(R)-1-Boc-3-methylpiperazine → (R)-tert-Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-3-methyl-1H-indol-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate

HRID 516689Notes

Reaction equation

HRID 516689 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:11]3[C:12]([CH3:20])=[CH:13][N:14]([CH:17]([CH3:19])[CH3:18])[C:15]=3[CH:16]=2)=[CH:4][CH:3]=1.[CH3:34][C@H:35]1[NH:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]1.CC(C)([O-])C.[Na+]>[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCOCC1>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:40]3[CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][C@H:35]3[CH3:34])=[N:7][CH:6]=2)[CH:16]=[C:15]2[C:11]=1[C:12]([CH3:20])=[CH:13][N:14]2[CH:17]([CH3:19])[CH3:18])=[O:22]

Participants

6

Reactant 3

HCID 2756811(R)-1-Boc-3-methylpiperazineHCID 23676156Sodium t-butoxideHCID 866773496-(6-chloropyridin-3-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide

Product 1

HCID 68210133(R)-tert-Butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-3-methyl-1H-indol-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylateYield 15.8%

Reagents, catalysts & solvents 2

HCID 86677350Pd XPhosCatalystHCID 312751,4-DioxaneSolvent

Procedure

Added 6-(6-chloropyridin-3-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (131 mg, 0.283 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (70.8 mg, 0.354 mmol), sodium tert-butoxide (59.8 mg, 0.623 mmol) and 1,4-Dioxane (2 mL) to a microwave vial and degassed for 10 minutes. Added Pd XPhos (10.45 mg, 0.014 mmol) and heated to 100° C. for 16 hours. Concentrated, added DCM and water. Filtered, separated phases. Extracted aqueous phase twice more with DCM. Combined DCM extracts and and washed with water, brine, dried (MgSO4), filtered and rotovapped off DCM. The residue was purified via Biotage (0% to 5% MeOH:DCM; 10 g-HP-silica gel column) Obtained 28 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J=6.32 Hz, 3H), 1.44-1.57 (m, 15H), 2.06 (s, 3H), 2.28 (s, 3H), 2.39 (s, 3H), 2.87-3.36 (m, 3H), 3.57 (s, 1H), 3.86-4.30 (m, 3H), 4.50 (d, J=9.35 Hz, 1H), 4.58-4.79 (m, 3H), 5.87 (s, 1H), 6.64 (d, J=8.59 Hz, 1H), 7.01 (s, 1H), 7.45 (s, 1H), 7.76 (d, J=8.08 Hz, 1H), 8.46 (d, J=2.27 Hz, 1H), 12.42 (br. s., 1H). LCMS: [M+H]+ 627.5.

Workup

  1. customdegassed for 10 minutes
  2. concentrationConcentrated
  3. additionadded DCM and water
  4. filtrationFiltered
  5. customseparated phases
  6. washCombined DCM extracts and and washed with water, brine
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. customThe residue was purified via Biotage (0% to 5% MeOH:DCM; 10 g-HP-silica gel column)

Sources & evidence

ORD record
ord-d10cfb4f00f44e01b229b71919c3bfaf
Source dataset
uspto-grants-2015_08
Patent number
US09114141B2

Reaction notes

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