4-Chloro-6-(1-methyl-piperidin-4-yl)-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione → 8-Chloro-6-(1-methyl-piperidin-4-yl)-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

HRID 1771904Notes

Reaction equation

HRID 1771904 reaction equation
[Cl:1][C:2]1[C:13]2[C:12](=O)[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:38])[NH:25][CH:26]=[CH:27][C:28]=1[NH:29][CH:30]([CH3:37])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[NH:6]2>CC(O)=O.CO.[Zn]>[Cl:1][C:2]1[C:13]2[CH2:12][N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:38])[NH:25][CH:26]=[CH:27][C:28]=1[NH:29][CH:30]([CH3:37])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[NH:6]2

Participants

5

Reactant 1

HCID 1363340154-Chloro-6-(1-methyl-piperidin-4-yl)-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione

Product 1

HCID 1363340168-Chloro-6-(1-methyl-piperidin-4-yl)-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 176Acetic AcidSolventHCID 887MethanolSolvent

Conditions

Temperature
90 °C

Procedure

4-Chloro-6-(1-methyl-piperidin-4-yl)-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione (49 mg, 0.089 mmol) was mixed with zinc dust (196 mg, 1.0 mmol) in HOAc (10 mL). After it was heated at 90° C. for 40 min, the reaction mixture was cooled to 50° C. and diluted with a mixed solvent of MeOH:DCM (45 mL/5 mL) and filtered. The filtrate was evaporated at 95° C. (the bath temperature) under reduced pressure to dryness. The residue was diluted with a mixed solvent of DCM/MeOH (1:5) and basified with 28% aqueous NH4OH solution and concentrated. Chromatography of the residual crude with a mixed solvent of CH3CN/CH2Cl2/MeOH/28% aqueous NH4OH (63:10:37:1) followed by HPLC re-purification afforded the title compound in TFA salt form (6.2 mg, 11%). 1H NMR (DMSO-d6) δ 1.37 (d, J=6 Hz, 3H, CH3), 1.95-2.13 (4H), 2.52 (m, 2H), 2.80 (s, 3H, CH3), 3.15 (m, 2H), 3.50-3.65 (4H), 4.05 (m, 1H), 4.31 (m, 1H), 4.50 (br s, 2H), 6.18 (d, J=8 Hz, 1H), 6.89 (m, 1H), 7.01 (m, 1H), 7.29 (m, 1H), 7.37 (m, 1H), 7.99 (s, 1H), 9.60 (br s, 1H), 11.22 (d, J=6 Hz, 1H), 11.30 (d, J=6 Hz, 1H); ESI-MS m/z 537.3 (MO.

Workup

  1. temperaturethe reaction mixture was cooled to 50° C.
  2. filtrationDCM (45 mL/5 mL) and filtered
  3. customThe filtrate was evaporated at 95° C. (the bath temperature) under reduced pressure to dryness
  4. additionThe residue was diluted with a mixed solvent of DCM/MeOH (1:5)
  5. concentrationconcentrated
  6. customChromatography of the residual crude with a mixed solvent of CH3CN/CH2Cl2/MeOH/28% aqueous NH4OH (63:10:37:1) followed by HPLC re-purification

Sources & evidence

ORD record
ord-d461953d3ec64a7ca6186afe9c7e6ea1
Source dataset
uspto-grants-2016_02
Patent number
US09249147B2

Reaction notes

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