Dichloromethane → Isobutyl chloroformate

Participants

Reaction Steps

A suspension of 1.200 g (5.10 mmoles) of N-benzyloxycarbonyl-(S)-(-)-2-azetidine-carboxylic acid (abbreviation Z-(S)-AzeOH, prepared from (S)-(-)-2-azetidinecarboxylic acid (Aldrich) according to the method of Wunsch) in 60 ml of dry methylene chloride (CH2Cl2) was brought in an argon atmosphere to a temperature of approximately -20° C. On stabilization of the temperature, the following were added in quick succession: 0.690 ml (5.27 mmoles) of isobutylchloroformate (IBCF) and 0.650 ml (5.34 mmoles) of 4-methylpiperidine (NMP), leaving the system under stirring for approximately 2 minutes. A solution, pre-cooled to approximately -15° C. for 30 minutes, of 1.850 g (5.03 mmoles) of (L)-Leu-(L)-TrpOMe.HCl (Novabiochem) and 0.620 ml (5.10 mmoles) of NMP in 25 ml of anhydrous N,N-dimethylformamide (DMF) was then added, leaving, under stirring and static argon, the temperature free to rise to room temperature. After approximately 3.5 hours of reaction, the white precipitate was filtered away and washed with a little CH2Cl2. The latter was put back into the pale yellow coloured organic solution, which was extracted in succession using 5% NaHCO3 (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO4 (3×30 ml) and finally saturated aqueous NaCl (3×30 ml), discarding the aqueous phases. The organic phase extracted, of a pale yellow colour, was left in a cold chamber under argon and on anhydrous Na2SO4 for 12 hours. The desiccant was then filtered away and the organic solution, concentrated to a small volume, leaves a dense residual oil which, when taken up with a minimum amount of CH2Cl2, was purified using flash-chromatography in a normal phase (SiO2, eluant CH2 Cl2 /n-hexane: 2/1). The chromatographic fractions of interest were concentrated to a small volume and ground with anhydrous ethyl ether. The whiteish solid thus obtained was filteres and left for 24 hours under vacuum on P2O5. 2.040 g (75.0%) of an analytically pure rubbery white solid were recovered.

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