5alpha-Dihydroprogesterone → Ganaxolone

HRID 1811504Notes

Reaction equation

HRID 1811504 reaction equation
[CH3:1][Mg]Cl.[CH3:4][C:5](=[O:26])[C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@H:13]([CH2:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[CH3:4][C:5]([C@@H:6]1[C@@:23]2([CH3:24])[CH2:22][CH2:21][C@@H:20]3[C@@:18]4([CH3:19])[CH2:17][CH2:16][C@:15]([OH:25])([CH3:1])[CH2:14][C@@H:13]4[CH2:12][CH2:11][C@H:10]3[C@@H:9]2[CH2:8][CH2:7]1)=[O:26]

Participants

6

Reactant 2

HCID 928105alpha-DihydroprogesteroneHCID 178418332HCID 178418332, compound

Product 1

HCID 6918305GanaxoloneYield 75.9%

Reagents, catalysts & solvents 3

HCID 24193Titanium TetrachlorideCatalystHCID 76524Titanium tetraethoxideCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Titanium tetrachloride (350 uL, 3.2 mmol) is added in a dropwise fashion to a solution of titanium tetraethoxide (2.42 g, 10.6 mmol) in tetrahydrofuran (anhydrous, 30 mL) cooled to 0° C. After stirring for 20 min at 0° C., methyl magnesium chloride (3M, 4.3 mL 12.9 mmol) in tetrahydrofuran solution is added dropwise while maintaining the temperature below 5° C. After stirring for an additional 20 minutes at 5° C., 5α-pregnane-3,20-dione (2.53 g, 8 mmol) was added in one portion. The reaction is warmed to 40° C. and stirred for 4 hours. The reaction mixture is quenched with 20 mL of methanol and the solvent removed in vacuo. The reaction mixture is partitioned between 100 ml of 3N HCl and 100 mL of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and brine and the solvent removed in vacuo to afford crude ganaxolone as a white solid of 75.9% pure ganaxolone by HPLC (Table 1, entry 3).

Workup

  1. temperaturewhile maintaining the temperature below 5° C
  2. stirringAfter stirring for an additional 20 minutes at 5° C.
  3. temperatureThe reaction is warmed to 40° C.
  4. stirringstirred for 4 hours
  5. customThe reaction mixture is quenched with 20 mL of methanol
  6. customthe solvent removed in vacuo
  7. customThe reaction mixture is partitioned between 100 ml of 3N HCl and 100 mL of ethyl acetate
  8. washThe organic layer is washed with 1N sodium hydroxide and brine
  9. customthe solvent removed in vacuo

Sources & evidence

ORD record
ord-3d7251f442244920a9d06c1387a9423d
Source dataset
uspto-grants-2013_01
Patent number
US08362286B2

Reaction notes

Loading…