Hydrazine → N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

HRID 1961162Notes

Reaction equation

HRID 1961162 reaction equation
[Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([NH:16][C@@H:17]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[O:15])[S:12][CH:13]=2)[N:4]([CH3:41])[N:3]=1.NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:17]([NH:16][C:14]([C:11]1[S:12][CH:13]=[C:9]([C:5]2[N:4]([CH3:41])[N:3]=[C:2]([Cl:1])[C:6]=2[CH2:7][CH3:8])[CH:10]=1)=[O:15])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38]

Participants

5

Reactant 2

HCID 9321HydrazineHCID 578266164-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

Product 1

HCID 57826605N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamideYield 83%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (190 mg, 0.32 mmol) in tetrahydrofuran (1.58 ml) and methanol (1.58 ml) at 25° C. was added hydrazine (0.08 ml, 2.53 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in Ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (145 mg, 0.26 mmol, 83% yield) as a yellow solid: LCMS (ES) m/z=471, 473 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (br. s., 1H) 7.87-7.99 (m, 6H) 7.69 (d, J=7.71 Hz, 1H)) 7.57 (d, J=7.83 Hz, 1H) 7.40-7.44 (m, 1H) 4.43-4.48 (m, 1H) 3.74 (s, 3H) 2.99-3.06 (m, 4H) 2.40 (d, J=7.58 Hz, 2H) 1.04 (t, J=7.58 Hz, 3H).

Workup

  1. concentrationAfter 12 h the solution was concentrated
  2. customdry loaded onto silica
  3. custompurified by column chromatography (5% MeOH in DCM (1% NH4OH))
  4. additionThe free base was transferred to the HCl salt by addition of excess 4M HCl in Ether (2 ml) to the residue in DCM (2 ml)

Sources & evidence

ORD record
ord-883132e837494d35bc6c186ff6ca522a
Source dataset
uspto-grants-2013_04
Patent number
US08410158B2

Reaction notes

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