Acetone → 8-fluoro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one

HRID 1607006Notes

Reaction equation

HRID 1607006 reaction equation
[C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[C:10](=[O:18])[N:9]([CH3:19])[CH2:8][C:7]=12)#[CH:2].C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.[CH3:36][C:37]([CH3:39])=[O:38]>O1CCCC1.CCCCCC.O>[F:17][C:15]1[CH:14]=[CH:13][C:12]2[N:6]3[CH:5]=[N:4][C:3]([C:1]#[C:2][C:37]([OH:38])([CH3:39])[CH3:36])=[C:7]3[CH2:8][N:9]([CH3:19])[C:10](=[O:18])[C:11]=2[CH:16]=1

Participants

8

Reactant 4

HCID 180AcetoneHCID 12679HexamethylphosphoramideHCID 198515463-ethynyl-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-oneHCID 178418339Butyllithium

Product 1

HCID 198515648-fluoro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Procedure

1.27 g (5 mmol) of 3-ethynyl-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was suspended in 10 ml of tetrahydrofuran and treated dropwise within 20 minutes at a maximum of -5° with 6.4 ml (10 mmol) of 1.6M butyllithium in hexane. After stirring in an ice-bath for 2 hours the mixture was cooled to -70° and there was added thereto in succession 1.7 ml of hexamethylphosphoric acid triamide and 0.6 g (10 mmol) of acetone. The mixture was left to come to room temperature within 4.5 hours, left to stand overnight and poured into about 120 ml of water. After acidification with 4N hydrochloric acid the mixture was extracted four times with ether and six times with ethyl acetate, the combined extracts were dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel while eluting with ethyl acetate and after crystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 163°-164°.

Workup

  1. temperaturewas cooled to -70°
  2. additionthere was added
  3. waitThe mixture was left
  4. waitto come to room temperature within 4.5 hours
  5. waitleft
  6. waitto stand overnight
  7. extractionAfter acidification with 4N hydrochloric acid the mixture was extracted four times with ether and six times with ethyl acetate
  8. dry with materialthe combined extracts were dried over magnesium sulphate
  9. customevaporated
  10. washAfter chromatography of the residue on silica gel while eluting with ethyl acetate
  11. customafter crystallization from ethyl acetate

Sources & evidence

ORD record
ord-8232f14e5b3a4e40a72268b482574279
Source dataset
uspto-grants-1989_09
Patent number
US04863920

Reaction notes

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