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

HRID 254033Notes

Reaction equation

HRID 254033 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][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:41]=[CH:40][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:37]([OH:39])=O)[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.C([O:47][CH2:48][C@@H:49]([C:51]([O:53]C(C)(C)C)=[O:52])[NH2:50])(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[BH4-].[Na+].C([O-])(=O)C.[NH4+]>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:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:41]=[CH:40][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:37]([NH:50][C@H:49]([C:51]([OH:53])=[O:52])[CH2:48][OH:47])=[O:39])[CH:34]([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1

Participants

9

Reactant 7

HCID 79724-MethylmorpholineHCID 8471TriethylamineHCID 517165Ammonium AcetateHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4311764Sodium borohydrideHCID 16211506H-Ser(tBu)-OtBu HClHCID 66842727N-([4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-valine

Product 1

HCID 68423873N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-valyl-L-serine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

N-([4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-valine (6.9 mg, 11.8 μmol) was dissolved in DCM (3 ml). tert-Butyl O-(tert-butyl)-L-serinate hydrochloride (3.7 mg, 14.2 μmol) and N-methylmorpholine (5.5 μl, 50 μmol) were added. After 5 minutes, TBTU (4.6 mg, 14.3 μmol) was added and the reaction mixture was stirred overnight. The formation of the ester was confirmed. M/z: 780.57 (M−1). The mixture was extracted between DCM (5 ml) and aqueous KHSO4 (5 ml, pH of 2). The organic phase was washed with aqueous NaHCO3 (5 ml, pH of 9). The aqueous phase was extracted with DCM (2×5 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated. Formic acid (1.5 ml) was added and the reaction mixture was stirred overnight. The formiate of the intermediate acid was obtained. The solvent was removed under reduced pressure, toluene (3×1 ml) was added and evaporated. The residue was dissolved in MeOH (1.5 ml) and triethylamine (90 μl, 0.65 mmol) was added and the reaction mixture was stirred for 1 hour. Sodium borohydride (4.0 mg, 0.11 mmol) was added and the reaction mixture was stirred for 1 hour. Ammonium acetate (15 mg) was added. The solvent was removed under reduced pressure and the residue was purified on preparative HPLC using a C8 column. A gradient from 20% to 50% MeCN in 0.1M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (5.3 mg, 67%). HRMS calcd for C33H35F2N3O8S 671.2113, found 672.2192 [M+H]+.

Workup

  1. extractionThe mixture was extracted between DCM (5 ml) and aqueous KHSO4 (5 ml, pH of 2)
  2. washThe organic phase was washed with aqueous NaHCO3 (5 ml, pH of 9)
  3. extractionThe aqueous phase was extracted with DCM (2×5 ml)
  4. dry with materialThe combined organic phases were dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. additionFormic acid (1.5 ml) was added
  8. stirringthe reaction mixture was stirred overnight
  9. customThe formiate of the intermediate acid was obtained
  10. customThe solvent was removed under reduced pressure, toluene (3×1 ml)
  11. additionwas added
  12. customevaporated
  13. dissolutionThe residue was dissolved in MeOH (1.5 ml)
  14. stirringthe reaction mixture was stirred for 1 hour
  15. stirringthe reaction mixture was stirred for 1 hour
  16. customThe solvent was removed under reduced pressure
  17. customthe residue was purified on preparative HPLC

Sources & evidence

ORD record
ord-4bc41bb2820f4141b14b376e561af64e
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

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