Dimethyl Sulfoxide → 1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(formyl)cyclopentane

HRID 1017774Notes

Reaction equation

HRID 1017774 reaction equation
C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:41])([F:40])[C:13]1[CH:14]=[C:15]([C@H:23]([O:25][C@H:26]2[CH2:30][CH2:29][C@@H:28]([CH2:31][OH:32])[C@@H:27]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH3:24])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[C:15]([C@H:23]([O:25][C@H:26]2[CH2:30][CH2:29][C@@H:28]([CH:31]=[O:32])[C@@H:27]2[C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH3:24])[CH:14]=[C:13]([C:12]([F:41])([F:11])[F:40])[CH:18]=1

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 160877232alpha-(4-Fluorophenyl)-3beta-[[(R)-alpha-methyl-3,5-bis(trifluoromethyl)benzyl]oxy]cyclopentane-1beta-methanol

Product 1

HCID 228974301-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(formyl)cyclopentaneYield 88.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
-70 °C

Procedure

To a solution of 5.4 mL (61.7 mmole) of oxalyl chloride in 100 mL of methylene chloride cooled to −70° C. was added dropwise 8.7 mL (123 mmole) of DMSO. The reaction was stirred for 10-15 minutes at −70° C. and then a solution of 11.11 g (24.7 mmole) of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(hydroxymethyl)cyclopentane, prepared as in Example 19, Step A, in 40 mL of methylene chloride was added dropwise at −70° C. The reaction was stirred for 1 hour before dropwise addition of 43 mL (246 mmole) of DIPEA in 25 mL of methylene chloride. After 5 minutes, the dry ice/acetone bath was removed and the reaction was warmed to room temperature in a water bath and stirred for 1 hour. The reaction was then diluted with methylene chloride and water containing 150 mL of 2N hydrochloric acid and the layers were separated. The aqueous layer was reextracted with methylene chloride and the organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by FC (10% ethyl acetate/hexanes) to give 9.8 g of title compound as a waxy solid.

Workup

  1. waitAfter 5 minutes
  2. customthe dry ice/acetone bath was removed
  3. temperaturethe reaction was warmed to room temperature in a water bath
  4. stirringstirred for 1 hour
  5. additionThe reaction was then diluted with methylene chloride and water containing 150 mL of 2N hydrochloric acid
  6. customthe layers were separated
  7. washeach washed with a portion of brine
  8. dry with materialdried over sodium sulfate
  9. customevaporated
  10. customThe residue was purified by FC (10% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-6b23669155fe4871b26dbd5fb7883a59
Source dataset
uspto-grants-2002_11
Patent number
US06479518B2

Reaction notes

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