Chlorodifluoromethane → N-Boc-(R)-2-(5-bromo-2-difluoromethoxy-benzyl)-morpholine

HRID 2253006Notes

Reaction equation

[OH-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][O:13][C@H:12]([CH2:16][C:17]2[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=2[OH:24])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.Cl[CH:54]([F:56])[F:55]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:3]([N:10]1[CH2:15][CH2:14][O:13][C@H:12]([CH2:16][C:17]2[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=2[O:24][CH:54]([F:56])[F:55])[CH2:11]1)([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4]

Participants

Conditions

Temperature: 10 °C

Procedure

To a solution of sodium hydroxide (186 mg, 4.64 mmol) in water (1.0 mL) was added tetra n-butylammonium bromide (50 mg, 0.155 mmol) followed by N-Boc-(R)-2-(5-bromo-2-hydroxybenzyl)morpholine (576 mg, 1.55 mmol), example 1, intermediate (a) in dioxane (8.0 mL). The reaction mixture was cooled to 10° C. and chlorodifluoromethane gas passed into the reaction mixture whilst the vessel was stoppered. After 15 mins, the solution was warmed to 23° C. whilst continuing to pass the gas into the solution. After 30 mins, the gas flow was ceased and the reaction stirred for 17 hrs before concentration and partition of the residue between ethyl acetate and water. The crude product was purified by silica gel chromatography, eluting with 10% ethyl acetate/iso-hexane, affording N-Boc-(R)-2-(5-bromo-2-difluoromethoxy-benzyl)-morpholine as an oil (357 mg, 55%).

Workup

temperaturethe solution was warmed to 23° C.
waitAfter 30 mins
custompartition of the residue between ethyl acetate and water
customThe crude product was purified by silica gel chromatography
washeluting with 10% ethyl acetate/iso-hexane

Sources & evidence

ORD record: ord-609eb748caca4404b95ea53e5d5a27ec
Source dataset: uspto-grants-2008_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07323466B2

Reaction notes

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