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

HRID 246156

Reaction equation

HRID 246156 reaction equation
[OH:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:9]=1)=[O:7])[CH3:4].[OH-].[K+].[CH2:38]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[CH3:38][O:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:9]=1)=[O:7])[CH3:4]

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 14797Potassium HydroxideHCID 2855718-Crown-6HCID 712861022-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide

Product 1

HCID 712860682-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amideYield 49%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

In a 10 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide (44 mg, 0.085 mmol) was dissolved in THF (0.85 ml) to give a colorless solution. The reaction was cooled in an ice bath. Crushed KOH (64 mg, 1.14 mmol), catalytic 18-crown-6, and iodomethane (9 μl, 0.147 mmol) were added successively to the cooled solution. 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%-100% EtOAc) to afford 22 mg (49%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a white solid. MS: [M+Na]+=551.

Workup

  1. customto give a colorless solution
  2. temperatureThe reaction was cooled in an ice bath
  3. customwas removed
  4. additionthen diluted with dichloromethane (10 mL)
  5. washwashed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL)
  6. dry with materialThe organic layer was dried over Na2SO4
  7. concentrationconcentrated
  8. customThe crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-100% EtOAc)

Sources & evidence

ORD record
ord-a01a6f5cfaa04c8ab9037bae77d13a9f
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Linked notes

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