Hydrochloric Acid → (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol

Temperature

30 °C

To a 500 mL jacketed three neck round bottom flask equipped with an Ace Glass mechanical stirrer (75 mm diameter teflon stirrer blade), and a pH electrode connected to an automatic titrator for pH-controlled addition of base on-demand via a delivery tube into the vessel, was added water (120 mL), triethanolamine (1.8 g) and then hydrochloric acid to adjust the pH to 7.0. Magnesium sulfate was added as a 1M solution (120 μL, 0.12 mmoles, 14.4 mg of MgSO4). The solution was heated to 30° C. with heating fluid circulating through the flask's jacket. Glucose (20 g) was added followed by Na-NADP (120 mg), GDH (0.50 g) and KRED having SEQ ID No. 38 (0.50 g). The pH stat was set to maintain the pH at 7.0±0.1 by the addition of 4N NaOH through the delivery tube. 2′,6′-dichloro-3′-fluoroacetophenone (50 g) was added to start the reaction. The electrode required periodic rinsing to remove enzyme derived material. Additional glucose was added in portions as the reaction proceeded: 10 g at 104 min (after 17.5 mL of 4 N NaOH had been added), 5 g at 275 min (after 35.2 mL of 4 N NaOH had been added), 5 g at 379 min (after 42 mL of 4 N NaOH had been added), and 8 g at 488 min (after 47 mL of 4 N NaOH had been added). The reaction was stopped after 24 hr. Heptane (150 mL) was then added and the mixture was heated to 40° C. for 45 min. After cooling to 30° C. the resulting mixture was poured into a separatory funnel and the majority of the bottom aqueous layer was drained. The top layer, a heptane emulsion, was filtered (350 mL, 85 mm diameter coarse filter) through a celite pad under vacuum. The filter was washed with heptane (150 mL) and the filtrate was transferred to a separatory funnel and the two phases were separated. The heptane phase was concentrated on a rotary vacuum evaporator (˜50° C., ˜150 mmHg increasing to 40 mmHg) to yield (S)-1-[2′,6′-dichloro-3′-fluorophenyl]-ethanol as an oil (47.8 g, 94%) which crystallized upon standing.

1. additiona pH electrode connected to an automatic titrator for pH-controlled addition of base on-demand via a delivery tube into the vessel
2. temperaturewith heating fluid
3. temperatureto maintain the pH at 7.0±0.1
4. customthe reaction
5. washThe electrode required periodic rinsing
6. customto remove enzyme
7. additionAdditional glucose was added in portions as the reaction
8. addition10 g at 104 min (after 17.5 mL of 4 N NaOH had been added), 5 g at 275 min
9. addition(after 35.2 mL of 4 N NaOH had been added), 5 g at 379 min
10. addition(after 42 mL of 4 N NaOH had been added), and 8 g at 488 min
11. addition(after 47 mL of 4 N NaOH had been added)
12. additionHeptane (150 mL) was then added
13. temperaturethe mixture was heated to 40° C. for 45 min
14. temperatureAfter cooling to 30° C. the resulting mixture
15. additionwas poured into a separatory funnel
16. filtrationThe top layer, a heptane emulsion, was filtered
17. filtration(350 mL, 85 mm diameter coarse filter) through a celite pad under vacuum
18. washThe filter was washed with heptane (150 mL)
19. customthe filtrate was transferred to a separatory funnel
20. customthe two phases were separated
21. concentrationThe heptane phase was concentrated on a rotary vacuum evaporator (˜50° C., ˜150 mmHg increasing to 40 mmHg)

ORD record

ord-ed2ade4bb0684f9086fd69b8746d1848

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08852909B2