Hexamethylphosphoramide → 8-fluoro-4,5-dihydro-3-[(1-hydroxycyclobutyl)-ethynyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one

HRID 1607008Notes

Reaction equation

HRID 1607008 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.[C:36]1(=[O:40])[CH2:39][CH2:38][CH2:37]1>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:36]4([OH:40])[CH2:39][CH2:38][CH2:37]4)=[C:7]3[CH2:8][N:9]([CH3:19])[C:10](=[O:18])[C:11]=2[CH:16]=1

Participants

8

Reactant 4

HCID 12679HexamethylphosphoramideHCID 14496CyclobutanoneHCID 198515463-ethynyl-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-oneHCID 178418339Butyllithium

Product 1

HCID 703943158-fluoro-4,5-dihydro-3-[(1-hydroxycyclobutyl)-ethynyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Procedure

3.83 g (15 mmol) of 3-ethynyl-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was suspended in 30 ml of tetrahydrofuran and treated dropwise within 30 minutes at a maximum of -5° with 20 ml (30 mmol) of 1.6M butyllithium in hexane. After stirring for two hours in an ice-bath the mixture was cooled to -70° and 5 ml of hexamethylphosphoric acid triamide and 2 g (28 mmol) of cyclobutanone was added thereto in succession. The mixture was left to come to room temperature within 5 hours, stirred overnight and poured into 300 ml of water. After acidification with 4N hydrochloric acid the mixture was extracted five times with ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and crystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-[ (1-hydroxycyclobutyl)-ethynyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 177°-179°.

Workup

  1. temperaturewas cooled to -70°
  2. waitThe mixture was left
  3. waitto come to room temperature within 5 hours
  4. stirringstirred overnight
  5. extractionAfter acidification with 4N hydrochloric acid the mixture was extracted five times with ethyl acetate
  6. washThe combined organic extracts were washed with water
  7. dry with materialdried over magnesium sulphate
  8. customevaporated
  9. washBy chromatography of the residue on silica gel while eluting with ethyl acetate and crystallization from ethyl acetate

Sources & evidence

ORD record
ord-6f95c277477e4777a99d400d557e873a
Source dataset
uspto-grants-1989_09
Patent number
US04863920

Reaction notes

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