4-Methylmorpholine → tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}ethyl]carbamate

HRID 1923970Notes

Reaction equation

HRID 1923970 reaction equation
CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:21](=[O:49])[NH:22][C@@H:23]([C:36](=[O:48])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:17][C:18](O)=[O:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:50]([O:54][C:55]([NH:57][CH2:58][CH2:59][NH:60][CH2:61][CH2:62][NH:63][C:64](=[O:70])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[C:50]([O:54][C:55]([NH:57][CH2:58][CH2:59][N:60]([CH2:61][CH2:62][NH:63][C:64]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:70])[C:18]([CH2:17][C@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:10])([CH3:9])[CH3:11])[C:21](=[O:49])[NH:22][C@@H:23]([C:36](=[O:48])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)=[O:19])=[O:56])([CH3:53])([CH3:52])[CH3:51]

Participants

5

Reactant 3

HCID 79724-MethylmorpholineHCID 15157893tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamateHCID 67520717(3S)-3-{[(tert-butoxy)carbonyl]amino}-3-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}propanoic acid

Product 1

HCID 59366822tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}ethyl]carbamateYield 72%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of CDMT (37 mg, 0.20 mmol) in DCM (10 mL) and cooled to 0° C. was added N-methylmorpholine (0.023 mL, 0.20 mmol). The mixture was stirred for min before adding (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}propanoic acid (110 mg, 0.18 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate X was then added and the mixture stirred at r.t. overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was then purified on a silica gel column (100:1 CHCl3/MeOH) and finally crystallized from ethyl ether/hexane to give tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}ethyl]carbamate XI (110 mg, 0.13 mmol, 72% yield). 1H NMR (CDCl3) 1.43 (s, 18H), 1.50 (s, 9H), 1.69 (brs, 2H), 2.03 (brs, 2H), 2.78 (brs, 2H), 3.23 (brs, 2H), 3.46 (brs, 4H), 4.60 (brs, 4H), 4.96-5.11 (m, 1H), 5.98-6.14 (m, 1H), 6.91-7.01 (m, 1H), 7.28-7.38 (m, 3H), 7.47-7.58 (m, 3H), 7.88-8.03 (m, 2H), 8.12 (d, J=7 Hz, 1H), 8.52 (s, 1H), 8.81 (brs, 1H), 9.31 (brs, 1H); 19F NMR (DMSO-d6) −61.75 (s, 3F); ESIMS found for C43H58F3N7O9 m/z 874 (M+H).

Workup

  1. stirringThe solution was stirred for 60 min at 0° C
  2. stirringthe mixture stirred at r.t. overnight
  3. washThe solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine
  4. dry with materialdried over anhydrous MgSO4
  5. customThe crude product was then purified on a silica gel column (100:1 CHCl3/MeOH)
  6. customfinally crystallized from ethyl ether/hexane

Sources & evidence

ORD record
ord-e8c5086d26254418af1cc841d49fc150
Source dataset
uspto-grants-2012_05
Patent number
US08178490B2

Reaction notes

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