Hydrazine → N-[(1S)-2-amino-1-(cyclohexyl methyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

HRID 2392059Notes

Reaction equation

HRID 2392059 reaction equation
[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:36])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@H:16]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:14])[S:10][C:11]=1[CH3:12].NN>O1CCCC1.CO>[NH2:25][CH2:24][C@@H:16]([NH:15][C:13]([C:9]1[S:10][C:11]([CH3:12])=[C:7]([C:6]2[N:5]([CH3:36])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:14])[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1

Participants

5

Reactant 2

HCID 9321HydrazineHCID 578266504-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

Product 1

HCID 24996595N-[(1S)-2-amino-1-(cyclohexyl methyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamideYield 61.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (231 mg, 0.44 mmol) in tetrahydrofuran (2.20 ml) and methanol (2.20 ml) at 25° C. was added hydrazine (0.14 ml, 4.40 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 then transferred to the HCl salt adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexyl methyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (124 mg, 0.27 mmol, 60% yield) as a yellow solid: LCMS (ES) m/z=394, 396 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (br. s., 1H) 7.97 (br. s., 3H) 7.86 (s, 1H) 7.70 (s, 1H) 4.24-4.26 (m, 1H) 3.71 (s, 3H) 2.90-2.99 (m, 2H) 2.36 (s, 3H) 1.75-1.79 (m, 1H) 1.61 1.64 (m, 4H) 1.48-1.51 (m, 1H) 1.31-1.36 (m, 2H) 1.10-1.14 (m, 2H) 0.91-0.94 (m, 2H).

Workup

  1. concentrationthe solution was concentrated
  2. customdry loaded onto silica
  3. custompurified by column chromatography (5% MeOH in DCM (1% NH4OH))
  4. additionadding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml)

Sources & evidence

ORD record
ord-0f6e27c3d0ea44c28568737e5e4bc8b5
Source dataset
uspto-grants-2012_09
Patent number
US08273782B2

Reaction notes

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