Sodium Iodide → 2-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide

HRID 245957

Reaction equation

HRID 245957 reaction equation
[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23](Br)[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].[I-:36].[Na+].CN[C@@H]1CCCC[C@H]1NC.[Cl:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[NH:54][N:53]=[CH:52]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C1(C)C=CC=CC=1>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([N:54]4[C:55]5[C:51](=[CH:50][C:49]([Cl:48])=[CH:57][CH:56]=5)[CH:52]=[N:53]4)[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([I:36])[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2]

Participants

9

Reactant 5

HCID 5238Sodium IodideHCID 62657Potassium Phosphate, TribasicHCID 696811H-Indazole, 5-chloro-HCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 866578732-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide

Product 2

HCID 712888882-(5-chloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amideYield 22%HCID 866779272-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amideYield 33%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A 5 ml microwave vial was charged with 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (252 mg, 0.45 mmol), sodium iodide (112 mg, 0.75 mmol) and copper(I) iodide (8 mg, 0.04 mmol). The vial was evacuated, backfilled with argon then toluene (0.4 ml) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.015 ml, 0.095 mmol) were added via syringe. The vial was sealed and the reaction mixture was stirred at 110° C. in an oil bath for 22 h. The reaction was cooled to room temperature and 5-chloro-1H-indazole (57 mg, 0.37 mmol) and potassium phosphate tribasic (167 mg, 0.79 mmol) were added. The vial was again evacuated, backfilled with argon, sealed and stirred at 110° C. in an oil bath for 19 h. The reaction was cooled to room temperature, filtered through Celite and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by chromatography over silica gel with MeOH/CH2Cl2 (0.5% NH4OH) (gradient 0-2.5% MeOH) to give 53 mg (22%) of 2-(5-chloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a yellow oil and 76 mg (33%) of 2-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a light brown solid.

Workup

  1. customThe vial was evacuated
  2. customThe vial was sealed
  3. temperatureThe reaction was cooled to room temperature
  4. customThe vial was again evacuated
  5. customsealed
  6. stirringstirred at 110° C. in an oil bath for 19 h
  7. temperatureThe reaction was cooled to room temperature
  8. filtrationfiltered through Celite
  9. washwashed with ethyl acetate
  10. concentrationThe filtrate was concentrated
  11. customthe residue was purified by chromatography over silica gel with MeOH/CH2Cl2 (0.5% NH4OH) (gradient 0-2.5% MeOH)

Sources & evidence

ORD record
ord-7c81bd9e3c2a4ece90bef28ffa5595b7
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Linked notes

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