Tetrahydrofuran → (R)-ethyl 5-(benzyloxycarbonylamino)-2-(3-(4-(tert-butoxycarbonylamino)benzyl)ureido)pentanoate

HRID 1397882Notes

Reaction equation

HRID 1397882 reaction equation
[NH2:1][C@H:2]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:22]([O:26][C:27](=[O:37])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[CH:31][CH:30]=1)([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.C1C[O:48][CH2:47]C1>>[CH2:15]([O:14][C:12]([NH:11][CH2:10][CH2:9][CH2:8][C@@H:2]([NH:1][C:47]([NH:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:37])=[CH:34][CH:33]=1)=[O:48])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 2794659Tert-butyl N-(4-(aminomethyl)phenyl)carbamateHCID 86584445(R)-ethyl 2-amino-5-(benzyloxycarbonylamino)pentanoate

Product 1

HCID 86723917(R)-ethyl 5-(benzyloxycarbonylamino)-2-(3-(4-(tert-butoxycarbonylamino)benzyl)ureido)pentanoate

Conditions

Temperature
-10 °C

Procedure

(R)-ethyl 2-amino-5-(benzyloxycarbonylamino)pentanoate (1 equivalent, 146 mg, 0.50 mmol) was dissolved in anhydrous THF (4 mL) and trisphosgene (0.33 equivalent, 49 mg, 0.17 mmol) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, and then refluxed for 2 h. Tert-butyl-N-[4-(aminomethyl)phenyl]carbamate (1 equivalent, 110 mg, 0.50 mmol) and triethylamine (2 equivalent, 138 μl, 1 mmol) were added successively and the resulting solution was stirring at room temperature overnight. The reaction mixture was concentrated, washed by 30 ml of NaHCO3 and extracted by 3×30 ml EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (EDP/EtOAc) to afford the urea protected (146 mg, 54%) as a colourless oil Rf=0.59 (EtOAc). 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (s, 5H), 7.20 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 6.84-6.66 (m, 1H), 5.62-5.42 (m, 2H), 5.28-5.10 (m, 1H), 5.00 (s, 2H), 4.46-4.29 (m, 1H), 4.18 (d, J=5.5 Hz, 2H), 4.05 (q, J=7.1 Hz, 3H), 3.16-3.00 (m, 2H), 1.82-1.28 (m, 4H), 1.43 (s, 9H), 1.16 (t, J=7.2 Hz, 3H).

Workup

  1. temperatureto warm to room temperature
  2. temperaturerefluxed for 2 h
  3. stirringthe resulting solution was stirring at room temperature overnight
  4. concentrationThe reaction mixture was concentrated
  5. washwashed by 30 ml of NaHCO3
  6. extractionextracted by 3×30 ml EtOAc
  7. dry with materialThe organic phase was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude product was purified by flash chromatography (EDP/EtOAc)

Sources & evidence

ORD record
ord-852735a43d2f431abc15a5b3aafa5dfe
Source dataset
uspto-grants-2014_12
Patent number
US08901295B2

Reaction notes

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