Sodium Hydroxide → 3-(2-Fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide

HRID 1366784Notes

Reaction equation

HRID 1366784 reaction equation
C(O[C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])C.[OH-].[Na+].[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH2:34])[CH2:29][O:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(O)C>[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH:34][C:4]([C:6]2[S:14][C:9]3=[CH:10][N:11]=[CH:12][CH:13]=[C:8]3[C:7]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])=[O:5])[CH2:29][O:28]1

Participants

9

Reactant 6

HCID 14798Sodium HydroxideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 11298047(R)-O-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamineHCID 597039023-(2-Fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester

Product 1

HCID 597038943-(2-Fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amideYield 66.9%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

A mixture of 3-(2-fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester (50 mg, 0.11 mmol), 1N aqueous NaOH solution (0.12 ml, 0.12 mmol) and ethanol (2 ml) was heated at 65° C. for 45 minutes. The reaction mixture was concentrated then azeotroped with toluene (2×2 ml) to give a solid residue. The solid residue was dissolved in anhydrous THF (4 ml) and O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (27 mg, 0.23 mmol), EDCI (27 mg, 0.14 mmol), HOBt (21 mg, 0.16 mmol) and DIPEA (59 μl, 0.34 mmol) were added. After stirring for 19 hours the solvent was evaporated and the residue partitioned between ethyl acetate (20 ml) and water (15 ml). The organic layer was isolated, dried over sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by flash chromatography (Si-SPE, pentane:ethyl acetate, gradient 80:20 to 0:100) to afford the title compound as an orange oil (40 mg, 66%). LCMS (method B): RT=3.30 min, M+H+=544.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customthen azeotroped with toluene (2×2 ml)
  3. customto give a solid residue
  4. customwas evaporated
  5. customthe residue partitioned between ethyl acetate (20 ml) and water (15 ml)
  6. customThe organic layer was isolated
  7. dry with materialdried over sodium sulphate
  8. filtrationfiltered
  9. customevaporated
  10. customto give a brown oil
  11. customThe oil was purified by flash chromatography (Si-SPE, pentane:ethyl acetate, gradient 80:20 to 0:100)

Sources & evidence

ORD record
ord-1714bdf776c34173808da1bf981c487a
Source dataset
uspto-grants-2011_02
Patent number
US07893085B2

Reaction notes

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