Diisopropylethylamine → L-Valyl-L-citrulline

HRID 2063228Notes

Reaction equation

HRID 2063228 reaction equation
[NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[O:15])=[O:7])[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[O:15])=[O:7])[CH:3]([CH3:4])[CH3:5]

Participants

4

Reactant 2

HCID 81531DiisopropylethylamineHCID 58021046Fmoc-Val-Cit-OH

Product 1

HCID 9921644L-Valyl-L-citrullineYield 58%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a room temperature solution of Fmoc-Val-Cit (2.18 g, 4.4 mmol, U.S. Pat. No. 6,214,345 to Firestone et al.) in anhydrous DMF (10 mL) was added DEA (10 mL). The reaction mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was concentrated in vacuo to thick oil, and then was added drop wise to a flask containing diethyl ether (˜500 mL) to precipitate the crude product. The white precipitate was collected by filtration and washed with ethyl acetate (2×250 mL). After drying material in vacuo, it was dissolved in DMSO (30 mL), and maleimidocaproic acid-N-hydroxysuccinimide ester (1.42 g, 1.05 eq, Molecular Biosciences, Inc., Boulder Colo.) was added, followed by the addition or DIEA (0.843 mL, 1.1 eq). The reaction mixture was stirred ˜6 h, the DMSO solution was concentrated in vacuo to a volume of ˜2 mL. Product was purified on a semi-preparative HPLC system (stationary phase: C12, mobile phase: 0.1% TFA/H2O/MeCN) to give 1.19 g (2.55 mmol, 58% yield). ES-MS m/z 468.23 [M+H]+. 1H NMR (d6-DMSO) □: 8.15 (d, J=7.2 Hz, 1H), 7.75 (d, J=9.2 Hz, 1 H), 7.00 (s, 1 H), 5.93 (br s, 1 H), 5.38 (br s, 1 H), 4.21 (dd, J1=6.8 Hz, J2=2.148, 1 H), 4.1 (m, 1 H), 2.94 (br s, 2 H), 2.22-2.05 (m, 2 H), 1.93 (q, J=6.8, 1 H), 1.68 (m, 1 H), 1.6-1.2 (m, 7 H), 1.17 (t, J=7.6, 2 H), 0.86-0.80 (dd, J1=6.8 Hz, J2=9.0, 6 H).

Workup

  1. customTo a room temperature
  2. concentrationThe reaction mixture was concentrated in vacuo to thick oil
  3. additionwas added drop wise to a flask
  4. additioncontaining diethyl ether (˜500 mL)
  5. customto precipitate the crude product
  6. filtrationThe white precipitate was collected by filtration
  7. washwashed with ethyl acetate (2×250 mL)
  8. customAfter drying material in vacuo, it
  9. dissolutionwas dissolved in DMSO (30 mL)
  10. stirringThe reaction mixture was stirred ˜6 h
  11. concentrationthe DMSO solution was concentrated in vacuo to a volume of ˜2 mL
  12. customProduct was purified on a semi-preparative HPLC system (stationary phase: C12, mobile phase: 0.1% TFA/H2O/MeCN)
  13. customto give 1.19 g (2.55 mmol, 58% yield)

Sources & evidence

ORD record
ord-662bbf5c0533487b87d83c5da6ab7326
Source dataset
uspto-grants-2012_10
Patent number
US08288352B2

Reaction notes

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