Triethylamine → (S)-tert-Butyl (3-(benzyloxy)-1-(5-bromo-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate

HRID 1052363Notes

Reaction equation

HRID 1052363 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.C(N(CC)CC)C.[CH2:29]([O:36][CH2:37][CH2:38][C@H:39]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:40]([NH:42][N:43]1[CH:47]=[CH:46][C:45]([Br:48])=[C:44]1[C:49](=[O:59])[NH:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[C:53]([F:58])[CH:52]=1)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:29]([O:36][CH2:37][CH2:38][C@H:39]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:40]1[N:50]([C:51]2[CH:56]=[C:55]([F:57])[CH:54]=[C:53]([F:58])[CH:52]=2)[C:49](=[O:59])[C:44]2=[C:45]([Br:48])[CH:46]=[CH:47][N:43]2[N:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 24408BromineHCID 516892Sodium BicarbonateHCID 86722061(S)-tert-Butyl 4-(benzyloxy)-1-(3-bromo-2-(3,5-difluorophenylcarbamoyl)-1H-pyrrol-1-ylamino)-1-oxobutan-2-ylcarbamate

Product 1

HCID 131736114(S)-tert-Butyl (3-(benzyloxy)-1-(5-bromo-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamateYield 80%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Triphenylphosphine (1.29 g, 4.92 mmol) was dissolved in 21 mL anhydrous dichloromethane. Bromine (253 μl, 4.94 mmol) was added dropwise under argon atmosphere and the reaction was stirred at room temperature for 30 min. Triethylamine (1.96 mL, 4 mmol) and (S)-tert-butyl (4-(benzyloxy)-1-((3-bromo-2-((3,5-difluorophenyl)carbamoyl)-1H-pyrrol-1-yl)amino)-1-oxobutan-2-yl)carbamate (2.15 g, 3.52 mmol) were added and the reaction mixture was heated at 60° C. for 2 h. The mixture was poured into 75 mL 4% aqueous solution sodium bicarbonate and extracted with dichlorometane. The organics were dried over sodium sulphate, filtered and evaporated. The residue was re-dissolved in 19 mL tetrahydrofuran and 2 mL dichloromethane and, under argon conditions, sodium methanethiolate was added and the reaction was stirred at room temperature for 1 h. The mixture was poured into 4% aqueous solution sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulphate, filtered and concentrated. The residue was purified using Isolera® Purification System (0% to 20%, hexane-ethyl acetate) to obtain 1.66 g (74% yield) of the title compound as a white solid.

Workup

  1. temperaturethe reaction mixture was heated at 60° C. for 2 h
  2. extractionextracted with dichlorometane
  3. dry with materialThe organics were dried over sodium sulphate
  4. filtrationfiltered
  5. customevaporated
  6. dissolutionThe residue was re-dissolved in 19 mL tetrahydrofuran
  7. addition2 mL dichloromethane and, under argon conditions, sodium methanethiolate was added
  8. stirringthe reaction was stirred at room temperature for 1 h
  9. additionThe mixture was poured into 4% aqueous solution sodium bicarbonate
  10. extractionextracted with ethyl acetate
  11. washThe organic layer was washed with water, brine
  12. dry with materialdried over sodium sulphate
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customThe residue was purified
  16. customIsolera® Purification System (0% to 20%, hexane-ethyl acetate)

Sources & evidence

ORD record
ord-f0c7f3419c1845faaab90136e990412b
Source dataset
uspto-grants-2016_07
Patent number
US09388189B2

Reaction notes

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