Sodium Sulfate → Tert-butyl 4-(5-chloro-2-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate

HRID 46310

Reaction equation

Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[C:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].S([O-])(O)(=O)=O.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.CCCCCC>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:26]2([OH:29])[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:28][CH2:27]2)[CH:7]=1

Participants

Conditions

Temperature: -70 °C

Procedure

To a stirred solution of 2-bromo-4-chloroanisole (164 g, 0.74 mol) in tetrahydrofuran (1 L), cooled at −70° C. and under an atmosphere of argon, was added butyl lithium (2.7 M in heptane, 280 ml) over a period of 1 hour. The mixture was stirred for 30 minutes, maintaining the temperature at −70° C., before the addition of N-boc-4-piperidone (145 g, 0.73 mol) in tetrahydrofuran (250 ml) over a period of 1 hour. The reaction temperature was warmed to −40° C. over 2 hours before the addition of sodium hydrogen sulphate (5M aqueous, 160 ml), sodium sulphate (300 g) and hexane (500 ml). The mixture was stirred for 10 hours. The organic layer was decanted, filtered through silica gel (300 g, 63/100 μm) washing with ethyl acetate:hexane (4:6, by volume, 2×400 ml). The filtrate was evaporated in vacuo and the residue recrystallized from ethyl acetate:hexane to afford the title compound as white crystals, 100 g, 39% yield.

Workup

stirringThe mixture was stirred for 10 hours
customThe organic layer was decanted
filtrationfiltered through silica gel (300 g, 63/100 μm)
washwashing with ethyl acetate:hexane (4:6, by volume, 2×400 ml)
customThe filtrate was evaporated in vacuo
customthe residue recrystallized from ethyl acetate

Sources & evidence

ORD record: ord-eee2c5700986480da74e4c1a25da7e63
Source dataset: uspto-grants-2013_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08541588B2

Linked notes

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