Cyclopropylacetylene → (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 389404Notes

Reaction equation

HRID 389404 reaction equation
C([Li])CCC.[CH:6]1([C:9]#[CH:10])[CH2:8][CH2:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@@:21]23[C:27]([CH3:29])([CH3:28])[C@@:24]([CH3:30])([CH2:25][CH2:26]2)[C:23](=[O:31])[O:22]3)=[O:20])=[C:14]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@@:21]23[C:27]([CH3:28])([CH3:29])[C@@:24]([CH3:30])([CH2:25][CH2:26]2)[C:23](=[O:31])[O:22]3)=[O:20])=[C:14]([C@@:32]([OH:37])([C:10]#[C:9][CH:6]2[CH2:8][CH2:7]2)[C:33]([F:34])([F:35])[F:36])[CH:13]=1

Participants

5

Reactant 3

HCID 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 178418339Butyllithium

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-carboxamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

2.5 M n-Butyllithium (14.8 mL, 37.16 mmol) was added slowly to a solution of cyclopropyl acetylene (2.46 g, 37.16 mmol) in tetrahydrofuran (20 mL) in an ice-salt-bath under argon, and 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, 5 g, 12.39 mmol) was added. The reaction mixture was stirred for 0.5 hour. The reaction was quenched with 10% citric acid aqueous, the mixture was extracted with ethyl acetate and the two layers were separated. The organic layer was evaporated to dryness to give crude oil which was further crystallized with ethyl acetate and petroleum ether to give (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 powder. 1H NMR spectrum of the product was identical to that of Example 5.

Workup

  1. customThe reaction was quenched with 10% citric acid aqueous
  2. extractionthe mixture was extracted with ethyl acetate
  3. customthe two layers were separated
  4. customThe organic layer was evaporated to dryness
  5. customto give crude oil which
  6. customwas further crystallized with ethyl acetate and petroleum ether

Sources & evidence

ORD record
ord-99b2451ae1044678903593a52f865233
Source dataset
uspto-grants-2013_02
Patent number
US08378143B2

Reaction notes

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