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

HRID 254035Notes

Reaction equation

HRID 254035 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](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:9]2[C:23]2[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](O)=[O:30])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Cl.[NH2:35][CH2:36][C:37]([NH:39][C@@H:40]([C:44]([O:46]C(C)(C)C)=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[BH4-].[Na+].C([O-])(=O)C.[NH4+]>C(Cl)Cl>[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][CH:15]([OH:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:9]2[C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]([NH:35][CH2:36][C:37]([NH:39][C@@H:40]([C:44]([OH:46])=[O:45])[CH:41]([CH3:42])[CH3:43])=[O:38])=[O:30])=[CH:32][CH:33]=2)=[CH:4][CH:3]=1

Participants

8

Reactant 6

HCID 79724-MethylmorpholineHCID 517165Ammonium AcetateHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4311764Sodium borohydrideHCID 66842797(4-{(2R,3R)-1-(4-Fluorophenyl)-4-oxo-3-[(2-oxo-2-phenylethyl)thio]azetidin-2-yl}phenoxy)acetic acidHCID 86613090tert-butyl glycyl-D-valinate hydrochloride

Product 1

HCID 66843029N-[(4-{(2R,3R)-1-(4-fluorophenyl)-3-[(2-hydroxy-2-phenylethyl)thio]-4-oxoazetidin-2-yl}phenoxy)acetyl]glycyl-D-valine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(4-{(2R,3R)-1-(4-Fluorophenyl)-4-oxo-3-[(2-oxo-2-phenylethyl)thio}azetidin-2-yl]phenoxy)acetic acid (15 mg, 0.043 mmol), tert-butyl glycyl-D-valinate hydrochloride, (14.3 mg, 0.054 mmol) and N-methylmorpholine (14 μl, 0.13 mmol) were dissolved in DCM (2 ml). After 5 minutes, TBTU (16.9 mg, 0.053 mmol) was added and the reaction mixture was stirred for 2.5 h. The formation of the ester was confirmed. M/z: 678.35 (N+H). The solvent was removed under reduced pressure. The residue was dissolved in EtOAc:DCM (1:3) and purified on silica gel (1 g) using EtOAc:DCM (1:3) as eluent. The fractions were collected and concentrated. The residue (0.029 g) was dissolved in DCM (3 ml) and TFA (0.5 ml) was added. The reaction mixture was stirred overnight. The solvent was removed under reduced pressure and toluene was added and removed under reduced pressure. The yellowish residue was dissolved in MeOH (2 ml) and sodium borohydride (16.2 mg, 0.43 mmol) was added. The reaction mixture was stirred for 10 minutes. Ammonium acetate (31.4 mg) was added and the solvent was removed under reduced pressure. The residue was purified with preparative HPLC on a C8 column. A gradient from 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (7.6 mg, 28%). H-NMR (400 MHz, DMSO-d6): 0.79 (d, 3H), 0.81 (d, 3H) 1.95-2.05 (m, 1H), 2.84-2.96 (m, 2H), 3.79 (d, 2H), 3.98-4.04 (m, 1H), 4.27 (d, 0.5H), 4.30 (d, 0.5H), 4.51 (s, 2H), 4.66-4.75 (m, 1H), 5.02 (d, 0.5H), 5.04 (d, 0.5H), 6.98 (d, 2H), 7.10-7.17 (m, 2H), 7.19-7.32 (m, 7H), 7.36 (d, 2H), 7.77 (t, 1H), 8.26 (t, 1H). M/z: 622.1 (M−H) and 624.2 (M+H).

Workup

  1. customThe solvent was removed under reduced pressure
  2. dissolutionThe residue was dissolved in EtOAc:DCM (1:3)
  3. custompurified on silica gel (1 g)
  4. customThe fractions were collected
  5. concentrationconcentrated
  6. dissolutionThe residue (0.029 g) was dissolved in DCM (3 ml)
  7. additionTFA (0.5 ml) was added
  8. stirringThe reaction mixture was stirred overnight
  9. customThe solvent was removed under reduced pressure and toluene
  10. additionwas added
  11. customremoved under reduced pressure
  12. dissolutionThe yellowish residue was dissolved in MeOH (2 ml)
  13. stirringThe reaction mixture was stirred for 10 minutes
  14. customthe solvent was removed under reduced pressure
  15. customThe residue was purified with preparative HPLC on a C8 column

Sources & evidence

ORD record
ord-d11efbccdd8b4967ac127706c53eda76
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

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