O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate → (2s)-{[(2r)-2-({[4-((2r,3r)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}amino)-2-phenylacetyl]amino}(phenyl)acetic acid

HRID 254019Notes

Reaction equation

HRID 254019 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:44]=[CH:43][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:45][C@@H:46]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:47]([O:49]C(C)(C)C)=[O:48].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>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:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:44]=[CH:43][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34]([NH:45][C@@H:46]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:47]([OH:49])=[O:48])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 7016394(S)-tert-Butyl 2-amino-2-phenylacetateHCID 66842725(2R)-({[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl)amino)(phenyl)acetic acid

Product 1

HCID 66843076(2s)-{[(2r)-2-({[4-((2r,3r)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}amino)-2-phenylacetyl]amino}(phenyl)acetic acid

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(2R)-({[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}amino)(phenyl)acetic acid (0.040 g, 0.065 mmol) was dissolved in CH2Cl2 (5 ml). tert-Butyl (2S)-amino(phenyl)acetate (0.016 g, 0.078 mmol) and N-methyl-morphiline (0.020 g, 0.195 mmol) were added. After 5 minutes, TBTU (0.027 g, 0.084 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The resulting tert-butyl ester was purified on silica gel and eluted with EtOAc/CH2Cl2 (25/75). The pure fractions were concentrated. The residue was dissolved in CH2Cl2 (3 ml) and TFA (0.5 ml). The reaction mixture was stirred overnight at room temperature. The resulting acid was concentrated and the remaining trace of TFA was removed by co-evaporation with toluene (3 ml). The acid was dissolved in MeOH (3 ml) and NaBH (0.010 g, 0.260 mmol) was added. After 5 minutes, full conversion to the corresponding alcohol was obtained. The reaction was quenched by the addition of 1 ml of 0.1M NH4OAc buffer. Concentration followed by purification on preparative HPLC using a gradient of 20-50% CH3CN in 0.1M NH4OAc buffer as mobile phase and freeze-drying of the pure fractions afforded the title compound (0.037 g, 76%) as a colourless solid. M/z: 750.6 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 2.87-2.94 (m, 2H), 4.25-4.28 (m, 1H), 4.58-4.78 (m, 3H), 5.01-5.07 (m, 2H), 5.65-5.74 (m, 1H), 6.94-7.39 (m, 22H), 8.53-8.72 (m, 2H).

Workup

  1. customThe resulting tert-butyl ester was purified on silica gel
  2. washeluted with EtOAc/CH2Cl2 (25/75)
  3. concentrationThe pure fractions were concentrated
  4. dissolutionThe residue was dissolved in CH2Cl2 (3 ml)
  5. stirringThe reaction mixture was stirred overnight at room temperature
  6. concentrationThe resulting acid was concentrated
  7. customthe remaining trace of TFA was removed by co-evaporation with toluene (3 ml)
  8. dissolutionThe acid was dissolved in MeOH (3 ml)
  9. waitAfter 5 minutes

Sources & evidence

ORD record
ord-2eba73e83e0b47e989f9032dce5ef611
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

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