Tetrahydrofuran → HCID 11160421, compound

Temperature

-48 °C

To a toluene stream containing methyl (3S)-2-(4-fluorophenyl)-3-hydroxycyclopent-1-enecarboxylate in 21 L toluene was added 12 Liters of dry THF and the reaction mixture was cooled to −48° C. To the cooled solution was added drop-wise over 45 min 3.8 Liters (13.46 mol) of 70% Red-Al in toluene. The reaction mixture was allowed to warm to −25° C. over 2.5 h and was added to a solution of 21 L of 2M NaHSO4. The mixture was stirred for 30 min and the layers separated. The toluene layer was then washed with 15 L of water. The toluene layer was then azeotropically dried (50° C., 25 inHg) to a final volume of 21 L (KF 130 ug/mL) and used in the next step. To the toluene solution was added 820 mL (3.6 mol) of 25 wt % NaOMe in MeOH at 50° C. and the mixture heated to 75° C. for 1 h. The mixture was then cooled to 50° C. and 17 L of water, 1 L of MeOH, and 4.5 L of 6N NaOH was added. The mixture was stirred at 20-25° C. overnight. The layers were separated, and the toluene layer discarded. The aqueous layer was then washed with 15 L of MTBE and the MTBE layer discarded. The aqueous layer was then made acidic with conc. HCl (2.1 L, pH 1). The mixture was extracted with 40 L of IPAC. The IPAC layer containing the product (1.35 kg, 69% assay) was then treated with 500 g of Darco for 30 min at 25° C. and filtered over a pad of solka floc, rinsing the pad with and additional 5 L of IPAC. The IPAC solution was then azeotropically dried (45° C., 25 inHg) to a final volume of 15 L (KF<200) and cooled to 20° C. To the IPAC solution was added 3.04 L of n-heptane and the mixture seeded with 5 g of (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentane-1-carboxylic acid. After a good seed bed had been formed (30 min) the rest of the n-heptane (40.4 L) was added drop-wise over 1 hour. The slurry was cooled to 10° C. and filtered. The cake was washed with 2 L of 5:1 n-heptane/IPAC and then with 1 L of heptane. The cake was then dried under vacuum/N2 sweep at 20-25° C. overnight to provide (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentane-1-carboxylic acid as a colorless solid.

1. temperatureto warm to −25° C. over 2.5 h
2. customthe layers separated
3. washThe toluene layer was then washed with 15 L of water
4. dry with materialThe toluene layer was then azeotropically dried (50° C., 25 inHg) to a final volume of 21 L (KF 130 ug/mL)
5. additionTo the toluene solution was added 820 mL (3.6 mol) of 25 wt % NaOMe in MeOH at 50° C.
6. temperaturethe mixture heated to 75° C. for 1 h
7. temperatureThe mixture was then cooled to 50° C.
8. addition17 L of water, 1 L of MeOH, and 4.5 L of 6N NaOH was added
9. stirringThe mixture was stirred at 20-25° C. overnight
10. customThe layers were separated
11. washThe aqueous layer was then washed with 15 L of MTBE
12. extractionThe mixture was extracted with 40 L of IPAC
13. additionThe IPAC layer containing the product (1.35 kg, 69% assay)
14. additionwas then treated with 500 g of Darco for 30 min at 25° C.
15. filtrationfiltered over a pad of solka floc
16. washrinsing the pad with and additional 5 L of IPAC
17. dry with materialThe IPAC solution was then azeotropically dried (45° C., 25 inHg) to a final volume of 15 L (KF<200)
18. temperaturecooled to 20° C
19. additionTo the IPAC solution was added 3.04 L of n-heptane
20. customAfter a good seed bed had been formed (30 min) the rest of the n-heptane (40.4 L)
21. additionwas added drop-wise over 1 hour
22. temperatureThe slurry was cooled to 10° C.
23. filtrationfiltered
24. washThe cake was washed with 2 L of 5:1 n-heptane/IPAC
25. dry with materialThe cake was then dried under vacuum/N2 sweep at 20-25° C. overnight

ORD record

ord-10b17121d9dc46ba9ff86a02b9f86989

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07893091B2