Sodium hydride → 2-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide

HRID 246247Notes

Reaction equation

HRID 246247 reaction equation
[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].Br.[CH3:44][N:45]([CH2:47][CH2:48]Br)[CH3:46]>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:48][CH2:47][N:45]([CH3:46])[CH3:44])[N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 457913472-Bromoethyldimethylammonium bromideHCID 712888432-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide

Product 1

HCID 712890492-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amideYield 43.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

In a 10 mL pear-shaped flask, 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (280 mg, 0.48 mmol) was combined with DMF (8 ml) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 70 mg, 1.74 mmol) was added and the reaction was stirred at 0° C. for 10 min. Dimethylaminoethyl bromide hydrobromide (169 mg, 0.73 mmol) was added and the reaction was stirred at 0° C. for 30 min then allowed to warm up to room temperature and stirred for 2 h. The reaction was quenched with 5 ml of brine and 10 ml of water then extracted with EtOAc (2×). The combined organics were washed with water and brine then dried and purified by SiO2 chromatography (0% to 10% MeOH/CH2Cl2 to isolate 135 mg (43%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a foaming solid. MS: (M+H)+=651.

Workup

  1. customto give a yellow solution
  2. stirringthe reaction was stirred at 0° C. for 30 min
  3. temperatureto warm up to room temperature
  4. stirringstirred for 2 h
  5. customThe reaction was quenched with 5 ml of brine and 10 ml of water
  6. extractionthen extracted with EtOAc (2×)
  7. washThe combined organics were washed with water and brine
  8. customthen dried
  9. custompurified by SiO2 chromatography (0% to 10% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-12ec56f0b8cc4967895d4719ed76add7
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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