Lithium diisopropylamide → 17-Difluoromethylene-3-tetrahydropyranyloxy-8alpha-estra-1,3,5(10)-triene

HRID 369062Notes

Reaction equation

HRID 369062 reaction equation
[F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-]C(C)C)(C)C.[Li+].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C@@H:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C:42](=O)[CH2:41][CH2:40]4)[CH2:37][CH2:36][C:35]=2[CH:34]=1>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]([F:3])=[C:42]1[CH2:41][CH2:40][C@H:39]2[C@@H:38]3[C@H:47]([CH2:46][CH2:45][C@:43]12[CH3:44])[C:48]1[CH:49]=[CH:50][C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:34][C:35]=1[CH2:36][CH2:37]3

Participants

7

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 156181363-Tetrahydropyranyloxy-8alpha-estra-1,3,5(10)-trien-17-oneHCID 15635908(Difluoromethyl)(oxo)diphenyl-lambda~5~-phosphane

Product 1

HCID 1530850217-Difluoromethylene-3-tetrahydropyranyloxy-8alpha-estra-1,3,5(10)-trieneYield 59.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent2×

Procedure

A solution of 3.5 g of difluoromethyldiphenylphosphine oxide in 100 ml of tetrahydrofuran is slowly mixed with 7 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 2 g of 3-tetrahydropyranyloxy-8α-estra-1,3,5(10)-trien-17-one in 50 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 2 hours. For working-up, it is diluted with ethyl acetate and water, suctioned off on Celite, rewashed 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. 1.3 g of 17-difluoromethylene-3-tetrahydropyranyloxy-8α-estra-1,3,5(10)-triene is obtained as colorless crystals with a melting point of 90-91° C., [α]D22 =-9.2° (c=0.5% 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 2 hours
  4. washwashed with water as well as with saturated sodium chloride solution
  5. customdried on sodium sulfate
  6. concentrationconcentrated by evaporation in a vacuum
  7. customchromatographed on silica gel with hexane/ethyl acetate/triethylamine

Sources & evidence

ORD record
ord-cf9b2dde5ab145cf9c406b556fc01bd7
Source dataset
uspto-grants-2000_10
Patent number
US06136800

Reaction notes

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