Tetrahydrofuran → HCID 178472054, compound

HRID 1047173Notes

Reaction equation

HRID 1047173 reaction equation
[F:1][C:2]1[N:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=[O:14].C(N([CH2:22][CH3:23])CC)C.[NH2:24][C@@H:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:26][OH:27].C1[CH2:36][O:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([C:22](=[CH:23][NH:24][C@@H:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:26][OH:27])[C:36]([O:35][CH2:34][CH3:33])=[O:14])=[O:6]

Participants

8

Reactant 5

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 2734079(2S)-2-Amino-3,3-dimethyl-1-butanolHCID 58334609HCID 58334609, compound

Product 1

HCID 178472054HCID 178472054, compound

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 2,6-difluoro-5-iodonicotinic acid (4 g, 14.04 mmol, 1 equiv.) in toluene (30 mL) was added thionyl chloride (5.12 mL, 70.18 mmol, 5 equiv.) followed by DMF (0.5 mL). The reaction was stirred at 110° C. for 1 h. The reaction was concentrated. The residue was re-suspended in THF (15 mL) and added dropwise to a solution of ethyl-3-(dimethylamine)acrylate (2.1 mL, 14.04, 1.1 equiv.) and triethylamine (2.15 mL, 15.44 mmol, 1.1 equiv.) in THF (15 mL). The reaction was stirred at 67° C. for 2 h and cooled to 23° C. (S)-2-amino-3,3-dimethylbutan-1-ol (1.81 g, 15.44 mmol, 1.1 equiv.) was subsequently added and stirred at 23° C. for 30 min. The reaction was quenched with water (40 mL) and ethyl acetate (40 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL), and the organics were dried and concentrated. The compound was purified via silica gel chromatography and concentrated to provide (S)-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-(1-hydroxy-3,3-dimethylbutan-2-ylamino)acrylate Intermediate 80 (4.49 g, 66%). Calcd for C17H21F2IN2O4 [M+H]+: 482.9.

Workup

  1. concentrationThe reaction was concentrated
  2. stirringThe reaction was stirred at 67° C. for 2 h
  3. additionwas subsequently added
  4. stirringstirred at 23° C. for 30 min
  5. customThe reaction was quenched with water (40 mL) and ethyl acetate (40 mL)
  6. extractionThe aqueous layer was extracted with ethyl acetate (2×40 mL)
  7. customthe organics were dried
  8. concentrationconcentrated
  9. customThe compound was purified via silica gel chromatography
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-573f3b1113d2474682eddf18cbb0ba30
Source dataset
uspto-grants-2013_10
Patent number
US08569484B2

Reaction notes

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