1-Bromo-6-chlorohexane → 7alpha-(6-Chlorohexyl)-11beta-fluoro-estr-4-ene-3,17-dione

HRID 1837228Notes

Reaction equation

HRID 1837228 reaction equation
Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8].[Mg].[Br-].[Li+].[F:12][C@H:13]1[CH2:30][C@@:28]2([CH3:29])[C@@H:24]([CH2:25][CH2:26][C:27]2=[O:31])[C@H:23]2[C@H:14]1[C@@H:15]1[C:20]([CH:21]=[CH:22]2)=[CH:19][C:18](=[O:32])[CH2:17][CH2:16]1>C1COCC1.CN1CCCN(C)C1=O.C[Si](C)(C)Cl.[Cu]I.C(O)(=O)C>[Cl:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C@@H:22]1[CH2:21][C:20]2[C@H:15]([CH2:16][CH2:17][C:18](=[O:32])[CH:19]=2)[C@@H:14]2[C@@H:23]1[C@H:24]1[C@@:28]([CH2:30][C@@H:13]2[F:12])([CH3:29])[C:27](=[O:31])[CH2:26][CH2:25]1

Participants

10

Reactant 4

HCID 805161-Bromo-6-chlorohexaneHCID 82050Lithium BromideHCID 5462224MagnesiumHCID 1117374411beta-Fluoroestra-4,6-diene-3,17-dione

Product 1

HCID 699179387alpha-(6-Chlorohexyl)-11beta-fluoro-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 30 ml of a solution of 41 ml of 1-bromo-6-chlorohexane in 270 ml of THF is added under nitrogen to a suspension of 6.8 g of magnesium chips in 100 ml of THF. After the reaction has started, the residual solution is added in drops in such a way that the internal temperature does not exceed 35° C. In a second flask, 48.1 g of lithium bromide is added to a suspension of 26.4 g of copper(I) iodide in 120 ml of THF at 0° C., whereby the internal temperature climbs to 40° C. Without cooling, 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 30 minutes at 40° C. A clear solution is obtained, which is added in drops to the Grignard solution that is cooled to −40° C. Then, it is stirred for 30 more minutes at −30° C. and mixed drop by drop at −50° C. with a solution of 23.5 g of 11β-fluor-estra-4,6-diene-3,17-dione in 230 ml of THF, 24.6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 55 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed −40° C. It is stirred for 1 hour under cold conditions, then 32 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 overnight 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, 25.2 g of 7α-(6-chlorohexyl)-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 is added in drops to the Grignard solution that
  7. temperatureis cooled to −40° C
  8. stirringThen, it is stirred for 30 more minutes at −30° C.
  9. customdoes not exceed −40° C
  10. stirringIt is stirred for 1 hour 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 overnight 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-1bdc3ed82f1b46199a04b07f4bc92ce0
Source dataset
uspto-grants-2004_08
Patent number
US06780855B2

Reaction notes

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