4-Methylmorpholine → N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-D-valine

HRID 603903Notes

Reaction equation

HRID 603903 reaction equation
[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:40])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:70][C@@H:71]([C:75]([OH:77])=[O:76])[CH:72]([CH3:74])[CH3:73]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:40])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:70][C@@H:71]([C:75]([OH:77])=[O:76])[CH:72]([CH3:74])[CH3:73])=[O:36])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 71563D-ValineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 67271334N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycine

Product 1

HCID 67271666N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-D-valine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
30 °C

Procedure

To a stirred solution of N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycine (12.8 mg, 0.023 mmol) in DMF (2 ml) was added N-methylmorpholine (15 μl, 0.091 mmol). TBTU (8.8 mg, 0.027 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. D-valine (4.5 mg, 0.038 mmol) was added and the mixture was stirred at ambient temperature overnight. The solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was passed through a phase separator and concentrated under reduced pressure. The residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained. H-NMR (400 MHz, DMSO-d6): 0.80 (bs, 6H), 1.92-2.04 (m, 1H), 2.77-2.90 (m, 2H), 3.77 (bs, 2H), 3.94-4.10 (b, 1H), 4.22-4.30 (m, 1H), 4.49 (s, 2H), 4.56-4.64 (m, 1H), 4.99-5.03 (m, 1H), 5.90-5.94 (m, 2H), 6.70-6.79 (m, 2H), 6.82 (s, 1H), 6.96 (d, 2H), 7.09-7.15 (m, 2H), 7.18-7.24 (m, 2H), 7.34 (d, 2H), 8.23 (bs, 1H). M/z: 666.67 (M−1).

Workup

  1. stirringthe mixture was stirred at ambient temperature overnight
  2. customThe solution was purified with preparative HPLC on a C8 column, UV 240/260 nm
  3. customThe pure fractions were collected
  4. customthe MeCN was removed under reduced pressure
  5. extractionextracted with DCM
  6. concentrationconcentrated under reduced pressure
  7. dissolutionThe residue was dissolved in MeCN

Sources & evidence

ORD record
ord-3143ed88c62343c59050f7b2a70b4331
Source dataset
uspto-grants-2011_03
Patent number
US07906502B2

Reaction notes

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