Calanolide A

Scheme 31.8. Optimization of a Friedel-Crafts acylation and the synthesis of 26 using automated synthesis equipment coupled with statistical DOE (MediChem).

Scheme 31.8. Optimization of a Friedel-Crafts acylation and the synthesis of 26 using automated synthesis equipment coupled with statistical DOE (MediChem).

In another application of the automated process development technology, researchers at MediChem were able to improve the yields of 4(5)-(3-pyridyl)imidazole 26 from 20% to 74% [27].

Pollard of Avantis CropScience gave a useful and interesting account on issues related to a stepwise and unified approach to automation across all three phases of process development, using existing standard laboratory equipment and inexpensive commercial software packages. In addition, a detailed discussion of an automation system (computer-aided reactor system; CAR) was given that has evolved and has been developed at Aventis CropScience over the last 10 years. The discussion extends to a variety of examples, including calorimetry, DOE, crystallization studies, and plant simulation along with equipment and computer issues. The CAR can be used across all three phases of development activities and also to datalog and monitor a small pilot plant, presenting a single interface to chemists at all scales. The system controls a variety of external equipment including Gilson autosam-plers, HPLC equipment, many types of heater/circulator, as well as traditional laboratory equipment. The CAR provides round-the-clock capabilities of sophisticated multireaction control and datalogging on reactors ranging from 10 mL to 10 L [28].

The CAR system originated as a single automated laboratory reactor (ALR) which was used largely for DOE work, but owing to its flexibility and power it has been used in many areas:

• ALRs control multiple automated laboratory reactors, on many scales from 100 mL to 10 L, for optimization, validation, DOE, and ''kilo-lab'' work.

• Calorimetry: addition of an internal heater and controllable power supply gives calorimetric capabilities.

• Plant simulation: multiple independently controlled reactors, hold/feed vessels, and crystallizers can be used to simulate full-sized plant operation in the laboratory.

• Crystallization studies: using optical sensors to detect the onset of crystallization and control crystallization processes.

• Optimization, DOE, and kinetics: using an HPLC and autosampler directly from three small reactors, a fully automated parallel system has been produced.

• Route scouting: the autosampler system combined with a modified Stem-type heating block allows the study of the influence of solvent/catalyst/base, etc. of ten parallel reactions.

Data logged from the system are generally handled in Excel, a suitable graphing package, or a statistical package.

The latest and most flexible version of the CAR system runs a set of three custom-built jacketed reactors attached to a Gilson analytical autosampler and a high-throughput HPLC system. Even though the author states that the system has been used considerably for DOE optimization work, it appears to be most suitable for process characterization or validation or both. The throughput is rather slow but it offers a precise reaction control under realistic conditions as well as a high degree of analytical capability. Each reactor is equipped with an overhead stirrer, reflux condenser, thermopocket and sample port, and two nondedicated ports for additions, pH probe, etc. The reactor volume is 50-150 mL, and each reactor has an independent heater/circulator to heat the jacket up to 200 °C. Any other traditional laboratory equipment can also be utilized - balances, pumps, pH meters, etc. The autosampler is programmed to collect samples directly from each reactor on command from the control system. The system can slow or stop the agitation during sampling and alter the sampling height to sample different phases. Samples can be diluted and then injected automatically onto the HPLC. A standard analytical LIMS (Laboratory Information Management System) system allows easy visual examination of "stacked" chromatograms for qualitative assessment of reaction profiles or more sophisticated kinetic analyses. The author also mentions a variation of the three-reactor optimization system described above that is constructed around a Gilson autosampler/HPLC and Stem or Variomag heating block with modified glassware. This system is technically more simple than the optimization system described above and is still in development.

The Auto-MATE is a miniature computer-controlled multiple reactor system (25-100 mL) that was designed to fill the gap between rapid process screening and optimization by robotic systems and process characterization and validation by large automated laboratory reactors (> 1 L). Between four and 16 independent reactors can be controlled simultaneously from a single computer interface, although the configuration of four reactors is most common. The system consists of a small container that constitutes an oil jacket with a central recess into which a close-fitting miniature reactor is placed. Reactors of different sizes and materials can be used interchangeably with the jacket. The reactor cover has an integral stirrer mounted on it and has ports for a thermocouple, pH probe, heater, reflux condenser, etc. The electrical heater that is placed within the reactor maintains the temperature (isothermal or nonisothermal), enabling the precise and rapid control of the reactor temperature and optionally allows calorimetric data to be acquired using the power compensation technique. Using this information, it is possible to determine reaction endpoints and to establish a first-pass screen for hazard assessment in scale-up. Reactions under elevated pressures, such as hydrogenations, can be carried out with the Auto-MATE using high-pressure reactors. Researchers at HEL demonstrated that the Auto-MATE was useful for process analysis and for refinement and scale-up in conjunction with calorimetric data [29].

To meet the increasing demands being created by the combinatorial revolution in drug discovery and the demanding timelines forced on chemical development departments, Pfizer development laboratories were interested in a flexible automated system that mimics a plant reactor with the capability of controlling reaction conditions very precisely [30]. Since no commercial instruments met their requirements, the custom system was built around a Zymark XP Track Robot especially to accelerate the late-stage process development, i.e. optimization coupled with DOE and validation. The key features of the system include:

• plant reactor mimics;

• self-cleaning and draining for continuous operation;

• solids dispensing;

• accurate liquid handling;

• online analysis;

• flexible software.

Two plant reactormimics of the system consist of cone-bottomed glass reactors with 50-400 mL capacity equipped with a five-port flange lid incorporated in an automated addition port, overhead stirring, a condenser, a thermocouple, and a spare port for probe technology. The triple-jacketed vessel has a temperature range of —20 °C to 150 °C, controlled inert gas flow, and automated drain valve for post-reaction collection and manipulation if necessary.

Throughput limitations of two reactors were resolved by incorporating automated self-draining/self-cleaning modules into the system to allow continuous operation. The system is capable of dispensing solids at any time during the reaction, including seeding for crystallization studies.

The software was developed internally in LabView, conforming to the evolving standard of Laboratory Equipment Control Interface Specification (LECIS). The resulting software was extremely flexible, functional, and modular. It was demonstrated that the system performs well when applied to process optimizations and validations that are time-consuming, tedious, and difficult to control when conducted manually.

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