p-Toluenesulfonic acid → 18,18-Difluoro-17beta-hydroxy-17-methyl-androst-4-en-3-one

HRID 372746Notes

Reaction equation

HRID 372746 reaction equation
[F:1][CH:2]([F:23])[C@:3]12[CH2:20][CH2:19][C@H:18]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:16]3([CH3:17])[CH2:15][CH2:14][C:13](=[O:21])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22].[CH2:24](OC(O)O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CI>O1CCOCC1.CO.O>[F:1][CH:2]([F:23])[C@:3]12[CH2:20][CH2:19][C@H:18]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:16]3([CH3:17])[CH2:15][CH2:14][C:13](=[O:21])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C@@:4]2([OH:22])[CH3:24]

Participants

8

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 6328Methyl iodideHCID 5231668OrthoameisensaureathylesterHCID 7061623818,18-Difluoro-androst-4-ene-3,17-dione

Product 1

HCID 7061647218,18-Difluoro-17beta-hydroxy-17-methyl-androst-4-en-3-one

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

500 mg of 18,18-difluoro-androst-4-ene-3,17-dione are dissolved in 20 ml of dioxane and, after adding 1 ml of orthoformic acid ethyl ester and 30 mg of p-toluenesulphonic acid, the mixture is stirred for 8 hours at room temperature. The reaction mixture is then poured into water (containing traces of pyridine) and extracted twice with ethyl acetate and the extracts are washed until neutral, dried and evaporated in an aspirator vacuum. The crude amorphous enol ether (3-ethoxy-18,18-difluoro-androsta-3,5-dien-17-one) is dissolved direct in 30 ml of absolute ether and the solution is added dropwise to an ethereal solution of methyl magnesium iodide prepared from 300 mg of magnesium turnings and an equivalent amount of methyl iodide, whilst stirring and cooling. The reaction mixture is refluxed for 2 hours and then worked up in the customary manner. The crude carbinol is subjected to hydrolysis direct, without purification. For this purpose, the compound is dissolved in 10 ml of 66% strength acetic acid and the solution is stirred for 2 hours at 30° C. It is then diluted with water and extracted with ethyl acetate and the extracts are washed until neutral (twice with saturated sodium bicarbonate solution and with water), dried and evaporated in an aspirator vacuum. Chromatography of the crude product over 100 times the amount by weight of silica gel (system: hexane/ethyl acetate, 3:1) gives 18,18-difluoro-17β-hydroxy-17-methyl-androst-4-en-3-one.

Workup

  1. extractionextracted twice with ethyl acetate
  2. washthe extracts are washed until neutral,
  3. customdried
  4. customevaporated in an aspirator vacuum
  5. dissolutionThe crude amorphous enol ether (3-ethoxy-18,18-difluoro-androsta-3,5-dien-17-one) is dissolved direct in 30 ml of absolute ether
  6. additionthe solution is added dropwise to an ethereal solution of methyl magnesium iodide
  7. customprepared from 300 mg of magnesium turnings
  8. temperaturecooling
  9. temperatureThe reaction mixture is refluxed for 2 hours
  10. customwithout purification
  11. dissolutionFor this purpose, the compound is dissolved in 10 ml of 66% strength acetic acid
  12. stirringthe solution is stirred for 2 hours at 30° C
  13. additionIt is then diluted with water
  14. extractionextracted with ethyl acetate
  15. washthe extracts are washed until neutral (twice with saturated sodium bicarbonate solution
  16. dry with materialwith water), dried
  17. customevaporated in an aspirator vacuum

Sources & evidence

ORD record
ord-09e2612de83946fbb4ffa000d1d43470
Source dataset
uspto-grants-1978_05
Patent number
US04092310

Reaction notes

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