Sodium Iodide → 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-(1-ethyl-2-oxo-pyrrolidin-3-yl)oxy-N-(5-methylpyrazin-2-yl)benzamide

HRID 600516Notes

Reaction equation

HRID 600516 reaction equation
[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:31]=[C:32]([C:34](=[O:43])[NH:35][C:36]4[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH:33]=3)[O:17][CH:18]([CH2:24][CH2:25]OS(C)(=O)=O)[C:19](OCC)=[O:20])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[I-].[Na+].[CH2:46]([NH2:48])[CH3:47]>C(#N)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:33]=[C:32]([CH:31]=[C:16]([O:17][CH:18]4[CH2:24][CH2:25][N:48]([CH2:46][CH3:47])[C:19]4=[O:20])[CH:15]=3)[C:34]([NH:35][C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:43])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 5238Sodium IodideHCID 6341EthylamineHCID 86621533Ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate2×

Product 1

HCID 249526633-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-(1-ethyl-2-oxo-pyrrolidin-3-yl)oxy-N-(5-methylpyrazin-2-yl)benzamideYield 116.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate (Intermediate 27) (27 mg, 0.04 mmol), sodium iodide (7 mg, 0.04 mmol) and ethylamine (2M in THF; 45 μL, 0.09 mmol) in acetonitrile (2 mL) were heated in a microwave at 120° C. for 90 minutes. Solvent evaporated under reduced pressure and the residue diluted with ethyl acetate (20 mL) and brine (20 mL). The organics were separated and the aqueous layer re-extracted with ethyl acetate (20 mL). The combined organics were dried (MgSO4) and concentrated and the residue purified by preparative HPLC, eluting with a gradient of 5 to 95% acetonitrile in water containing 0.2% trifluoroacetic acid on a Phenomenex Luna 10u C18(2) 100A column, to afford product (24 mg, 87%). 1H NMR δ (300 MHz, CDCl3) 1.19 (3H, t), 2.17-2.26 (1H, m), 2.34-2.44 (2H, m), 2.62-2.74 (4H, m), 3.39-3.59 (4H, m), 4.30 (2H, s), 4.76 (2H, s), 5.11 (1H, t), 6.95 (1H, t), 7.29 (1H, t), 7.39-7.42 (1H, m), 7.52 (1H, d), 8.10 (1H, d), 8.19 (1H, s), 8.36 (1H, d), 9.65 (1H, d); m/z 517 (M+H)+.

Workup

  1. customSolvent evaporated under reduced pressure
  2. additionthe residue diluted with ethyl acetate (20 mL) and brine (20 mL)
  3. customThe organics were separated
  4. extractionthe aqueous layer re-extracted with ethyl acetate (20 mL)
  5. dry with materialThe combined organics were dried (MgSO4)
  6. concentrationconcentrated
  7. customthe residue purified by preparative HPLC
  8. washeluting with a gradient of 5 to 95% acetonitrile in water containing 0.2% trifluoroacetic acid on a Phenomenex Luna 10u C18(2) 100A column

Sources & evidence

ORD record
ord-1a89d4f7f0e7472fb0480294b873d7ec
Source dataset
uspto-grants-2011_03
Patent number
US07902200B2

Reaction notes

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