Diisopropylamine → 1,1-Dimethyleth-1-yl (5S,E)-7-[4,5-bis-(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-5-hydroxy-3-oxo-6-heptenoate

HRID 2050583

Reaction equation

HRID 2050583 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]([CH:49]([CH3:51])[CH3:50])[N:31](/[CH:40]=[CH:41]/[C@@H:42]([OH:48])[CH2:43][C:44](OC)=[O:45])[C:32]=2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:24][CH:23]=1>C1CCCCC1.C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:29]=[C:30]([CH:49]([CH3:51])[CH3:50])[N:31](/[CH:40]=[CH:41]/[C@@H:42]([OH:48])[CH2:43][C:44](=[O:45])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:32]=2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:26][CH:27]=1

Participants

7

Reactant 4

HCID 7912DiisopropylamineHCID 10908tert-Butyl acetateHCID 14849800Methyl (3S,E)-5-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3-hydroxy-4-pentenoateHCID 178418339Butyllithium

Product 1

HCID 148498021,1-Dimethyleth-1-yl (5S,E)-7-[4,5-bis-(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-5-hydroxy-3-oxo-6-heptenoate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8078CyclohexaneSolvent

Procedure

A solution of dry diisopropylamine (0.77 ml) in dry cyclohexane (15.6 ml) at 3° under nitrogen was treated dropwise with n-butyl lithium solution (1.55M in hexanes, 3.54 ml). After 15 min t-butyl acetate (0.74 ml) was added dropwise. After 30 min the mixture was cannulated into a solution of methyl(3S,E)-5-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3-hydroxy-4-pentenoate (334 mg) in dry THF (7.8 ml) at 3° under nitrogen over 15 min. After 1 h the mixture was quenched with saturated aqueous ammonium chloride solution (3.5 ml) and then diluted with water. The mixture was then and extracted with ethyl acetate (3×20 ml). The combined extracts were dried and evaporated to a gummy solid (518 mg) which was treated with ether (4 ml) and then cyclohexane (4 ml) and cooled in an ice bath. The solid was collected, washed and dried to give the title compound (239 mg) as a white powder; δ(CDCl3) 1.41 (d, J 7.5 Hz, 6H, CH(CH3)2), 1.46 (s, 9H, C(CH3)3), 2.59 (d, J 7.5 Hz, 2H, C(OH)CH2CO), 3.02 (bs, 1H, OH), 3.14 (septet, J 7.5 Hz, 1H, --CH(CH3)2), 3.35 (s, 2H, CH2CO2R), 4.63 (m, 1H, CHOH), 5.39 (dd, J 14 and 7 Hz, 1H, N--CH=CH--C), 6.70 (d, J 14 Hz, 1H, N--CH=CH--C), 6.90 and 7.10 (2 t, J 9 Hz, each 2H, C-3 and C-5 protons of 4-fluorophenyls), 7.17-7.47 (m, 4H, C-2 and C-6 protons of 4-fluorophenyls). Also present was a trace of the enol form, δ values include 1.52 (s, --C(CH3)3), 4.51 (m, CHOH), 4.89 (s, C(OH)=CHCO2), 5.38 (dd, J 14 and 7 Hz, --N--CH=CH), 6.64 (d, J 14 Hz, NCH=CH). Chiral hplc detected none of the other enantiomer. A second crop of title compound (56 mg) was also obtained.

Workup

  1. customAfter 1 h the mixture was quenched with saturated aqueous ammonium chloride solution (3.5 ml)
  2. additiondiluted with water
  3. extractionextracted with ethyl acetate (3×20 ml)
  4. customThe combined extracts were dried
  5. customevaporated to a gummy solid (518 mg) which
  6. additionwas treated with ether (4 ml)
  7. temperaturecyclohexane (4 ml) and cooled in an ice bath
  8. customThe solid was collected
  9. washwashed
  10. customdried

Sources & evidence

ORD record
ord-8ca49e6e30f9477a92f91de7c55476dd
Source dataset
uspto-grants-1991_05
Patent number
US05013749

Linked notes

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