4-Methylmorpholine → ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate

HRID 500411Notes

Reaction equation

HRID 500411 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([CH:20]1[CH2:22][CH2:21]1)[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:24][C@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([NH:32][C@:33]2([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:35][C@H:34]2[CH:36]=[CH2:37])=[O:31])[CH2:26]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]([NH:8][C@@H:9]([CH2:13][N:14]([CH:20]1[CH2:22][CH2:21]1)[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([N:28]1[CH2:29][C@H:25]([OH:24])[CH2:26][C@H:27]1[C:30]([NH:32][C@:33]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:35][C@H:34]1[CH:36]=[CH2:37])=[O:31])=[O:12])=[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 593865472(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoic acidHCID 67330424(1R,2S)-ethyl 1-((3R,5S)-3-hydroxypyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate hydrochloride

Product 1

HCID 59386563ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylateYield 58.5%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

A solution of 2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoic acid (1.47 g, 4.71 mmoL) in 20 mL of DCM was treated sequentially with ethyl 1(R)-[4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate hydrochloride (prepared in example 5) (1.44 g, 4.71 mmoL), N-methyl morpholine (1.80 mL, 16.34 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 organic phase was 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 ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate as a white foam:

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 organic phase was 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-0e8fc63864774e40bb346e9161021393
Source dataset
uspto-grants-2010_08
Patent number
US07772183B2

Reaction notes

Loading…