Trifluoroacetic acid → (S,Z)-2-amino-N'-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate

HRID 1777213Notes

Reaction equation

HRID 1777213 reaction equation
[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC(=O)[NH:14][C@@H:15]([CH:43]([CH3:45])[CH3:44])[C:16]([NH:18][NH:19][C:20](=[O:42])/[CH:21]=[CH:22]\[N:23]1[CH:27]=[N:26][C:25]([C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)=[N:24]1)=[O:17])(C)(C)C>ClCCl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:14][C@@H:15]([CH:43]([CH3:45])[CH3:44])[C:16]([NH:18][NH:19][C:20](=[O:42])/[CH:21]=[CH:22]\[N:23]1[CH:27]=[N:26][C:25]([C:28]2[CH:29]=[C:30]([C:38]([F:40])([F:41])[F:39])[CH:31]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:33]=2)=[N:24]1)=[O:17]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 86703009(S,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate

Product 1

HCID 90021935(S,Z)-2-amino-N'-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetateYield 2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.25 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.19 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.81 mL, 2 eq.) was added dropwise followed by DIPEA (0.48 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (S,Z)-tert-butyl(1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.07 g, yield: 18%). In a 10 mL round-bottom flask, (S,Z)-tert-butyl(1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.05 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.01 g), which was triturated with petroleum ether and dried under reduced pressure to yield (S,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.006 g, yield: 2%).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg)
  2. customto afford the crude product (0.01 g), which
  3. customwas triturated with petroleum ether
  4. customdried under reduced pressure

Sources & evidence

ORD record
ord-907fba62d98445c590b77439f6aae26a
Source dataset
uspto-grants-2016_02
Patent number
US09266843B2

Reaction notes

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