Hydrogen Peroxide → HCID 59454532, compound

Example 4 (4.46 kg, 22.0 moles, 92.5% w/w) was mixed in H2O (40 L) at tjacket=30° C. NaOH (2.25 kg, 28.1 moles, 50% w/w) diluted in H2O (6 L) was added at such a rate so tinner remained below 35° C. The charging vessel was rinsed with H2O (1 L). If the pH was not ≧12, more NaOH was charged in the same concentration as previously. Hydrogen peroxide (4.89 kg, 50.3 moles, 35% w/w) was added at a rate to maintain tinner below 35° C. The charging vessel was rinsed with H2O (1 L) and the reaction slurry was left stirring for 0.5-1.0 h. Analysis of a sample on HPLC indicated full conversion at this point using the following gradient method (mobile phase 20-95% B; A: 5% CH3CN in H2O with 0.05% formic acid, B: 95% CH3CN in H2O with 0.05% formic acid, 8 min run) on Chromolith Performance RP-18e, 4.6×100 mm. The reaction mixture was cooled to tjacket=0° C. and left stirring for at least 0.5 h when the temperature was reached. The sodium salt of Example 5 was filtered off and washed with cold H2O (2×7 L). The solid was slurry washed on the filter with NaHSO4×H2O (2.76 kg, 20.0 moles) diluted in H2O (35 L). The slurry was kept stirring at tjacket=0° C. for 1 h. If the pH was not <3.7, it was adjusted with NaHSO4×H2O in H2O. The product was filtered off, washed with cold H2O (3×14 L). Drying under vacuum at 40° C. gave Example 5 (4.0 kg, 18.2 moles, 93.4% w/w), 83% yield. 1H-NMR (DMSO-d6): δ 12.40 (s, 1H), 7.94 (s, 1H), 7.79 (d, 2H, J=8 Hz), 7.32 (s, 1H), 7.23 (d, 2H, J=8 Hz), 2.44 (m, 1H), 1.88 (m, 1H), 1.47 (m, 1H), 1.39 (m, 1H); 13C-NMR (DMSO-d6): δ 173.83, 167.67, 143.94, 132.17, 127.68, 125.73, 25.21, 24.67, 17.11; LC-MS (ESI): m/z 206 (M+1). Rt=2.13 min with analytical method (mobile phase: 5-90% B; A: H2O with 0.1% formic acid, B: CH3CN, 8.6 min run) on Xbridge C18, 3.0×50 mm, 2.5 μm particle size. The product was analyzed on a chiral column with UV-detection using isocratic method (mobile phase: EtOH/Isohexane/TFA (15/85/0.1 v/v/v)) on Kromosil 3-Amycoat, 150×4.6 mm, 3 μm particle size, giving an enantiomeric purity of >99% ee, Rt=13.40 min (isomer 1) and 22.22 min (isomer 2).

1. additionwas added at such a rate so tinner
2. customremained below 35° C
3. washThe charging vessel was rinsed with H2O (1 L)
4. additionwas charged in the same concentration as previously
5. temperatureto maintain tinner below 35° C
6. washThe charging vessel was rinsed with H2O (1 L)
7. waitthe reaction slurry was left
8. customwith 0.05% formic acid, 8 min
9. temperatureThe reaction mixture was cooled
10. custom=0° C.
11. waitleft
12. stirringstirring for at least 0.5 h when the temperature
13. filtrationThe sodium salt of Example 5 was filtered off
14. washwashed with cold H2O (2×7 L)
15. washThe solid was slurry washed on the
16. stirringThe slurry was kept stirring at tjacket=0° C. for 1 h
17. filtrationThe product was filtered off
18. washwashed with cold H2O (3×14 L)
19. customDrying under vacuum at 40° C.
20. customgave Example 5 (4.0 kg, 18.2 moles, 93.4% w/w), 83% yield
21. customgiving an enantiomeric purity of >99% ee, Rt=13.40 min (isomer 1) and 22.22 min (isomer 2)

ORD record

ord-9ad630eae87a4c6d849f9df07a5045fa

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012452B2