Benzonitrile, 4-((3aR,4S,6R,6aS,8aS,8bR)-octahydro-4-hydroxy-6-methyl-7-oxo-3a,6-epoxy-3ah-pyrano(2,3,4-cd)isoindol-8(4H)-yl)-2-(trifluoromethyl)- → 4-((1R,2R,4R,5S,8S,12R)-2-hydroxy-2,4-dimethyl-6-oxo-9,13-dioxa-7-azatetracyclo[6.3.1.11,4.05,12]tridec-7-yl)-2-(trifluoromethyl)benzonitrile

HRID 563906Notes

Reaction equation

HRID 563906 reaction equation
[CH3:1][Mg]Br.[OH:4][C@H:5]1[CH2:15][C@@:14]2([CH3:17])[O:16][C@@:6]31[C@@H:18]1[C@@H:10]([N:11]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=4)[C:12](=[O:19])[C@H:13]21)[O:9][CH2:8][CH2:7]3>C1COCC1>[OH:4][C@:5]1([CH3:1])[CH2:15][C@@:14]2([CH3:17])[O:16][C@@:6]31[C@@H:18]1[C@@H:10]([N:11]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:29])([F:30])[F:31])[CH:21]=4)[C:12](=[O:19])[C@H:13]21)[O:9][CH2:8][CH2:7]3

Participants

4

Reactant 2

HCID 59635881Benzonitrile, 4-((3aR,4S,6R,6aS,8aS,8bR)-octahydro-4-hydroxy-6-methyl-7-oxo-3a,6-epoxy-3ah-pyrano(2,3,4-cd)isoindol-8(4H)-yl)-2-(trifluoromethyl)-HCID 178418573HCID 178418573, compound

Product 1

HCID 596358544-((1R,2R,4R,5S,8S,12R)-2-hydroxy-2,4-dimethyl-6-oxo-9,13-dioxa-7-azatetracyclo[6.3.1.11,4.05,12]tridec-7-yl)-2-(trifluoromethyl)benzonitrileYield 22%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Methylmagnesium bromide (3M in ether, 0.476 mL, 1.427 mmol) was added drop wise to a solution of Example 3 (280 mg, 0.714 mmol) in THF (10 mL) at −30° C. The resulting reaction mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 10-100% EtOAc/hexane, Flow rate: 40 mL/min) to give Example 37 (64 mg, 22% yield) as a white solid along with 204 mg of recovered starting material.

Workup

  1. customThe resulting reaction mixture
  2. customThe reaction mixture was quenched with saturated ammonium chloride (10 mL)
  3. extractionextracted with EtOAc (2×20 mL)
  4. dry with materialThe combined organic layers were dried over magnesium sulfate
  5. concentrationconcentrated in vacuo
  6. custompurified by flash chromatography on silica gel using
  7. washan automated ISCO system (40 g column, eluting with 10-100% EtOAc/hexane, Flow rate: 40 mL/min)

Sources & evidence

ORD record
ord-45a4d914953b4f05951ba60aa20cee1d
Source dataset
uspto-grants-2011_11
Patent number
US08067582B2

Reaction notes

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