4-Methylmorpholine → [(N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino](diphenyl)acetic acid

HRID 254032Notes

Reaction equation

HRID 254032 reaction equation
CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([OH:58])=O)=[O:53])=[CH:48][CH:47]=2)=[CH:26][CH:25]=1.CN1CCOCC1.[C:68]1([C:74]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)([C:76]([OH:78])=[O:77])[NH2:75])[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1.[BH4-].[Na+].C([O-])(=O)C.[NH4+]>CN(C=O)C.CO>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][CH:37]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[OH:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([NH:75][C:74]([C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:76]([OH:78])=[O:77])=[O:58])=[O:53])=[CH:48][CH:47]=2)=[CH:28][CH:29]=1

Participants

9

Reactant 6

HCID 79724-MethylmorpholineHCID 182892,2-DiphenylglycineHCID 517165Ammonium AcetateHCID 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 66843246[(N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino](diphenyl)acetic acidYield 44%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
30 °C

Procedure

TBTU (0.016 g, 0.050 mmol) was added to a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.020 g, 0.037 mmol) and NMM (0.012 ml, 0.109 mmol) in DMF (2 ml) at 30° C. After 30 min, 2,2-diphenylglycine (0.009 g, 0.037 mmol, 98%) was added and the mixture was stirred at 30° C. for 2.5 h. The reaction was quenched with water (0.2 ml) and the mixture was diluted with MeOH (2 ml). NaBH4 (0.020 g, 0.529 mmol) was added and the mixture was stirred for 10 min. Ammonium acetate buffer (0.1M, 3 ml) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC, using a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, the title compound (0.012 g, 44% yield) was obtained as a white solid. M/z: 752.0. 1H NMR (DMSO, 400 MHz): δ 2.83-2.95 (m, 2H), 3.75 (d, 2H), 4.24-4.28 (m, 1H), 4.54 (s, 1H), 4.68-4.75 (m, 1H), 5.02-5.06 (m, 1H), 6.95-7.03 (m, 2H), 7.04-7.38 (m, 20H), 8.43-8.51 (m, 1H), 8.90 (s, 1H).

Workup

  1. customThe reaction was quenched with water (0.2 ml)
  2. additionthe mixture was diluted with MeOH (2 ml)
  3. stirringthe mixture was stirred for 10 min
  4. customwas removed under reduced pressure
  5. customThe remaining solution was purified by preparative HPLC
  6. customAfter freeze-drying

Sources & evidence

ORD record
ord-42bf2d7979af4bc4867bf579fbd26f0e
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

Loading…