4-Methylmorpholine → N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2 (4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutaminyl-D-phenylalanine

HRID 254024Notes

Reaction equation

HRID 254024 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:43]=[CH:42][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:39]([OH:41])=O)[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:45][C@@H:46]([C:54]([O:56]C(C)(C)C)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CS(C)=O>[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:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:39]([NH:45][C@@H:46]([C:54]([OH:56])=[O:55])[CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:41])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])=[CH:42][CH:43]=2)=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 15942423tert-butyl (2R)-2-amino-3-phenylpropanoate hydrochlorideHCID 66842599N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamine

Product 1

HCID 86619082N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2 (4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutaminyl-D-phenylalanine

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 6344DichloromethaneSolvent

Procedure

N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamine (15 mg, 0.0244 mmol), tert-butyl D-phenylalaninate hydrochloride (8 mg, 0.0310 mmol) and N-methylmorpholine (10 mg, 0.099 mmol) were dissolved in methylene chloride (0.5 ml). TBTU (10 mg, 0.0313 mmol) was added and the mixture was stirred for 1 h at room temperature. The solvent was evaporated and the residue was dissolved in formic acid (0.5 ml). The mixture was heated to 45-50° C. and stirred at this temperature for 6 h. The reaction mixture was evaporated under reduced pressure. Methanol (5 ml) was added and evaporated. The residue was dissolved in methanol (1 ml). Two drops of TEA was added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC using acetonitrile/ammonium acetate buffer (40:60) as eluent. After freeze-drying 12 mg (64%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 1.55-1.97 (m, 4H), 2.77-3.10 (m, 4H), 4.20-4.38 (m, 3H), 4.49 (s, 2H), 4.66-4.78 (m, 1H), 4.99-5.07 (m, 1H), 6.70 (s, 1H), 6.88-7.40 (m, 19H), 8.00-8.20 (m, 2H).

Workup

  1. customThe solvent was evaporated
  2. dissolutionthe residue was dissolved in formic acid (0.5 ml)
  3. temperatureThe mixture was heated to 45-50° C.
  4. stirringstirred at this temperature for 6 h
  5. customThe reaction mixture was evaporated under reduced pressure
  6. additionMethanol (5 ml) was added
  7. customevaporated
  8. dissolutionThe residue was dissolved in methanol (1 ml)
  9. additionTwo drops of TEA was added
  10. stirringthe mixture was stirred overnight at room temperature
  11. customThe solvent was evaporated
  12. customthe residue was purified by preparative HPLC
  13. dry with materialAfter freeze-drying 12 mg (64%) of the title compound
  14. customwas obtained

Sources & evidence

ORD record
ord-cb5d20a6e6e146429f7715c01c90e2ac
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

Loading…