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4-Methylmorpholine → 1-{[1-(2-tert-Butoxycarbonylamino-non-8-enoyl)-4-(isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester

HRID 346926
Notes
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Reaction equation

HRID 346926 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH2:22]([O:24][C:25]([C:27]1([NH:32][C:33]([CH:35]2[CH2:39][CH:38]([O:40][C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=[CH:43][N:42]=3)[CH2:37][NH:36]2)=[O:34])[CH2:29][CH:28]1[CH:30]=[CH2:31])=[O:26])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH2:22]([O:24][C:25]([C:27]1([NH:32][C:33]([CH:35]2[CH2:39][CH:38]([O:40][C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=[CH:43][N:42]=3)[CH2:37][N:36]2[C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:34])[CH2:29][CH:28]1[CH:30]=[CH2:31])=[O:26])[CH3:23]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 11507316(2S)-N-Boc-amino-non-8-enoic acidHCID 1317262291-{[4-(Isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester, bis hydrochloride

Product 1

HCID 68746749
1-{[1-(2-tert-Butoxycarbonylamino-non-8-enoyl)-4-(isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester
Yield 79.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

2(S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids)(1.0 g, 3.68 mmol) dissolved in 100 mL of DMF was treated sequentially with 1-{[4-(isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester, bis hydrochloride (1.46 g, 3.68 mmol), N-methyl morpholine (1.4 mL, 12.9 mmol), and HATU (PE biosystems) (1.68 g, 4.42 mmol). The reaction mixture was stirred at rt under N2 for 24 h, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give 2.2 g of the crude product. Flash chromatography (20–50% ethyl acetate/hexane) gave 1.9 g (79%) of 1-{[1-(2-tert-butoxycarbonylamino-non-8-enoyl)-4-(isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester as a glassy colorless solid:

Workup

  1. concentrationconcentrated in vacuo
  2. customThe residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate)
  3. washThe organic phase was washed with sat. aq. NaHCO3
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customto give 2.2 g of the crude product

Sources & evidence

ORD record
ord-f1401eefb6f1455e90316b0f58e3400a
Source dataset
uspto-grants-2007_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07173004B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes