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Rac-Efavirenz → 6-chloro-1-(1S)-camphanoyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

HRID 2394252
Notes
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Reaction equation

HRID 2394252 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([C:16]#[C:17][CH:18]3[CH2:20][CH2:19]3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:21]=1.[C:22]12([CH3:34])[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]2[C:31](Cl)=[O:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:31]([CH:23]3[CH2:24][CH:25]4[C:28]([CH3:30])([CH3:29])[C@@:22]3([CH3:34])[CH2:27][CH2:26]4)=[O:32])[C:9](=[O:11])[O:8][C:7]([C:16]#[C:17][CH:18]3[CH2:20][CH2:19]3)([C:12]([F:13])([F:14])[F:15])[C:6]=2[CH:21]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 3203Rac-EfavirenzHCID 8471TriethylamineHCID 534427834,7,7-Trimethyl-3-bicyclo[2.2.1]heptanecarbonyl chloride

Product 1

HCID 702720696-chloro-1-(1S)-camphanoyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-oneYield 39.6%

Reagents, catalysts & solvents 2

HCID 14284
4-(Dimethylamino)pyridine
Catalyst
HCID 6344DichloromethaneSolvent

Procedure

To a solution containing (±) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (12.97 g, 0.041 mol), 4-dimethylaminopyridine (1.02 g, 0.0083 mol), and (-) camphanic acid chloride (14.22 g, 0.06556 mol) in 350 mL of dry dichloromethane, stirred under argon in an ice bath, was added triethylamine (22.84 mL, 0.164 mol). The cooling bath was removed and the reaction was allowed to proceed at room temperature. After 75 min. the reaction was judged complete by thin layer chromatography (SiO2, 4% EtOAc in CHCl3), and the solution was diluted with 500 mL of CHCl3 then washed with 10% citric acid (2×), water (1×), and brine (1×). Drying (MgSO4), filtration, and removal of the solvent in vacuo left a colorless foam. This material was triturated with 200 mL of boiling hexane. On cooling to room temperature the desired diastereomeric camphanate imide precipitated. The solid was collected on a frit, washed with a little cold hexanes and dried in vacuo to give 7.79 g of 6-chloro-1-(1S)-camphanoyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as white crystals.

Workup

  1. customThe cooling bath was removed
  2. customto proceed at room temperature
  3. additionthe solution was diluted with 500 mL of CHCl3
  4. washthen washed with 10% citric acid (2×), water (1×), and brine (1×)
  5. customDrying
  6. filtration(MgSO4), filtration, and removal of the solvent in vacuo
  7. waitleft a colorless foam
  8. customThis material was triturated with 200 mL of boiling hexane
  9. customprecipitated
  10. customThe solid was collected on a frit
  11. washwashed with a little cold hexanes
  12. customdried in vacuo

Sources & evidence

ORD record
ord-6487e399aed34d928b88c25d4e9fc718
Source dataset
uspto-grants-1998_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05811423

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes