METHOD AND APPARATUS FOR SYNTHESIZING, CHARACTERIZING, ASSAYING COMBINATORIAL LIBRARIES

Abstract: Devices and processes for synthesizing, purifying and analyzing large numbers of compounds for use in combinatorial libraries, are disclosed. The processes involve generating a series of compounds in multi-well plates or multi-tube racks, purifying the reaction mixtures, analyzing the purified compounds, and optionally performing bioassays on the compounds. The information regarding the compounds is stored in a central database. The devices include one or more multi-tube configurations, a purification device, means for transferring the contents of the tubes, a solvent evaporator, analytical instrumentation, and, optionally a weighing instrument. The multi-tube configuration(s) optionally include a cover, which can be placed on or removed from the configuration by computer control. By correlating the orientation of tubes from one stage to the next, it is possible to use a single bar code or other identifying mark for each multi-tube configuration rather than for each individual tube. This simplifies data collection for large numbers of compounds. An interface also described herein permits one to use racks from one vendor and other components from other vendors.

Description: Method and Apparatus for Synthesizing, Characterizing, Assaying Combinatorial Libraries Field of the Invention This invention is generally in the area a new method and apparatus for the synthesis, purification, characterization and assay of combinatorial libraries of compounds. This application also relates to interfaces designed to attach to multi-tube racks which hold a plurality of tubes for conducting chemical synthesis, purification and the like, and also to attach to a deck on a component used in automated chemical synthesis. This application further relates to multi-tube racks for placing a large number of tubes for conducting chemical synthesis, purification and the like. Background of the Invention Combinatorial chemistry is generally used to prepare, purify, characterize and/or assay a large number of chemical compounds at one time. This approach can be used to identify promising compounds for further development. In combinatorial chemistry experiments, chemical libraries (large collections of compounds of varied structure) are often produced by reacting a core compound with various moieties to provide a plurality of compounds with the same core structure but with a variety of substituents. Structure/activity relationships (SARs) can then be determined by evaluating the compounds for activity. A limitation with combinatorial chemistry is not only in generating new compounds, but purifying, analyzing and screening the compounds. Often, so many compounds can be synthesized that a bottleneck is created at the purification, chemical analysis, and bioassay stages. Several methodologies have been developed to synthesize, purify, analyze and screen combinatorial libraries. Some of these involve preparing compounds in multi-well plates. and others involve multi-tube configurations. A limitation of using multi-well plates is that it the scale of the reactions tends to be rather limited due to the size of the wells, and it can be difficult to determine chemical yield, since it is difficult to obtain the weight of individual samples in a plurality of wells. Synthesizing compounds in multi-tube configurations allows one to scale up the synthesis somewhat, but suffers from the disadvantage that the tubes are not fixed in position, so that human error can occur if the tubes are misplaced. Further, there is little standardization in the combinatorial chemistry field. For example, multi-tube configurations often include 48 or 96 tubes. However, automated purification and chemical analysis equipment is not necessarily designed around the number of tubes in the multi-tube configurations used to prepare the compounds. This makes it difficult to track the identity and properties of compounds as they progress through stages of synthesis, purification and chemical analysis. Prior attempts at overcoming these limitations have typically involved placing individual labels eg., bar codes on each tube in a multi-tube configuration. The bar codes allow one to keep track of tubes which might have been misplaced due to human error, and also to keep track of tubes moved to and from different multi-tube racks with varying numbers of tubes per rack. An example of a combinatorial approach that uses bar codes to track the synthesis, purification and chemical analysis of libraries of compounds is a system developed by MDS Panlabs. This system synthesizes compounds at a 1 mmole scale in multi-tube configurations, subjects the compounds to preparative scale HPLC, and analyzes the compounds by flow inject mass spectrometry. Each tube in the configuration is identified with a bar code, and is moved from stages of synthesis, purification and chemical analysis using robotic arms. The bar codes are typically attached using an adhesive, which can evaporate at any stage when the tubes are subject to conditions involving increased temperatures and/or reduced pressures. Given the size of many combinatorial libraries, it may be a tremendous burden to place, and keep track of, individual bar-codes on a plurality of tubes. It would be advantageous to provide new devices and processes for analyzing and screening large numbers of compounds without the need to generate bar codes for each tube used to synthesize, characterize or otherwise handle the compounds. The present invention provides such devices and processes. Another problem associated with the lack of standardization in combinatorial chemistry is that multi-tube racks from one vendor are