ABSTRACT
Kimberly B. Humphries, Konrad Möbus, Tracy D. Dunn, and Baoshu Chen
Degussa Corporation, 5150 Gilbertsville Hwy, Calvert City, KY 42029 Abstract The carbobenzyloxy group (Cbz or Z) is a very useful protecting group in organic synthesis, in particular for the synthesis of proteins and peptides, which are used as drug intermediates. The Cbz group can be easily removed via catalytic hydrogenation. Typically, Pd supported on activated carbon powder is the catalyst of choice for such reaction (1). In this work, we report a more active 5%Pd on activated carbon catalyst for the deprotection of Cbz-phenylalanine. This new Degussa Cbz catalyst is highly active and shows a shorter reaction time compared to the state of the art catalyst. The protected amino acid Cbzphenylalanine was dissolved in alcoholic solvent and stirred under H2 in the presence of Pd/C. The initial reaction between hydrogen and the Cbzphenylalanine produced toluene and a carbamic acid intermediate. This unstable intermediate rapidly decomposes to yield CO2 and the unprotected amino acid. The progress of the reaction was monitored by the infrared detection of CO2 in the off-gas. Introduction The chemical pathways to the complex molecules produced by the fine chemical, pharmaceutical and agrichemical industries often involve multi-step synthesis. Protective groups are commonly used to block reactive sites that would otherwise react in an undesired fashion. A variety of protective groups have been successfully introduced and are now well established in organic synthesis. A common group for the protection of amines is the carbobenzyloxy group, also called Cbz or Z group. This group can be easily removed in the presence of a heterogeneous catalyst and hydrogen under ambient conditions (2). For the development of heterogeneous catalysts there is a need for tests that can easily distinguish between different catalysts, thus providing a tool for fast catalyst development. For hydrogenation reactions most often the consumed hydrogen can be measured directly, and this correlates to the catalyst’s activity. This is also true for the hydrogenolysis of benzyl ethers. However, this technique cannot be applied to the hydrogenolysis of benzyl carbamates, since one equivalent of CO2 is produced for each hydrogen consumed, keeping the pressure in the reactor constant. Taking samples at certain time intervals during the course of the reaction and determining the product via HPLC analysis is very time consuming and therefore not very practical for the determination of the performance of a catalyst. This contribution describes an online test method for
determining the catalyst activity for the cleavage of benzyl carbamates and the development of an improved catalyst using this method. Results and Discussion The deprotection of the Cbz protected amino acid proceeds via a two step mechanism (Figure 1). The first step comprises the catalytic hydrogenolysis of the benzyloxy group of the Cbz-protected amino acid (1). Toluene (3) is formed from the O-benzyl group as well as an unstable carbamic acid intermediate (2). This intermediate decomposes to form the unprotected amino acid (4) and carbon dioxide (5).
