Diethyl Ether → 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 360027Notes

Reaction equation

HRID 360027 reaction equation
[NH2:1][CH2:2][CH2:3][C@H:4]1OC[O:7][C@@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:23]([C:33](=O)[CH:34]([CH3:36])[CH3:35])[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])=[CH:17][CH:16]=1.C(OCC)C.[Cl-].[NH4+]>CS(C)=O.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:1]([CH2:2][CH2:3][C@H:4]3[CH2:5][C@H:6]([OH:7])[CH2:10][C:11](=[O:12])[O:13]3)[C:33]([CH:34]([CH3:36])[CH3:35])=[C:23]([C:24]([NH:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:25])[C:22]=2[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:19][CH:20]=1

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 25517Ammonium ChlorideHCID 99098724-(4-Fluorophenyl)-2-(2-methyl-1-oxopropyl)-4-oxo-3,N-diphenylbutanamideHCID 15045150(+/-)-cis-6-(2-Aminoethyl)-1,3-dioxane-4acetic 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-carboxamideYield 23.1%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Procedure

A solution of 0.26 g (1.21 mmol) of (±)-cis-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) of (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N, β-diphenylbenzenebutaneamide 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 and extracted with 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-fluorophenyl)-2-(1methyl ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.15 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. additionA drop of concentrated hydrochloric acid is added to the ethyl acetate solution
  7. concentrationThe solution is concentrated in vacuo
  8. dissolutionthe concentrate is redissolved in 30 mL of ethyl acetate
  9. additiontreated with one drop of concentrated hydrochloric acid
  10. concentrationconcentrated in vacuo
  11. dissolutiondissolved in 6 mL of toluene
  12. customTrans-(±)-5-(4-fluorophenyl)-2-(1methyl ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes
  13. customis isolated by filtration

Sources & evidence

ORD record
ord-96a22d61496d4f78a9cbee2921b6e68f
Source dataset
uspto-grants-1991_03
Patent number
US05003080

Reaction notes

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