H

(R = not disclosed) Scheme 31.3. Lewis acid-catalyzed reaction using REACTarray and SK233.

The high-throughput process development group at Schering AG has developed a robotics system that consists of three main parts: a parallel synthesis robot (Bohdan process development workstation), a second robot for the preparation of analytical samples (custom-tailored Bohdan sample preparation workstation), and four Dio-nex HPLC devices [21]. The synthesis robot can perform 12 parallel reactions with up to 25 mL maximum reaction volume, each reaction can be individually heated or cooled between —40 °C and +140 °C and stirred by magnetic stir bars under inert gas. For all reactions, the block and the inner reaction temperature can be measured. Both robots have two different types of cannulas to transfer air- or moisture-sensitive reagents and slurries into the reaction vessels. A barcode system facilitates the analytical sample handling and data management. The data identified by the corresponding barcodes are easily exchanged in an automated manner in the network environment. To achieve a high throughput of the analytical samples, rapid HPLC analysis methods on short columns are used. Finally, the analytical results are transferred into Excel spreadsheets.

In the first 10 months after installation of the automated reaction optimization system, over 1200 reactions have been performed for the successful optimization of 26 different synthetic steps. One example was the aldol condensation between m-methoxy-benzaldehyde 13 and acetaldehyde 14 to m-methoxy-cinnamaldehyde 15 (Scheme 31.4). After 60 experiments with the synthesis robot and 480 fast HPLC analyses, the yield was improved to 65% from 10-20%. It took only seven working days to achieve this result, and the improved yield was smoothly reproduced on a 65-kg scale in the pilot plant.

13 14

I base | solvent

Scheme 31.4. High-throughput carbodiimide-mediated amide bond formation reaction.

Symyx Technologies and Argonaut jointly developed Endeavor™ (http://www. argotech.com) for performing parallel reactions at elevated pressures and temperatures (Fig. 31.2). In addition to traditional solution-phase chemistry, Endeavor™ can be used to perform reactions such as hydrogenations, carbonylations, and olefin polymerization as well as to optimize both homogeneous and heterogeneous catalysts. Reactors with magnetically coupled overhead impellers, individual control of temperature and pressure in each vessel, and the monitoring of gas uptake allow process chemists to track and compare the course of reactions under different conditions [22].

Researchers at Pfizer employed Endeavor™ for a case study of partial hydrogenations of 4-nitroacetophenone (Scheme 31.5) [23]. The optimization consisted of two steps: (1) an initial screen crossing a discontinuous variable (the choice of catalyst) with a continuous variable (modifier stoichiometry), and (2) optimization for selected catalysts by a full factorial analysis of four continuous variables (catalyst loading, pressure, temperature, and modifier stoichiometry). Thus, eight catalysts were first screened both with and without methanesulfonic acid (MsOH, 1.1 equiv.) at 30 °C and 50 psi of H2. Reductions were run eight at a time on a 500-mg scale in 5 mL of ethanol. The yields were determined by HPLC. The best con-

Fig. 31.2. Endeavor™ for performing parallel reactions at elevated pressures and temperatures (jointly developed by Symyx Technologies and Argonaut).

ditions from this initial screen gave 17 in 85% yield, 18 in 90% yield, and 19 in 96% yield using 5% Pd/CaCO3/Pb with 0 equiv. of MsOH, 10% Pd/C with 0 equiv. of MsOH, and 10% Pd/C with 1.1 equiv. of MsOH, respectively. These three conditions were then optimized for the two catalysts involved by examining low and high points for catalyst loading (5% and 20%), pressure (25 and 100 psi), temperature (25 °C and 60 °C), and, for Pd/C, the amount of MsOH (0 and 1.5 equiv.). The best conditions from this full factorial screen gave 17 in 97% yield, 18 in 95% yield, and 19 in 99% yield. The measurement of hydrogen uptake helped to set reaction times and parameter ranges for the full factorial analysis, allowed for quickly

19 18

Scheme 31.5. Partial hydrogenations of 4-nitroacetophenone 16 using Endeavor™ (Pfizer).

19 18

Scheme 31.5. Partial hydrogenations of 4-nitroacetophenone 16 using Endeavor™ (Pfizer).

spotting under- and overreduction, aided predicting robust reaction endpoints, and provided data for analyzing kinetic behavior. These techniques can be applied to the rapid optimization of reactivity and selectivity for the hydrogenation of a variety of polyfunctional molecules.

Researchers at Argonaut have also developed the automated chemical development platform Surveyor™ (http://www.argotech.com) especially for conducting process screening and optimization with a consortium of six companies: Pfizer, Agouron Pharmaceuticals, Aventis Pharmaceuticals, Eli Lilly & Company, and Rohm & Haas. Surveyor has ten individually controllable reaction vessels with automated reagent/solvent addition. The system is also capable of sample extraction/ quenching/injection for online HPLC analysis. It uses simple graphical software to set up experiments and to control temperature, temperature ramp rates, reagent addition, agitation, sampling, and analysis.

Researchers at Argonaut have demonstrated the automated optimization for the multistep synthesis of chiral imidazolidinones, useful auxiliaries for the asymmetric synthesis and key intermediates for some human immunodeficiency virus (HIV) protease inhibitors [24]. This study included the initial route scouting, the reaction condition screening, and the optimization, followed by a scale-up run using the conventional laboratory set-up. Two routes were compared and variables such as choice of reagents, time, temperature, and concentration were examined using Surveyor (Scheme 31.6). Each route was evaluated and compared from a scale-up standpoint, and the optimized conditions for the selected route were subsequently applied on a 6-g scale, affording the imidazolidin-2-one 20 in 90% isolated yield.

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