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

HRID 1838907Notes

Reaction equation

HRID 1838907 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

30 ml of a solution of 41 ml of 1-bromo-6-chlorohexane in 270 ml of THF are first added under nitrogen to a suspension of 6.8 g of magnesium turnings in 100 ml of THF. After starting the reaction, the remaining solution is added dropwise such that the internal temperature does not exceed 35° C. In a second flask, 48.1 g of lithium bromide are added to a suspension of 4 g of copper(I) iodide in 120 ml of THF at 0° C., the internal temperature rising to 40° C. 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one are then added without cooling and the mixture is stirred at 40° C. for 30 minutes. A clear solution is obtained, which is added dropwise to the Grignard solution cooled to −40° C. The mixture is then stirred at −30° C. for 30 minutes and treated dropwise at −50° C. with a solution of 23.5 g of 11β-fluorooestra-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 such that the internal temperature does not exceed −40° C. The mixture is stirred in the cold for 1 h, then 32 ml of glacial acetic acid are added dropwise, the cooling bath is removed and the mixture is stirred at room temperature for 1 hour. For work-up, the reaction mixture is added to 1.5 l of water, diluted with the same amount of ethyl acetate, the precipitate is removed by means of Celite, washed with ethyl acetate, and the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium hydrogencarbonate and sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. After chromatographing the crude product on silica gel using a hexane-ethyl acetate gradient, 25.2 g of 7α-(6-chlorohexyl)-11β-fluorooestr-4-ene-3,17-dione are obtained.

Workup

  1. customthe reaction
  2. additionthe remaining solution is added dropwise such that the internal temperature
  3. customdoes not exceed 35° C
  4. customrising to 40° C
  5. temperaturewithout cooling
  6. customA clear solution is obtained
  7. additionwhich is added dropwise to the Grignard solution
  8. temperaturecooled to −40° C
  9. stirringThe mixture is then stirred at −30° C. for 30 minutes
  10. customdoes not exceed −40° C
  11. stirringThe mixture is stirred in the cold for 1 h
  12. customthe cooling bath is removed
  13. stirringthe mixture is stirred at room temperature for 1 hour
  14. additionFor work-up, the reaction mixture is added to 1.5 l of water
  15. additiondiluted with the same amount of ethyl acetate
  16. customthe precipitate is removed by means of Celite
  17. washwashed with ethyl acetate
  18. extractionthe aqueous phase is extracted 3 times with ethyl acetate
  19. washwashed with sodium hydrogencarbonate and sodium chloride solution
  20. dry with materialdried over magnesium sulphate
  21. concentrationconcentrated in vacuo
  22. customare obtained

Sources & evidence

ORD record
ord-51398942ee934385a548f906104324a6
Source dataset
uspto-grants-2004_01
Patent number
US06677324B1

Reaction notes

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