ABSTRACT
The administration of compounds by a dry-powder inhaler presents significant challenges to the development and discovery chemist, owing to the stringent requirements placed upon the physical characteristics of the active pharmaceutical ingredient and the high complexity of the molecules concerned. The current state of synthetic chemistry technology is such that commercial syntheses of these compounds are demanding but achievable. While synthetic chemistry will remain a major component of the development of inhaled therapies, the main challenge facing practitioners in this area is the early identification of a suitable solid form. Further advances in the prediction of solid-form properties would significantly enable this field and may allow triage of molecules to be carried out at the design stage of projects.
Subject(s)
Chemistry, Pharmaceutical , Dosage Forms , Administration, Inhalation , PowdersABSTRACT
Two methods to produce (2S)-5-amino-2-(1-n-propyl-1H-imidazol-4-ylmethyl)-pentanoic acid were investigated. Diastereoisomeric salt resolution, using the quinidine salt, gave the desired intermediate in 98% ee and 33% yield. Asymmetric hydrogenation of various substrates gave high conversions, with up to 83% ee. Integration of these two approaches via asymmetric hydrogenation of a quinidine salt substrate followed by crystallization provided the desired intermediate in 94% ee and 76% yield.
Subject(s)
Amino Acids/chemical synthesis , Combinatorial Chemistry Techniques , Imidazoles/chemistry , Pentanoic Acids/chemical synthesis , Quinidine/chemistry , Amino Acids/analysis , Molecular Structure , Pentanoic Acids/analysis , Pentanoic Acids/chemistry , StereoisomerismABSTRACT
A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.