Morpholine → HCID 68959039, compound

HRID 2378070Notes

Reaction equation

HRID 2378070 reaction equation
N1CCOC[CH2:2]1.C[Mg]Br.C[O:11][C:12]([C:14]1([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[C:18]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:16][CH2:15]1)=O>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[C:32]([Si:29]([CH3:31])([CH3:30])[O:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]2[C:18]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[C:17]([C:14]3([C:12](=[O:11])[CH3:2])[CH2:16][CH2:15]3)[O:21][N:20]=2)=[CH:27][CH:26]=1)([CH3:33])([CH3:34])[CH3:35]

Participants

6

Reactant 3

HCID 8083MorpholineHCID 68957642HCID 68957642, compoundHCID 178418573HCID 178418573, compound

Product 1

HCID 68959039HCID 68959039, compound

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 22635083Tetrahydrofuran tolueneSolvent

Conditions

Temperature
0 °C

Procedure

A solution consisting of morpholine (7.5 mL) in THF (100 mL) is cooled to 0° C. (ice/salt bath) and a solution of methylmagnesium bromide (55 mL of a 1.4 M solution in toluene/THF 3:1 v/v) is added by addition funnel while the temperature is maintained between 0 and 5° C. (over 15 minutes.) The orange reaction mixture is stirred at 0° C. for 30 minutes and subsequently a mixture consisting of 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarboxylic acid methyl ester (12.8 g) in THF (50 mL) is added by addition funnel over 5 minutes. The flask is removed from the ice bath. The reaction mixture is cooled to 0° C. and a solution consisting of methylmagnesium bromide (55 mL of a 1.4 M solution in toluene/THF 3:1 v/v) is added over 10 minutes. After 20 min further methylmagnesium bromide (55 mL of a 1.4 M solution in toluene/THF 3:1 v/v) is added over 10 minutes. The ice bath is removed and the reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is poured into an ice/ammonium chloride solution. The mixture is twice extracted with ethyl acetate and the combined extracts are dried and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with a gradient (1% to 5% ethyl acetate in hexanes) afforded 1-(1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-ethanone (4.8 g); MS (APCI+) m/z 434 (MH+.)

Workup

  1. temperatureis maintained between 0 and 5° C. (over 15 minutes.) The orange reaction mixture
  2. additionis added by addition funnel over 5 minutes
  3. customThe flask is removed from the ice bath
  4. temperatureThe reaction mixture is cooled to 0° C.
  5. additionis added over 10 minutes
  6. additionAfter 20 min further methylmagnesium bromide (55 mL of a 1.4 M solution in toluene/THF 3:1 v/v) is added over 10 minutes
  7. customThe ice bath is removed
  8. temperatureto warm to room temperature overnight
  9. additionThe reaction mixture is poured into an ice/ammonium chloride solution
  10. extractionThe mixture is twice extracted with ethyl acetate
  11. customthe combined extracts are dried
  12. concentrationconcentrated under reduced pressure
  13. customThe concentrate is purified by flash silica gel column chromatography
  14. washElution with a gradient (1% to 5% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-6cb89019b8c2445a8253ad55b1736ce4
Source dataset
uspto-grants-2008_12
Patent number
US07470715B2

Reaction notes

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