4-Methylmorpholine → HCID 44359985, compound

HRID 861303Notes

Reaction equation

HRID 861303 reaction equation
[N:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.[NH2:26][C@H:27]([C:31]([N:33]1[CH2:53][CH2:52][CH2:51][C@H:34]1[C:35]([NH:37][C@H:38]([C:42]([C:44]([C:47]([F:50])([F:49])[F:48])([F:46])[F:45])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:26][C@H:27]([C:31]([N:33]3[CH2:53][CH2:52][CH2:51][C@H:34]3[C:35]([NH:37][CH:38]([CH:39]([CH3:40])[CH3:41])[C:42](=[O:43])[C:44]([F:45])([F:46])[C:47]([F:48])([F:49])[F:50])=[O:36])=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:16])=[CH:17][CH:18]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1

Participants

5

Reactant 3

HCID 79724-MethylmorpholineHCID 5594164-(Morpholine-4-sulfonyl)benzoic acidHCID 10431989HCID 10431989, compound

Product 1

HCID 44359985HCID 44359985, compoundYield 50%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-22 °C

Procedure

To a solution of the benzoic acid derivative prepared above (0.240 g, 0.885 mmol) and NMM (0.446 g, 4.43 mmol, 0.489 ml) in CH2Cl2 (8.9 ml) at -22° C. under N2 was added IBCF (0.121 g, 0.885 mmol, 0.115 ml), and the reaction stirred at -22° C. for 20 min. The HCL.Val-Pro-Val-C2F5 (0.400 g, 0.885 mmol) was added in several portions, and the reaction was stirred at -22° C. for 0.5 h, followed by 4 h at room temperature. The reaction was diluted with CH2Cl2 (30 ml) and then washed successively with 10% HCl (2×15 ml), sat. NaHCO3 (2×15 ml), brine (1×15 ml), and dried over MgSO4. Solvent removal under vacuum gave an off-white foam which was purified by flash chromatography (silica gel; 25/75, hexane/EtOAc) to give 0.295 g (50%) of the title compound as a white solid. TLC: Rf 0.49 (EtOAc). 1H NMR: δ 8.02-7.93 (m, 2H, aryl), 7.85-7.77 (m, 2.25H, aryl and NH), 7.70 (d, J=7.3 Hz, 0.75H, NH), 6.93 (d, J=9.0 Hz, 1H, NH), 5.04-4.96 (m, 1H, α-CH of Val), 4.86 (dd, J=8.7, 6.7 Hz, 1H, α-CH of Val), 4.71 (dd, J=8.1, 2.0 Hz, 0.25H, α-CH of Pro), 4.61 (dd, J=8.1, 3.0 Hz, 0.75H, α-CH of Pro), 3.92-3.64 (m, 6H, CH2OCH2 and CH2N of Pro), 3.07-2.96 (m, 4H, CH2NCH2), 2.55-1.82 (series of m, 6H, 2×β-CH of Val, CH2CH2 of Pro), 1.12-0.85 (m, 12H, 4×CH3). 19F NMR: δ 82.12 (s, CF3, major), -82.16 (s, CF3, minor), -121.50 and -122.74 (AB quartet, J=296 Hz, CF2, minor), -121.56 and -122.60 (AB quartet, J=299 Hz, CF2, major). MS (DCI/CH4): m/z (rel intensity) 669 (MH+, 55), 317 (100). Anal. (C28H37F5N4O7S.0.33H2O): C, H, N: calcd, 8.30; found, 7.82.

Workup

  1. additionwas added IBCF (0.121 g, 0.885 mmol, 0.115 ml)
  2. stirringthe reaction was stirred at -22° C. for 0.5 h
  3. waitfollowed by 4 h at room temperature
  4. washwashed successively with 10% HCl (2×15 ml), sat. NaHCO3 (2×15 ml), brine (1×15 ml)
  5. dry with materialdried over MgSO4
  6. customSolvent removal under vacuum
  7. customgave an off-white foam which
  8. customwas purified by flash chromatography (silica gel; 25/75, hexane/EtOAc)

Sources & evidence

ORD record
ord-cca3948745d04a3bb3d5ca7c6f24f80e
Source dataset
uspto-grants-1998_02
Patent number
US05714470

Reaction notes

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