O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate → N-[(2R)-2-({[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}amino)-2-phenylacetyl]-L-alanine

HRID 254016Notes

Reaction equation

HRID 254016 reaction equation
FC1C=CC(N2[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)=CC=1.Cl.[NH2:46][C@H:47]([C:49]([O:51]C(C)(C)C)=[O:50])[CH3:48].CN(C(ON1N=[N:71][C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][C:65]1=2)=[N+](C)C)C.[B-](F)(F)(F)[F:74]>C(Cl)Cl>[F:74][C:69]1[CH:70]=[CH:65][C:66]([N:71]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: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:46][C@H:47]([C:49]([OH:51])=[O:50])[CH3:48])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:67][CH:68]=1

Participants

5

Reactant 3

HCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 11275390tert-Butyl alaninate hydrochlorideHCID 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 66843155N-[(2R)-2-({[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}amino)-2-phenylacetyl]-L-alanine

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 L-alaninate hydrochloride (0.014 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 was allowed to stir for 1 h after which the resulting tert-butyl ester was purified by chromatography on silica gel and eluted with EtOAc/CH2Cl2 25/75. Pure fractions were concentrated and dissolved in CH2Cl2 (4 ml) and trifluoroacetic acid (0.5 ml). After 1.5 h at room temperature, full conversion to the corresponding acid was obtained. The reaction mixture was concentrated and the residue of TFA was removed by co-evaporation with toluene (3 ml). The crude acid was dissolved in MeOH (3 ml) and NaBH4-(0.010 g, 0.260 mmol) was added. Full conversion to the corresponding alcohol was obtained after 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc buffer (1 ml). The mixture was concentrated and the residue was purified by preparative HPLC using a gradient of 20-50% CH3CN in 0.1M NH4OAc buffer as mobile phase. Freeze-drying afforded the title compound (0.020 g, 45%) as a colourless solid. M/z: 688.4 (M−1). 1H NMR [(CD3)2SO), 400 MH] δ 2.30-2.35 (m, 3H), 2.86-2.94 (m, 2H), 3.15-3.31 (m, 1H), 4.26-4.28 (m, 1H), 4.59 (d, 1H), 4.64 (d, 1H), 4.70-4.76 (m, 1H), 5.04-5.07 (m, 1H), 5.46 (d, 1H), 6.94-7.36 (m, 17H), 8.43-8.55 (m, 2H).

Workup

  1. customwas purified by chromatography on silica gel
  2. washeluted with EtOAc/CH2Cl2 25/75
  3. concentrationPure fractions were concentrated
  4. dissolutiondissolved in CH2Cl2 (4 ml)
  5. customfull conversion to the corresponding acid was obtained
  6. concentrationThe reaction mixture was concentrated
  7. customthe residue of TFA was removed by co-evaporation with toluene (3 ml)
  8. dissolutionThe crude acid was dissolved in MeOH (3 ml)

Sources & evidence

ORD record
ord-24d1dc833268483990652305a3a5c457
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

Loading…