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-lysine

HRID 603905Notes

Reaction equation

HRID 603905 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]CC(O)=O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.C(OC(NCCCC[C@H](C(OC(C)(C)C)=O)N)=O)(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O1C2C=CC(C(O)CS[C@H]3C(=O)N(C4C=CC(F)=CC=4)[C@@H]3C3C=CC(OCC(N[CH2:125][C:126]([NH:128][C@@H:129]([C:142]([O:144]C(C)(C)C)=[O:143])[CH2:130][CH2:131][CH2:132][CH2:133][NH:134]C(OC(C)(C)C)=O)=[O:127])=O)=CC=3)=CC=2OC1>C(Cl)Cl>[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:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:125][C:126]([NH:128][C@@H:129]([C:142]([OH:144])=[O:143])[CH2:130][CH2:131][CH2:132][CH2:133][NH2:134])=[O:127])=[O:32])=[CH:38][CH:39]=3)=[CH:9][C:4]=2[O:3][CH2:2]1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 56777341H-D-Lys(boc)-otbu hclHCID 67270896tert-butyl N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-N6-(tert-butoxycarbonyl)-D-lysinateHCID 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 67271513N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-D-lysine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

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 (11.3 mg, 0.020 mmol) in DCM (2 ml) were added tert-butyl N6-(tert-butoxycarbonyl)-D-lysinate hydrochloride (9.5 mg, 0.028 mmol), N-methylmorpholine (15 μl, 0.091 mmol) and TBTU (11.0 mg, 0.034 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. The formation of the intermediate tert-butyl N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-N6-(tert-butoxycarbonyl)-D-lysinate was confirmed. M/z: 852.23 (M−1). The solvent was removed under reduced pressure and the residue was dissolved in formic acid (2 ml). The mixture was stirred at ambient temperature for 48 hours. The solvent was co-evaporated with toluene and the residue 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 MeCN was removed under reduced pressure and the residue was lyophilised to give the title. H-NMR (400 MHz, DMSO-d6): 1.08-1.32 (m, 2H), 1.37-65 (m, 4H), 2.63 (t, 2H), 2.77-2.92 (m, 2H), 3.70 (d, 2H), 3.76-3.82 (m, 1H), 4.25 (d, 0.5H), 4.28 (d, 0.5H), 4.50 (s, 2H), 4.57-4.64 (m, 1H), 5.00 (d, 0.5H), 5.02 (d, 0.5H), 5.90-5.94 (m, 2H), 6.70-6.81 (m, 2H), 6.83 (s, 1H), 6.96 (d, 2H), 7.08-7.16 (m, 2H), 7.17-7.24 (m, 2H), 7.34 (d, 2H), 7.45-7.55 (m, 1H), 8.37-8.43 (m, 1H). M/z: 697.32 (M+1) and 695.39 (M−1).

Workup

  1. customThe solvent was removed under reduced pressure
  2. dissolutionthe residue was dissolved in formic acid (2 ml)
  3. stirringThe mixture was stirred at ambient temperature for 48 hours
  4. customthe residue was purified with preparative HPLC on a C8 column, UV 240/260 nm
  5. customThe MeCN was removed under reduced pressure
  6. customto give the title

Sources & evidence

ORD record
ord-f2c26b6e1ca447fe99f4d27a77219e1a
Source dataset
uspto-grants-2011_03
Patent number
US07906502B2

Reaction notes

Loading…