Ethylmorpholine → CBZ-His(CBZ)-Trp-OBn

HRID 1061088Notes

Reaction equation

HRID 1061088 reaction equation
[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:19]([OH:21])=O)[CH2:3][C:4]1[N:8]=[CH:7][N:6](C(OCC2C=CC=CC=2)=O)[CH:5]=1.C(N1[CH2:39][CH2:38]OCC1)C.Cl[C:41]([O:43][CH2:44][CH:45]([CH3:47])[CH3:46])=[O:42].[NH2:48][C@H:49]([C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][CH:52]=1.F[C:71](C(O)=O)(F)F.C([O-])(O)=O.[Na+]>C1COCC1.CN(C=O)C.CCOC(C)=O>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:19]([NH:48][C@H:49]([C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][CH:52]=1)=[O:21])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([C:41]([O:43][CH2:44][C:45]2[CH:47]=[CH:39][CH:38]=[CH:71][CH:46]=2)=[O:42])[CH:5]=1

Participants

9

Reactant 5

HCID 7525EthylmorpholineHCID 62365Isobutyl chloroformateHCID 516892Sodium BicarbonateHCID 13141799Z-His(Z)-OHHCID 67691340Trp-OBn.TFA

Product 1

HCID 131723778CBZ-His(CBZ)-Trp-OBnYield 91%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-18 °C

Procedure

To a solution of CBZ-L-His(CBZ)-OH (0.136 g, 0.32 mmol) and N-ethyl morpholine (32 L, 0.25 mmol) in THF (1 mL) and DMF (0.1 mL) at −18° C. was added i-butyl chloroformate (42 L, 0.32 mmol). After an activation period of 10 min a solution of 7 (0.100 g, 0.25 mmol) and N-ethyl morpoholine (42 L, 0.33 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred under nitrogen at −18° C. for 1 h then overnight at room temperature. The reaction mixture was cooled to 0° C. followed by addition of NaHCO3 (1 mL, 5% aqueous solution). After 10 min this solution was warmed to room temperature and diluted with EtOAc (5 mL). The aqueous layer was removed and washed 1 with 5 mL EtOAc. The organics were combined and washed 3 with 10 mL 1 N HCl, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (70% EtOAc/haxanes) to provide 8 as a white solid (0.159 g, 91%). mp=62-64° C.; 1H NMR (CDCl3) 8.08 (br s, 1H), 7.94 (br s, 1H), 7.43 (m, 6H), 7.31 (m, 12H), 7.10 (m, 2H), 7.01 (m, 1H), 6.79 (br s, 1H), 6.45 (br d, J=6.6 Hz, 1H), 5.34 (d, J=12.0 Hz, 1H), 5.31 (d, J=12.0 Hz, 1H), 4.88-5.11 (m, 5H), 4.60 (br s, 1H), 3.23 (br m, 2H), 3.00 (dd, J=14.8, 5.2 Hz, 1H), 2.92 (dd, J=14.8, 5.2 Hz, 1H) ppm; 13C NMR (CDCl3) 171.3, 170.6, 156.14, 147.9, 138.3, 136.5, 136.3, 135.9, 135.2, 133.7, 129.2, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.3, 123.3, 121.9, 119.4, 118.4, 114.9, 111.1, 109.2, 70.0, 67.0, 66.9, 54.5, 52.6, 29.7, 27.4 ppm; IR (KBr) 3347, 3034, 2927, 1752, 1734, 1670, 1405, 1247, 1012, 742, cm−1; HRMS submitted.

Workup

  1. customovernight
  2. customat room temperature
  3. temperatureThe reaction mixture was cooled to 0° C.
  4. temperatureAfter 10 min this solution was warmed to room temperature
  5. customThe aqueous layer was removed
  6. washwashed 1 with 5 mL EtOAc
  7. washwashed 3 with 10 mL 1 N HCl
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated
  10. customThe residue was purified by flash column chromatography (70% EtOAc/haxanes)

Sources & evidence

ORD record
ord-b4f87f31782f4030bbcdc64005e0a00f
Source dataset
uspto-grants-2003_02
Patent number
US06525154B1

Reaction notes

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