The present invention relates to microwave assisted chemistry techniques and apparatus, and in particular, relates to a method and apparatus for microwave assisted high throughput chemical synthesis.
Microwave assisted chemical synthesis refers to the use of electromagnetic radiation within the microwave frequencies to provide the energy required to initiate, drive, or accelerate certain chemical reactions. As chemists have long been aware, the application of heat energy is one of the most significant factors in increasing the rate of a wide variety of chemical reactions. Thus, generally familiar devices such as the Bunsen burner, other types of gas burners, hot plates, and other similar devices have historically been used to initiate or accelerate various chemical reactions.
Microwave assisted reactions, however, can be completed in a much shorter period of time. It will be understood that this time savings has a particularly significant advantage in any situation in which large number of samples must be tested on an almost continuous basis, or high throughput analysis. Understood by those familiar with the electromagnetic spectrum, the term “microwave” is often used generically to refer to radiation with wavelengths of between about 1000 and 500,000 microns (μ), and corresponding frequencies of between about 1×109 and 5×1011 Hertz (Hz). These are arbitrary boundaries, however, and other sources refer to microwaves as having frequencies of between about 108 Hz and 1012 Hz and wavelengths of between about 300 centimeters (cm) and 0.3 millimeters (mm).
Microwave assisted chemistry is relatively new compared to some other techniques, however, it has become well established and accepted in a number of analytical applications. For example, the use of microwave energy is well suited for the accelerated decomposition and analysis of fat and oil content in a sample, as disclosed in U.S. Pat. No. 6,548,304 to Collins and assigned to CEM Corporation of Matthews, N.C. As another example, published US Patent Application No. 2003/0089706 to Jennings, and assigned to CEM Corporation, discloses the use of microwave energy for chemical synthesis processes. These and many other examples provide sufficient evidence as to the usefulness and enormous potential that the utilization of microwave energy has in chemical synthesis, particularly the field of combinatorial chemistry.
The field of combinatorial chemistry stands to benefit greatly from the proper utilization of microwave energy. Combinatorial chemistry has emerged as one of the most promising approaches to chemical library synthesis for the purpose of drug discovery. Traditional methods that use sequential and parallel methods of organic synthesis generally comprise a starting array of reagents that are dispensed to specialized tubes, where additional reagents may be added. This is followed by the application of heat or light energy, which is followed by an additional dispensing of the products to a product array (such as a microtiter plate).
This conventional methodology suffers from two main drawbacks. First, it is far too slow to meet the current demand for chemical library generation. Despite accelerating this process by running the reactions in a parallel manner, the complexity and expense soon outweighs the benefit of the moderate gain in speed. Secondly, current methodology typically requires set volumes of liquid in a given synthesis run. This limits the flexibility of the process to generate compounds via different reactions.
The generation of chemical libraries, also referred to as chemical compound libraries, or small molecule libraries, is necessary for screening against a rapidly growing range of therapeutic targets resulting from genomics research. Novel compounds are also useful for testing on current therapeutic targets to search for drugs with maximum efficacy and minimal side effects.
Given the current demand for novel compounds in drug discovery research, there is a need for improving the adaptation of microwave energy to synthesize chemical libraries at an exponentially faster pace.
Progress is occurring in these areas. For example, the VOYAGER™, DISCOVER™, NAVIGATOR™ and EXPLORER™ instruments available from CEM Corporation, Matthews, N.C., USA (the assignee of the present invention) offer significant advantages in microwave assisted chemistry particularly in the areas of small sample size, appropriate application of energy and automated sample handing. Relevant patents and applications describing these devices include U.S. Pat. Nos. 6,607,920; 6,744,024; 6,867,400; 6,989,519; and 7,144,739; and published U.S. application No. 20030199099. The contents of all of these are incorporated entirely herein by reference.
Nevertheless, the current technology with respect to adapting microwave energy to high throughput chemical library synthesis is limited in several ways. First, microwave assisted synthesis reactions are typically run in series (even if automated), rather than in parallel. This compromises the speed advantage that microwave synthesis has over conventional techniques because more time is spent moving tubes into and out of the microwave chamber.
Secondly, the current technology is limited with respect to the use of liquid and solid reagents under pressure. The speed advantage gained with the use of microwaves is negated by the need for sealing or “crimping” the reaction tube(s) to maintain the proper pressure for the reaction. The mechanism required for crimping the tubes further adds expense and moving parts to the process. Opening such tubes or vessels likewise requires mechanical decrimping steps. All of these steps, even if automated, add time, mechanical complexity and expense.
Stated in an alternative fashion, the use of microwaves to treat continuously flowing compositions (“flow-through”) in some fashion is generally well understood; e.g. commonly assigned U.S. Pat. No. 5,420,039 (for flow through digestion). Similarly, carrying out pressurized or pressure-generating reactions using microwave assistance is also well established; e.g. commonly assigned U.S. Pat. No. 6,287,526 (for high pressure reactions in closed vessel systems). Nevertheless, combining each of these relative advantages in an efficient fashion—i.e., an instrument that maintains both a high-throughput and the capability to carry out reactions at elevated pressures—remains a desired goal in this art.
Accordingly, the need exists for instruments and associated methods that take advantage of microwave assisted chemistry, that increase the rate of throughput, that are or can be automated, that are efficiently-sized for widespread laboratory use, that are economically efficient, and that can handle high-pressure reactions concurrently with their high-throughput advantages.