Methyl 3-bromobenzoate → HCID 66653196, compound

Temperature

-78 °C

In a 1 L 3-neck flask fitted with thermocouple, addition funnel, and mechanical stirrer, stir a solution of tert-butyl 1-pyrrolidinecarboxylate (42.0 mL, 232.5 mmol) and (−)-sparteine (54.0 mL, 232.7 mmol) in anhydrous MTBE (350 mL) for 10 min at room temperature then cool to −78° C. To this add sec-BuLi (170 mL of a 1.4 M solution in cyclohexane, 238.0 mmol) dropwise via addition funnel directly into the solution over 90 min keeping the temperature <−73° C. Stir the resulting solution at −78° C. for 3 h. Add a solution of ZnCl2 (235.0 mL of a 1M solution in Et2O, 235.0 mmol) to the solution dropwise with rapid stirring keeping the temperature <−70° C. over 1 h. Stir the resulting light suspension at −75° C. for 20 min, warm to 0° C. over 1 h, then to 20° C. over 15 min. Stir the reaction at room temperature for 40 min. Charge the reaction, in the room temperature water bath, with methyl 3-bromobenzoate (43.4 g, 197.8 mmol), palladium(II) acetate (2.61 g, 11.62 mmol) and tri-tert-butyl-phosphonium tetrafluoroborate (4.172 g, 13.95 mmol) all homogenized and in one portion. A thick suspension develops within 5 min accompanied by a mild exotherm. Stir the suspension 24 h at room temperature. Add MTBE (400 mL) to the reaction to facilitate filtration. Add ammonium hydroxide (16 mL) to the reaction and stir at room temperature 2 h. Filter the slurry over a pad of diatomaceous earth (4×10 cm) washing with Et2O (5×300 mL). Concentrate the organic at room temperature to a volume of 1 L then chill to 5° C. Wash the cold filtrate with cold 1M HCl (1 L) then water (2×μL) and brine (300 mL). Extract the aqueous layers with EtOAc (400 mL) and dry the combined organics (Na2SO4) and concentrate at 35° C. The crude product was purified by silica gel chromatography eluting with 100% hexane to 20% EtOAc/hexane. Pool and concentrate fractions containing product in vacuo at 40° C. to give (R)-2-(3-methoxycarbonyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as an oil (49.62 g).

1. customIn a 1 L 3-neck flask fitted with thermocouple, addition funnel, and mechanical stirrer
2. customthe temperature <−73° C
3. stirringwith rapid stirring
4. customthe temperature <−70° C.
5. customover 1 h
6. stirringStir the resulting light suspension at −75° C. for 20 min
7. temperaturewarm to 0° C. over 1 h
8. waitto 20° C. over 15 min
9. stirringStir
10. customthe reaction at room temperature for 40 min
11. additionCharge
12. customthe reaction
13. waitA thick suspension develops within 5 min
14. stirringStir the suspension 24 h at room temperature
15. filtrationfiltration
16. customAdd ammonium hydroxide (16 mL) to the reaction
17. stirringstir at room temperature 2 h
18. filtrationFilter the slurry over a pad of diatomaceous earth (4×10 cm)
19. washwashing with Et2O (5×300 mL)
20. concentrationConcentrate the organic at room temperature to a volume of 1 L
21. temperaturethen chill to 5° C
22. washWash the cold filtrate with cold 1M HCl (1 L)
23. extractionExtract the aqueous layers with EtOAc (400 mL)
24. dry with materialdry the combined organics (Na2SO4)
25. concentrationconcentrate at 35° C
26. customThe crude product was purified by silica gel chromatography
27. washeluting with 100% hexane to 20% EtOAc/hexane
28. concentrationPool and concentrate fractions
29. additioncontaining product in vacuo at 40° C.

ORD record

ord-056f3f86b01d485a84e112c8a14e0fc0

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09079880B2