Reaction #337481

Reaction equation

TBTU

Acetic acid

[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid

tert-butyl L-glutaminate hydrochloride

N-methylmorpholine

NaBH4

→

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

Solvents

methylene chloride

DMSO

Conditions

Workup

1. 1
   OtherThe solvent was evaporated
2. 2
   workup.DISSOLUTIONthe residue was dissolved in formic acid (1 ml)
3. 3
   TemperatureThe mixture was heated to 45-50° C.
4. 4
   workup.STIRRINGstirred at this temperature for 4 h
5. 5
   OtherThe reaction mixture was evaporated under reduced pressure
6. 6
   workup.ADDITIONToluene (5 ml) was added
7. 7
   Otherevaporated
8. 8
   workup.DISSOLUTIONThe residue was dissolved in methanol (1 ml)
9. 9
   workup.STIRRINGthe mixture was stirred for 15 min at room temperature
10. 10
    Otherthe reaction mixture was evaporated under reduced pressure
11. 11
    OtherThe residue was purified by preparative HPLC
12. 12
    DryingAfter freeze-drying 47 mg (74%) of the title compound
13. 13
    Otherwas obtained

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 at room temperature. The solvent was evaporated and the residue was dissolved in formic acid (1 ml). The mixture was heated to 45-50° C. and stirred at this temperature 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 at room temperature. 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).

Source