Search

A new, enantioselective synthesis of Orlistat suitable for large-scale production is described, wherein the first enantiomerically pure intermediate methyl (R)-3-hydroxy-tetradecanoate is prepared via asymmetric hydrogenation of methyl 3-oxotetradecanoate. The relevant criteria associated with the application of the asymmetric hydrogenation technology are addressed, such as the activity, the selectivity and the availability of the catalyst as well as the quality of the hydrogenation substrate and the hydrogen gas.

The pilot-plant-scale synthesis of (S)-2-(4-fluorophenyl)-3-methylbutanoic acid by asymmetric hydrogenation of 2-(4-fluorophenyl)-3-methylbut-2-enoic acid with the [Ru((R)-MeOBIPHEP)(OAc)2]-catalyst is described. The hydrogenation was performed in a continuous mode in a cascade stirred-tank reactor system at 270 bar pressure. The (S)-2-(4-fluorophenyl)-3-methylbutanoic acid is an important optically active intermediate in the synthesis of mibefradil, a new type of calcium antagonist.

Reversible and selective monoamine oxidase-A inhibitors (RIMA's) like moclobemide (Aurorix®) have rehabilitated the use of MAO inhibitors as drugs of choice in depression. Starting from the structure of moclobemide, we tried to identify novel types of MAO inhibitors by bioisosteric replacement of the amide group. 2-Aminomethyl-5-phenylpyrroles retained some in vitro activity and served as a starting point for the construction of restricted rotation analogues. 3,4-Dihydro-6-phenylpyrrolo[1,2-a]pyrazines were the most interesting members of a family of 6-, 7-, and 8-phenyl-substituted pyrrolo[1,2-a]pyrazines and were subsequently optimized. A 'lipophilic linker' between phenyl and pyrrole ring proved exceedingly useful to improve affinity and led to the benzo[g]pyrazino[1,2-a]indolering system. Synthetic procedures starting from substituted 1-tetralones allowed the synthesis of substituted derivatives of this ring system. Once the optimal substitution pattern had been identified, facile synthesis of derivatives was achieved from aromatic triflates by Stille or Suzuki coupling. In this series selective and reversible monoamine oxidase-A inhibitors as well as mixed MAO-A and B inhibitors were identified. Affinity of this compounds for MAO was in the nanomolar or even sub-nanomolar range (for monoamine oxidase-A). In conclusion, benzo[g]pyrazino[1,2-a]indoles have been identified as a new class of reversible and highly potent monoamine oxidase inhibitors.