Lithium diisopropylamide → 17-Difluoromethylene-3-methoxy-estra-1,3,5(10),15-tetraene

HRID 850840Notes

Reaction equation

HRID 850840 reaction equation
C(OP([CH:9]([F:11])[F:10])(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[CH:39]=[CH:38][C:37]2[C@@H:36]3[C@H:27]([C@H:28]4[C@@:32]([CH2:34][CH2:35]3)([CH3:33])[C:31](=O)[CH:30]=[CH:29]4)[CH2:26][CH2:25][C:24]=2[CH:23]=1>O1CCCC1>[F:11][C:9]([F:10])=[C:31]1[CH:30]=[CH:29][C@H:28]2[C@H:27]3[C@H:36]([CH2:35][CH2:34][C@:32]12[CH3:33])[C:37]1[CH:38]=[CH:39][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[CH2:25][CH2:26]3

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 2758305Phosphonic acid, (difluoromethyl)-, diethyl esterHCID 11098027Estra-1,3,5(10),15-tetraen-17-one, 3-methoxy-

Product 1

HCID 1530728017-Difluoromethylene-3-methoxy-estra-1,3,5(10),15-tetraeneYield 47.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 9.4 g of diethyl-(difluoromethyl)-phosphonate in 150 ml of tetrahydrofuran is slowly mixed with 25 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 5.6 g of 3-methoxy-estra-1,3,5(10),15-tetraen-17-one in 173 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 6 hours. For working-up, half the volume is concentrated by evaporation in a vacuum, diluted with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate/triethylamine. 3.0 g of 17-difluoromethylene-3-methoxy-estra -1,3,5(10),15-tetraene is obtained as colorless crystals with a melting point of 122-123° C., [α]D22 -120.9° (c=0.515% in pyridine).

Workup

  1. stirringstirred for 15 minutes
  2. temperatureslowly heated at a bath temperature of from -50° C. to 100° C.
  3. temperaturerefluxed for 6 hours
  4. concentrationhalf the volume is concentrated by evaporation in a vacuum
  5. additiondiluted with ethyl acetate
  6. washwashed with water as well as with saturated sodium chloride solution
  7. customdried on sodium sulfate
  8. concentrationconcentrated by evaporation in a vacuum
  9. customchromatographed on silica gel with hexane/ethyl acetate/triethylamine

Sources & evidence

ORD record
ord-e4103ab4f7154f459e983063a8d1dbef
Source dataset
uspto-grants-2000_01
Patent number
US06018062

Reaction notes

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