ABSTRACT
In this work, we exploit computational fluid dynamics (CFD) to evaluate stirred tank reactor (STR) process engineer parameters (PEP) and design a scale-down system (SDS) to be representative of the formulation and filling process steps for an Aluminum adjuvanted vaccine drug product (DP). To study the shear history in the SDS we used the concept of number of passages, combined with an appropriate stirring speed down scale strategy comprising of either (i) tip speed equivalence, widely used as a scale-up criterion for a shear-sensitive product, or (ii) rotating shear, a shear metric introduced by Metz and Otto in 1957 but never used as scaling criterion. The outcome of the CFD simulations shows that the tip equivalence generates a worst-case SDS in terms of shear, whereas the rotating shear scaling approach could be used to design a more representative SDS. We monitored the trend over time for "In Vitro Relative Potency" as DP Critical Quality Attribute for both scaling approaches, which highlighted the crucial role of choosing the appropriate scaling-down approach to be representative of the manufacturing scale during process characterization studies.
Subject(s)
Hydrodynamics , Vaccines , Computer Simulation , Adjuvants, Immunologic/chemistry , Chemistry, Pharmaceutical/methods , Technology, Pharmaceutical/methodsABSTRACT
Convenient accesses to enantiomerically pure 2-, 2,3-, 2,6-, 2,3,6-substituted piperidines and 1,4-substituted indolizine are described. At first, indium-mediated aminoallylation and -crotylation of aldehydes with (R)-phenylglycinol or (1R,2S)-1-amino-2-indanol gave homoallylamines with high stereocontrol. Then, these products, submitted to a Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation, afforded perhydrooxazolo[3,2-a]piridines whose oxazolidines are opened with nucleophiles. Finally, the removal of the chiral auxiliaries delivered the enantiomerically pure piperidines.
Subject(s)
Hydrocarbons, Cyclic/chemistry , Piperidines/chemical synthesis , Models, Molecular , Molecular StructureABSTRACT
Linear hydroformylation of N-protected allyl- or homoallylamines (cyclohydrocarbonylation: CHC), followed by a reductive amination constitute the two key steps toward convenient routes to aza-heterocycles.
Subject(s)
Alkaloids/chemistry , Heterocyclic Compounds/chemistry , Piperidines/chemistry , Quinolizidines/chemistry , Amination , Cyclization , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
Carbonylation reaction is a very effective transformation for the synthesis of esters, amides, and heterocyclic compounds. Heterogeneous catalyzed carbonylation reactions can be carried out using the association of Pd/C and microwave dielectric heating. Alkoxy carbonylation can be performed with stoichiometric amounts of different primary and secondary alcohols in DMF in the presence of DBU as the base. Analogously, iodobenzene, CO, and amines can be transformed into the corresponding amides in good yields after a simple filtration to remove the catalyst. Pd/C was also successfully employed in microwave-assisted cyclocarbonylation of o-iodoaniline with acyl chlorides to give benzoxazinones. Pd/C can be recycled two times without a considerable difference in the reaction yields.
Subject(s)
Iodides/chemistry , Microwaves , Amides/chemical synthesis , Amides/chemistry , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Catalysis , Cyclization , Esters/chemical synthesis , Esters/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Ligands , Palladium/chemistryABSTRACT
A multicomponent reaction between H(2), CO, an unsaturated carboxylic acid derivative, and binucleophiles has been discovered. This process represents a combination of diversity-oriented synthesis and multicomponent reactions including amidation and hydroformylation, followed by nucleophilic addition to an N-acyliminium ion allowing the generation of six new bonds. Using pi-nucleophiles, the sequence turns into a multicomponent Pictet-Spengler reaction.
Subject(s)
Carbon Monoxide/chemistry , Carboxylic Acids/chemistry , Heterocyclic Compounds/chemical synthesis , Hydrogen/chemistry , Imines/chemistry , Heterocyclic Compounds/chemistry , Molecular Structure , StereoisomerismABSTRACT
The development of hydroformylative domino reactions of easily accessible vinyl acetamides is described. Extremely regioselective hydroformylation of terminal double bounds provides a transient N-acyliminium that can be trapped by various nucleophiles to give several aza-heterocylic scaffolds in a diastereoselective manner.
