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

HRID 1366786Notes

Reaction equation

HRID 1366786 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:18]([O:20]CC)=O)=[C:4]([F:23])[CH:3]=1.[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(OCC)(=O)C.C(O)C>[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH:34][C:18]([C:10]2[S:11][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:17]3[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:23])=[O:20])[CH2:29][O:28]1

Participants

10

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 59703899Ethyl 3-(4-bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylate

Product 1

HCID 597039053-(4-Bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amideYield 77%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

A mixture of ethyl 3-(4-bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylate (63 mg, 0.16 mmol), 1N aqueous NaOH solution (0.17 ml, 0.17 mmol) and ethanol (2 ml) was heated at 65° C. for 45 minutes. The resultant reaction mixture was concentrated in vacuo then the residue was azeotroped with toluene (2×2 ml) to give a solid residue. The resultant solid residue was suspended in anhydrous THF (2 ml) before O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (38 mg, 0.32 mmol), EDCI (38 mg, 0.20 mmol), HOBt (30 mg, 0.22 mmol) and DIPEA (83 μl. 0.48 mmol) were added. After stirring for 66 hours at ambient temperature, the reaction mixture was concentrated in vacuo to afford a yellow residue. The resultant residue was dissolved in ethyl acetate (50 ml) and washed with water (20 ml), before the organic layer was isolated, dried over sodium sulfate, then concentrated in vacuo to afford a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane:ethyl acetate, gradient 60:40 to 0:100) to afford the title compound as a yellow foam (61 mg, 77%). LCMS (method B): RT=3.02 min, M+H+=496/498.

Workup

  1. customThe resultant reaction mixture
  2. concentrationwas concentrated in vacuo
  3. customthe residue was azeotroped with toluene (2×2 ml)
  4. customto give a solid residue
  5. additionwere added
  6. concentrationthe reaction mixture was concentrated in vacuo
  7. customto afford a yellow residue
  8. washwashed with water (20 ml), before the organic layer
  9. customwas isolated
  10. dry with materialdried over sodium sulfate
  11. concentrationconcentrated in vacuo
  12. customto afford a yellow oil
  13. customThe oil was purified by flash chromatography (Si-SPE, pentane:ethyl acetate, gradient 60:40 to 0:100)

Sources & evidence

ORD record
ord-39c0261fd4fe462ba2a9c634036db539
Source dataset
uspto-grants-2011_02
Patent number
US07893085B2

Reaction notes

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