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

HRID 1603366Notes

Reaction equation

HRID 1603366 reaction equation
Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Cl:7].[Mg].II.BrCBr.[Br-].[Li+].N1C=CC=NC1=O.[F:23][C@H:24]1[CH2:41][C@@:39]2([CH3:40])[C@@H:35]([CH2:36][CH2:37][C:38]2=[O:42])[C@H:34]2[C@H:25]1[C@@H:26]1[C:31]([CH:32]=[CH:33]2)=[CH:30][C:29](=[O:43])[CH2:28][CH2:27]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:33]1[CH2:32][C:31]2[C@H:26]([CH2:27][CH2:28][C:29](=[O:43])[CH:30]=2)[C@@H:25]2[C@@H:34]1[C@H:35]1[C@@:39]([CH2:41][C@@H:24]2[F:23])([CH3:40])[C:38](=[O:42])[CH2:37][CH2:36]1

Participants

13

Reactant 7

HCID 807IodineHCID 3024DibromomethaneHCID 684012(1H)-PyrimidinoneHCID 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-Solvent

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 to a suspension of 7.2 g of magnesium chips in 100 ml of THF under nitrogen. After the reaction starts, which can be achieved by adding iodine and dibromomethane, the remaining 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 is 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-fluoro-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 cold, then 34.7 ml of glacial acetic acid is added in drops, the cooling bath is removed, and it is stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.51 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-fluoro-estr-4-ene-3,17-dione is obtained.

Workup

  1. customAfter the reaction starts, which
  2. additionthe remaining solution is added in drops in such a way that the internal temperature
  3. customdoes not exceed 35° C
  4. customclimbs to 40° C
  5. temperatureWithout cooling
  6. customA clear solution is obtained
  7. additionwhich is added in drops to the Grignard solution that
  8. temperatureis cooled to -50° C
  9. stirringThen, it is stirred for 15 more minutes at -30° C.
  10. customdoes not exceed -65° C
  11. stirringIt is stirred for 30 minutes cold
  12. customthe cooling bath is removed
  13. stirringit is stirred for 1 more hour at room temperature
  14. additionthe reaction mixture is added to 1.51 of water
  15. additiondiluted with the same amount of ethyl acetate
  16. customthe precipitate is separated on Celite
  17. extractionthe aqueous phase is extracted 3 times with ethyl acetate
  18. washwashed with sodium bicarbonate and common salt solution
  19. customdried on magnesium sulfate
  20. concentrationconcentrated by evaporation in a vacuum
  21. customAfter the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient

Sources & evidence

ORD record
ord-6040a2d4e5094807aacae6407503476d
Source dataset
uspto-grants-1999_11
Patent number
US05986115

Reaction notes

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