Acetic Acid → N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamine

HRID 254115Notes

Reaction equation

HRID 254115 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:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:36][C@H:37]([C:43]([O:45]C(C)(C)C)=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[BH4-].[Na+].C(O)(=O)C>C(Cl)Cl.CS(C)=O>[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:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([NH:36][C@H:37]([C:43]([OH:45])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1

Participants

9

Reactant 6

HCID 176Acetic AcidHCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4311764Sodium borohydrideHCID 15602445H-Gln-OtBu hydrochlorideHCID 66842813[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid

Product 1

HCID 66842599N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamine

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
47.5 °C

Procedure

[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (50 mg, 0.103 mmol), tert-butyl L-glutaminate hydrochloride (30 mg, 0.124 mmol) and N-methylmorpholine (40 mg, 0.396 mmol) were dissolved in methylene chloride (1 ml). TBTU (40 mg, 0.125 mmol) was added and the mixture was stirred for 90 min. The solvent was evaporated and the residue was dissolved in formic acid (1 ml). The mixture was heated to 45-50° C. for 4 h. The reaction mixture was evaporated under reduced pressure. Toluene (5 ml) was added and evaporated. The residue was dissolved in methanol (1 ml). NaBH4 (30 mg, 0.793 mmol) was added and the mixture was stirred for 15 min. Acetic acid (50 mg, 0.83 mmol) was added and the reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC using acetonitrile/ammonium acetate buffer (35:65) as eluent. After freeze-drying 47 mg (74%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 1.72-2.16 (m, 4H), 2.81-2.95 (m, 2H), 4.08-4.20 (m, 1H), 4.26-4.31 (m, 1H), 4.50 (s, 2H), 4.65-4.78 (m, 1H), 5.03-5.08 (m, 1H), 6.68 (s, 1H), 6.89-7.44 (m, 14H), 8.29 (d, 1H).

Workup

  1. customThe solvent was evaporated
  2. dissolutionthe residue was dissolved in formic acid (1 ml)
  3. customThe reaction mixture was evaporated under reduced pressure
  4. additionToluene (5 ml) was added
  5. customevaporated
  6. dissolutionThe residue was dissolved in methanol (1 ml)
  7. stirringthe mixture was stirred for 15 min
  8. customthe reaction mixture was evaporated under reduced pressure
  9. customThe residue was purified by preparative HPLC
  10. dry with materialAfter freeze-drying 47 mg (74%) of the title compound
  11. customwas obtained

Sources & evidence

ORD record
ord-9f4f8e78bf374a12b061395a8a9b7422
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

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