Trifluoroacetic acid → N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethy]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-alanyl-D-valine

HRID 254029Notes

Reaction equation

HRID 254029 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:39]=[CH:38][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:35]([OH:37])=O)[CH3:34])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.C([O:45][C:46](=[O:52])[C@@H:47]([CH:49]([CH3:51])[CH3:50])[NH2:48])(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[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:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:35]([NH:48][C@@H:47]([C:46]([OH:52])=[O:45])[CH:49]([CH3:51])[CH3:50])=[O:37])[CH3:34])=[O:31])=[CH:38][CH:39]=2)=[CH:6][CH:7]=1

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 45108216H-D-Val-OtBu hydrochlorideHCID 66842883N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-alanine

Product 1

HCID 66842877N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethy]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-alanyl-D-valineYield 79.1%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-([2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-alanine (0.015 g, 0.027 mmol), D-valine tert-butyl ester hydrochloride (0.008 g, 0.038 mmol) and N-methylmorpholine (0.030 ml, 0.272 mmol) in DCM (4 ml) was stirred for 5 min. TBTU (0.013 g, 0.041 mmol) was added. After 3 h, the conversion to the ester (M/z: 710.2) was completed and TFA (3 ml) was added. After 4 h, the mixture was diluted with toluene (2 ml) and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (4 ml) and NaBH4 was added in small portions to the solution (a total of 0.065 g, 1.72 mmol) until the reduction was complete. Ammonium acetate buffer (0.1M, 3 ml) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC, using a gradient of 20-50% MeCN in a 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.014 g (77% yield) of the title compound was obtained as a white solid. M/z: 656.1. 1H NMR (DMSO, 400 MHz): δ 0.75-0.83 (m, 6H), 1.22 (d, 3H), 1.95-2.07 (m, 1H), 3.83-3.96 (m, 2H), 3-98-4.06 (m, 1H), 4-24-4.31 (m, 1H), 4.40-4.54 (m, 3H), 4.67-4.76 (m, 1H), 5.01-5.07 (m, 1H), 6.91-7.98 (m, 2H), 7.05-7.17 (m, 4H), 7.19-7.25 (m, 2H), 7.29-7.39 (m, 4H), 7.84-7.95 (m, 1H). 8.07 (d, 1H),

Workup

  1. waitAfter 4 h
  2. customthe solvent was removed under reduced pressure
  3. dissolutionThe residue was dissolved in MeOH (4 ml)
  4. additionNaBH4 was added in small portions to the solution (a total of 0.065 g, 1.72 mmol) until the reduction
  5. additionAmmonium acetate buffer (0.1M, 3 ml) was added and most of the methanol
  6. customwas removed under reduced pressure
  7. customThe remaining solution was purified by preparative HPLC
  8. customAfter freeze-drying

Sources & evidence

ORD record
ord-d1d1d9e048a64a2c9b8d87a6ba1383f9
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

Loading…