Small-Scale Reaction Optimization

The first task was to find a combination of catalyst components with the lowest contribution to the price per kilogram product. Palladium contributes negligibly to the cost price, since the oxidation works well with a very small amount of 

The reaction temperature was optimized by experiments with the same conversion curves while using different temperatures and then comparing the product selectivity of 3,3-dimethoxy methyl propionate. This was done by careful adjustment of the methyl acrylate Pd ratio. The same conversion curve is obtained when methyl acrylate Pd is decreased from 40 000 to 25 000 while decreasing the reaction temperature from 80 to 70 °C (Chart 11.2b). 

Both at 70 and 80 °C, selectivity starts to decrease above 60% conversion, but more rapidly at 80 °C (product yield at 95% conversion 60% at 80 C 75% yield at 70 °C). Selectivity loss at higher conversions can be explained by competing addition of coproduced water instead of methanol to the 3-methoxyacrylate intermediate. In contrast to the stable 3,3-dimethoxy methyl propionate acetal product formed by methanol addition, the hemiacetal 3-methoxy-3-hydroxy methyl propionate generated by addition of water is prone to overoxidation, especially at higher reaction temperatures. Consequently, 3,3-dimethoxy methyl propionate selectivity benefits from increasing the methanol/methyl acrylate ratio. The results of variation of methanol/methyl acrylate ratio on activity and selectivity are depicted in Chart 11.2c,d, respectively (Pd/Cu/Fe/methyl acrylate 1/500/500/25000 oxygen pressure 0.2 MPa). Whereas conversion rates are equal at different methanol/methyl acrylate ratios, 3,3-dimethoxy methyl propionate selectivity erodes to 50% above 90% conversion at a low methanol/methyl acrylate 

Chart 11.2 Investigation of reaction parameters [9]. (a) Effect of catalyst composition on the reaction rate at different pressures (Pd = 4.4x 10 mol, 

MA = 0.11 mol, MeOFI = 0.98 mol, lOOOrpm, 0.2 MPa pure oxygen, varying reaction 

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The currently available instmmentation from Biotage is the Initiator reactor for small-scale reactions in a single-mode cavity (Fig. 3.20). This instmment is closely related to the former Creator, but is now equipped with a touch-screen for on-the-fly control or changes of parameters, and no external PC is needed. The enhanced version, the Initiator Sixty, in succession to the Optimizer EXP, is equipped with a... 

Prepare the reaction using the same conditions as the small-scale reactions and incubate in a 37 °C water bath for 2-4 h before comparing the yield against the optimal small-scale reaction by loading 2 pi of each on a denaturing PAGE. 

The main drawback with balloons is that they have a tendency to burst and this can have grave consequences, especially if you are working on a small scale. A spaghetti tubing manifold (Fig. 9.13) will provide a similar low pressure inert gas source, but is much more reliable. It is particularly useful if you need to set up several small scale reactions running in parallel to one another. This is often the case if you need to optimize the conditions for a reaction. 

Gc also provides quantitative analysis and is widely used for determination of product ratios from diastereoselective reactions, down to about 200 1. This makes it an ideal technique for optimization studies, where a large number of small-scale reactions are carried out under different conditions and product ratios are measured simply by syringing out a few microlitres from each and then injecting them into the gc instrument. 

To select the most suitable solvent for a desired reaction, screening of various solvents is usually necessary, since the prediction of the best solvents by the simulation is still difficult. The screening has to be condurted to optimize the reaction conditions with respect to (1) the type and scale of the reaction, (2) the stability of the biocatalyst, (3) the hydrophobicity of the solvents, (4) the solubilities of the substrate and product, (5) the recovery of the product and enzyme, (6) environmental and safety concerns, and (7) the cost of the biocatalyst, substrate, and product. For example, to conduct a dehydration reaction using hydrolytic enzyme, a water-free nonaqueous solvent must be selected instead of water. On the other hand, the level of the dehydration should not be too much, as noted previously, to take away the water from enzyme necessary for its activity. Supercritical CO is better to be used in relatively large scale using a flow reactor than using in the very small-scale batch reaction because product recovery in the small-scale reaction in batch CO reactor needs extraction with organic solvents. 

