Diisopropylethylamine → 4-[2-(2-{[2-(Tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetoxy)-4-methyl-pentanoyl]-piperazine-1-carboxylic acid benzyl ester

HRID 2062252Notes

Reaction equation

HRID 2062252 reaction equation
[C:1]([O:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]([N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:52]([O:59][C:60]([N:62]1[CH2:67][CH2:66][N:65]([C:68](=[O:75])[CH:69](O)[CH2:70][CH:71]([CH3:73])[CH3:72])[CH2:64][CH2:63]1)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C1COCC1.C(Cl)Cl.O>[CH2:52]([O:59][C:60]([N:62]1[CH2:63][CH2:64][N:65]([C:68](=[O:75])[CH:69]([O:16][C:15](=[O:17])[CH2:14][N:12]([C:10](=[O:11])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:18])[CH3:13])[CH2:70][CH:71]([CH3:72])[CH3:73])[CH2:66][CH2:67]1)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 513582342-(2-((tert-Butoxycarbonyl)(methyl)amino)-N-methylacetamido)acetic acidHCID 670985604-(2-Hydroxy-4-methyl-pentanoyl)-piperazine-1-carboxylic acid benzyl ester

Product 1

HCID 670984054-[2-(2-{[2-(Tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetoxy)-4-methyl-pentanoyl]-piperazine-1-carboxylic acid benzyl esterYield 41%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
65 °C

Procedure

To {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid (427 mg, 1.57 mmol) in 2 mL of THF was added sequentially HBTU (624 mg, 1.2 mmol), diisopropyl ethylamine (860 μL, 4.71 mmol) at room temperature. After 5 min, 4-(2-hydroxy-4-methyl-pentanoyl)-piperazine-1-carboxylic acid benzyl ester (403 mg 1.2 mmol) in 2 mL of THF was added to the reaction mixture, and the solution was heated at 65° C. for 12 h. The reaction mixture was cooled and diluted with 20 mL of CH2Cl2 and 10 mL of water. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give an oil. The residue was subjected to purification by normal phase LC using 30-100% EtOAc-hexanes to give 4-[2-(2-{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetoxy)-4-methyl-pentanoyl]-piperazine-1-carboxylic acid benzyl ester (283 mg, 41% yield). LC/MS: m/z 577 (M+H)+ at 3.43 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).

Workup

  1. temperatureThe reaction mixture was cooled
  2. customThe organic layer was separated
  3. dry with materialdried over Na2SO4
  4. customthe solvent was removed under reduced pressure
  5. customto give an oil
  6. customThe residue was subjected to purification by normal phase LC

Sources & evidence

ORD record
ord-bc09bac69d4841c8800ba6e3e1252d12
Source dataset
uspto-grants-2012_10
Patent number
US08283354B2

Reaction notes

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