Trifluoroacetic acid → N-(6-(4-(5-amino-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

HRID 538104Notes

Reaction equation

HRID 538104 reaction equation
[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[N:11][C:10]([NH:13][C:14](=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)=[CH:9][CH:8]=1)#[N:2].N[NH:29][C:30]([NH2:32])=[S:31].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH2:32][C:30]1[S:31][C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[N:12]=[N:11][C:10]([NH:13][C:14](=[O:27])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=3)=[CH:9][CH:8]=2)=[N:2][N:29]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 2723789ThiosemicarbazideHCID 86687874N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

Product 1

HCID 74982828N-(6-(4-(5-amino-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
65 °C

Procedure

1118 (1.0 equiv., 0.154 mol, 58.2 g) was charged into a 500 mL round bottom flask along with thiosemicarbazide (1.2 equiv., 0.184 mol, 16.8 g). TFA (5 vol., 291 mL) slowly added to reaction vessel while stirring. The reaction slurry was heated in a 65° C. bath with an open top reflux condenser. The reaction usually goes to completion after 5 hours (determined by LC/MS). Toluene (10 vol., 582 mL) added to deep red solution, azeotroped by rotary evaporation (bath≦30° C.) to a red oil. Slowly transferred oil to a well stirred 6000 mL Erlenmeyer flask containing 7.5% sodium bicarbonate solution (69 vol., 4.0 L) cooled in a 0° C. bath. The crystals were filtered through a Büchner funnel and rinsed twice with diethyl ether (5 vol., 2×250 mL). Dried under high vacuum to a constant weight to afford N-(6-(4-(5-amino-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 657; yield of 55.7 g (80%). 1H NMR (300 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.21 (d, J=9.2 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.51-7.26 (m, 4H), 6.99 (s, 2H), 3.88 (s, 2H), 2.87 (m, 4H), 1.71 (m, 4H).

Workup

  1. temperaturereflux condenser
  2. customThe reaction
  3. customazeotroped by rotary evaporation (bath≦30° C.) to a red oil
  4. additionSlowly transferred oil to a well stirred 6000 mL Erlenmeyer flask containing 7.5% sodium bicarbonate solution (69 vol., 4.0 L)
  5. temperaturecooled in a 0° C. bath
  6. filtrationThe crystals were filtered through a Büchner funnel
  7. washrinsed twice with diethyl ether (5 vol., 2×250 mL)
  8. customDried under high vacuum to a constant weight

Sources & evidence

ORD record
ord-1f9d2b230a09404c8affd370253fc61b
Source dataset
uspto-grants-2014_10
Patent number
US08865718B2

Reaction notes

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