4-Methylmorpholine → HCID 86619965, compound

HRID 1797806Notes

Reaction equation

HRID 1797806 reaction equation
[C:1]([O:5][C:6]([C@@H:8]([CH2:12][N:13]([CH:19]1[CH2:21][CH2:20]1)[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]([OH:11])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:23][C@@H:24]1[CH2:28][C@@H:27]([C:29]([NH:31][C@:32]2([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][C@H:33]2[CH:35]=[CH2:36])=[O:30])[NH:26][CH2:25]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([C@@H:8]([CH2:12][N:13]([CH:19]1[CH2:21][CH2:20]1)[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]([N:26]1[C@H:27]([C:29]([NH:31][C@:32]2([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][C@H:33]2[CH:35]=[CH2:36])=[O:30])[CH2:28][C@@H:24]([OH:23])[CH2:25]1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

8

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 67330424(1R,2S)-ethyl 1-((3R,5S)-3-hydroxypyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate hydrochlorideHCID 68798749HCID 68798749, compound

Product 1

HCID 86619965HCID 86619965, compoundYield 59.9%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

A solution of crude (S)-2-(tert-butoxycarbonyl)-3-(cyclopropyl(pent-4-enyl)amino)propanoic acid 1b (1.47 g, 4.71 mmoL) in 20 mL of DCM was treated sequentially with (1R,2 S)-ethyl 1-((3R,5S)-3-hydroxypyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate hydrochloride (1.44 g, 4.71 mmoL), N-methyl morpholine (1.80 mL, 16.3 mmoL), and HATU (2.14 g, 5.53 mmoL). The reaction mixture was stirred at rt under N2 for 3 h, and then concentrated in vacuo. The residue was dissolved in water, and 1N HCl was added until the pH=5. This aqueous solution was extracted with EtOAc (3×). The combined organic phases were washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 1.55 g (58%) of (1R,2S)-ethyl 1-((3R,5S)-1-((S)-2-(tert-butoxycarbonyl)-3-(cyclopropyl(pent-4-enyl)amino)propanoyl)-3-hydroxypyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate 1c as a white foam: LC-MS (Phenomenex-Luna S10 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 4 mL/min. Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 1.38 min), MS m/z 564 (M++1).

Workup

  1. concentrationconcentrated in vacuo
  2. dissolutionThe residue was dissolved in water
  3. addition1N HCl was added until the pH=5
  4. extractionThis aqueous solution was extracted with EtOAc (3×)
  5. washThe combined organic phases were washed with sat. aq. NaHCO3
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. customto give the crude product

Sources & evidence

ORD record
ord-f68971fe2e7e4e339d15476b1dc9ce26
Source dataset
uspto-grants-2013_01
Patent number
US08343477B2

Reaction notes

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