Iodine → 7alpha-(5-Chloropentyl)-11beta-fluor-estr-4-ene-3,17-dione

HRID 1837221Notes

Reaction equation

HRID 1837221 reaction equation
Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Cl:7].[Mg].II.BrCBr.[Br-].[Li+].[F:16][C@H:17]1[CH2:34][C@@:32]2([CH3:33])[C@@H:28]([CH2:29][CH2:30][C:31]2=[O:35])[C@H:27]2[C@H:18]1[C@@H:19]1[C:24]([CH:25]=[CH:26]2)=[CH:23][C:22](=[O:36])[CH2:21][CH2:20]1>C1COCC1.CN1CCCN(C)C1=O.C[Si](C)(C)Cl.[Cu]I.C(O)(=O)C>[Cl:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C@@H:26]1[CH2:25][C:24]2[C@H:19]([CH2:20][CH2:21][C:22](=[O:36])[CH:23]=2)[C@@H:18]2[C@@H:27]1[C@H:28]1[C@@:32]([CH2:34][C@@H:17]2[F:16])([CH3:33])[C:31](=[O:35])[CH2:30][CH2:29]1

Participants

12

Reactant 6

HCID 807IodineHCID 3024DibromomethaneHCID 82050Lithium BromideHCID 960701-Bromo-5-chloropentaneHCID 5462224MagnesiumHCID 1117374411beta-Fluoroestra-4,6-diene-3,17-dione

Product 1

HCID 688713657alpha-(5-Chloropentyl)-11beta-fluor-estr-4-ene-3,17-dione

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 176Acetic AcidSolventHCID 6397ChlorotrimethylsilaneSolventHCID 8028TetrahydrofuranSolvent4×HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Solvent2×

Conditions

Temperature
40 °C

Procedure

First 20% of a solution of 39 ml of 1-bromo-5-chloropentane in 300 ml of THF is added under nitrogen to a suspension of 7.2 g of magnesium chips in 100 ml of THF. After the reaction has started, which can be achieved by adding iodine and dibromomethane, the residual solution is added in drops in such a way that the internal temperature does not exceed 35° C. In a second flask, 51.2 g of lithium bromide is added to a suspension of 28.1 g of copper(I) iodide in 130 ml of THF at 0° C., whereby the internal temperature climbs to 40° C. Without cooling, 49.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 15 minutes at 40° C. A clear solution is obtained, which was added in drops to the Grignard solution that is cooled to −50° C. Then, it is stirred for 15 more minutes at −30° C. and mixed at −70° C. drop by drop with a solution of 25 g of 11β-fluor-estra-4,6-diene-3,17-dione in 260 ml of THF, 26 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 59 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed −65° C. It is stirred for 30 minutes under cold conditions, then 34.7 ml of glacial acetic acid is added in drops, the cooling bath is removed and stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.5 l of water, diluted with the same amount of ethyl acetate, the precipitate is separated on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 22.1 g of 7α-(5-chloropentyl)-11β-fluor-estr-4-ene-3,17-dione is obtained.

Workup

  1. additionthe residual solution is added in drops in such a way that the internal temperature
  2. customdoes not exceed 35° C
  3. customclimbs to 40° C
  4. temperatureWithout cooling
  5. customA clear solution is obtained
  6. additionwhich was added in drops to the Grignard solution that
  7. temperatureis cooled to −50° C
  8. stirringThen, it is stirred for 15 more minutes at −30° C.
  9. customdoes not exceed −65° C
  10. stirringIt is stirred for 30 minutes under cold conditions
  11. customthe cooling bath is removed
  12. stirringstirred for 1 more hour at room temperature
  13. additionthe reaction mixture is added to 1.5 l of water
  14. additiondiluted with the same amount of ethyl acetate
  15. customthe precipitate is separated on Celite
  16. extractionthe aqueous phase is extracted 3 times with ethyl acetate
  17. washwashed with sodium bicarbonate and common salt solution
  18. customdried on magnesium sulfate
  19. concentrationconcentrated by evaporation in a vacuum
  20. customAfter the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient

Sources & evidence

ORD record
ord-1360f47e0cd74feaa88afcd63b0557dc
Source dataset
uspto-grants-2004_08
Patent number
US06780855B2

Reaction notes

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