Methyl iodide → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methyl-butyl)-amide

HRID 246182

Reaction equation

HRID 246182 reaction equation
[OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[K+].[CH2:41]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[CH3:41][O:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6]

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 14797Potassium HydroxideHCID 2855718-Crown-6HCID 712860992-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide

Product 1

HCID 712859412-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methyl-butyl)-amideYield 50.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

In a 10 mL round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (73 mg, 0.135 mmol) was dissolved in THF (1.4 ml) to give a colorless solution. The reaction was cooled in an ice bath and crushed KOH (76 mg, 1.35 mmol), 18-crown-6 (36 mg, 0.135 mmol), and iodomethane (9 μl, 0.135 mmol) were added successively. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-70% EtOAc) to afford 38 mg (50%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methyl-butyl)-amide as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ: 9.18 (s, 1H), 8.64 (s, 1H), 8.52 (dd, J=9.1, 5.3 Hz, 1H), 8.15 (d, J=9.4 Hz, 1H), 7.72 (dd, J=9.6, 2.1 Hz, 1H), 7.13 (td, J=9.1, 1.9 Hz, 1H), 5.73 (s, 2H), 4.41 (td, J=9.0, 5.1 Hz, 1H), 4.17 (s, 3H), 3.60 (t, J=7.9 Hz, 2H), 3.44-3.55 (m, 2H), 3.27 (s, 3H), 1.48-1.72 (m, 3H), 0.91 (d, J=6.0 Hz, 3H), 0.86 (d, J=6.0 Hz, 3H), 0.85 (t, J=7.6 Hz, 2H), −0.08 (s, 9H).

Workup

  1. customto give a colorless solution
  2. temperatureThe reaction was cooled in an ice bath
  3. additionwere added successively
  4. customwas removed
  5. additionthen diluted with dichloromethane (10 mL)
  6. washwashed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL)
  7. dry with materialThe organic layer was dried over Na2SO4
  8. concentrationconcentrated
  9. customThe crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-70% EtOAc)

Sources & evidence

ORD record
ord-532adff43e0a4630b9e33cf3bb4b9f40
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Linked notes

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