Diisopropylethylamine → (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-methyl-N-(2-morpholinoacetyl)acrylohydrazide

HRID 508687Notes

Reaction equation

HRID 508687 reaction equation
[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[N:26]([C:28](=[O:36])[CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[NH2:27].[CH2:37](P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:26]([C:28](=[O:36])[CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[NH:27][CH3:37])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 86703006(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acidHCID 86703007N-methyl-2-morpholinoacetohydrazide

Product 1

HCID 86703008(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-methyl-N-(2-morpholinoacetyl)acrylohydrazideYield 12%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-60 °C

Procedure

In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.3 g, 1.0 eq.) was dissolved in THF:EtOAc (15 mL, 2:1) and cooled to −60° C. where N-methyl-2-morpholinoacetohydrazide (0.23 g, 1.5 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.27 mL, 2.5 eq.) was added dropwise followed by DIPEA (0.45 mL, 3 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 (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-methyl-N-(2-morpholinoacetyl)acrylohydrazide (0.052 g, yield: 12%).

Workup

  1. additionwas introduced dropwise
  2. concentrationThe reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg)
  3. customto afford the crude product that
  4. customwas purified by column chromatography (60/120 silica gel)
  5. washthe desired compound started eluting from 3% methanol/dichloromethane)
  6. additionFractions containing the desired compounds

Sources & evidence

ORD record
ord-a83b445fb2a34db2a330991de79774ff
Source dataset
uspto-grants-2015_08
Patent number
US09096543B2

Reaction notes

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