N-Methoxy-N-methylacetamide → methyl 5-acetyl-3-chloro-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-fluorobenzoate

HRID 245404Notes

Reaction equation

[Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[C:11]([N:21]2[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]2)=[C:12]([CH:17]=[CH:18][C:19]=1[F:20])[C:13]([O:15][CH3:16])=[O:14].CON(C)[C:32](=[O:34])[CH3:33]>C1COCC1>[C:32]([C:18]1[C:19]([F:20])=[C:10]([Cl:9])[C:11]([N:21]2[CH2:22][C@H:23]([CH3:28])[O:24][C@H:25]([CH3:27])[CH2:26]2)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:34])[CH3:33]

Participants

Conditions

Temperature: -50 °C

Procedure

To a stirred solution of LDA (3.1 eq) at −50° C. in THF was added methyl 3-chloro-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-fluorobenzoate (Intermediate 47, 1.5 g, 4.96 mmol) in anhydrous THF (10 mL) dropwise and the solution was stirred for 1 h at −50° C. N-methoxy-N-methylacetamide (1.66 g, 14.9 mmol) in THF (5 mL) was added dropwise and stirring was continued for additional 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the residue was purified over silica gel chromatography column using ethyl acetate-pet. ether gradient to obtain the title compound. Yield: 800 mg, (47%)

Workup

stirringstirring
waitwas continued for additional 1 h
customThe reaction mixture was quenched with saturated aqueous ammonium chloride
extractionextracted with ethyl acetate
washThe organic layer was washed with brine
dry with materialdried over anhydrous sodium sulphate
customThe solvent was removed under vacuum
customthe residue was purified over silica gel chromatography column

Sources & evidence

ORD record: ord-0ff46622f7314ddeb952c8d535fefb70
Source dataset: uspto-grants-2014_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08658641B2

Reaction notes

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