Acetylene → HCID 57277291, compound

HRID 651659Notes

Reaction equation

HRID 651659 reaction equation
[CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[C:7](I)=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[C:14]([O:18][C:19](=[O:30])[NH:20][C@H:21]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]#[CH:28])[C:22]1=[O:29])([CH3:17])([CH3:16])[CH3:15].C#C.N12CCCN=C1CCCCC2>C(#N)C.CO.CN(C=O)C.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:28]=[C:27]1[CH2:26][N:23]1[CH2:24][CH2:25][C@H:21]([NH:20][C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:30])[C:22]1=[O:29])=[O:13])[CH3:2]

Participants

13

Reactant 4

HCID 6326Acetylene2×HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 53727461HCID 53727461, compoundHCID 53895069HCID 53895069, compound

Product 1

HCID 57277291HCID 57277291, compoundYield 10.7%

Reagents, catalysts & solvents 8

HCID 83717Copper iodideCatalystHCID 178418476HCID 178418476, compoundCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (2-iodo-pyridin-3-yl)-carbamic acid ethyl ester (0.6 g, 2.05 mmol), (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester (0.49 g, 2.05 mmol), Pd(PPh3)2Cl2 (72 mg), copper iodide (12 mg) and triethylamine (1.1 mL) in 4 mL of acetonitrile is heated in a sealed tube at 100° C. for 18 hours. After cooling, the reaction mixture is diluted with MeOH and filtered through a Celite pad. The filtrate is concentrated in vacuo. The residue is diluted with EtOAc and washed with water (4×). The combined aqueous layers are extracted with EtOAc (2×). The combined organic layers are washed with water, then dried over MgSO4, filtered and concentrated to yield the crude intermediate coupled acetylene. IS MS, [M+H]+=403. The crude acetylene intermediate is dissolved in 16 mL of DMF and treated with 1,8-diazabicyclo[5.4.0]undec-7ene (DBU) (0.58 mL, 4.1 mmol). The mixture is heated at 60° C. for 2 hours. After cooling, the resulting mixture is diluted with water and EtOAc and the layers are separated. The organic layer is washed with water and then dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with 90% EtOAc/CH2Cl2 to yield the title compound (0.07 g, 0.22 mmol) as a beige solid.

Workup

  1. temperatureAfter cooling
  2. filtrationfiltered through a Celite pad
  3. concentrationThe filtrate is concentrated in vacuo
  4. additionThe residue is diluted with EtOAc
  5. washwashed with water (4×)
  6. extractionThe combined aqueous layers are extracted with EtOAc (2×)
  7. washThe combined organic layers are washed with water
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto yield the crude intermediate
  12. temperatureThe mixture is heated at 60° C. for 2 hours
  13. temperatureAfter cooling
  14. customthe layers are separated
  15. washThe organic layer is washed with water
  16. dry with materialdried over MgSO4
  17. filtrationfiltered
  18. concentrationconcentrated
  19. customThe crude product is purified by column chromatography
  20. washeluting with 90% EtOAc/CH2Cl2

Sources & evidence

ORD record
ord-55497a7a1e414501a7aaa5d7665fd099
Source dataset
uspto-grants-2001_08
Patent number
US06281227B1

Reaction notes

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