N-((1,1-dimethylethoxy)carbonyl)-beta-alanine → (3-{4-[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]piperazin-1-yl}-3-oxo propyl)carbamic Acid Tert-butyl Ester

HRID 1024687Notes

Reaction equation

HRID 1024687 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C.[C:45]([C:47]1[CH:76]=[CH:75][C:50]([O:51][C:52]2[C:57]([C:58]([N:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)=[O:59])=[CH:56][CH:55]=[C:54]([O:66][C:67]3[CH:72]=[CH:71][C:70]([C:73]#[N:74])=[CH:69][CH:68]=3)[N:53]=2)=[CH:49][CH:48]=1)#[N:46]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]([N:63]1[CH2:64][CH2:65][N:60]([C:58]([C:57]2[C:52]([O:51][C:50]3[CH:49]=[CH:48][C:47]([C:45]#[N:46])=[CH:76][CH:75]=3)=[N:53][C:54]([O:66][C:67]3[CH:68]=[CH:69][C:70]([C:73]#[N:74])=[CH:71][CH:72]=3)=[CH:55][CH:56]=2)=[O:59])[CH2:61][CH2:62]1)=[O:13])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 5

HCID 76809N-((1,1-dimethylethoxy)carbonyl)-beta-alanineHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 668186984-[2,6-Bis-(4-cyanophenoxy)pyridine-3-carbonyl]piperazineHCID 178418300HCID 178418300, compound

Product 1

HCID 66818267(3-{4-[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]piperazin-1-yl}-3-oxo propyl)carbamic Acid Tert-butyl Ester

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

A solution of 3-tert-butoxycarbonylamino-propionic acid, 0.177 g (0.94 mmol), in 3 ml of DMF was added dropwise to a stirred suspension of 0.72 g (3.76 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and hydroxybenzotriazole (HOBT) 0.508 g (3.76 mmol) in 5 ml of DMF at RT. That was followed by the addition of N,N-diisopropylethylamine (DIPEA) 0.242 g (1.88 mmol) while the temperature was maintained below 5. The mixture was stirred for 10 min and a solution of 4-[2,6-Bis-(4-cyano phenoxy)pyridine-3-carbonyl]piperazine (0.4 g, 0.94 mmol) in DMF (10 ml) was added followed by stirring overnight at RT. The reaction mixture was concentrated under reduced pressure and partitioned between water (150 ml) and ethyl acetate (150 ml) after the pH was adjusted to 2-3 with 6 N HCl. The organic phase was washed with 1 M Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.45 g of the required product. Percentage purity (LCMS): 10.3%. (M+1)=596.2 (with BOC).

Workup

  1. temperaturewas maintained below 5
  2. stirringby stirring overnight at RT
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. custompartitioned between water (150 ml) and ethyl acetate (150 ml) after the pH
  5. washThe organic phase was washed with 1 M Na2CO3 and saturated brine solution
  6. dry with materialdried over sodium sulphate
  7. concentrationconcentrated
  8. customThe crude oily residue was purified by column chromatography

Sources & evidence

ORD record
ord-486098bd30804ff8bfa794aa14d4d3d8
Source dataset
uspto-grants-2014_05
Patent number
US08722930B2

Reaction notes

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