1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → tert-butyl (1S)-2-methyl-1-((4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)carbonyl)-2-(methylthio)propylcarbamate

HRID 1162301Notes

Reaction equation

HRID 1162301 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([CH3:17])([S:15][CH3:16])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:41][C:42]1[N:46]2[C:47](=[O:56])[N:48]([CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:49][C:45]2=[CH:44][N:43]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:14][C:13]([S:15][CH3:16])([CH3:17])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:53]1[CH2:52][CH2:51][CH:50]([N:48]2[CH2:49][C:45]3=[CH:44][N:43]=[C:42]([CH3:41])[N:46]3[C:47]2=[O:56])[CH2:55][CH2:54]1)=[O:12]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 23084094HCID 23084094, compoundHCID 86612129(2S)-2-((tert-butoxycarbonyl)amino)-3-methyl-3-(methylthio)butanoic acid

Product 1

HCID 86612128tert-butyl (1S)-2-methyl-1-((4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)carbonyl)-2-(methylthio)propylcarbamateYield 74.9%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 8471TriethylamineSolvent

Procedure

To a solution of (2S)-2-((tert-butoxycarbonyl)amino)-3-methyl-3-(methylthio)butanoic acid (T. Fukami et al., J. Med. Chem., 39, 2313 (1996); 1.3 g) and HOBt (1.14 g) in acetonitrile (30 ml) was added WSC (1.42 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, a solution of 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (1.43 g), DBU (1.47 ml) and triethylamine (2.2 ml) in acetonitrile (10 ml) was added thereto. The reaction mixture was mixed at room temperature for 15 hours, the solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound as colorless powder (1.7 g, 71%).

Workup

  1. additionthe reaction mixture was mixed at room temperature for 15 minutes
  2. additionThe reaction mixture was mixed at room temperature for 15 hours
  3. distillationthe solvent was then distilled off under reduced pressure
  4. dissolutionthe residue was dissolved in ethyl acetate
  5. washThe ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution
  6. dry with materialdried over anhydrous sodium sulfate
  7. distillationThe solvent was distilled off under reduced pressure
  8. customthe residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=5/1)

Sources & evidence

ORD record
ord-e253aaa476a34e25aef21eb46fab0efc
Source dataset
uspto-grants-2010_10
Patent number
US07820673B2

Reaction notes

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