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

HRID 254026Notes

Reaction equation

HRID 254026 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:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:68]1([CH2:74][C@H:75]([C:77]([OH:79])=[O:78])[NH2:76])[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1.[BH4-].[Na+]>CN(C=O)C.C(O)(=O)C.C(#N)C.C([O-])(=O)C.[NH4+].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][CH2:33][C:34]([NH:76][C@@H:75]([C:77]([OH:79])=[O:78])[CH2:74][CH:68]3[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]3)=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1

Participants

10

Reactant 5

HCID 79724-MethylmorpholineHCID 736026(2R)-2-amino-3-cyclohexylpropanoic acidHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4311764Sodium borohydrideHCID 66842760N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio)-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine

Product 1

HCID 66842660N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-cyclohexyl-D-alanine

Reagents, catalysts & solvents 4

HCID 176Acetic AcidCatalystHCID 679Dimethyl SulfoxideSolventHCID 6228DimethylformamideSolventHCID 21894531Acetonitrile ammonium acetateSolvent

Procedure

N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (30 mg, 0.0555 mmol) and N-methylmorpholine (30 mg, 0.296 mmol) were dissolved in DMF (0.5 ml). TBTU (23 mg, 0.0717 mmol) was added and the mixture was stirred for 15 min at room temperature. 3-Cyclohexyl-D-alanine (15 mg, 0.0876 mmol) was added and the stirring was continued overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (1 ml). NaBH4 (10 mg, 0.264 mmol) was added and the mixture was stirred for 10 min at room temperature. Three drops of acetic acid was added to the reaction mixture. The product was isolated by preparative HPLC using acetonitrile/ammonium acetate buffer (40:60) as eluent. After freeze-drying 19 mg (49%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 0.68-0.93 (m, 2H), 1.0-1.75 (m, 1H), 2.78-3.00 (m, 2H), 3.73 (s, 2H), 4.00-4.14 (m, 1H), 4.23-4.35 (m, 1H), 4.51 (s, 2H), 4.65-4.78 (m, 1H), 4.99-5.09 (m, 1H), 6.90-7.44 (m, 12H), 7.72-7.86 (m, 1H), 8.26 (t, 1H).

Workup

  1. waitthe stirring was continued overnight at room temperature
  2. customThe solvent was evaporated under reduced pressure
  3. dissolutionthe residue was dissolved in methanol (1 ml)
  4. stirringthe mixture was stirred for 10 min at room temperature
  5. customThe product was isolated by preparative HPLC
  6. dry with materialAfter freeze-drying 19 mg (49%) of the title compound
  7. customwas obtained

Sources & evidence

ORD record
ord-e6ca6404afc24d728857e5df93bd086b
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

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