Sodium hydride → 2-[6-fluoro-1-(6-morpholin-4-yl-pyridin-3-ylmethyl)-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 246253Notes

Reaction equation

HRID 246253 reaction equation
[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[NH:20][N:19]=3)[N:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:10]=1)=[O:8])[CH3:5].[H-].[Na+].Cl.Cl[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[N:45][CH:46]=1>CN(C=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH2:40][C:41]4[CH:46]=[N:45][C:44]([N:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[CH:43][CH:42]=4)[N:19]=3)[N:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH3:5]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 712883712-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amideHCID 866779664-(5-(Chloromethyl)pyridin-2-yl)morpholine hydrochloride

Product 1

HCID 712883572-[6-fluoro-1-(6-morpholin-4-yl-pyridin-3-ylmethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amideYield 53.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

2-(6-Fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (80 mg, 0.16 mmol) was combined with DMF (8 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 19 mg, 0.48 mmol) was added and the reaction was stirred at 0° C. for 10 min. 4-(5-(Chloromethyl)pyridin-2-yl)morpholine hydrochloride (60 mg, 0.24 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with 5 mL of brine and 10 mL of water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford 58 mg (53%) of 2-[6-fluoro-1-(6-morpholin-4-yl-pyridin-3-ylmethyl)-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 foaming solid. MS: (M+H)+=675.

Workup

  1. customto give a yellow solution
  2. stirringthe reaction mixture was stirred at 0° C. for 30 min
  3. temperaturethen warmed to room temperature
  4. stirringstirred for 2 h
  5. customThe reaction mixture was quenched with 5 mL of brine and 10 mL of water
  6. extractionextracted with ethyl acetate (2×30 mL)
  7. washThe combined organic layers were washed with water and brine
  8. customthen dried
  9. concentrationconcentrated in vacuo
  10. customThe crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane)

Sources & evidence

ORD record
ord-91fecedf1b2d4991a8880b157a1c1e12
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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