Tetrahydrofuran → Ethyl 12-ethynyl-9-phenyl-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(10),3,5,8,11,13-hexaene-5-carboxylate

HRID 1435798Notes

Reaction equation

HRID 1435798 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](C)=[N:13]N=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.BrC1C=CC2C(C=1)=C(C1C=CC=CC=1)N=[CH:31][C:32](=[O:34])N=2.[H-].[Na+].N1(P(Cl)(N2CCOCC2)=O)CC[O:47][CH2:46][CH2:45]1.[K+].[Br-].[CH2:61]1COC[CH2:62]1>C(O)CCC>[C:61]([C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:45]([C:46]([O:34][CH2:32][CH3:31])=[O:47])=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1)#[CH:62]

Participants

8

Reactant 6

HCID 8028TetrahydrofuranHCID 24758Sodium hydrideHCID 253877Potassium BromideHCID 12506606Bis(morpholino)phosphinyl chlorideHCID 12562546BromazolamHCID 219309577-Bromo-5-phenyl-1,4-benzodiazepine-2-one

Product 1

HCID 21930923Ethyl 12-ethynyl-9-phenyl-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(10),3,5,8,11,13-hexaene-5-carboxylate

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Procedure

8-Bromo-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 8.3 A solution of 1 (1 g, 3.07 mmol of 7-bromo-5-phenyl-1,4-benzodiazepine-2-one) in dry THF (20 mL) was cooled in an ice-water bath and a 60% dispersion of sodium hydride (152.2 mg) was added in one portion. After 20 minutes, di-4-morpholinylphosphinic chloride (943.9 mg, 4.76 mmol) was added at 0° C. and this was stirred for 30 minutes and allowed to warm to room temperature (Ning, R Y., et al., (1976) J Org Chem 41: 2724-2727). The mixture was stirred for 1.5 hours. To this mixture was then added a solution of acetylhydrazide (521.9 mg, 7.14 mmol) in dry butanol (5 mL) and stirring was continued at room temperature for 10 min. The solvents were evaporated and the residue was dissolved in butanol (10 mL) and heated to reflux for 5 hours. Butanol was removed under reduced pressure and the residue was partitioned between CH2Cl2 (50 mL) and water (50 mL). The water layer was extracted by CH2Cl2 (3×30 mL). The combined organic layer was washed by brine (30 mL). The organic layer was dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by flash chromatography (silica gel) to provide pure 8 [539.5 mg (40% yield)] as a white solid: mp 268.5-270° C.; IR (KBr) 2358, 1607, 1538, 1484, 1311, 1000, 801, 697 cm−1; 1H NMR (CDCl3) δ 2.82(s, 3H), 4.11(d,1H, J=12.8Hz), 5.49 (d,1H, J=12.8Hz), 7.21-7.68(m, 7H), 7.75 (dd, 1H, J=0.58 Hz and 1.5Hz); MS (EI) m/e (relative intensity) 354 (34), (M+, 16), 352 (34), 325(33), 323 (34), 273 (63), 245 (31), 232 (19), 204 (100), 183(23), 177 (36), 151 (24). Anal. Calcd. for C17H13BrN4: C, 57.81; H, 3.71; N, 15.86. Found C, 57.57; H,3.64: N, 15.70.

Workup

  1. stirringThe mixture was stirred for 1.5 hours
  2. stirringstirring
  3. waitwas continued at room temperature for 10 min
  4. customThe solvents were evaporated
  5. dissolutionthe residue was dissolved in butanol (10 mL)
  6. temperatureheated
  7. temperatureto reflux for 5 hours
  8. customButanol was removed under reduced pressure
  9. customthe residue was partitioned between CH2Cl2 (50 mL) and water (50 mL)
  10. extractionThe water layer was extracted by CH2Cl2 (3×30 mL)
  11. washThe combined organic layer was washed by brine (30 mL)
  12. dry with materialThe organic layer was dried (Na2SO4)
  13. customthe solvent was removed under vacuum
  14. customThe residue was purified by flash chromatography (silica gel)
  15. customto provide pure 8 [539.5 mg (40% yield)] as a white solid

Sources & evidence

ORD record
ord-49ee0e88b5b9402ab6058b52c288e900
Source dataset
uspto-grants-2009_11
Patent number
US07618958B2

Reaction notes

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