Process Screening

In process screening some basic knowledge of the reaction already exists. For example, if a certain Lewis acid has been selected in a Friedel-Crafts acylation, then different solvents at different temperatures should be screened. In general, process screening and route scouting proceed at the same scale and parameters are screened with similar equipment, therefore both areas are discussed in one section.

What parameters are screened in process screening? A number of reaction conditions are screened in small-volume batch runs. The interesting target parameters are often only conversion and selectivity with an accuracy of +10%. Sometimes, a yes/mediocre/no answer or a relative order (X is better than Y ...) are sufficient results from the process screening, especially in the early stage. The reaction variables screened are solvents, temperatures, additives, catalysts or other reagents, protecting groups, stoichiometry, reaction time, etc. for each synthetic step. The data acquisition is usually restricted to thin layer chromatography (TLC), gas chro-matography (GC), or high-performance liquid chromatography (HPLC) analysis of the reaction mixture, either only at the end-point or in addition to one or two measurements at intermediate run times.

What are the requirements for parallel process screening equipment? In this development phase, most chemists use standard apparatus such as 50- to 100 mL flasks with magnetic stirrers. If sufficient starting material is available, batches of 25-50 mmol are preferred. The more sophisticated the intermediates and the more valuable the 2-3 g of''step 8 material'' are, the more opportune are microscale reactions: however, the handling of small amounts of substances becomes more difficult when changing from the few grams scale to the few milligrams scale.

To transfer a standard flask set-up into a parallel screening set, it is desirable to keep the most common features constant, including working under an inert atmosphere (degas/nitrogen purge), mixing (preferably stirring), cooling/heating, reflux, adding liquids through a dropping funnel, adding solids altogether through an opening under counternitrogen flow, collecting small samples for analysis during the reaction, and no cross-contamination by neighboring cells. Some special features such as distilling a reaction component out of the reaction mixture for equilibration shifting are sometimes necessary.

The preferred vessel size is around 20-50 mL, it should not be smaller than 5 mL and not larger than 100 mL. The temperature range should be —50 °C to 200 °C. Sometimes, systems operate at up to 120-140 °C, which is often not high enough. An independent temperature control for each reaction vessel would be the best case, but often this increases apparatus costs exponentially. We regard 6-12 simultaneous reactions per set as a good throughput, especially when the temper ature for all vessels per set is the same. In the case of automated workstations in a dedicated laboratory, a higher throughput can be realized.

Examples of commercially available automated workstations For standard chemistry, the full range of automated organic synthesizers can be considered. Most of them are based on an automated dispenser or x, y,z robotics. Within the widely known systems are the Benchmark station from Advanced ChemTech, the Tecan Genesis ChemSystem Workstation, the Chemspeed workstations ASW 1000 and

2000, Zinsser's Sophas, Bohdan's Neptune or the Anachem SK 233 (Table 30.2). For the different applications in primary screening and process screening, every user has to make his/her own decision: which reaction volume, temperature range, or mixing form is best suited to screened chemistry? The Anachem SK 233 station is one which has been used for process development purposes to a larger extent recently. In collaboration with Glaxo, a special reflux unit was developed, which is now commercially available as Reactarray SK 233.

Preferably for late-stage process screening, the Bohdan process development workstation offers 12 magnetically stirred reaction vessels with independent temperature control per run. The Bohdan process development workstation and the Reactarray SK 233 are both good options for automated late-stage process screening. Recently, HEL has offered a system named Chem-Scan, consisting of a compact x, y,z robot with a maximum of three reaction blocks, each with ten stirred 10-mL reactor cells. The reaction blocks are available either with one temperature control for all cells or with individual temperature control for each cell. (See Fig. 30.6 for examples of apparatus for each process development phase, or visit the web sites of the companies; for internet addresses, see Tables 30.2 and 30.3.)

Examples of commercially available low-automated multiple reaction stations Examples of commercially available low-automated multiple reaction stations are given in Table 30.2. The list in this table is not exhaustive, but it gives a diverse selection of appliances for parallel screening, which allow syntheses of 0.5-100 mL at temperatures from —80 °C to 250 °C. An important criterion is whether or not the system has individual temperature control for each vessel. Equipment without this feature is roughly an order of magnitude less expensive than the apparatus with it. The price categories listed in Table 30.2 refer to the basic set-up in mid-

2001, but this information is supplied without liability. Most simple reaction stations use test tubes as vessels, e.g. H + P blocks, Stem blocks, Argonaut FirstMate, or Radleys Carousel. The stirring is mostly based on magnetically driven stirring bars. An interesting alternative is given by Argonaut: the stirring bar is moved vertically by a large pneumatically driven magnetic bar in the middle of the apparatus.

To fill the gap between nonautomated and fully automated stations, Argonaut has produced a system called Quest. Originally designed for organic solid-phase synthesis, the Quest 210 (20 x 10 mL) and the Quest 205 (10 x 100 mL) are also suitable for process screening.

Every user has to make his/her own decision as to whether there are additional requirements for the application under consideration, e.g. an independent inert gas supply for each vessel. The ease of adding liquids and solids during the reac-

30.3 Parallelization in Process Development | 843 liquid handling reagents

reaction block

Anachem-SK233 Process Screening (automated)

Systag-Flexylab Process Optimization

Mettler-Lab-Max Process Validation

Fig. 30.6. Examples of commercially available equipment.

