Synthesis batch

For the Michael addition of 2,4-pentanedione enolate to ethyl propiolate, improvements in conversion were determined. This example serves also to demonstrate that proper process conditions are mandatory to have success with micro-reactor processing. A conversion of only 56% was achieved when using electroosmotically driven flow with a two-fold injection, the first for forming the enolate and the second for its addition to the triple bond (batch synthesis 89%) [151]. Using instead a stopped-flow technique to enhance mixing, a conversion of 95% was determined. 

OS 16] ]R 5] ]P 13] Using continuous flow in an electroosmotic-driven micro reactor gave a quantitative yield of the dipeptide in only 20 min (600 V for Dmab-/ -alanine 700 V for the Fmoc ester) [5, 88]. Batch synthesis under the same conditions gave only a 40-50% yield [5] (46% in [5]), needing 24 h. 

Carbocations are highly reactive species that can be used for C-C bond formation. One driver for using continuous micro chemical processing is to employ also unstable cations, which are not amenable to batch synthesis because they decompose before they can actually be used [66, 67]. 

OS 44] ]R 4a] ]P 33] At room temperature, no reaction is observed in the presence or absence of a base using a batch synthesis [7]. Using a base, sodium carbonate (aqueous, 0.2 M, 20 ml water), at 75-80 °C results in 10% conversion after 8 h. The best micro reactor conversion was 68%, using no base and operating at room temperature. 

OS 52[ [R 4b[ [P 38] To achieve comparable extents of conversion, 24 h operation was needed for batch synthesis, whereas micro-reactor operation needs only about 20 min [8],... 

Conversion/selectivity/yield - benchmarking to conventional batch synthesis... 

OS 75] ]R 4b] ]P 55] For the reaction of 4-bromobenzaldehyde with the silyl enol ether of acetophenone, 100% conversion with respect to the silyl enol ether was achieved in 20 min for a given set of electrical fields (375, 409, 381 and 0 V cm ) [15]. The corresponding batch synthesis time was about 1 day. 

OS 79] ]R 17] ]no protocol] 4-Methoxybenzaldehyde and methyl diethoxyphos-phonoacetate were reacted by means of the Wittig-Horner-Emmons reaction [85] (see a more detailed description in [42]). A modified micro reaction system consisting of two mixers, for deprotonation of the phosphonates and introduction of the aldehyde, connected to an HPLC capillary of 0.8 m length and 0.25 mm diameter was employed. The micro reactor showed higher yields than laboratory batch synthesis. 

Milestone [23] have produced a range of MW reactor systems for organic synthesis, including a quartz or ceramic MW reactor (MRS) for high pressure (up to 4 MPa) and temperature reactions, designed for large volume batch synthesis and a multiple batch reactor MPR/HPR for up to 12 vessels, with volumes 2-270 mL for operation at 3.5-10 MPa. 

Assumptions Synthesis of phenylpyruvic acid Batch synthesis process for precursors overal yield of 95+% of theoretical to pheny Ihydantoin overall yield of 90+% of theoretical from phenylhydantoin to phenylpyruvic acid recovery and recycle of acetic acid no byproduct crec taken for acetic acid formed from acetic anhydride addition. Conversion of phenylpyruvic acid and aspartic acid. Bioreactor productivity of-18 g PHE/L/h (four columns in parallel) 98% overall conversion no byproduct credit taken for pymvic acid (recovery cost assumed to be of by revenue from sale) 80% recovery of L-PHE downstream of bioreactor. 

Ecofriendly Fast Batch Synthesis of Dioxolanes, Dithiolanes, and Oxathio-lanes Without Solvent Under Microwave Irradiation (Perio et al., 1998)... 

Perio, B., Dozias, M.-J. and Hamelin, J., Ecoffiendly fast batch synthesis of dioxolanes, dithiolanes, and oxathiolanes without solvent under microwave irradiation, Org. Process. Res. Dev., 1998,2, 428. 

Kamihira et al. (1987) Batch Synthesis of aspartame precursors through esterification Thermolysin... 

The scale-up of microwave-assisted reactions is of significant interest to many industrial laboratories. Scale-up can be accomplished in different ways, and these methods are presented in more detail in the following section. After an initial discussion of batch synthesis we will present the currently commercially available instrumentation for flow processing, which can be divided into SF or CF techniques. 

Batch synthesis in single-mode reactors is definitely limited in scale as the size of the utilized microwave cavities is restricted to being monomodal. However, the Biotage Initiator EXP series allows a 100-fold linear scale-up when employing the different available vessel sizes, going from 0.2 mL to 20 mL operation volume (Fig. 1). Repetitive reaction cycles using the au-... 

Similarly, the CEM Discover platform (Fig. 2) allows a 100-fold scale-up of small-scale batch synthesis when switching from the standard vial (0.5-5.0 mL operation volume) to the large reaction vessel (50 mL maximum filling volume). Automation is only possible for the small standard vials with the Explorer robotic extension (24 x 5.0 mL) but the large vessel can be utilized for SF processing as well [27,39]. 

Whereas batch synthesis on the small scale is the standard procedure in microwave-assisted synthesis and has been extensively reviewed ( [50-52] and references cited therein), protocols in the 50 mL range are rather rare. In this section, scale-up of volumes > 50 mL in sealed vessels will be discussed. An important issue for the process chemist is the potential of direct scalability of microwave reactions, allowing rapid translation of previously optimized small-scale conditions to a larger scale. Several authors have reported independently the feasibility of directly scaling reaction conditions from small-scale single-mode (typically 0.5-5 mL) to larger scale multimode... 

Quantitative yield of the dipeptide in only 20 min was achieved when using electroosmotic-driven microreactor, whereas batch synthesis under the same conditions gave only 46% yield needing 24 h [6,9]. 

For this readion, 100% conversion with respect to the silyl enol ether was achieved in 20 min [15]. The corresponding time for batch synthesis amounted to about 1 day. 

The use of aryllithium instead of the Grignard reagent resulted in a higher ratio of cis-isomer formation [34], In reaction calorimetric studies, it was found that both steps, the formation of 3-methoxyphenyllithium and its addition to ketone, are pretty exothermic with worst-case temperature rises of up to 62 and 133 °C, respectively. The lithium intermediate has to be kept at very low reaction temperatures to prevent decomposition. We concluded that a continuous reaction may be a good alternative to batch synthesis to improve the reaction yield and to minimize the safety concerns because of the exothermicity of the reaction sequence. 

Figure 6. Flow diagram for a proposed modified batch synthesis process promoted by a nucleation agent...

Parent Id (structure) Compound Id (Salt) Batch (Synthesis)... 

Figure 11.5 Batch synthesis of fnictooligosaccharides catalyzed by immobilized Pectinex Ultra SP-L in Sepabeads EC-EPJ. (a) Product distribution and (b) total fhjctooligosaccharide. Experimental conditions 630g/l of sucrose, O.JU/ml (standard DNS assay), 50mM sodium acetate buffer (pH 5.4), and 60°C. Adapted from Ref. [56].

In addition, supported reagents have been demonstrated to be effective under reaction conditions when either thermal or microwave heating - is employed. They have also been utilised in traditional batch synthesis, stop-flow methods and continuous flow processes. ° However, one caveat is that the immobilisation of reagents can change their reactivity. For example, polymer-supported borohydride selectively reduces a,P-unsaturated carbonyl compounds to the a,P-unsaturated alcohoF in contrast to the behaviour of the solution-phase counterpart, which additionally causes double bond reduction. 

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