Raloxifene → 4'-tert-Butyldimethylsilyl-6-hydroxy Raloxifene

HRID 619360Notes

Reaction equation

HRID 619360 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[O:19])=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[Si:44](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>C1COCC1.CN(C=O)C>[Si:44]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:22][CH:21]=2)=[O:19])=[CH:4][CH:3]=1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]

Participants

5

Reactant 3

HCID 5035RaloxifeneHCID 218852-DimethylaminopyridineHCID 28928tert-Butyldimethylsilyl chloride

Product 1

HCID 106034474'-tert-Butyldimethylsilyl-6-hydroxy RaloxifeneYield 45%

Reagents, catalysts & solvents 1

HCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Procedure

A solution was prepared consisting of 10 g (21.1 mmol) of [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone and 6 g (49.1 mmol) of dimethylaminopyridine in 700 mL of THF-DMF (6:1)(v/v). This solution was stirred for one hour at ambient temperature and then cooled to 0° C. in an ice bath. To this solution was added 2.9 g (19.3 mmol) of tert-butyl-dimethylsilylchloride. The reaction mixture was stirred under a nitrogen atmosphere and allowed to warm to ambient temperature. After seventy-two hours, the reaction was quenched with the addition of a saturated solution of aqueous NH4Cl. The organic layer was separated and washed with water, brine, and finally dried by filtration through anhydrous Na2SO4 and evaporated to dryness. The crude product was triturated with CH2Cl2, allowed to stand for three hours, and filtered to remove unreacted starting material. This resulting product is a mixture of isomers, which are separated by chromatography on a silica gel column eluted with a linear gradient beginning with CHCl3 and ending with CHCl3 --MeOH (19:1)(v/v). The desired fractions were determined by tlc, combined, and evaporated to dryness. This yielded 5.1 g of the title compound, isolated as a yellow crystalline solid.

Workup

  1. customA solution was prepared
  2. temperaturecooled to 0° C. in an ice bath
  3. stirringThe reaction mixture was stirred under a nitrogen atmosphere
  4. temperatureto warm to ambient temperature
  5. waitAfter seventy-two hours
  6. customthe reaction was quenched with the addition of a saturated solution of aqueous NH4Cl
  7. customThe organic layer was separated
  8. washwashed with water, brine
  9. dry with materialfinally dried by filtration through anhydrous Na2SO4
  10. customevaporated to dryness
  11. customThe crude product was triturated with CH2Cl2
  12. waitto stand for three hours
  13. filtrationfiltered
  14. customto remove unreacted
  15. additiona mixture of isomers, which
  16. customare separated by chromatography on a silica gel column
  17. washeluted with a linear gradient
  18. customevaporated to dryness

Sources & evidence

ORD record
ord-e3ad0f46d8db45c2af78493aa089dc11
Source dataset
uspto-grants-1999_09
Patent number
US05958969

Reaction notes

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