Lithium Hydroxide → (2S,4R)-1-(tert-Butoxycarbonyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid

Step (c) 1M borane in THF (10 mL, 10 mmol) followed by boron trifluoride diethyl etherate (1.25 mL, 10 mmol) were added to a solution of (2S,4R)-1-tert-butyl 2-ethyl 4-(4-fluorobenzyl)-5-oxopyrrolidine-1,2-dicarboxylate (1.8 g, 5 mmol) in methylene chloride (20 mL) at 0° C. The reaction was allowed to warm to ambient temperature while stirring for 1 hour. The mixture was cooled to 0° C. and then saturated ammonium chloride (25 mL) was slowly added. Water was added to dissolve precipitated solids and then the mixture was extracted with methylene chloride. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in methanol (15 mL) and then water (5 mL) followed by lithium hydroxide (1.05 g, 25 mmol) were added to the solution. The mixture was stirred at ambient temperature for 1 hour, concentrated under reduced pressure and diluted with water (20 mL). The aqueous solution was partitioned with methyl tert-butyl ether and the aqueous phase was separated, filtered, cooled to 0° C., acidified (pH≦3) with 6N hydrochloric acid and extracted twice with methylene chloride. The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid (1.31 g, 81%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.22-7.18 (m, 2H), 7.03-6.99 (m, 2H), 4.29-4.22 (m, 2H), 3.57-3.50 (m, 1H), 3.07 (dd, J=8.0, 10.4, 1H), 2.68-2.65 (m, 2H), 2.58-2.50 (m, 1H), 2.04-1.97 (m, 2H), 1.44, 1.41 (2 s, 9H); MS (EI) for C17H22FNO4. found 322.1 (M-H)−.

1. temperatureThe mixture was cooled to 0° C.
2. dissolutionto dissolve
3. customprecipitated solids
4. extractionthe mixture was extracted with methylene chloride
5. washThe extract was washed with brine
6. dry with materialdried over anhydrous sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated
9. dissolutionThe residue was dissolved in methanol (15 mL)
10. additionwere added to the solution
11. stirringThe mixture was stirred at ambient temperature for 1 hour
12. concentrationconcentrated under reduced pressure
13. additiondiluted with water (20 mL)
14. customThe aqueous solution was partitioned with methyl tert-butyl ether
15. customthe aqueous phase was separated
16. filtrationfiltered
17. temperaturecooled to 0° C.
18. extractionextracted twice with methylene chloride
19. extractionThe combined extract
20. washwas washed with brine
21. dry with materialdried over anhydrous sodium sulfate
22. filtrationfiltered
23. concentrationconcentrated

ORD record

ord-8e3ceb5cd316407bbd58b2eddaabe531

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08791102B2