6-Hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid → 6-Hydroxy-2,5,7,8-tetramethylchroman 2-acetyl 4-(4,4'difluorobenzhydryl)piperazine

HRID 263928Notes

Reaction equation

HRID 263928 reaction equation
C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[C:18]([CH3:34])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][C:22](C)([CH2:29]C(O)=O)[CH2:21][CH2:20]2.[F:35][C:36]1[CH:55]=[CH:54][C:39]([CH:40]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[CH:38][CH:37]=1.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[OH:16][C:17]1[C:18]([CH3:34])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][CH:22]([CH3:29])[CH2:21][CH2:20]2.[C:17]([CH:50]1[CH2:49][N:48]([CH:40]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[C:39]2[CH:54]=[CH:55][C:36]([F:35])=[CH:37][CH:38]=2)[CH2:53][CH2:52][NH:51]1)(=[O:16])[CH3:26]

Participants

6

Reactant 4

HCID 55926-Hydroxy-2,5,7,8-tetramethylchroman-2-acetic acidHCID 10868DicyclohexylcarbodiimideHCID 1529321-(Bis(4-fluorophenyl)methyl)piperazineHCID 27960291-Hydroxybenzotriazole hydrate

Product 1

HCID 700576666-Hydroxy-2,5,7,8-tetramethylchroman 2-acetyl 4-(4,4'difluorobenzhydryl)piperazineYield 87.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of dicyclohexyl carbodiimide (Aldrich, 3.55 g, 17.23 mmol) in methylene chloride (50 mL) was added dropwise to a slurry comprised of 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid (4.14 g, 15.66 mmol), 4,4'-difluorobenzhydryl piperazine (Schweizerhall, 4.51 g, 15.66 mmol), and 1-hydroxybenzotriazole hydrate (Aldrich, 2.33 g, 17.23 mmol) in methylene chloride (150 mL) which was cooled by an ice/water bath. After the addition was complete, the reaction mixture was allowed to come to ambient temperature and was stirred at ambient temperature for 12 h. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed (flash, silica gel, 95:5 methylene chloride/methanol) to give an oil which crystallized from a mixture of ethyl acetate and hexane. The solid was crystallized from ethanol to give 3.67 g (43.8% yield) of the desired product as a white solid.

Workup

  1. temperaturewas cooled by an ice/water bath
  2. additionAfter the addition
  3. customto come to ambient temperature
  4. filtrationThe reaction was filtered
  5. concentrationthe filtrate was concentrated in vacuo
  6. customThe residue was chromatographed (flash, silica gel, 95:5 methylene chloride/methanol)
  7. customto give an oil which
  8. customcrystallized from a mixture of ethyl acetate and hexane
  9. customThe solid was crystallized from ethanol

Sources & evidence

ORD record
ord-1511ec7d6fbc4f868987943b4b05c8fd
Source dataset
uspto-grants-1997_07
Patent number
US05646149

Reaction notes

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