Diethyl Ether → (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide

HRID 389403Notes

Reaction equation

HRID 389403 reaction equation
C([Mg]Br)C.CCOCC.[CH:10]1([C:13]#[CH:14])[CH2:12][CH2:11]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@:25]23[C:31]([CH3:33])([CH3:32])[C@@:28]([CH3:34])([CH2:29][CH2:30]2)[C:27](=[O:35])[O:26]3)=[O:24])=[C:18]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])[CH:17]=1>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@:25]23[C:31]([CH3:32])([CH3:33])[C@@:28]([CH3:34])([CH2:29][CH2:30]2)[C:27](=[O:35])[O:26]3)=[O:24])=[C:18]([C@@:36]([OH:41])([C:14]#[C:13][CH:10]2[CH2:12][CH2:11]2)[C:37]([F:38])([F:39])[F:40])[CH:17]=1

Participants

6

Reactant 4

HCID 3283Diethyl EtherHCID 138823CyclopropylacetyleneHCID 66888235(1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-ox abicyclo[2.2.1]heptane-1-carboxamideHCID 178418443HCID 178418443, compound

Product 1

HCID 50916497(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamideYield 99%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

Ethylmagnesium bromide 3M in ether (5.98 mL, 17.95 mmol) was added slowly to a solution of cyclopropyl acetylene (1.19 g, 17.95 mmol) in tetrahydrofuran (18 mL) in an ice-bath under argon and the mixture was stirred at 40° C. for 3 hours. Then (1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (9, 1.45 g, 3.59 mmol) was added in portions while the flask was in an ice-bath. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate and two layers were separated. The organic layer was evaporated to dryness to give 1.67 g of the compound as a crude oil. It was further crystallized with petroleum ether and ethyl acetate to furnish (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut 3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10) as a white or off-white solid. This solid was shown to be 98.8% de by HPLC.

Workup

  1. customwas in an ice-bath
  2. stirringThe reaction mixture was stirred at room temperature for 2 hours
  3. customThe reaction was quenched with saturated aqueous NH4Cl
  4. extractionthe mixture was extracted with ethyl acetate and two layers
  5. customwere separated
  6. customThe organic layer was evaporated to dryness

Sources & evidence

ORD record
ord-55d5c2dc1aeb4f1b868d7b0ad4916ec1
Source dataset
uspto-grants-2013_02
Patent number
US08378143B2

Reaction notes

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