4-Methylmorpholine → trans-4-(N-tert-Butoxycarbonylaminomethyl)-N-tert-Butoxycarbonyl-L-Proline 4-Phenoxyphenylamide

HRID 2185463Notes

Reaction equation

HRID 2185463 reaction equation
CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[C:20]([O:24][C:25]([NH:27][CH2:28][C@H:29]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41]([OH:43])=O)[CH2:30]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=2)=[CH:46][CH:45]=1.ON1C2C=CC=CC=2N=N1>O1CCCC1.CN(C)C=O>[O:50]([C:51]1[CH:52]=[CH:53][C:54]([NH:57][C:41](=[O:43])[C@@H:31]2[CH2:30][C@@H:29]([CH2:33][NH:32][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][N:27]2[C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[CH:55][CH:56]=1)[C:47]1[CH:48]=[CH:49][CH:44]=[CH:45][CH:46]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 8764(4-Aminophenoxy)benzeneHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 213415491-(1,1-Dimethylethyl) (2S,4S)-4-((((1,1-dimethylethoxy)carbonyl)amino)methyl)-1,2-pyrrolidinedicarboxylate

Product 1

HCID 54074172trans-4-(N-tert-Butoxycarbonylaminomethyl)-N-tert-Butoxycarbonyl-L-Proline 4-PhenoxyphenylamideYield 63.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

N-Methylmorpholine (60 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-L-proline (Compound D109 (D), 206 mg), 4-aminodiphenylether (104 mg), and 1-hydroxybenzotriazole (70 mg) in tetrahydrofuran (6 mL) and N,N-dimethylformamide (2 mL) at room temperature. After stirring at room temperature for 13 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium carbonate and then brine. After drying over anhydrous sodium sulfate, the organic layer was concentrated in vacuo. The residue was washed with hexane to give the title compound (182 mg) as colorless plates: 1H NMR (400 MHz, CDCl3) δ 1.44-1.49 (18 H), 1.70 (br s, 1H), 2.54 (br s, 2 H), 3.08 (br s, 1H), 3.20 (br s, 2 H), 3.52 (br s, 1 H), 4.52 (br s, 1 H), 4.64 (br s, 1 H), 6.96 (d, J=7.8 Hz, 4 H), 7.07 (t, J=7.3 Hz, 1H), 7.31 (t, J=7.8 Hz, 2 H), 7.47 (d, J=9.3 Hz, 2 H), and 9.49 (br s, 1 H); mass spectrum (EI+) m/e 511 (M+).

Workup

  1. customthe reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid
  2. washThe organic layer was washed with saturated sodium carbonate
  3. dry with materialAfter drying over anhydrous sodium sulfate
  4. concentrationthe organic layer was concentrated in vacuo
  5. washThe residue was washed with hexane

Sources & evidence

ORD record
ord-2a9a63344cf1446ca71da91bef5d6397
Source dataset
uspto-grants-2002_06
Patent number
US06399629B1

Reaction notes

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