Metoprolol, synthesis

The enandoselecdve nltro-aldol reacdon catalyzed by C/fi-LLB is effecdvely applied to the synthesis of three kmds of opdcally acdve fi-receptor blocking dnigs fS -metoprolol, " fS -propanolol, " and fS -pindolol " " fScheme 3.17i. 

The alkane hydroxylase from Pseudomonas oleovorans is particularly suitable for the epoxidation of terminal aliphatic double bonds and enables rapid access to the (3-blocker metoprolol (Scheme 9.14) [113,116]. Complementing this regioselectivity, chloroperoxidases are particularly suitable biocatalysts for the epoxidation of (ds substituted) subterminal olefins [112,117]. This enzyme also accepts terminal olefins and is utilized for the effident synthesis of P-mevalono-ladone [118]. 

The enantioselective nitro-aldol reaction catalyzed by (R)-LLB is effectively applied to the synthesis of three kinds of optically active (3-receptor blocking drugs (5)-metoprolol,123a (S)-propanolol,123b and ( -pindolol1230 (Scheme 3.17). 

Similarly, this reaction has also been applied in the synthesis of other fi-rcccptor blocking drugs such as (Vj-metoprolol,117 (Vj-pindolol,118 and the HIV protease inhibitors KNI-227 and KNI-272.119... 

H. Sasai, T. Suzuki, N. Itoh, M. Shibasaki, Catalytic Asymmetric Synthesis of Propranolol and Metoprolol Using La-Li-BINOL Complex, Appl. Organomet. Chem... 

These results have led to an interesting industrial apphcation for the synthesis of the j5-blockers Metoprolol and Atenolol. Thus, epoxidation of the prochiral allyl ethers by several bacteria, including the P. oleovorans strain mentioned above, led to the corresponding (S)-epoxides which showed excellent enantiomeric purities (Fig. 3). Further on, these chirons (i.e. chiral building blocks) were transformed into the corresponding (S)-enantiomers of the drugs developed by the Shell and Gist-Brocades companies [44]. Refinement of this approach... 

Aigbirhio, F., Pike, V.W., Francotte, E., Waters, S.L., Banfield, B., Jaeggi, K.A., Drake, A., 1992. 5-[l-(2,3-Diaminophenoxy)]-3 -(A -t-butylamino)propan-2 -ol simplified asymmetric synthesis with CD and chiral HPLC analysis. Tetrahedron Asymmetry 3, 539-554. Antoni, G., Ulin, J., Langstrom, B., 1989. Synthesis of the "C-labelled p-adrenergic receptor ligands atenolol, metoprolol and propranolol. Appl. Radial. Isot. 7, 561-564. 

O.E., Vaalburg, W., 1993. Synthesis and evaluation of l -[ F]fluoro-metoprolol as a potential tracer for the visualization of 3-adrenocep-tors with PET. Nucl. Med. Biol. 20, 637-642. 

R)-Isopropylideneglycerol is a useful C3-synthon in the synthesis of (S)-P-block-ers e.g. (S)-metoprolol. (R)-Isopropylideneglyceric acid can also be used as starting material for the synthesis of biologically active compounds. 

R) -1 sopropylideneglycerol is a useful C3-synthon in the synthesis of (S)-P-blockers, e. g. (S)-metoprolol. Also, (R)-isopropylideneglyceric acid may be used as the starting material for the synthesis of biologically active products. The resolution is carried out by selective microbial oxidation of the (S)-enantiomer (Fig. 19-9). The chemical synthesis of (R)-isopropylideneglycerol starts either from unnatural L-mannitol or from L-ascorbic acid (Fig. 19-10). In comparison to the biotransformation, here stoichiometric quantities of lead tetra acetate are needed. 

Special Note. The subsequent replacement of the acetamido functional moiety with other groups that are certainly capable of hydrogen bonding ultimately gave rise to the synthesis of a series of highly specific cardioselective Pj-blockers that were eventually employed as potent drngs, namely Atenolol Betaxolol Metoprolol. 

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