4-Methylmorpholine → N-({4-[(2R,3R)-1-(4-fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-methyl-D-valine

HRID 254058Notes

Reaction equation

HRID 254058 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]([OH:24])[C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([OH:33])=O)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:65][CH2:66][C:67]([NH:69][C@@H:70]([C:75]([OH:77])=[O:76])[C:71]([CH3:74])([CH3:73])[CH3:72])=[O:68].[BH4-].[Na+]>CN(C=O)C.CO>[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]([OH:24])[C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:65][CH2:66][C:67]([NH:69][C@@H:70]([C:75]([OH:77])=[O:76])[C:71]([CH3:72])([CH3:73])[CH3:74])=[O:68])=[O:33])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4311764Sodium borohydrideHCID 66842720{4-[(2R,3R)-1-(4-fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetic acidHCID 86613089Glycyl-3-methyl-D-valine

Product 1

HCID 66842891N-({4-[(2R,3R)-1-(4-fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-methyl-D-valineYield 22.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of {4-[(2R,3R)-1-(4-fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.020 g, 0.039 mmol) and NMM (0.020 ml, 0.182 mmol) in DMF (3 ml) at RT was added TBTU (0.020 g, 0.062 mmol). The reaction mixture was stirred for 60 min after which glycyl-3-methyl-D-valine (0.008 g, 0.043 mmol) was added. The mixture was stirred for 18 h before the reaction was quenched by the addition of water (1 ml). The mixture was diluted with MeOH (1 ml) and NaBH4 (0.040 g, 1.06 mmol) was added. After 10 min the reaction was quenched by the addition of a 0.1M ammonium acetate buffer (2 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product as a white solid (0.006 g, 22% yield).

Workup

  1. additionwas added
  2. customwas quenched by the addition of water (1 ml)
  3. additionwas added
  4. customAfter 10 min the reaction was quenched by the addition of a 0.1M ammonium acetate buffer (2 ml) and most of the methanol
  5. customwas removed under reduced pressure
  6. customThe remaining solution was purified by preparative HPLC
  7. customFreeze-drying of the pure fractions

Sources & evidence

ORD record
ord-0179c5411341487aacdbccc239ac57f4
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

Loading…