Dichloromethane → Oxalyl chloride

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

One of the 3 parts of the compound of formula (I) in which R1 --(R2)m --(R3)n --(R4)p represents Boc-Arg(benzyloxycarbonyl)2 -Arg(benzyloxycarbonyl)2 -Pro-, R, R5 and R6 represent hydroxyl radicals and R7 represents a hydrogen atom obtained in Example 9 is treated for 90 minutes with 5 ml of a trifluoroacetic acid/distilled water mixture (95/5 by volume). The medium is then brought to dryness on a rotary evaporator (2.6 kPa, 45° C., 45 minutes) and 15 ml of distilled water are then added to the medium. The suspension obtained is frozen to -80° C. and then lyophilized (96 hours). The product is dissolved in 1 ml of dimethylformamide containing 0.0625 ml of diisopropylethylamine (0.36 mmol). 50 μl (50 μmol) of a solution of 1-adamantylacetic acid chloride (obtained by reaction of 38.8 mg (200 μmol) of 1-adamantylacetic acid with 17.2 μl (200 μmol) of oxalyl chloride in 200 μl of dichloromethane in the presence of a drop of dimethylformamide for 15 minutes at a temperature in the region of 20° C.) are then added to the peptide solution and the reaction is carried out at a temperature in the region of 20° C. for 1 hour. The solvent is then removed by virtue of a Speed Vac (Savant) centrifugal evaporator equipped with a vane pump for 18 hours at a temperature in the region of 20° C. The residue is dissolved in 2 ml of a dichloromethane/methanol mixture (1/1 by volume) and then 100 mg of 10% palladium-on-charcoal and 100 mg of ammonium formate are added. The reaction is carried out for 150 minutes with periodic stirring to a vortex. The reaction medium is filtered on a 0.45 μm Millex HV filter (Millipore) and the filter washed with 5 ml of methanol. The solvent is then evaporated under reduced pressure (2.6 kPa, 45° C., 30 minutes). The product is finally purified by high performance liquid chromatography on a 100 Å C18 column (250×10 mm, Bio-Rad), elution being carried out with a gradient from 15 to 40% of acetonitrile containing 0.07% of trifluoroacetic acid (by volume) in water containing 0.07% of trifluoroacetic acid (by volume) at a flow rate of 6 ml/minute, over 30 minutes, and then lyophilized. 2.9 mg of the ditrifluoroacetate of the compound of formula (I) in which R1 --(R2)m --(R3)n --(R4)p represents 1-adamantylacetyl-Arg-Arg-Pro-, R, R5 and R6 represent hydroxyl radicals and R7 represents a hydrogen atom are thus obtained in the form of a white powder [Mass spectrum on Sciex API III, in ESMS (Electrospray Mass Spectrometry): M/z=601.6 (M+2H)2+ ].

Herkunft & Nachweise