Triethylamine → 5-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amide

HRID 2076201Notes

Reaction equation

HRID 2076201 reaction equation
CC1(C)[O:6][C@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([CH:27]=[N:28][CH:29]=3)[C:17]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[O:11])[CH2:4][O:3]1.CCN(CC)CC.C(#N)C.O>CO.ClCCl>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:27]=[N:28][CH:29]=2)[C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:11]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 18373917Acetonitrile--water (1/1)HCID 866377245-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide

Product 1

HCID 591401885-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amideYield 23%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (364 mg, 0.7 mmol) in methanol (0.5 ml) and dichloromethane (0.5 ml) was loaded onto an SCX-2 cartridge. The cartridge was flushed with methanol and the desired product was eluted using a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated under reduced pressure and the residue was azeotroped with dichloromethane. Purification of the resultant residue by flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) followed by preparative HPLC (Gemini 5 micron C6-Phenyl 250×21.20 mm column, 20 mmol Et3N per liter solvent, gradient acetonitrile/water, 5 to 98%, ramp time 25 minutes) afforded the title compound as a yellow solid (77.6 mg, 23%). LCMS (method A): RT=5.13 min, [M+H]+=487. 1H NMR (DMSO-d6): 8.01 (1H, s), 7.58 (1H, dd, J=10.68, 1.92 Hz), 7.42 (1H, s), 7.38 (1H, d, J=9.34 Hz), 7.30 (1H, dd, J=8.43, 1.82 Hz), 6.91 (1H, d, J=9.32 Hz), 6.32 (1H, t, J=8.68 Hz), 3.72-3.67 (1H, m), 3.60-3.51 (2H, m), 3.30 (2H, d, J=4.94 Hz).

Workup

  1. customThe cartridge was flushed with methanol
  2. washthe desired product was eluted
  3. concentrationconcentrated under reduced pressure
  4. customthe residue was azeotroped with dichloromethane
  5. customPurification of the resultant residue by flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane)

Sources & evidence

ORD record
ord-df3ce63dda16469cbfc3283d7d887232
Source dataset
uspto-grants-2011_04
Patent number
US07923456B2

Reaction notes

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