2-Bromo-4-fluoroanisole → Tert-butyl 4-(5-fluoro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate

HRID 270035

Reaction equation

C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15].[O:16]1[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:17]1>O1CCCC1.O>[F:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH3:15])=[C:7]([CH2:17][C:18]2([OH:16])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:12]=1

Participants

Conditions

Temperature: 20 °C

Procedure

A solution of iso-propylmagnesium chloride in tetrahydrofuran (2M, 130 ml) was added dropwise over 30 minutes to a stirred solution of 2-bromo-4-fluoroanisole (34.2 ml) in anhydrous tetrahydrofuran (400 ml) at 30° C. under nitrogen. After a further 16 hours at 30° C., copper(I) bromide dimethyl sulphide complex (0.4 g) was added followed by a solution of 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid, 1,1-dimethylethyl ester (56.2 g) in anhydrous tetrahydrofuran (I 10 ml). After a further 3 hours at 30° C., the solution was cooled to 20° C., diluted with water (600 ml) and extracted with tert.-butyl methyl ether (600 ml) then ethyl acetate (600 ml). Combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give crude sub-title compound (86 g) as a solid.

Workup

additioncopper(I) bromide dimethyl sulphide complex (0.4 g) was added
waitAfter a further 3 hours at 30° C.
extractionextracted with tert.-butyl methyl ether (600 ml)
dry with materialCombined organic extracts were dried over anhydrous magnesium sulphate
filtrationfiltered
customevaporated under reduced pressure

Sources & evidence

ORD record: ord-f2ad4b7489a14157a1f0ce36e660c5c1
Source dataset: uspto-grants-2008_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07449475B2

Linked notes

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