Thoughts on Parallel Synthesis: Argonaut Ships Quest 210 Parallel Synthesizer

Argonaut Technologies, Inc. (San Carlos, Calif.) believes combinatorial chemistry-the parallel, simultaneous synthesis of many compounds-will revolutionize drug discovery the way solid phase chemistry changed peptide synthesis several decades ago. Evidently many pharmaceutical companies believe the same thing.

Argonaut has begun shipping its Quest 210 synthesizer, a parallel chemistry laboratory capable of carrying out 20 different reactions simultaneously, either in solution or on solid phase supports. Elizabeth Mitchell, director of administration at Argonaut, told Pharmaceutical Online, "Drug companies are purchasing multiple units for multiple sites. Biotechnology companies, in particular, are excited about Quest 210 because of its low price point ($25,000 to $30,000)."

Argonaut Technologies' Quest 210 Parallel Synthesizer

Parallel synthesis is something most pharmaceutical chemists have done, albeit not always systematically. Argonaut's synthesizers allow scientists working on lead compounds to create many variations on a particular structure, for example substituting chloride for bromide or methyl for ethyl, as easily as running a single reaction. Individual reaction vessels are protected from the atmosphere and can be heated, treated with liquid or gaseous reagents, and in general subjected to the same manipulations as ordinary reactions carried out in individual flasks.

Argonaut also markets the Nautilus 2400, a parallel synthesizer that carries out 24 reactions, each of which can be individually temperature-controlled. In addition to the two instruments, Argonaut sells several types of polymeric resin for carrying out solid-phase synthesis.

Some of the Quest 210's success stories:

• Parallel synthesis of amino-ketones via Grignard addition to resin-bound amides, leading to a series of amino-ketones in high yield and high purity
• Solution-phase synthesis of aryl sulfonamides and product isolation by liquid-phase extraction
• Solid-phase synthesis of biaryls using palladium-catalyzed coupling reactions

Combinatorial chemistry raises questions and presents challenges to pharmaceutical chemists. Namely, what types of target molecules, and what types of chemical transformations lend themselves to the parallel approach?

If solution-phase peptide or oligonucleotide synthesis is any guide the answer to both questions is "linear." That is, molecules whose synthesis involves serial additions of carbon (or other) units to an existing base molecule will work best. The parallel approach should also work well with one- to five-step variations on a synthetic theme, such as serial alkylations, substitution reactions, and even oxidations/reductions or catalytic couplings. Another area where combinatorial chemistry is helpful is in optimizing reaction conditions, e.g. changing solvent or adding secondary reagents either to speed up the reaction or change product selectivity.

As combinatorial systems go, Argonaut's synthesizer is low-capacity. Pharmaceutical companies are typically interested in combinatorial "libraries" of thousands of compounds. Many large drug firms already have combinatorial groups that use proprietary techniques to generate hundreds or thousands of compounds per day. Some of these firms have pieced together parallel synthesis systems using robotics and multiple reaction vessels. But when it comes to fine-tuning a lead compound or process optimization through smaller-scale parallel synthesis, Argonaut's instruments are the only self-contained devices on the market capable of performing reproducible chemistry.

Three other firms, CombiChem, Inc. (San Diego, Calif.), Diversomer Technologies (Ann Arbor, Mich.), and David Sarnoff Laboratory (Princeton, N.J.) plan to introduce higher-capacity instruments. Sarnoff, through its Orchid Biocomputer spinoff, has patented extensively on technology it hopes will bring parallel synthesis into the true combinatorial domain with a chip-sized synthesizer capable of carrying out thousands of chemical reactions.

Parallel synthesis will bring experimental and production chemists in the pharmaceutical industry closer together by forcing bench chemists to simplify their synthetic schemes. Drug discovery chemists must now think of complex syntheses in terms of simpler, easy-to-handle blocks of sequential reactions, which will lead to technology that is more easily transferred from the bench to the pilot plant and beyond.

by Angelo DePalma

For more information:
Elizabeth Mitchell, Argonaut Technologies, Inc., 887 Industrial Road, Suite G, San Carlos CA 94070. Tel: 650-598-1350.