Bohdan workstation PDW 200 Process Screening (automated)

HEL-Automate Process Optimization

Mettler-Lab-Max Process Validation

Fig. 30.6. Examples of commercially available equipment.

Tab. 30.2. Workstations for route scouting and parallel process screening.

Workstation

Number of simultaneous reactions

Vessel size (mLj, agitation Temperature control, individual (yes/no)

Price Internet; categorya http://www

Advanced ChemTech, Benchmark Bohdan, Neptune™, MiniBlock™

ChemSpeed, MSW500, ASW 2000

Reactarray Workstation, Anachem

SK 233 Tecan, Genesis

HEL-Chem-Scan

Bohdan, Process Development

Workstation Advanced ChemTech, LabMate Calypso Reaction Block System STEM Reaction Block System H + P, Variomag H + P, 48 er Block Bohdan MiniBlock Radleys, Carousel Argonaut, Quest 210

Argonaut, Quest 205

Argonaut FirstMate Radleys, GreenHouse Parallel Synthesizer

8, 16, 40 and 96-well reactors 12 x 48 6x6 112 28

96-well reactors or reactor blocks

10 12

6 10

12 24

4.5 mL, shaker 40 mL, shaker 13 mL, shaker 75 mL, shaker 25 mL, magnetic

10 mL

25 mL magnetic

25 mL, magnetic 100 mL, magnetic 10 mL, magnetic 40 mL, shaker 10-15 mL, magnetic 5-10 mL magnetic, vertical 100 mL magnetic, vertical magnetic, vertical 0.5-3 mL magnetic, vertical

(—80)-300 °C, no (optional) D (—20)—140 °C, yes E

5-150 °C, no (—80)—200 °C, no (—80)—200 °C, no (—40)—120 °C, no RT-160 °C, no (—40)—130 °C, no (2 temp. C

parallel) (—40)—130 °C, no (2 temp. C parallel)

peptide.com bohdan.com

E chemspeed.com

E Reactarray.com

Tecan.com

Helgroup.co.uk Bohdan.com peptide.com charybtech.com stemcorp.com hp-lab.de hp-lab.de Bohdan.com Radleys.co.uk Argotech.com

Argotech.com magnetic, vertical Argotech.com Radleys.co.uk

Radleys, Metz Parallel Reaction Station 6 Hel-Chem-Scan, High-Pressure 8

Argonaut, Endeavor 8

Parr Multiple Reactor System Series 6 5000

a Price categories: A= <10 T€; B = 10-25 T€; C = 25-75 T€;

D = 75-125 T€; E = 125-175 T€. b Numerous names of companies and equipment used in this table are registered trademarks.

150 mL, magnetic 10 mL, magnetic, 100 bar 5-8 mL, mechanical, 33 bar

75 mL, magnetic 200 bar

5-150 °C, no RT-200 °C, no RT-200 °C, yes (max. 20 °C difference between two neighbors) RT-300 °C, yes

A Radleys.co.uk

D Helgroup.co.uk

D Argotech.com

C Parrinst.de tion, the option of collecting samples at reflux conditions, and the flexibility and connectability to other glassware and equipment need to be taken into account.

Sometimes a system appears to be the best despite offering only a few features; often, these systems provide a high degree of freedom and flexibility for arranging a personalized and chemistry-oriented set-up. In our laboratories, we have used one set-up over ten times: a simple block set-up based on a H + P block for six or 12 standard 100-mL side-cap bottles. These bottles are available with one or two additional screw cap arms originally made for enzyme chemistry. These arms are suitable for liquid and solid addition, sample collection, etc. Instead of a closed screw cap, we use three-bore Teflon caps, which are available with standard screw threads for Bola fittings. A stop cock for argon/vacuum, a reflux condenser, Teflon tubing, for example to connect a dosimeter pump, or an internal thermometer can be easily attached (Fig. 30.7). This set-up is more like a small vessel than a test tube. Each system is independent and built from mass-produced inexpensive equipment. This multiple reaction set-up has exhibited good properties in numerous standard reactions for fine chemical processes, including Grignard and diazo-nium salt chemistry. Of course, it is not automated, but it enables the bench chemist to carry out up to 12 experiments in parallel.

For high pressure reactions different pieces of apparatus are required. There are only a few systems available on the market that are suitable for higher pressure hydrogenation or carbonylation chemistry. Argonaut Technologies offers a workstation called Endeavor for reactions up to 33 bar. It has individual temperature control (restricted to 20 °C temperature difference between vessels) from room temperature to 200 °C and mechanical stirring for eight vessels each containing

Fig. 30.7. Nonautomated multiple reactor block.

5-8 mL. For reactions at these low pressures we regard the Endeavor workstation as a good system. Parr instruments offers a multiple autoclave system for high-pressure applications up to 200 bar and 300 °C. Six autoclaves, each containing 75 mL, can be run with magnetic stirring at the same temperature. Besides variants working with inlets for a single autoclave, such as similar systems developed by SmithKline Beecham, Parr, and others, this multiple reaction station is suitable for process screening of, for example, asymmetric hydrogenations and reactions that need very high temperatures (200 °C and 300 °C). A pressure range up to 100 bar is offered by the HEL High Pressure Chem-Scan. Here, eight 10-mL reactors for temperatures up to 200 °C can be configured in one row; the stirring is accomplished by a specially fixed magnetic anchor agitator.

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