Reacción #337481

Ecuación de reacción

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

Disolventes

methylene chloride

DMSO

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroThe solvent was evaporated
2. 2
   workup.DISSOLUTIONthe residue was dissolved in formic acid (1 ml)
3. 3
   TemperaturaThe mixture was heated to 45-50° C.
4. 4
   workup.STIRRINGstirred at this temperature for 4 h
5. 5
   OtroThe reaction mixture was evaporated under reduced pressure
6. 6
   workup.ADDITIONToluene (5 ml) was added
7. 7
   Otroevaporated
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
    Otrothe reaction mixture was evaporated under reduced pressure
11. 11
    OtroThe residue was purified by preparative HPLC
12. 12
    SecadoAfter freeze-drying 47 mg (74%) of the title compound
13. 13
    Otrowas obtained

Procedimiento

[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).

Fuente