Potassium Phosphate, Tribasic → 8-(4-Cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester

HRID 2067009Notes

Reaction equation

HRID 2067009 reaction equation
[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1Cl)=[O:4].[CH:15]1([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=2)[CH2:17][CH2:16]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:22][C:21]1[CH:23]=[CH:24][C:18]([CH:15]2[CH2:16][CH2:17]2)=[CH:19][C:20]=1[F:25])=[O:4]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 201000714-Cyclopropyl-2-fluoroanilineHCID 59565199Methyl 8-chloroimidazo[1,5-a]pyridine-7-carboxylate

Product 1

HCID 595651918-(4-Cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl esterYield 42%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A suspension of 8-chloro-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (105 mg, 0.50 mmol), 4-cyclopropyl-2-fluoroaniline (101 mg, 0.60 mmol), Pd2dba3 (18 mg, 0.02 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (37 mg, 0.08 mmol) and K3PO4 (148 mg, 0.70 mmol) in toluene (2 mL) was degassed and then heated to 100° C. for 24 hours. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate. The resultant solution was washed with water and brine, then loaded onto a 10 g Isolute® SCX-2 cartridge which was eluted with methanol followed by a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, ethyl acetate in dichloromethane) to afford the title compound as a yellow oil (68 mg, 42%). LCMS (method B): RT=3.45 min, [M+H]+=326.

Workup

  1. customwas degassed
  2. temperatureThe reaction mixture was then cooled to room temperature
  3. additiondiluted with ethyl acetate
  4. washThe resultant solution was washed with water and brine
  5. washwas eluted with methanol
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-133bfdfddf244a67b412b2d095e8ed77
Source dataset
uspto-grants-2012_10
Patent number
US08293763B2

Reaction notes

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