often incompatible with components in automated synthesizers from other vendor(s). It would be advantageous to provide an apparatus for use in automated chemical synthesis which allows entire multi-tube racks to be moved from one machine to another and which provides for the racks to be locked in place when positioned in the machines, which is compatible with components used in automated chemical synthesis from one vendor and multi-tube racks from another vendor. The present invention provides such an apparatus. It would also be advantageous to provide a multi-tube rack which holds tubes securely but which allows room for error in the movement of the robotic arms which add and remove tubes from the rack without breaking the tubes. The present invention provides such a rack. Summary of the Invention The present invention is directed to devices and processes for synthesizing, purifying and analyzing large numbers of compounds, in particular, those generated for use in combinatorial and/or lead generation and/or lead optimization libraries. The processes involve generating a series of compounds in multi-well plates or multi- tube racks, storing the location of the individual tubes in a computerized device, transferring the contents of each tube to a chromatographic device for purification/characterization, removing the solvent from each eluted fraction containing the compound of interest, chemically analyzing the compounds, and then optionally submitting them for bioassays, while maintaining the ability to correlate the position of the tubes in the original multi-well plate or multi-tube configuration to the position of the tubes generated or used in the next stage of the operation. The devices include one or more multi-tube configurations, a chromatographic or other purification device, means for transferring the contents of the tubes to the purification device, a solvent evaporator, means for adding solvent to the solvent-evaporated tubes, analytical instrumentation, and a means for transferring some or all of the contents to, and optionally from, the analytical instrumentation. Optionally the devices include a weighing instrument. In one embodiment, the multi-tube configuration(s) include a cover, which may be placed on or removed from the configuration by computer control. This permits computer under computer to move tubes from the multi-tube configuration to other locations, such as a weighing station, and also protects the tubes from being moved manually. This overcomes the need to place an identifier, e.g., a bar code, on each tube to minimize the types of human error which result in misplaced tubes, and minimizes the error associated with evaporation of adhesives on the bar code label, which can often be greater than ten percent of the weight of the sample. In some embodiments, the number of tubes in the multi-tube configurations in each step is constant. Alternatively, the number of tubes can vary from one stage to the next. However, a correlation between the orientation of the tubes from one stage can be made with the orientation of the tubes in a subsequent stage. By correlating the orientation of tubes from one stage to the next, it is possible to use a single bar code or other identifying mark for each multi-tube configuration rather than for each individual tube. This simplifies data collection for large numbers of compounds. Compounds which can be evaluated using the process and methods described herein include, for example, pharmaceutical compounds and agricultural chemicals, such as insecticides, pesticides, and herbicides. In one embodiment, the compounds are arranged in the multi-tube configurations in the form of configurations of different chemical compounds with a common structure, and are each modified in a controlled fashion to create a combinatorial library of structurally related compounds. The common structure preferably has one, and more preferably, at least two sites capable of undergoing a reaction to change the structure, usually by the addition of other molecules. In one embodiment, the compounds are not synthesized using the devices and processes described herein, but are purified, analyzed and optionally subjected to bioassays after having been previously prepared. The steps described above can be carried out globally on the configuration or individually on each tube. For example, during the synthesis step, reagents can be added globally to each of the tubes. During the purification step, the contents of the tubes can be individually transferred to a purification device. When the solvent is removed from the tubes, the entire rack can be placed in a solvent removal device. When the reaction products are characterized, the contents of each tube can individually be sent to analytical instruments. Depending on the particular device which is used, those of skill in the art can readily optimize the process by performing certain steps globally and certain steps individually on the tubes in the configurations. Interfaces for holding multi-tube racks in place in automated chemical synthesizers are also disclosed. The interfaces include a top and bottom side, where the top side attaches to the bottom of a multi-tube rack and the bottom side attaches to the top of a deck of a liquid handler or other component used in automated chemical synthesis as well as automated purification, automated analysis and automated distribution of samples. Those of skill in the art will appreciate that wherever automated chemical synthesis is mentioned herein, the interface will also be useful in automated purification, automated analysis and automated distribution of samples. The connections between the rack, interface and automated synthesizer keep the rack firmly mounted