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4-Methoxy-1-methyl-1H-indole-2-carboxylic acid → N-(5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide

HRID 245720
Notes
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Reaction equation

HRID 245720 reaction equation
[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([OH:15])=O)[N:7]2[CH3:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:40][C:41]1[C:42]([B:50]2[O:54][C:53]([CH3:56])([CH3:55])[C:52]([CH3:58])([CH3:57])[O:51]2)=[CH:43][C:44]([O:48][CH3:49])=[C:45]([CH:47]=1)[NH2:46]>ClCCl.N1C=CC=CC=1>[F:40][C:41]1[C:42]([B:50]2[O:54][C:53]([CH3:56])([CH3:55])[C:52]([CH3:58])([CH3:57])[O:51]2)=[CH:43][C:44]([O:48][CH3:49])=[C:45]([NH:46][C:13]([C:6]2[N:7]([CH3:12])[C:8]3[C:4]([CH:5]=2)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)=[O:15])[CH:47]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 31595784-Methoxy-1-methyl-1H-indole-2-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 673632955-Fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Product 1

HCID 67363936N-(5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide
Yield 44%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6344DichloromethaneSolvent

Procedure

4-Methoxy-1-methyl-1H-indole-2-carboxylic acid (0.225 mmol, 46.1 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.247 mmol, 94 mg) were added to a solution of 5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.225 mmol, 60 mg) in dichloromethane (2.5 mL) and pyridine (0.5 mL) at 0° C. After stirring the reaction mixture overnight at room temperature it was concentrated in vacuo. Water was added to the residue and extracted with dichloromethane. The organic extracts were washed with water. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptanes/ethyl acetate) to give impure N-(5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (45 mg). The latter compound and 1-bromo-8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (35 mg) were reacted using the procedures described in example 4 step 4c and purification using column chromatography (silica gel, heptanes/ethyl acetate) gave N-(5-fluoro-2-methoxy-4-(8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (9.7 mg)

Workup

  1. concentrationwas concentrated in vacuo
  2. additionWater was added to the residue
  3. extractionextracted with dichloromethane
  4. washThe organic extracts were washed with water
  5. dry with materialThe combined organic layers were dried (sodium sulfate)
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by column chromatography (silica gel, heptanes/ethyl acetate)

Sources & evidence

ORD record
ord-a1bc7369c22346d78f2b6136a274d241
Source dataset
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08658794B2

Reaction notes

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