Trifluoroacetic acid → (R,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 1777218Notes

Reaction equation

HRID 1777218 reaction equation
[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[F:8][C:9]([F:46])([F:45])[C:10]1[CH:11]=[C:12]([C:20]2[N:24]=[CH:23][N:22](/[CH:25]=[CH:26]\[C:27]([NH:29][NH:30][C:31](=[O:44])[C@H:32]([NH:36]C(=O)OC(C)(C)C)[CH:33]([CH3:35])[CH3:34])=[O:28])[N:21]=2)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>ClCCl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:36][C@H:32]([CH:33]([CH3:35])[CH3:34])[C:31]([NH:30][NH:29][C:27](=[O:28])/[CH:26]=[CH:25]\[N:22]1[CH:23]=[N:24][C:20]([C:12]2[CH:11]=[C:10]([C:9]([F:45])([F:46])[F:8])[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=2)=[N:21]1)=[O:44]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 86703010(R,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 90016541(R,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 35%

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 (0.05 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.038 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.16 mL, 2 eq.) was added dropwise followed by DIPEA (0.095 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 (R,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 (0.017 g, yield: 26%). In a 10 mL round-bottom flask, (R,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 (0.2 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 (0.02 g), which was triturated with petroleum ether and dried under reduced pressure to yield (R,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 (0.007 g, yield: 35%).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg)
  2. customto afford the crude product (0.02 g), which
  3. customwas triturated with petroleum ether
  4. customdried under reduced pressure

Sources & evidence

ORD record
ord-5f971cd0db2c4156b0be807d9ae3004d
Source dataset
uspto-grants-2016_02
Patent number
US09266843B2

Reaction notes

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