Lithium Hydroxide → isopropyl 4-(1-(3-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-2-methyl-1H-indol-1-yl)ethyl)piperidine-1-carboxylate

HRID 1527017Notes

Reaction equation

HRID 1527017 reaction equation
Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[C:17]=1[CH3:33])=[O:15].CN(C=O)C.C1COCC1.C(N(C(C)C)C(C)C)C.[C:53](Cl)(=[O:58])[O:54][CH:55]([CH3:57])[CH3:56].[Li+].[OH-]>>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:28][CH2:29][N:30]([C:53]([O:54][CH:55]([CH3:57])[CH3:56])=[O:58])[CH2:31][CH2:32]2)[CH3:26])[C:17]=1[CH3:33])=[O:15]

Participants

7

Reactant 6

HCID 3939Lithium HydroxideHCID 6228DimethylformamideHCID 7917Isopropyl chloroformateHCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 117780708HCID 117780708, compound2×

Product 1

HCID 117807954isopropyl 4-(1-(3-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-2-methyl-1H-indol-1-yl)ethyl)piperidine-1-carboxylateYield 55.2%

Conditions

Temperature
0 °C

Procedure

A 250 mL round bottom flask was charged with a magnetic stir bar, (R or S)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide hydrochloride (0.467 g, 0.987 mmol) (Compound 326), DMF (2.468 ml, 0.987 mmol), THF (2.468 ml, 0.987 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.638 g, 4.94 mmol). The reaction was cooled to 0° C. and isopropyl carbonochloridate (0.160 ml, 1.086 mmol) was added drop wise via syringe. The reaction was allowed to stir for 2 h to rt and was then treated with 5 N LiOH for 1 h to remove any acylated pyridone. This material was extracted with ethyl acetate, washed with brine, dried with MgSO4 and filtered and conc. in vacuo. The resulting material was purified via silica gel chromatography (50 g) using ethyl acetate/MeOH (5:1) as eluent to afford pure title compound as a pale yellow solid (0.300 g, 0.545 mmol, 55.2% yield). LCMS 523 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 11.59 (br. s., 1 H), 7.74 (d, J=7.8 Hz, 1 H), 7.69 (t, J=4.9 Hz, 1 H), 7.62 (d, J=7.8 Hz, 1 H), 7.13-7.01 (m, 2 H), 6.15 (s, 1 H), 4.78-4.67 (m, 1 H), 4.32 (d, J=4.9 Hz, 2 H), 4.23-4.12 (m, 1 H), 4.12-4.02 (m, 1 H), 3.84 (s, 3 H), 3.82-3.74 (m, 1 H), 2.79-2.66 (m, 1 H), 2.58 (s, 3 H), 2.46-2.34 (m, 2 H), 2.20 (s, 3 H), 1.96-1.88 (m, 1 H), 1.58-1.46 (m, 4 H), 1.15 (d, J=6.0 Hz, 6 H), 0.95-0.89 (m, 1 H), 0.74-0.65 (m, 1 H).

Workup

  1. additionA 250 mL round bottom flask was charged with a magnetic stir bar
  2. customto remove any acylated pyridone
  3. extractionThis material was extracted with ethyl acetate
  4. washwashed with brine
  5. dry with materialdried with MgSO4
  6. filtrationfiltered and conc. in vacuo
  7. customThe resulting material was purified via silica gel chromatography (50 g)

Sources & evidence

ORD record
ord-58b7ec9a4eb44491aea654979abede0c
Source dataset
uspto-grants-2015_07
Patent number
US09085583B2

Reaction notes

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