Anisole → 2-tert-Butyl-5-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one

HRID 872185Notes

Reaction equation

HRID 872185 reaction equation
[C:1]([C:5]1[S:6][C:7]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:25]=[C:24]([NH:26][C:27]5[CH:31]=[C:30]([CH:32]6[CH2:34][CH2:33]6)[NH:29][N:28]=5)[C:23](=[O:35])[N:22](COCC[Si](C)(C)C)[N:21]=4)[C:15]=3[CH3:44])[CH2:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.FC(F)(F)C(O)=O>[C:1]([C:5]1[S:6][C:7]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:25]=[C:24]([NH:26][C:27]5[CH:31]=[C:30]([CH:32]6[CH2:34][CH2:33]6)[NH:29][N:28]=5)[C:23](=[O:35])[NH:22][N:21]=4)[C:15]=3[CH3:44])[CH2:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 7519AnisoleHCID 62406Trifluoromethanesulfonic acidHCID 666346912-tert-Butyl-5-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one

Product 1

HCID 569292332-tert-Butyl-5-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-oneYield 50%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

To a mixture of 2-tert-butyl-5-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 111b in dichloromethane (5 mL) and trifluoro-acetic acid (5 mL) was added anisole (0.11 mL, 1.0 mmol) and trifluoromethanesulfonic acid (0.054 mL, 0.61 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated. The residue was purified by reverse phase HPLC: C-18 column eluted with 20 to 60% acetonitrile in water with 1% ammonium hydroxide to afford 2-tert-butyl-5-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 111 (50 mg, 50%). M+1 502.2. 1H NMR (400 MHz, DMSO) δ 12.94 (s, 1H), 12.02 (s, 1H), 9.06 (s, 1H), 7.82 (s, 1H), 7.50 (dd, J=5.8, 3.5, 1H), 7.38 (dd, J=8.0, 5.6, 2H), 5.87 (d, J=2.0, 1H), 4.96 (s, 2H), 2.13 (s, 3H), 1.84 (td, J=8.4, 4.2, 1H), 1.47 (s, 9H), 0.98-0.82 (m, 2H), 0.71-0.59 (m, 2H).

Workup

  1. concentrationThe mixture was concentrated
  2. customThe residue was purified by reverse phase HPLC
  3. washC-18 column eluted with 20 to 60% acetonitrile in water with 1% ammonium hydroxide

Sources & evidence

ORD record
ord-66e876974f314b1099c3062e64d8bf35
Source dataset
uspto-grants-2015_03
Patent number
US08975260B2

Reaction notes

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