Pyridine → HCID 89705315, compound

HRID 1478452Notes

Reaction equation

HRID 1478452 reaction equation
[CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([O:21][CH:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:19][C:18](=O)[CH2:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[CH3:31])([CH3:3])[CH3:2].[CH2:32]([Mg]Br)[CH3:33].N1C=CC=CC=1.S(Cl)(Cl)=O>C1COCC1>[CH2:32]([C:18]1[CH2:19][CH:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[O:21][C:14]2([CH2:13][CH2:12][N:11]([C:9]([C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH3:31])[CH:7]=3)=[O:10])[CH2:16][CH2:15]2)[CH:17]=1)[CH3:33]

Participants

6

Reactant 4

HCID 1049PyridineHCID 24386Thionyl ChlorideHCID 89704569HCID 89704569, compoundHCID 178418443HCID 178418443, compound

Product 1

HCID 89705315HCID 89705315, compoundYield 59.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 3-(4-isopropoxy-3-methyl-benzoyl)-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-8-one (148 mg, 0.35 mmol) in THF (1.8 mL) was cooled to 0° C. and treated with ethyl-magnesium bromide (42 μL of 1 M, 0.42 mmol). The reaction mixture was stirred for 2 h and was quenched by the addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was diluted with dichloromethane (2 mL) and treated with pyridine (34 μL, 0.42 mmol). The reaction mixture was cooled to 0° C. and treated with thionyl chloride (28 μL, 0.39 mmol) dropwise. The reaction mixture was stirred for 90 min, quenched with ice-cold water (5 mL), and diluted with CH2Cl2 (80 mL). The mixture was washed with dilute HCl (5%, 2×15 mL), water (2×20 mL), and sodium bicarbonate (5%, 15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified on silica gel utilizing a gradient 50-100% ethyl acetate in hexanes to yield [8-ethyl-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-7-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (90 mg) ESI-MS m/z calc. 434.26, found 435.3 (M+1)+; Retention time: 1.74 minutes (3 min run).

Workup

  1. customwas quenched by the addition of saturated aqueous ammonium chloride
  2. extractionThe mixture was extracted with ethyl acetate (3×100 mL)
  3. washthe combined organics were washed with saturated aqueous sodium chloride
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. additionThe resultant oil was diluted with dichloromethane (2 mL)
  8. stirringThe reaction mixture was stirred for 90 min
  9. customquenched with ice-cold water (5 mL)
  10. additiondiluted with CH2Cl2 (80 mL)
  11. washThe mixture was washed with dilute HCl (5%, 2×15 mL), water (2×20 mL), and sodium bicarbonate (5%, 15 mL)
  12. dry with materialThe organic layer was dried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customThe crude product was purified on silica gel utilizing a gradient 50-100% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-97effcbeda1f4e42b0cc4332020a7d35
Source dataset
uspto-grants-2016_08
Patent number
US09403839B2

Reaction notes

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