Reaction optimisation methods

Yan B, Gremlich HU, Moss S, Coppola GM, Sun Q, Liu LJ (1999) Comparison of various FTIR and FT Raman methods applications in the reaction optimisation stage of combinatorial chemistry. J Comb Chem 1 46-54... 

B. Yan, Chapter 3 Solid-Phase Reaction Optimisation Using FTIR Methods, in Analytical Methods in Combinatorial Chemistry, Technomic, Pennsylvania,... 

S.-A. Leung, R.F. Winkle, R.C.R. Wootton and A.J. deMello, A method for rapid reaction optimisation in continuous-flow microfluidic reactors using online Raman spectroscopic detection, Analyst, 130, 46-51... 

Despite the area of microwave-assisted chemistry being 20 years old, the technique has only recently received widespread global acceptance. This is a consequence of the recent availability of commercial microwave systems specific for synthesis, which offer improved opportunities for reproducibility, rapid synthesis, rapid reaction optimisation and the potential discovery of new chemistries. The beneficial effects of microwave irradiation are finding an increased role in process chemistry, especially in cases when usual methods require forcing conditions or prolonged reaction times. 

Equation 8.18 presented the general, non-linear optimisation method for calorimetric measurements based on a reaction model, and Equation 8.20 presented the general, non-linear optimisation method for spectroscopic measurements based on a reaction model. A comparison of these two equations reveals that the non-linear parameters dit...tNp, which are defined by the reaction model, are common to both equations. Only the linear parameters in these equations (E and Ar H. ..v,..) are different. As the linear parameters in both... 

Benzotropones (XXXIV) were first prepared more than seventy years ago utilising a condensation reaction between phthalaldehyde and acetonedicarboxylic acid [122-124]. It is interesting to note that this preparative method involved the use of a condensation reaction leading directly to a tropone ring system, for simple tropones have not been made in this way. Variants of this method have been used to prepare a number of benzotronones a recent optimised method provides yields of 70% [237]. Other more recent methods use o-di(bromomethyl)benzene as starting material [238]. 

W C, A Tempcz)rrk, R C Hawley and T Hendrickson 1990. Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics. Journal of the American Chemical Society 112 6127-6129. ensson M, S Humbel, R D J Froese, T Matsubara, S Sieber and K Morokuma 1996. ONIOM A Multilayered Integrated MO + MM Method for Geometry Optimisations and Single Point Energy Predictions. A Test for Diels-Alder Reactions and Pt(P(t-Bu)3)2 + H2 Oxidative Addition. Journal of Physical Chemistry 100 19357-19363. 

For the industrial production of riboflavin as pharmaceuticals, the traditional methodology comprising the dkect condensation of (13) with (14) in an acidic medium with continuous optimisation of the reaction conditions is stiU used (28). A great part of riboflavin manufactured by fermentative methods is used for feeds in the form of concentrates. The present world demand of riboflavin may be about 2500 t per year. Of this amount, 60%, 25%, and 15% are used for feeds, pharmaceuticals, and foodstuffs, respectively. The main producers are Hoffmann-La Roche, BASF, Merck Co., and others. 

The authors optimised conditions for the general reaction of 1,1-diphenylethylene and piperidine (Scheme 9.5). They obtained the highest TOF (288 h" ) and all linear product for this specific reaction when using complex 31 and 5 1 H iCO at 125°C for 24 h. An important note here is that the sterics of the substrate, 1,1-diarylethyl-enes, are responsible for generation of only linear products instead of the catalyst. With a one-pot method, the authors procured the active pharmaceuticals prozapine, fendilline, milverine, and diisopromine in 85%, 91%, 35% and 88% yield, respectively. The catalyst activities compare well to the established Rh-Xantphos system [33]. 

While additive analysis of polyamides is usually carried out by dissolution in HFIP and hydrolysis in 6N HC1, polyphthalamides (PPAs) are quite insoluble in many solvents and very resistant to hydrolysis. The highly thermally stable PPAs can be adequately hydrolysed by means of high pressure microwave acid digestion (at 140-180 °C) in 10 mL Teflon vessels. This procedure allows simultaneous analysis of polymer composition and additives [643]. Also the polymer, oligomer and additive composition of polycarbonates can be examined after hydrolysis. However, it is necessary to optimise the reaction conditions in order to avoid degradation of bisphenol A. In the procedures for the analysis of dialkyltin stabilisers in PVC, described by Udris [644], in some instances the methods can be put on a quantitative basis, e.g. the GC determination of alcohols produced by hydrolysis of ester groups. 

The development phase invokes many instances where reactions must be optimised quickly because of changes in the route to or specification of the drug substance. The final challenge is to converge upon the most appropriate and environmentally acceptable methods for manufacture. In identifying optimal synthesis conditions, real-time tuning of a mi-... 

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