1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 5-(4-Bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amide

HRID 2076205Notes

Reaction equation

HRID 2076205 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=O)=[C:4]([F:21])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:44][O:45][CH2:46][C@@H:47]([OH:49])[CH3:48].CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[OH:49][C@@H:47]([CH3:48])[CH2:46][O:45][NH:44][C:18]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:15]=[N:16][CH:17]=2)[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:21])=[O:20]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 591401635-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acidHCID 86637725(S)-1-aminooxypropan-2-ol hydrochloride

Product 1

HCID 441379365-(4-Bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amideYield 25%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (271 mg, 0.77 mmol) in dioxane (3.9 mL) was added HOBT (306 mg, 2.3 mmol) and EDCI (442 mg, 2.3 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes then (S)-1-aminooxy-propan-2-ol hydrochloride (294 mg, 2.3 mmol) and DIPEA (1.2 mL, 6.9 mmol) were added, the mixture was then stirred for 60 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate then washed with a saturated aqueous solution of sodium bicarbonate followed by water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 100%, ethyl acetate in dichloromethane, then gradient 0 to 10%, methanol in dichloromethane) to afford the title compound as a green/yellow solid (80 mg, 25%). LCMS (method A): RT=5.71 min, [M+H]+=423/425. 1H NMR (DMSO-d6): 8.10 (1H, s), 7.51 (1H, dd, J=10.87, 2.22 Hz), 7.43 (1H, s), 7.39 (1H, d, J=9.31 Hz), 7.18-7.14 (1H, m), 6.88 (1H, d, J=9.31 Hz), 6.51 (1H, t, J=8.85 Hz), 4.69 (1H, s), 3.68-3.59 (1H, m), 3.42 (2H, d, J=5.81 Hz), 0.95 (3H, d, J=6.35 Hz).

Workup

  1. stirringthe mixture was then stirred for 60 hours at ambient temperature
  2. washthen washed with a saturated aqueous solution of sodium bicarbonate
  3. customThe organic phase was isolated
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-48ccbbebfa5c45318cd2e209496ca87a
Source dataset
uspto-grants-2011_04
Patent number
US07923456B2

Reaction notes

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