HCID 71288350, compound → HCID 71288994, compound

HRID 246234Notes

Reaction equation

HRID 246234 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([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]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[Cu][C:42]#[N:43]>CN1CCCC1=O>[C:42]([C:2]1[CH:7]=[CH:6][C:5]([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]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[CH:14]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1)#[N:43]

Participants

4

Reactant 2

HCID 71288350HCID 71288350, compoundHCID 178418546HCID 178418546, compound

Product 1

HCID 71288994HCID 71288994, compound

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
200 °C

Procedure

To a 20 ml microwave vial was added 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-bromophenyl)-ethyl]-amide (62 mg, 0.10 mmol), copper (I) cyanide (18 mg, 0.20 mmol), and N-methyl-pyrrolidinone (6 ml) (HPLC grade, dried with 4A powdered molecular sieves). The resulting solution was purged with nitrogen then the vial sealed, and heated in an oil bath at 200° C. After 2.5 h the reaction was allowed to cool to room temperature over 17 h. The reaction was separated into two vials and each was independently subjected to heating in a microwave reactor at 200-230° C. for 2.5 h. The reactions were combined, diluted with water (50 ml), and extracted with ethyl acetate (50 ml) two times (5 ml of brine was added to clear phases). The organic layers were washed with brine (25 ml), combined, dried over magnesium sulfate, filtered, and further dried under a stream of nitrogen. The crude brown solid was purified by flash chromatography (4 g silicycle) with 0% to 60% EtOAc in hexanes. The appropriate fractions were combined and dried from a mixture dichloromethane and hexanes yielding 32 mg (56%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-phenyl)-ethyl]-amide as a light yellow solid.

Workup

  1. customThe resulting solution was purged with nitrogen
  2. temperatureto cool to room temperature over 17 h
  3. customThe reaction was separated into two vials
  4. temperatureto heating in a microwave reactor at 200-230° C. for 2.5 h
  5. additiondiluted with water (50 ml)
  6. extractionextracted with ethyl acetate (50 ml) two times (5 ml of brine was added to clear phases)
  7. washThe organic layers were washed with brine (25 ml)
  8. dry with materialdried over magnesium sulfate
  9. filtrationfiltered
  10. customfurther dried under a stream of nitrogen
  11. customThe crude brown solid was purified by flash chromatography (4 g silicycle) with 0% to 60% EtOAc in hexanes
  12. dry with materialdried from a mixture dichloromethane and hexanes yielding 32 mg (56%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-phenyl)-ethyl]-amide as a light yellow solid

Sources & evidence

ORD record
ord-fb45c6228d094ea5a5da08b87162ee41
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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