8-blockers, synthesis

The importance of immobilization was indicated in KR of racemic l-chloro-2-acetoxy-3-(l-naphthyloxy)-propane - a potential intermediate for p-blocker synthesis - by hydrolysis with PcL entrapped in Ca-alginate beads in batch reactors and in continuous PBRs [134]. The immobilized PcL in PBR was found to be at least three times more enantioselective than the native form in a batch reactor. 

Mohapatra, S.C. and Hsu, J.T. (1999) Optimizing lipase activity, enantios-electivity, and stability with medium engineering and immobilization for P blocker synthesis. Biotechnol. Bioeng., 64, 213-220. doi 10.1002/(SICI)1097-0290(19990720)64 2<213 AID-BIT10>3.0.CO 2-U... 

The synthetic utihty of the above transformations stems from the fact that many monoesters obtained as a result of hydrolysis may be converted to pharmaceutically important intermediates. For example, the optically active glycerol derivative (27) is a key intermediate in the production of P-blockers. Akyl derivative (25) may be converted into (5)-paraconic acid [4694-66-0] ((5)-5-oxo-3-tetrahydrofurancarboxyhc acid) that is a starting material for the synthesis of (3R)-A-factor. The unsaturated chiral cycHc monoacetate (31) is an optically active synthon for prostaglandins, and the monoester (29) is used for the synthesis of platelet activating factor (PAF) antagonists. 

Both saturated (50) and unsaturated derivatives (51) are easily accepted by lipases and esterases. Lipase P from Amano resolves azide (52) or naphthyl (53) derivatives with good yields and excellent selectivity. PPL-catalyzed resolution of glycidyl esters (54) is of great synthetic utiUty because it provides an alternative to the Sharpless epoxidation route for the synthesis of P-blockers. The optical purity of glycidyl esters strongly depends on the stmcture of the acyl moiety the hydrolysis of propyl and butyl derivatives of epoxy alcohols results ia esters with ee > 95% (30). 

Lipase-catalyzed enantioselective transesterification of 0-substituted-l,2-diols is another practical route for the synthesis of P-blockers. Lipase PS suspended in toluene catalyzes the transesterification of (63) with vinyl acetate to give the (5)-ester in 43% yield and >98% ee (78). The desired product, optically pure (R)-ttitylglycidol, is then easily obtained by treating the ester with alcohoHc alkaU. Moreover, Pseudomonas Hpase catalyzes the acylation of oxazohdinone (64) with acetic anhydride in very good yield and selectivity (74). PPL-catalyzed transesterification of a number of /n j -norbomene derivatives proceeds in about 30% yield and 92% ee (79,80). 

Various bioisosteric replacements for a phenolic hydroxyl have been explored. One such, a lactam NH, is incorporated into the design of the 3-adrenergic blocker, carteolol O)- The fundamental synthon is carbostyril derivative K This is reacted in the usual manner with epichlorohydrin to give which is in turn reacted with t-butylamine to complete the synthesis of carteolol (3 ), a drug that appears to have relatively reduced nonspecific myocardial depressant action. Carrying this de-... 

Benzothiazepines belong to the three classes of calcium channel blockers which are important cardiovascular drugs in the management of angina pectoris and hypertension. A diastereoselective one-pot synthesis of the trans-and ds-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-l,5-benzothiazepin-4-one nucleus, a key intermediate in the preparation of the calcium channel blocker Diltiazem, was carried out under microwave irradiation in an open vessel (Scheme 25). Control of the diastereoselectivity was achieved by vary-... 

Other drugs such as the neuroleptic, haloperidol, inhibit the induction of hsp70 mRNA in rodent neurons (Sharp et al.. 1992). Although this observation needs to be confirmed in the human population, it raises the possibility that an age-dependent defect in the production of HS proteins is exacerbated by a drug which is commonly used in demented elderly patients. The potential for certain pharmacologic agents to inhibit the HS response could increase the risk for untoward effects of atherosclerosis and hypoxia. A similar concern may be raised with certain calcium channel blockers which also have been found to reduce the synthesis of HS proteins in cardiac myocytes (Low-Friedrich and Schoeppe, 1991). 

Low-Friedrich, I. Schoeppe, W. (1991). Effects of calcium channel blockers on stress protein synthesis in cardiac myocytes. J. Cardiovasc. Pharmacol. 17,800-806. 

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]. 

Peukert S, Brendel J, Pirard B, Briiggemann A, Below P, Kleemann HW, Hem-merle H, Schmidt W. Identification, synthesis, and activity of novel blockers of the voltage-gated potassium channel Kvl.5. J Med Chem 2003 46 486-98. 

Peukert S, Brendel J, Pirard B, Strtibing C, Kleemann HW, Bohme T, Hemmerle H. Pharmacophore-based search, synthesis, and biological evaluation of anthra-nilic amides as novel blockers of the Kvl.5 channel. Bioorg Med Chem Lett 2004 14 2823-7. 

Figure 7.21 Synthesis of /3-blocker analogues with triazol functional moiety...

Martinez Lagos, F., Carballeira, J.D., Bermudez, J.L. et al. (2004) Highly stereoselective reduction of haloketones using three new yeasts application to the synthesis of (S)-adrenergic beta-blockers related to propranolol. Tetrahedron Asymmetry, 15 (5), 763-770. 

The synthesis of benzo[Z>]furan derivatives has become a very active field because these molecules have been recently identified as having a variety of biological activities. For example, they can function as inhibitors of protein tyrosine phosphatase IB with antihyperglycemic properties <00JMC1293>, as well as potent and short-acting p-blockers in the treatment of various cardiovascular diseases . An inexpensive, reusable clay has been utilized to catalyze a facile cyclodehydration under microwave without solvent to form 3-substituted benzo[2>]furans from substituted a-phenoxy acetophenones 104. One of the important features of this procedure is that all the selected cyclodehydration reactions are complete in less than 10 minutes <00SL1273>. 

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