反应详情

A suspension of 2.100 g (6.55 mmoles) of Z-(L)-Pro-(L)AlaOH (Sigma) in 80 ml of dry methylene chloride (CH2Cl2) was brought, under argon atmosphere, to a temperature of approximately -20° C. On stabilization of the temperature, the following were added in rapid succession: 0.850 ml (6.50 mmoles) of isobutylchloroformate (IBCF) and 0.790 ml (6.50 mmoles) of N-methylpiperidine (NMP), leaving the system under stirring for approximately 2 minutes. A solution pre-cooled to -15° C. for 30 minutes of 1.700 g (6.32 mmoles) of TrpOMe. HCl, prepared (according to Chan's method) from 1-Me-(DL)-TrpOH (Aldrich) and 0,770 ml (6.33 mmoles) of NMP in 25 ml of anhydrous N,N-dimethylformamide (DMF) was then added to the white suspension. Under stirring, the temperature of the system was allowed to rise to room temperature. After approximately 4 hours of reaction, the white precipitate was filtered away and washed with a little CH2Cl2. The latter was put back into the reaction solution of a yellowish colour, which was extracted in succession using 5% NaHCO3 (4×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO4 (4×30 ml) and finally saturated aqueous NaCl (3×30 ml), discarding the aqueous phases. The organic phase extracted was left in a cold chamber under argon and on anhydrous Na2SO4 for 24 hours. The desiccant was then filtered away and the solution concentrated to a small volume under vacuum. The residual yellowish liquid was dripped under stirring into 150 ml of n-hexane, obtaining a large amount of white precipitate, which was filtered after resting for several hours in a cold chamber, leaving the white solid under vacuum on P2O5 for 12 hours. 2.700 g (85.0%) of a white solid were recovered, which on analysis was shown to be Z-(L)-Pro-(L)-Ala-(1)-Me-(DL)-TrpOMe. The two diastereoisomers were separated by flash-chromatography in an inverse phase (resin C18, eluant H2O/CH3CN 60:40), collecting and uniting the fractions of interest. On elimination under vacuum of most of the organic phase, an abundant white flocculent precipitation was obtained which, after several hours at rest in a cold chamber, was filtered under vacuum. The filtered solid was dried for 24 hours on P2O5 under vacuum. 1.0 g (31.5%) of an analytically pure white solid corresponding to Z-(L)-Pro-(L)-Ala-(1)-Me-(L)-TrpOMe were recovered.

1. customwas brought, under argon atmosphere, to a temperature of approximately -20° C
2. additionOn stabilization of the temperature, the following were added in rapid succession