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-tyrosine

HRID 254025Notes

Reaction equation

HRID 254025 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](O)=[O:40])[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:55]([O:57]C(C)(C)C)=[O:56])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[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: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:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:39]([NH:45][C@@H:46]([C:55]([OH:57])=[O:56])[CH2:47][C:48]3[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=3)=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])=[CH:42][CH:43]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 66842599N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamineHCID 86619083tert-butyl D-tyrosinate hydrochloride

Product 1

HCID 66843298N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutaminyl-D-tyrosine

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 (22 mg, 0.0359 mmol), tert-butyl D-tyrosinate hydrochloride (10 mg, 0.0421 mmol) and N-methylmorpholine (14 mg, 0.138 mmol) were dissolved in methylene chloride (0.5 ml). TBTU (14 mg, 0.0436 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in formic acid (1 ml). The mixture was stirred at 45-50° C. for 4 h and was then evaporated under reduced pressure. Methanol (10 ml) was added and evaporated. The residue was dissolved in methanol (2 ml). Three drops of TEA were 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 15 mg (54%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 1.60-2.00 (m, 4H), 2.69-3.0 (m, 4H), 4.09-4.18 (m, 1H), 4.22-4.35 (m, 3H), 4.49 (s, 2H), 4.65-4.78 (m, 1H), 4.97-5.08 (m, 1H), 6.56 (d, 2H), 6.70 (s, 1H), 6.86-7.40 (m, 18H), 7.77-7.91 (m, 1H), 8.12 (d, 1H), 9.10 (bs, 1H).

Workup

  1. customThe solvent was evaporated
  2. dissolutionthe residue was dissolved in formic acid (1 ml)
  3. stirringThe mixture was stirred at 45-50° C. for 4 h
  4. customwas then evaporated under reduced pressure
  5. additionMethanol (10 ml) was added
  6. customevaporated
  7. dissolutionThe residue was dissolved in methanol (2 ml)
  8. additionThree drops of TEA were added
  9. stirringthe mixture was stirred overnight at room temperature
  10. customThe solvent was evaporated
  11. customthe residue was purified by preparative HPLC
  12. dry with materialAfter freeze-drying 15 mg (54%) of the title compound
  13. customwas obtained

Sources & evidence

ORD record
ord-39f76b1008274dbca10474778b49ab3a
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

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