Tetrahydrofuran → {6-Chloro-3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indazol-1-yl}-acetic acid tert-butyl ester

HRID 246245Notes

Reaction equation

HRID 246245 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].C1COCC1.CC(C)([O-])C.[K+].Br[CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55]>[NH4+].[Cl-].O>[C:57]([O:56][C:54](=[O:55])[CH2:53][N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:22]([C:19]2[N:20]=[C:21]3[C:13]([C:11](=[O:12])[NH:10][C@H:8]([CH3:9])[C:7]([N:5]4[CH2:6][CH:3]([C:1]#[N:2])[CH2:4]4)=[O:40])=[CH:14][N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:16]3=[N:17][CH:18]=2)=[N:23]1)([CH3:60])([CH3:59])[CH3:58]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 79177tert-Butyl bromoacetateHCID 23665647Potassium tert-butoxideHCID 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 71279425{6-Chloro-3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indazol-1-yl}-acetic acid tert-butyl esterYield 37%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
0 °C

Procedure

In a 20 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 (80 mg, 0.14 mmol) was combined with THF (3 ml) to give a light yellow solution. It was cooled to 0° C. and potassium tert-butoxide (19 mg, 0.17 mmol) was added. It was stirred at 0° C. for 30 min and tert-butyl 2-bromoacetate (22 μl, 0.14 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. The reaction mixture was diluted with aqueous NH4Cl and water, then extracted with Et2O (2×30 ml). The combined organics were washed with water and brine then dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (5% to 80% EtOAc/CH2Cl2) to isolate 35 mg (37%) {6-Chloro-3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indazol-1-yl}-acetic acid tert-butyl ester as a foaming solid. MS: (M+H)+=694.

Workup

  1. customto give a light yellow solution
  2. stirringthe reaction was stirred at 0° C. for 1 h
  3. extractionextracted with Et2O (2×30 ml)
  4. washThe combined organics were washed with water and brine
  5. dry with materialthen dried over MgSO4
  6. concentrationconcentrated
  7. customThe crude residue was purified by SiO2 chromatography (5% to 80% EtOAc/CH2Cl2)

Sources & evidence

ORD record
ord-50945fb57f354b3bbd11105e1ef808e4
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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