Triethylamine → (1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-{4-[4-(2-amino-ethylcarbamoyl)-phenyl]-buta-1,3-diynyl}-benzamide

HRID 900558Notes

Reaction equation

HRID 900558 reaction equation
[OH:1][C@H:2]([CH3:34])[C@H:3]([NH:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17]C#CC2C=CC(CN3CCOCC3)=CC=2)=[CH:12][CH:11]=1)[C:4](=[O:7])[NH:5][OH:6].C([CH:54]([NH2:67])[CH2:55][NH:56][C:57](=[O:66])[C:58]1[CH:63]=[CH:62][C:61]([C:64]#[CH:65])=[CH:60][CH:59]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C.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>[OH:1][C@H:2]([CH3:34])[C@H:3]([NH:8][C:9](=[O:33])[C:10]1[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:65]#[C:64][C:61]2[CH:60]=[CH:59][C:58]([C:57](=[O:66])[NH:56][CH2:55][CH2:54][NH2:67])=[CH:63][CH:62]=2)=[CH:14][CH:15]=1)[C:4](=[O:7])[NH:5][OH:6]

Participants

8

Reactant 3

HCID 8471TriethylamineHCID 60125983(1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-[4-(4-morpholin-4-ylmethyl-phenyl)buta-1,3-diynyl]-benzamideHCID 86595068N-(2-trityl-amino-ethyl)-4-ethynyl-benzamide

Product 1

HCID 59829947(1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-{4-[4-(2-amino-ethylcarbamoyl)-phenyl]-buta-1,3-diynyl}-benzamideYield 4%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

Resin 4 (150 mg, 0.116 mmol) was swelled in DCM (2 mL) for 1 h and drained. A solution of 4-ethynylbenzamide 3 (151 mg, 0.350 mmol) and Et3N (150 μL, 1.10 mmol) in DMF (2.0 mL) was added and the resin agitated for 5 min. A mixture of PdCl2(PPh3)2 (21 mg, 0.030 mmol) and CuI (28 mg, 0.147 mmol) was added and the resin was agitated for 60 h. The resin was drained, washed with DMF (3×2 mL), DCM (3×2 mL) and cleaved with 10% TFA/DCM (1.5 mL) for 20 min. The solution was collected and the resin was rinsed with additional 10% TFA/DCM (1.0 mL). The cleavage fractions were combined, treated with neat TFA (2.0 mL), stirred for 1 h at rt and concentrated by rotary evaporation to give a crude brown residue. Purification by RP-HPLC (C18 column, CH3CN gradient 5-65%, 0.1% TFA, UV analysis 300 nm, 26 min) and lyophilization of the collected fractions afforded 2.0 mg (4% yield) of (1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-{4-[4-(2-amino-ethylcarbamoyl)-phenyl]-buta-1,3-diynyl}-benzamide. LRMS (ES+) m/z 449.1 (C24H24N4O5+H requires 449.18); RP-HPLC (300 nm, 26 min run) 17.0 min.

Workup

  1. additionwas added
  2. stirringthe resin was agitated for 60 h
  3. washwashed with DMF (3×2 mL), DCM (3×2 mL)
  4. waitcleaved with 10% TFA/DCM (1.5 mL) for 20 min
  5. customThe solution was collected
  6. washthe resin was rinsed with additional 10% TFA/DCM (1.0 mL)
  7. additiontreated with neat TFA (2.0 mL)
  8. stirringstirred for 1 h at rt
  9. concentrationconcentrated by rotary evaporation
  10. customto give a crude brown residue
  11. customPurification by RP-HPLC (C18 column, CH3CN gradient 5-65%, 0.1% TFA, UV analysis 300 nm, 26 min) and lyophilization of the collected fractions

Sources & evidence

ORD record
ord-deda7dd695904191bebf1c05fc1d708f
Source dataset
uspto-grants-2008_04
Patent number
US07358359B2

Reaction notes

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