Diisopropylethylamine → 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester

HRID 1959509Notes

Reaction equation

HRID 1959509 reaction equation
[CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])=[C:6](SC)[S:7][CH3:8])[CH3:2].FC(F)(F)C(O)=O.[CH:21]1([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][NH2:34])[CH:27]=2)[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([S:7][CH3:8])=[N:34][N:33]([C:28]2[CH:27]=[C:26]([C:25](=[O:35])[NH:24][CH:21]3[CH2:23][CH2:22]3)[CH:31]=[CH:30][C:29]=2[CH3:32])[C:11]=1[NH2:12])=[O:13])[CH3:2]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 2747745Ethyl 3,3-Bis(methylthio)-2-cyanoacrylateHCID 67024207N-cyclopropyl-3-hydrazinyl-4-methylbenzamide 2,2,2-trifluoroacetate

Product 1

HCID 111762795-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl esterYield 68.3%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
65 °C

Procedure

To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester 15 (78.0 mg, 0.359 mmol) in ethanol (3 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.100 g, 0.313 mmol) and diisopropylethylamine (0.0626 ml, 0.359 mmol). The mixture was heated to 65° C. for 2 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc and ether was added to the residue and a solid precipitated. The solid was collected on a flitted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester 16 as a white solid (80 mg, 59%). HPLC (4 minute 10-90 gradient) tR 2.18 min; MS m/z 375.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (d, J=3.7, 1H), 7.90 (d, J=7.9, 1H), 7.78 (s, 1H), 7.49 (d, J=8.0, 1H), 6.81 (bs, 2H), 6.30 (s, 2H), 2.86 (m, 1H), 2.45 (s, 3H), 2.11 (s, 3H), 0.68 (m, 2H), 0.57 (m, 2H) ppm.HPLC (4 minute 10-90 gradient) tR1.66 min; MS m/z 378.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=2.6, 1H), 7.92 (d, J=7.9, 1H), 7.81 (s, 1H), 7.51 (d, J=7.9, 1H), 6.24 (bs, 2H), 4.22 (q, J=6.6, 2H), 2.88 (m, 1H), 2.35 (s, 3H), 2.14 (s, 3H), 1.29 (t, J=6.7, 3H), 0.72 (m, 2H), 0.58 (m, 2H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 166.0, 163.1, 151.8, 148.5, 139.4, 135.8, 132.9, 131.1, 128.2, 126.7, 91.3, 58.9, 23.0, 17.2, 14.4, 12.3, 5.6 ppm.

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. customSolvents were removed in vacuo
  3. additionEtOAc and ether was added to the residue
  4. customa solid precipitated
  5. customThe solid was collected on a flitted funnel
  6. washwas washed with EtOAc and ether

Sources & evidence

ORD record
ord-5ff64913f2e24e6fac5da073471fe316
Source dataset
uspto-grants-2013_04
Patent number
US08410160B2

Reaction notes

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