Triethylamine → Tert-butyl 4-(2-(3-amino-6-bromopyrazine-2-carbonyl)hydrazinecarbonyl)benzyl(methyl)carbamate

HRID 331506Notes

Reaction equation

HRID 331506 reaction equation
[NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:13]([O:17][C:18]([N:20]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:27]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:20]([CH3:21])[C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:31][CH:30]=2)=[O:28])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 224502424-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}benzoic acidHCID 580702563-Amino-6-bromopyrazine-2-carbohydrazide2×

Product 1

HCID 59472138Tert-butyl 4-(2-(3-amino-6-bromopyrazine-2-carbonyl)hydrazinecarbonyl)benzyl(methyl)carbamateYield 53.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

3-amino-6-bromo-pyrazine-2-carbohydrazide (12.91 g, 55.64 mmol), 4-[[tert-butoxycarbonyl(methyl)amino]methyl]benzoic acid (14.76 g, 55.64 mmol) and triethylamine (12.39 g, 17.07 mL, 122.4 mmol) were suspended in N,N-dimethylformamide (200 mL) and stirred at ambient temperature for 30 minutes. A further 3-amino-6-bromo-pyrazine-2-carbohydrazide (3 g, 12.93 mmol) was added and left to stir for 18 hours at ambient temperature. The reaction mixture was concentrated in vacuo to remove most of the N,N-dimethylformamide. The residue was then diluted with ethyl acetate and water. The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution followed by a brine wash. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to a yellow sticky solid. The solid was triturated with ethyl acetate to give a beige solid (this is the hydrazide starting material), the crude mother liquors were concentrated and purified by column chromatography (ISCO Companion XL, 330 g gold column) dry loaded and eluted with 30 to 70% ethyl acetate/petroleum ether to give a yellow sticky gum. This gum was then crystallised from petroleum ether to give tert-butyl 4-(2-(3-amino-6-bromopyrazine-2-carbonyl)hydrazinecarbonyl)benzyl(methyl)carbamate as a yellow powder (14.16 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.20 (m, 1H), 1.38-1.45 (br d, 9H), 2.80 (br s, 3H), 4.02-4.04 (m, 1H), 4.45 (s, 2H), 7.34 (d, 2H), 7.69 (br s, 2H), 7.89 (d, 2H), 8.44 (s, 1H) ppm.

Workup

  1. waitleft
  2. stirringto stir for 18 hours at ambient temperature
  3. concentrationThe reaction mixture was concentrated in vacuo
  4. customto remove most of the N,N-dimethylformamide
  5. additionThe residue was then diluted with ethyl acetate and water
  6. customThe organic layer was separated
  7. washwashed with saturated aqueous sodium bicarbonate solution
  8. washwash
  9. dry with materialThe organic extracts were dried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo to a yellow sticky solid
  12. customThe solid was triturated with ethyl acetate
  13. customto give a beige solid (
  14. concentrationwere concentrated
  15. custompurified by column chromatography (ISCO Companion XL, 330 g gold column)
  16. customdry
  17. washeluted with 30 to 70% ethyl acetate/petroleum ether
  18. customto give a yellow sticky gum
  19. customThis gum was then crystallised from petroleum ether

Sources & evidence

ORD record
ord-abb243e9a726425c86e21894c4020d29
Source dataset
uspto-grants-2014_11
Patent number
US08877759B2

Reaction notes

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