4-Methylmorpholine → tert-butyl (R)-4-((R)-3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate

HRID 1096663Notes

Reaction equation

HRID 1096663 reaction equation
[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[N:11]([CH2:12][CH2:13][N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=3[N:8]=2)[CH2:2]1.[C:29]([O:33][C:34]([NH:36][C@H:37]([CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)[CH2:38][C:39](O)=[O:40])=[O:35])([CH3:32])([CH3:31])[CH3:30].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][N:11]1[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[N:8]=[C:7]1[C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:39](=[O:40])[CH2:38][C@H:37]([NH:36][C:34](=[O:35])[O:33][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:42][C:43]2[CH:52]=[CH:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=2)[CH2:2]1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 7021578(R)-3-((tert-butoxycarbonyl)amino)-4-(naphthalen-2-yl)butanoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 667869112-(2-(2-(piperidin-3-yl)-1H-benzo[d]imidazol-1-yl)ethyl)isoindoline-1,3-dione

Product 1

HCID 66791777tert-butyl (R)-4-((R)-3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamateYield 4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(R)-2-(2-(2-(piperidin-3-yl)-1H-benzo[d]imidazol-1-yflethypisoindoline-1,3-dione (129B) (500 mg of mixture) from previous step, was weighed into a 25 mL round-bottomed flask equipped for stirring under nitrogen. DMF (3 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (2.48 mmoles, 0.817 g) and N-methylmorpholine (7.44 mmoles, 0.818 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (2.73 mmoles, 1.04 g) was added and the resultant solution was stirred at room temperature for 3 hrs. The reaction solution was then directly purified by preparative LC/MS (35-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-4-((R)-3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (129C) as a clear oil. (0.105 mmoles, 0.072 g, 4% yield over 2-steps). ESI-MS: m/z 686.5 (M+H)+.

Workup

  1. customequipped
  2. stirringto stir at rt for 5 min
  3. customThe reaction solution was then directly purified by preparative LC/MS (35-95% CH3CN in H2O)
  4. customThe resultant fractions were collected
  5. customthe solvent was removed in-vacuo

Sources & evidence

ORD record
ord-a09b80cd26854eb587aaac841535c86c
Source dataset
uspto-grants-2012_03
Patent number
US08138168B1

Reaction notes

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