Pyrrolidine → 1-(3-Bromo-5-methoxymethoxy-phenyl)-pyrrolidine

Temperature

78 °C

A solution of pyrrolidine (1.66 g, 23.27 mmol), in dry tetrahydrofuran (20 ml) was cooled to −78° C. under argon atmosphere. A solution of n-BuLi (15.5 ml, 1.5 M in hexanes) was added via slow drop-wise addition over 5 minutes. After complete addition the cooling bath was removed and the mixture allowed to warm to ice bath temperature over 30 minutes. A second oven dried flask was charged with 1,3-dibromo-5-methoxymethoxy-benzene (5.74 g, 19.4 mmol) and lithium bromide (1.68 g, 19.4 mmol) and taken up in dry tetrahydrofuran (10 ml). This flask was then cooled to 78° C. under argon. The contents of the first flask (slurry containing the lithio salt of pyrrolidine) was taken up in a syringe with wide bore needle and added via drop-wise addition to the second flask (over 10 minutes). The mixture was allowed to slowly warm to ambient temperature over night. The mixture was quenched via the addition of 1 N HCl (23 ml), saturated aqueous NH4Cl (34 ml) and water (40 ml). Ethyl acetate (80 ml) was added and the material shaken in a separtatory funnel. The ethyl acetate phase was collected and washed with an equal volume of 50% diluted brine solution. The aqueous phases were back extracted with ethyl acetate (2×50 ml), the organics combined, dried (MgSO4), filtered and stripped to provide a yellow remainder. The oil was purified by silica gel chromatography using 4%-8% EtOAc in hexanes as eluant to provide 930 mg of 1-(3-Bromo-5-methoxymethoxy-phenyl)-pyrrolidine as a light yellow mobile oil.

1. additionAfter complete addition the cooling bath
2. customwas removed
3. temperatureto warm to ice bath temperature over 30 minutes
4. customA second oven dried flask
5. customwas taken up in a syringe
6. additionadded via drop-wise addition to the second flask (over 10 minutes)
7. temperatureto slowly warm to ambient temperature over night
8. customThe mixture was quenched via the addition of 1 N HCl (23 ml), saturated aqueous NH4Cl (34 ml) and water (40 ml)
9. additionEthyl acetate (80 ml) was added
10. customThe ethyl acetate phase was collected
11. washwashed with an equal volume of 50% diluted brine solution
12. extractionThe aqueous phases were back extracted with ethyl acetate (2×50 ml)
13. dry with materialdried (MgSO4)
14. filtrationfiltered
15. customto provide a yellow remainder
16. customThe oil was purified by silica gel chromatography

ORD record

ord-60b9e38c19204a0bb1629b926274a9f6

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08008298B2