Triethylamine → 4-(4-Pyridin-3-yl-buta-1,3-diynyl)-benzamide

HRID 900559Notes

Reaction equation

HRID 900559 reaction equation
O[C@@H]1CCN(C(C2C=CC(OC(F)(F)F)=CC=2)=O)[C@H]1C(NOCC1C=CC=CC=1)=O.COC(=O)C([NH:44][C:45](=[O:63])[C:46]1[CH:51]=[CH:50][C:49]([C:52]#[C:53][C:54]#[C:55][C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=C[CH:57]=2)=[CH:48][CH:47]=1)CNC(OC(C)(C)C)=O.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>[N:62]1[CH:59]=[CH:60][CH:61]=[C:56]([C:55]#[C:54][C:53]#[C:52][C:49]2[CH:50]=[CH:51][C:46]([C:45]([NH2:44])=[O:63])=[CH:47][CH:48]=2)[CH:57]=1

Participants

8

Reactant 3

HCID 8471TriethylamineHCID 578970282-{4-[4-(4-Amino-phenyl)-buta-1,3-diynyl]-benzoylamino}-3-tert-butoxycarbonylamino-propionic acid methyl esterHCID 59697601((2r,3r)-3-Hydroxy-1-{[4-(trifluoromethoxy)phenyl]carbonyl}pyrrolidin-2-yl)-n-(phenylmethoxy)carboxamide

Product 1

HCID 1317268314-(4-Pyridin-3-yl-buta-1,3-diynyl)-benzamide

Reagents, catalysts & solvents 4

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

Procedure

Resin 1 (142 mg, 0.109 mmol) was swelled in DCM (2 mL) for 1 h and drained. A solution of 3-ethynylpyridine 2 (38 mg, 0.368 mmol) and Et3N (200 μL 1.4 mmol) in DMF (2 mL) was added and the resin agitated for 5 min. A mixture of PdCl2(PPh3)2 (22 mg, 0.031 mmol) and CuI (25 mg, 0.131 mmol) was added and the resin was agitated for 72 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, 24 min) and lyophilization of the collected fractions afforded 4.4 mg (11% yield) of N-(2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-4-(4-pyridin-3-yl-buta-1,3-diynyl)-benzamide. LRMS (ES+) m/z 364.0 (C20H17N3O4+H requires 364.13); RP-HPLC (300 nm, 24 min run) 11.2 min.

Workup

  1. additionwas added
  2. stirringthe resin was agitated for 72 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, 24 min) and lyophilization of the collected fractions

Sources & evidence

ORD record
ord-f1a8d9965d424768b57d5950070ebc53
Source dataset
uspto-grants-2008_04
Patent number
US07358359B2

Reaction notes

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