1,1'-Carbonyldiimidazole → Rac-Efavirenz

HRID 440265Notes

Reaction equation

HRID 440265 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:19])([C:14]#[C:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([F:13])([F:12])[F:11].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:20](=[O:21])[O:19][C:9]([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)([C:10]([F:13])([F:11])[F:12])[C:3]=2[CH:4]=1

Participants

4

Reactant 2

HCID 682631,1'-CarbonyldiimidazoleHCID 98389352-(2-Amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol

Product 1

HCID 3203Rac-EfavirenzYield 100.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (15.00 g, 0.0518 mol) and 41.98 g (0.259 mol) of 1,1'-carbonyldiimidazole in 250 mL of dry THF was stirred under argon at 55° C. for 24 hours. The solvent was removed on a rotary evaporator and the residue was partitioned between 500 mL of ethyl acetate and 400 mL of water. The layers were separated and the aqueous phase was extracted once more with ethyl acetate. The combined ethyl acetate extracts were washed with 2×200 mL of 2% aqueous HCl, saturated aqueous NaHCO3, and brine. Drying over MgSO4, filtration, and removal of the solvent in vacuo provided 16.42 g of the title compound as a solid. Recrystallization from ethyl acetatehexane afforded 12.97 g of analytically pure (±) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white crystals. mp: 178°-180° C. 1H-NMR (CDCl3): 0.85 (m, 2H), 0.94 (m, 2H), 1.40 (m, 1H), 6.81 (d, J=8.5 Hz, 1H), 7.37 (dd, J=2.5, 8.5 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 8.87 (br s, 1H).

Workup

  1. customThe solvent was removed on a rotary evaporator
  2. customthe residue was partitioned between 500 mL of ethyl acetate and 400 mL of water
  3. customThe layers were separated
  4. extractionthe aqueous phase was extracted once more with ethyl acetate
  5. washThe combined ethyl acetate extracts were washed with 2×200 mL of 2% aqueous HCl, saturated aqueous NaHCO3, and brine
  6. dry with materialDrying over MgSO4, filtration, and removal of the solvent in vacuo

Sources & evidence

ORD record
ord-f48f57ee48524950a34e4c7f24b5bf00
Source dataset
uspto-grants-1996_05
Patent number
US05519021

Reaction notes

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