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

HRID 1607007Notes

Reaction equation

HRID 1607007 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)[N:9]([CH3:19])[CH2:8][C:7]=12)#[CH:2].C([Li])CCC.CN(C)P(=[O:34])(N(C)C)N(C)C.[CH3:36][C:37]([CH:39]1[CH2:41][CH2:40]1)=[O:38]>O1CCCC1.CCCCCC.O>[F:17][C:15]1[CH:14]=[CH:13][C:12]2[N:6]3[C:5](=[O:34])[NH:4][C:3]([C:1]#[C:2][C:37]([CH:39]4[CH2:41][CH2:40]4)([OH:38])[CH3:36])=[C:7]3[CH2:8][N:9]([CH3:19])[CH2:10][C:11]=2[CH:16]=1

Participants

8

Reactant 4

HCID 12679HexamethylphosphoramideHCID 13004Cyclopropyl methyl ketoneHCID 198515463-ethynyl-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-oneHCID 178418339Butyllithium

Product 1

HCID 703941178-fluoro-3-(3-cyclopropyl-3-hydroxy-1-butynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Procedure

2.55 g (10 mmol) of 3-ethynyl-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was suspended in 20 ml of tetrahydrofuran and treated dropwise within 30 minutes at -5° with 13 ml (20 mmol) of 1.6M butyllithium in hexane. After stirring in an ice-bath for 2 hours the mixture was cooled to -70° and 3.4 ml of hexamethylphosphoric acid triamide and 1.68 g (20 mmol) of cyclopropyl methyl ketone were added thereto in succession. The mixture was left to come to room temperature within 4 hours, stirred overnight and poured into about 200 ml of water. After acidification with 4N hydrochloric acid the mixture was extracted five times with ethyl acetate, the combined extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel while eluting with ethyl acetate and after crystallization from ethyl acetate there was obtained 8-fluoro-3-(3-cyclopropyl-3-hydroxy-1-butynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-one of melting point 191°-192°.

Workup

  1. temperaturewas cooled to -70°
  2. waitThe mixture was left
  3. waitto come to room temperature within 4 hours
  4. stirringstirred overnight
  5. extractionAfter acidification with 4N hydrochloric acid the mixture was extracted five times with ethyl acetate
  6. dry with materialthe combined extracts were dried over magnesium sulphate
  7. customevaporated
  8. customThe residue was chromatographed on silica gel
  9. washwhile eluting with ethyl acetate
  10. customafter crystallization from ethyl acetate

Sources & evidence

ORD record
ord-bea9f0e0c0234c6ebd0fbeafd21cd09c
Source dataset
uspto-grants-1989_09
Patent number
US04863920

Reaction notes

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