ABSTRACT
The International Consortium for Innovation & Quality (IQ) in Pharmaceutical Development recently established a working group focused on the development of a guidance to address Deuterated Active Pharmaceutical Ingredients. Deuteration of an Active Pharmaceutical Ingredient (API) in some cases can retard and/or alter API metabolism by exploiting the primary kinetic isotope effect. Several deuterated APIs have entered into the clinic, and one has recently been approved. In most cases, it is very difficult to nearly impossible to synthesize a 100% isotopically pure compound. This raises synthetic, analytical, and regulatory questions that warrant a science-based assessment and recommendations for synthetic methods, analytical methods, and specifications. A cross functional team of scientists with expertise in isotope chemistry, process chemistry, analytical chemistry, and drug metabolism and pharmacokinetics have been meeting under the auspices of IQ to define and address these questions. This paper strives to frame chemistry, manufacturing, and controls challenges.
Subject(s)
Deuterium/chemistry , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/chemical synthesis , Chemistry Techniques, Synthetic , Terminology as TopicABSTRACT
[reaction: see text]. A proline-based N-oxide is identified that serves as an effective catalyst for the reaction of allyltrichlorosilane with aryl and alpha,beta-unsaturated aldehydes at room temperature to afford the desired homoallylic alcohols in up to 92% ee. The chiral catalyst can be easily prepared from optically pure proline in three simple steps and 60% overall yield.
Subject(s)
Alcohols/chemical synthesis , Aldehydes/chemistry , Cyclic N-Oxides/chemistry , Proline/analogs & derivatives , Proline/chemistry , Alcohols/analysis , Catalysis , Molecular Structure , Silanes/chemistry , Stereoisomerism , TemperatureABSTRACT
[reaction: see text] Addition of mixed alkynylzinc reagents to various arylimines is catalyzed by chiral amino acid-based ligand 1 and Zr(Oi-Pr)(4).HOi-Pr to afford chiral propargylamines in up to 90% ee. Oxidative removal of the o-anisidyl group affords the free amine, which can then be acylated.
Subject(s)
Alkynes/chemistry , Imines/chemical synthesis , Pargyline/analogs & derivatives , Pargyline/chemical synthesis , Propylamines/chemical synthesis , Zirconium , Acylation , Amino Acids/chemistry , Aniline Compounds/chemistry , Catalysis , Ligands , Oxidation-Reduction , StereoisomerismABSTRACT
Chiral, single enantiomer pharmaceuticals have become increasingly more important. Therefore, research aimed at providing new methods for their selective preparation has taken on an even greater importance. One of the most efficient strategies for the synthesis of non-racemic, chiral molecules is asymmetric catalysis. There are many variables involved in the discovery of a new catalytic asymmetric transformation; hence, methods for the rapid screening of large numbers of catalysts have been developed. Herein, these techniques and strategies for the rapid discovery of novel asymmetric catalysts are reviewed.
