6.3 kg) in DI water (42 L). After stirring for 15 minutes, the organic phase was separated and filtered through a pad of diatomaceous earth. The pad was washed with methylene chloride (2×2 L), and the filtrate was transferred into a 100-L reactor. A cold solution (0 to 5° C.) of solid sodium hydroxide (3.36 kg) in brine (42 L) was slowly added to the gently stirred reaction mixture. After 1 h, the organic phase was separated, dried over anhydrous sodium sulfate, filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give a brown oil. This was purified via silica-gel chromatography using five columns. Each column was performed as follows. A 20 cm diameter glass column was loaded with a slurry of silica gel (5 kg) in 30% ethyl acetate/heptane with 0.5% triethylamine added. Crude product (˜1.2 kg) was adsorbed onto silica gel (1.5 kg) and loaded on the column. Polarity was gradually increased from 30% to 40% ethyl acetate/heptane with 0.5% triethylamine. Combined purified material from all columns afforded the title compound (3.93 kg, 89% yield) as an amber oil. 1H NMR (300 MHz, CDCl3, δ) 7.54-7.50 (m, 5H), 7.32-7.18 (m, 10H), 3.80-3.76 (d, J=12.5 Hz, 1H), 3.65-3.61 (d, J=12.5 Hz, 1H), 3.31 (s, 1H), 3.03-2.92 (m, 1H), 1.77-1.69 (m, 2H) and 1.37-1.13 (m, 2H).

1. temperaturewhile maintaining the internal temperature between −30 to −40° C
2. temperaturewhile maintaining the temperature between −30 to −40° C
3. stirringAfter stirring for 20 minutes
4. temperaturewhile maintaining the temperature between −30 to −40° C
5. additionUpon completion of the addition
6. customThe reaction mixture was carefully quenched into a 100-L reactor
7. additioncontaining a cold aqueous solution (0 to 5° C.) of iron (II) sulfate heptahydrate (10.5 kg) and tartaric acid (6.3 kg) in DI water (42 L)
8. stirringAfter stirring for 15 minutes
9. customthe organic phase was separated
10. filtrationfiltered through a pad of diatomaceous earth
11. washThe pad was washed with methylene chloride (2×2 L)
12. customthe filtrate was transferred into a 100-L reactor
13. additionA cold solution (0 to 5° C.) of solid sodium hydroxide (3.36 kg) in brine (42 L) was slowly added to the gently stirred reaction mixture
14. customthe organic phase was separated
15. dry with materialdried over anhydrous sodium sulfate
16. filtrationfiltered through a pad of diatomaceous earth
17. concentrationconcentrated under reduced pressure
18. customto give a brown oil
19. customThis was purified via silica-gel chromatography
20. additionadded
21. temperaturePolarity was gradually increased from 30% to 40% ethyl acetate/heptane with 0.5% triethylamine
22. customCombined purified material from all columns

ORD record

ord-678d2e7a46394d61b96f84eb585efc73

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08933225B2