Synthesis of Mibefradil

Mibefradil is the first calcium antagonist known to selectively block T-type calcium channels. It is highly effective against hypertension and angina pectoris, and significantly improves the benefit-risk balance in comparison with drugs which have similar targets. 

Chemically, mibefradil is a relatively simple molecule that contains two stereocenters, and was originally obtained as a single isomer by a highly efficient resolution process coupled with the racemization and recycling of the undesired enantiomer. More recently, however, a more convenient procedure toward enantiomerically pure mibefradil was developed. 

Central to this route was an asymmetric hydrogenation of an early intermediate catalyzed by a Ru complex containing a chiral non-racemic diphosphine ligand [61,62]. The reaction sequence is described in Fig. 19. 

4-Fluorophenylacetic acid was transformed into the unsaturated acid 48 by reaction with 2 mol equiv. of i-PrMgCl, followed by acetone addition, dehydration, and crystallization. The tetra-substituted double bond was then hydrogenated under high pressure in an ad hoc designed continuous-stirred tank reactor system and in the presence of the Ru complex 49 (substrate/catalyst ratio =1000) to afford (.5)-acid 50 in 93.5% e.e. Crystallization of its sodium salt upgraded the e.e. to 98%. 

The thus established stereocenter served in the following steps. Conversion of 50 to 51 was achieved by acyl chloride formation followed by Friedel-Crafts reaction with ethylene and A1C13. Addition of the lithium enolate of t-butylacetate occurred from the less-hindered face of the cyclic ketone to give, after reduction and tosylation, adduct 52. Tosylate displacement with amine 53, esterification with methoxyacetylchloride, and addition of HC1 gave mibefradil 54. 

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Scheme 4. Resolution and enantioselective hydrogenation in the synthesis of mibefradil...

Figure 19. Stereoselective synthesis of mibefradil. Reagents a, i-PrMgCl, THF b, acetone c, H2S04 d, H2, 270 bar, MeOH/TEA e, MeONa f, HC1 g, SOCl2 h, ethylene, A1C1, i, LiCH2COOBu-t j, RedAl k, TCI, TEA 1, TEA m, MeOCH2COCl, TEA n, HC1.

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