4-Toluenesulfonyl chloride → 5-Bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine

HRID 1749051Notes

Reaction equation

HRID 1749051 reaction equation
[NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CC#N>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[O:18][C:13]([C:14]([CH3:15])([CH3:16])[CH3:17])=[N:12][N:11]=2)[C:2]([NH2:1])=[N:7][CH:6]=1

Participants

5

Reactant 3

HCID 73974-Toluenesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 867276593-amino-6-bromo-N'-pivaloylpyrazine-2-carbohydrazide

Product 1

HCID 867276555-Bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amineYield 17%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
67.5 °C

Procedure

To 3-amino-6-bromo-N′-pivaloylpyrazine-2-carbohydrazide (2301 g, 7.28 mol) in MeCN (10.8 L) was added DIPEA (3.044 L, 17.48 mol) and p-toluenesulfonyl chloride (1665 g, 8.73 mol) portion-wise (˜280 g×6) at 50° C. over a period of 30 mins. The reaction temperature was maintained between 65-70° C. by controlling the rate of addition. After the addition was complete, the reaction mixture was stirred at 70° C. for 1 h. The mixture was cooled to room temperature and quenched with 5% NaHCO3 (aqueous, 24.2 L). The resulting suspension was stirred for 30 mini then filtered. The product was washed with water (14.8 L), pulled dry and dried at 50° C. for 16 h. The product was dissolved in DCM (12 L) and the phases separated. The organic phase was loaded onto a silica pad (6 kg) and the product was eluted with 20% EtOAc/DCM (8×10 L). Concentration of the product containing fractions gave 1987 g (92% yield) with a purity of 99.8% by HPLC of 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (36 g, 17%): 1H NMR Spectrum: (DMSO-d6) 1.43 (9H, s), 7.70 (2H, s), 8.39 (1H, s): Mass Spectrum [M+H]+=298.

Workup

  1. additionthe rate of addition
  2. additionAfter the addition
  3. temperatureThe mixture was cooled to room temperature
  4. customquenched with 5% NaHCO3 (aqueous, 24.2 L)
  5. stirringThe resulting suspension was stirred for 30 mini
  6. filtrationthen filtered
  7. washThe product was washed with water (14.8 L)
  8. custompulled dry
  9. customdried at 50° C. for 16 h
  10. dissolutionThe product was dissolved in DCM (12 L)
  11. customthe phases separated
  12. washthe product was eluted with 20% EtOAc/DCM (8×10 L)
  13. additionConcentration of the product containing fractions

Sources & evidence

ORD record
ord-062fcd1c384b42ce89a19fdc5d1f064b
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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