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

HRID 1061088노트

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HRID 1061088 반응식
[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

참가 물질

9

반응물 5

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

생성물 1

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

시약·촉매·용매 3

HCID 6228Dimethylformamide용매HCID 8028Tetrahydrofuran용매2회HCID 8857Ethyl Acetate용매

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온도
-18 °C

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-b4f87f31782f4030bbcdc64005e0a00f
출처 데이터셋
uspto-grants-2003_02
특허 번호
US06525154B1

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