At Bristol-Myers Squibb, the quinine-catalyzed alcoholysis of the anhydride 25 initially provided kilogram quantities of the (lS,2k)-monoester 24a with 90.8% ee. To improve the enantioselectivity of desired 24a, alternative enzymatic processes were evaluated [75]. Screening of various enzymes was carried out to prepare (lS,2k)-monoester 24a from dimethyl ester 26. After evaluating yield and optical purity of desired product, reaction rate, and cost of enzyme, the immobilized lipase from C. antarcUca (Novozym 435) was chosen for further development. After optimizing the reaction parameters such as pH, temperature, substrate and enzyme input, a small scale reaction of 50 mL (57.2 g) of dimethyl ester 26 afforded (lS,2k)-monoester 24a in 96% yield and >99.9% ee after 24 h reaction. 

The reaction conditions should be optimized prior to scale-up. As the in vivo system is mainly used for initial metabolite characterization, the goal of reaction optimization is finding suitable conditions (not necessary the optimal conditions) to enable rapid synthesis of small amounts of the desired metabolite at a reasonable cost. 

Because the yield of transcription can vary depending upon a large number of factors (type and quality of the DNA template, T7 RNA polymerase, ribonucleotide triphosphates, etc.), it is recommended to optimize the reaction conditions on a small scale before embarking on a large-scale mRNA prep. 

In this chapter, microwave scale-up to volumes > 100 mL in sealed vessels is discussed. An important issue for the process chemist is the potential for direct seal-ability of microwave reactions, allowing rapid translation of previously optimized small-scale conditions to a larger scale. Several authors have reported independently on the feasibility of directly scaling reaction conditions from small-scale singlemode (typically 0.5-5 mL) to larger scale multimode batch microwave reactors (20-500 mL) without reoptimization of the reaction conditions [24, 87, 92-94],... 

Microwave heating is often applied to already known conventional thermal reactions in order to accelerate the reaction and therefore to reduce the overall process time. When developing completely new reactions, the initial experiments should preferably be performed only on a small scale applying moderately enhanced temperatures to avoid exceeding the operational limits of the instrument (temperature, pressure). Thus, single-mode reactors are highly applicable for method development and reaction optimization. 

Microwave irradiation, in contrast to thermal heating, produces very efficient heat transfer resulting in even heating throughout the sample. The process can be optimized by giving careful thought to the dimensions of the reaction vessel and volume of reactants [9] it is fortunate that radiochemical syntheses are usually performed on a very small scale (< 5 cm3) where a high and stable E-field intensity is easier to maintain, especially if a monomodal cavity, rather than a multimodal mode, is adopted. 

As illustrated in Scheme 1, on a small scale under reflux in ace-tone/water, 5% of starting material remained after 12 h reaction time and approximately 20% of the by-product was formed (entry 1). When performing the reaction at the same concentration in a lab-scale micro-wave device (Emrys Optimizer, entry 2) at 120°C, the reaction was complete after 5 min and gave a product of significantly higher purity and in higher yield. In the next step, 400 ml of reaction mixture was reacted in an 8 vessel rotor batch microwave (entry 3) at the same temperature... 

It is desirable to maximize the RNA yield for each sample and this can be achieved by determining the optimal magnesium chloride concentration required for in vitro transcription. A series of 13 small-scale (25 pi) reactions with a range of magnesium chloride concentrations from 4 to 52 mM, increasing by 4 mM increments each, are typically used for magnesium chloride optimization. 

Efficient mixing. High surface-volume ratio Optimized heating transfer precise temperature control Side-reaction suppression Only soluble substrates-reagents are compatible. Limited reaction-time range small scale... 

Controlled microwave heating is a new enabling tool that helps the medicinal and combinatorial chemist to rapidly both optimize reaction conditions and perform small-scale target syntheses. In this short review, we have presented examples of microwave heating in high-speed medicinal chemistry. More specifically, we have mainly described microwave-enhanced synthesis of protease inhibitors using transition-metal catalysis. In all depicted examples, the main chemical effort was directed towards convenient and reliable pro-... 

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