Trimethylsilyl iodide → N-((6-amino-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamide

HRID 1476964Notes

Reaction equation

HRID 1476964 reaction equation
[C:1]([O:5]C(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[C:21]([CH3:32])=[CH:22][N:23]([CH:29]([CH3:31])[CH3:30])[C:24]=3[CH:25]=[C:26]([Br:28])[CH:27]=2)=[O:18])=[C:10]([O:33]C)[N:9]=1)(C)(C)C.[Si](I)(C)(C)C>C(#N)C.C(Cl)Cl>[NH4+:7].[OH-:5].[CH3:1][OH:5].[NH2:7][C:8]1[NH:9][C:10](=[O:33])[C:11]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[C:21]([CH3:32])=[CH:22][N:23]([CH:29]([CH3:30])[CH3:31])[C:24]=3[CH:25]=[C:26]([Br:28])[CH:27]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1

Participants

6

Reactant 2

HCID 85247Trimethylsilyl iodideHCID 71274276tert-butyl (5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)carbamate

Product 2

HCID 21894508Ammonium hydroxide methanolYield 5%HCID 54670365N-((6-amino-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamideYield 18.8%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
70 °C

Procedure

To a stirred solution of tert-butyl(5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.80 g, 1.467 mmol) in acetonitrile (20 mL) was added dropwise at RT TMSI (0.50 ml, 3.67 mmol). A reflux condenser was attached and the reaction was purged with N2 and heated to 70° C. After stirring for 30 minutes LCMS indicated that the reaction was complete (89% pure with 11% possible iodinated side product as the only other impurity). After 1 hr the reaction was quenched with MeOH (5 mL) and stirred for 30 minutes. The clear brown solution was evaporated to dryness under vacuum, taken up in CH2Cl2, washed with aq. Na2S2O3, (a ppt. formed that was filtered off), dried (Na2SO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-10 g, 0 to 7% (5% NH4OH/MeOH) in CH2Cl2) gave the product N-((6-amino-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamide (59.6 mg, 0.138 mmol, 9.4% yield) as a white solid. Note: The ppt. that was filtered off during the aq. Na2S2O3 wash was later shown to contain product. This solid was washed with water and dried under vacuum to give additional product as an off-white solid (602 mg, 1.4 mmol, 95%, 100% pure by LCMS). 1H NMR (400 MHz, DMSO-d6) δ=10.59 (br. s., 1H), 8.13 (t, J=4.4 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.33 (s, 1H), 6.99 (d, J=1.5 Hz, 1H), 5.83 (br. s., 2H), 5.19 (s, 1H), 4.74 (dt, J=6.6, 13.3 Hz, 1H), 4.22 (d, J=4.8 Hz, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.39 (d, J=6.6 Hz, 6H). MS(ES)+m/e 431.1 [M+H]+.

Workup

  1. customA reflux condenser was attached
  2. customthe reaction was purged with N2
  3. customAfter 1 hr the reaction was quenched with MeOH (5 mL)
  4. stirringstirred for 30 minutes
  5. customThe clear brown solution was evaporated to dryness under vacuum
  6. washwashed with aq. Na2S2O3
  7. customformed
  8. filtrationthat was filtered off),
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated under vacuum
  12. customPurification by silica gel chromatography (Analogix

Sources & evidence

ORD record
ord-bb6f4981b1204f2582242d8d77d3eccf
Source dataset
uspto-grants-2016_08
Patent number
US09402836B2

Reaction notes

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