4-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione → 8-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one

HRID 929126Notes

Reaction equation

HRID 929126 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:43])[NH:25][CH:26]=[CH:27][C:28]=1[NH:29][CH2:30][CH:31]([OH:42])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[CH3:41])[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:43])[NH:25][CH:26]=[CH:27][C:28]=1[NH:29][CH2:30][CH:31]([OH:42])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[CH3:41])[NH:6]2

Participants

5

Reactant 1

HCID 1363511614-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione

Product 1

HCID 1363511168-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-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-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (50.1 mg, 0.083 mmol) was mixed with zinc dust (196 mg, 1.0 mmol) in HOAc (15 mL). After it was heated at 90° C. for 1 h, 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 CH2Cl2/MeOH/28% aqueous NH4OH (16:10:1) followed by HPLC re-purification afforded the title compound in TFA salt form (9.23 mg, 19%). 1H NMR (DMSO-d6) δ 1.95-2.12 (4H), 2.16 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.80 (s, 3H, CH3), 3.19 (m, 2H), 3.50-3.75 (4H), 4.07 (m, 2H), 4.12 (m, 1H), 4.30 (s, 1H), 4.49 (s, 2H), 6.22 (m, 1H), 6.80-6.95 (3H), 7.40 (1H), 7.95 (s, 1H), 9.64 (br s, 1H), 11.02 (br s, H, NH), 11.29 (br s, 1H, NH); ESI-MS m/z 591.3 (MH+).

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 CH2Cl2/MeOH/28% aqueous NH4OH (16:10:1) followed by HPLC re-purification

Sources & evidence

ORD record
ord-9d7d690f48eb42249cc585e37b8d45a8
Source dataset
uspto-grants-2016_03
Patent number
US09290503B2

Reaction notes

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