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

HRID 2076215Notes

Reaction equation

HRID 2076215 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([OH:21])=O.Cl.[NH2:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:28][C@@H:26]([CH3:27])[CH2:25][O:24][NH:23][C:19]([C:11]1[N:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 591401265-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acidHCID 86637725(S)-1-aminooxypropan-2-ol hydrochloride

Product 1

HCID 441359795-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amideYield 10.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (85 mg, 0.21 mmol) in anhydrous DMF (1.0 mL) was added (S)-1-aminooxy-propan-2-ol hydrochloride (32.7 mg, 0.26 mmol, 1.2 eq.), DIPEA (0.13 mL, 0.77 mmol, 3.6 eq.), HOBt (36.0 mg, 0.26 mmol, 1.2 eq.) and EDCI (51.2 mg, 0.26 mmol, 1.2 eq.), and the reaction mixture was stirred at ambient temperature under N2 for 16 hours. The reaction mixture was poured into ethyl acetate, and the organic layer was washed with a saturated solution of sodium bicarbonate, 50% brine 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 40%, methanol in ethyl acetate) to give an oil. Crystallization from dichloromethane—ether—hexane afforded the title compound as a yellow solid (10.7 mg, 10.6%). 1H NMR (MeOD, 400 MHz) δ ppm 8.76 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.64 (dd, J=10.13, 1.84 Hz, 1H), 7.55-7.50 (m, 1H), 6.72 (t, J=8.49 Hz, 1H); LCMS (method E1): RT=5.14 min, [M+H]+=472.

Workup

  1. washthe organic layer was washed with a saturated solution of sodium bicarbonate, 50% brine and brine
  2. customThe organic phase was isolated
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto give an oil
  7. customCrystallization from dichloromethane—ether—hexane

Sources & evidence

ORD record
ord-1a9ee26021ae4e9c9f729b99a09ee367
Source dataset
uspto-grants-2011_04
Patent number
US07923456B2

Reaction notes

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