Water → 2-(2-chlorothiazol-5-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide

HRID 1898645Notes

Reaction equation

HRID 1898645 reaction equation
[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:37][C:38]1[S:39][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(OCC)(=O)C>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:40]4[S:39][C:38]([Cl:37])=[N:42][CH:41]=4)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 116012232-Chloro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole2×HCID 584385322-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide

Product 1

HCID 673860192-(2-chlorothiazol-5-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amideYield 36.6%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalyst2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
170 °C

Procedure

In a microwave vial, 1,4-dioxane (3 mL) was purged with argon gas. 2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (100 mg, 0.173 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (128 mg, 0.519 mmol), palladium tetrakis(triphenylphosphine) (10 mg, 0.009 mmol), and then cesium carbonate (113 mg, 0.346 mmol) were added. The reaction vessel was sealed and heated in a microwave reactor at 170° C. for 1 h. Additional 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (90 mg, 0.366 mmol) and palladium tetrakis(triphenylphosphine) (6 mg, 0.005 mmol) were added and the reaction was resubjected at 170° C. for 2 h. The reaction was cooled and water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to yield 39 mg (36%) of 2-(2-chlorothiazol-5-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide. (M+Na)+=638.

Workup

  1. customIn a microwave vial, 1,4-dioxane (3 mL) was purged with argon gas
  2. customThe reaction vessel was sealed
  3. temperatureThe reaction was cooled
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted twice more with ethyl acetate
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over sodium sulfate
  8. customAfter evaporation
  9. customthe residue was purified by silica gel chromatography (methanol/dichloromethane)

Sources & evidence

ORD record
ord-03fc87818d514e4c9977f69b865bdcf0
Source dataset
uspto-grants-2013_08
Patent number
US08518945B2

Reaction notes

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