4-Methylmorpholine → N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-seryl-D-phenylalanine

HRID 254027Notes

Reaction equation

HRID 254027 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:36](O)=[O:37])[CH2:34][OH:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.C([O:46][C:47](=[O:57])[C@@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH2:49])(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:36]([NH:49][C@@H:48]([C:47]([OH:57])=[O:46])[CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:37])[CH2:34][OH:35])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 15942423tert-butyl (2R)-2-amino-3-phenylpropanoate hydrochlorideHCID 66842695N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-([2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-serine

Product 1

HCID 66842972N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-seryl-D-phenylalanineYield 53%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-([2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-serine (diastereomeric mixture) (0.008 g, 0.014 mmol), D-phenylalanine tert-butyl ester hydrochloride (0.005 g, 0.018 mmol) and N-Methylmorpholine (0.006 ml, 0.055 mmol) in DCM (3 ml) was stirred at RT for 5 min. TBTU (0.008 g, 0.025 mmol) was added. After 3 days the conversion to the ester (M/z: 776.1) was complete and the mixture was concentrated under reduced pressure. The residue was dissolved in formic acid (3 ml) and the solution was stirred for 25 h. The mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (4 ml) and TEA (1 ml). The solution was stirred at 40° C. for 6 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.005 g (53% yield) of the title product was obtained as a white solid. M/z: 720.1. 1H NMR (DMSO, 400 MHz): δ 2.78-2.96 (m, 3H), 3.03-3.11 (m, 1H), 3.44-3.60 (m, 2H), 4.20-4.36 (m, 3H), 4.51 (s, 2H), 4.67-4.76 (m, 1H), 5.01-5.06 (m, 1H), 5.70 (bs, 1H), 6.90-6.98 (m, 2H), 7.05-7.25 (m, 1H), 7.29-7.37 (m, 4H), 7.84-8.00 (m, 2H).

Workup

  1. concentrationthe mixture was concentrated under reduced pressure
  2. dissolutionThe residue was dissolved in formic acid (3 ml)
  3. concentrationThe mixture was concentrated under reduced pressure
  4. dissolutionthe residue was dissolved in MeOH (4 ml)
  5. stirringThe solution was stirred at 40° C. for 6 h
  6. customThe solvent was removed under reduced pressure
  7. customThe residue was purified by preparative HPLC
  8. customAfter freeze-drying

Sources & evidence

ORD record
ord-286ce7e5ced747c3aa7009ceca72af80
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

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