Sodium Bicarbonate → O-(Nalpha-(Nalpha,Nepsilon-Bis(t-butoxycarbonyl)-L-lysinoyl)-Nepsilon-(t-butoxycarbonyl)-L-lysinoyloxy)methyl S-ethyl carbonothioate

HRID 1397119Notes

Reaction equation

HRID 1397119 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:38]([OH:40])=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:46](=[O:53])([O:50][CH2:51]I)[S:47][CH2:48][CH3:49]>O.C(Cl)Cl>[C:46](=[O:53])([S:47][CH2:48][CH3:49])[O:50][CH2:51][O:39][C:38](=[O:40])[C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:24][C:22](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 11436522(Ethylsulfanyl)(iodomethoxy)methanoneHCID 86666530(2S)-2-[[(2S)-2,6-Bis(tert-butoxycarbonylamino)hexanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoic acid

Product 1

HCID 86666532O-(Nalpha-(Nalpha,Nepsilon-Bis(t-butoxycarbonyl)-L-lysinoyl)-Nepsilon-(t-butoxycarbonyl)-L-lysinoyloxy)methyl S-ethyl carbonothioateYield 91%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent3×

Procedure

To a mixture of dipeptide 51 (969 mg, 1.69 mmol) in H2O (3.25 mL) and CH2Cl2 (3.25 mL) was added NaHCO3 (294 mg, 3.50 mmol) and TBAHSO4 (572 mg, 1.69 mmol). After stirring for 15 min, S-ethyl O-iodomethyl carbonothioate (322 mg, 1.30 mmol) in CH2Cl2 (1 mL) was added. The biphasic reaction was stirred vigorously for 2.5 h and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on silica gel, using a gradient of 0-50% EtOAc in CH2Cl2 as eluent to provide compound 52 (818 mg, 91%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 1.30-1.53 (m, 8H), 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 27H), 1.60-1.75 (m, 2H), 1.82-1.90 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 3.06-3.14 (m, 4H), 4.04-4.10 (m, 1H), 4.58-4.64 (m, 1H), 4.70 (bs, 2H), 5.18-5.21 (m, 1H), 5.78 (d, J=5.6 Hz, 1H), 5.90 (d, J=5.6 Hz, 1H) 6.67 (bd, J=6.8 Hz, 1H).

Workup

  1. customThe biphasic reaction
  2. stirringwas stirred vigorously for 2.5 h
  3. customThe layers were separated
  4. washthe organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customThe crude product was triturated with Et2O
  9. customthe solids were removed by filtration
  10. washrinsed with small portions of Et2O
  11. concentrationAfter concentration
  12. customthe combined filtrates were purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-8b49c8f5bddc45aea37aa59e98cc3726
Source dataset
uspto-grants-2014_12
Patent number
US08901072B2

Reaction notes

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