Dimethyl Sulfoxide → 5-(4-fluorophenyl)-1-(2-((2S,4S)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide

HRID 5701Notes

Reaction equation

HRID 5701 reaction equation
NCC[C@H:4]1[O:9][C:8]2([CH2:14]CCCC2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=O)[CH2:5]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:28]([C:38](=O)C(C)C)[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])=[CH:22][CH:21]=1.C(O[CH2:53][CH3:54])C.[Cl-].[NH4+:56].[CH3:57]S(C)=O>O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:56]([CH2:4][CH2:5][C@H:6]3[CH2:15][C@H:16]([OH:18])[CH2:14][C:8](=[O:9])[O:7]3)[C:38]([CH:53]([CH3:54])[CH3:57])=[C:28]([C:29]([NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:30])[C:27]=2[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:22][CH:21]=1

Participants

7

Reactant 5

HCID 679Dimethyl SulfoxideHCID 3283Diethyl EtherHCID 25517Ammonium ChlorideHCID 99098724-(4-Fluorophenyl)-2-(2-methyl-1-oxopropyl)-4-oxo-3,N-diphenylbutanamideHCID 15045142(2R-cis)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid

Product 1

HCID 139236655-(4-fluorophenyl)-1-(2-((2S,4S)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
105 °C

Procedure

A solution of 0.31 g (1.21 mmol) of (±)-cis-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid and 0.504 g (1.20 mmol) of (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers in 5 mL of dimethyl sulfoxide is heated at 105° C. for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with water (2×50 mL) and 5% sodium hydroxide solution (2×100 mL--to extract the intermediate acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 mL of ethyl acetate to remove the protecting group before lactonization. The extract is concentrated and dissolved in 30 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(±)-5-(4-fluoro-phenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.155 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two crops.

Workup

  1. temperatureThe solution is cooled
  2. customThe layers are separated
  3. washthe organic layer washed with water (2×50 mL) and 5% sodium hydroxide solution (2×100 mL
  4. extractionto extract the intermediate acid from unreacted diketone)
  5. extractionextracted with 30 mL of ethyl acetate
  6. customto remove the protecting group before lactonization
  7. concentrationThe extract is concentrated
  8. dissolutiondissolved in 30 mL of ethyl acetate
  9. additionA drop of concentrated hydrochloric acid is added to the ethyl acetate solution
  10. waitto stand 18 hours
  11. concentrationThe solution is concentrated in vacuo
  12. dissolutionthe concentrate is redissolved in 30 mL of ethyl acetate
  13. additiontreated with one drop of concentrated hydrochloric acid
  14. stirringThe solution is stirred two hours
  15. concentrationconcentrated in vacuo
  16. dissolutiondissolved in 6 mL of toluene
  17. customTrans-(±)-5-(4-fluoro-phenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes
  18. customis isolated by filtration

Sources & evidence

ORD record
ord-d79d449b7efe4df5a170b24db9b08aad
Source dataset
uspto-grants-1993_09
Patent number
US05245047

Reaction notes

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