on the deck. The interface described herein includes a top side and a bottom side. The bottom side includes a means for attaching to a liquid handler or other component involved in automated chemical synthesis, and the top side includes a means for attaching to a multi-tube rack. In one embodiment, the means for attaching to the liquid handler and rack involve using male/female connections, for example, a round peg fitting in an equally sized round hole. In another embodiment, the attachment is made by means of a magnetic linkage, preferably an electromagnetic linkage which can be un-linked by shutting off the electromagnet. In yet another embodiment, the attachment is made by means of a vise. Preferably, at least one end of the vise is transparent to permit one to view a bar code or other means for identifying a multi-tube tack through the vise. In still another embodiment, limited to use on the top side of the interface, the attachment is made using bench dogs adapted to fit into holes in the interface and clamp down on the multi-tube rack. The attachment means can be combined in any suitable combination which results in an attachment of the liquid handler or other component of the automated synthesizer or component used in combinatorial chemistry to the interface and also of the multi-tube rack to the interface. In a preferred embodiment, the liquid handler includes a studded deck and the rack is a Gilson® automated synthesis rack modified to include means for receiving the studs, which, when received do not allow movement of the plate over the surface of the deck. Preferably, the attachment is such that the rack can be easily moved from one machine to another, for example, from one liquid handler to another. This can be accomplished, for example, by lifting the rack off of the interface or deck, particularly where the male and female parts of the connection are connected by vertically inserting the male part into the female part. A multi-tube rack is disclosed is also disclosed. The rack includes a plurality of voids designed to receive a plurality of tubes. The voids are shaped such that they securely hold the tubes, yet provide some room for error in the movement of robotic arms which add and remove tubes from the rack such that tube breakage is minimized. A cross section of the void is shown in Figure 1. A cross section of the void with a tube disposed in the void is shown in Figure 2. When compounds are prepared in tubes, the compounds are typically present as a solution of the compound in a solvent, typically an organic solvent. Purification of the compounds can be done by pipetting the contents of the tubes to an HPLC and collecting the purified compound from the HPLC column, and then evaporating the solvent. The solvent can be evaporated in a number of ways. One way is by centrifugation under vacuum. Another way is by heating the tubes to drive off the solvent. The racks are preferably prepared from a material which conducts heat sufficiently well that solvents can be evaporated from the tubes by heating the tubes. Metals and glasses are examples of suitable materials. The racks preferably have high thermal stability and are preferably fitted with gas or liquid lines for heating or cooling. The racks may optionally include a cover, which is preferably fitted with gas (preferably N 2 ) and/or vacuum lines such that the contents of tubes in the voids can be provided with an inert atmosphere and/or vacuum. Brief Description of the Figures Figure 1 shows a cross section of a void in the multi-tube racks. Figure 2 shows a cross section of a void in the multi-tube racks, as well as a cross section of a tube placed in the void. Figure 3 is a view of an interface for interconnecting a multi-tube rack and a deck on a liquid handler. Detailed Description of the Invention First Embodiment - Method and Apparatus for Synthesizing, Characterizing, Assaying Combinatorial Libraries The present invention is directed to devices and processes for synthesizing, purifying, and analyzing large numbers of compounds, in particular, those generated for combinatorial libraries, lead generation, and or lead optimization libraries, using multi-well plates and/or multi-tube racks. As used herein, a combinatorial library is a library of compounds generated to find and/or generate lead compounds, and a lead optimization library is a library of compounds built around a previously identified lead compound. As used herein, substantially pure compounds are at least 40-60 percent pure, preferably 80 percent pure, and, more preferably, greater than 85 percent pure. As used herein, a tube is any suitable container that can contain from about 200 μg to about lg of a compound and preferably from about 1 mg to about 100 mg, of a compound throughout the processes defined herein. The processes of the present invention involve: a) synthesizing a series of compounds in multi-tube racks or multi-well plates, b) storing the location of the individual tubes or wells in a computerized device, c) individually transferring the contents of each tube or well to a device for purification, d) removing the solvent from each purified fraction, e) optionally weighing the individual tubes after the solvent has been removed to gain information regarding percent yield, f) performing one or more chemical analyses on the purified compounds, optionally g) transferring the compound to one or more multi-well plates for subsequent bioassay; and h) optionally performing bioassays on the purified compounds. At each stage in the process, the position of the tube (or well, if the compounds are synthesized in a multi-well plate) in the previous stage can be correlated with the position of the tubes in the subsequent stage. This avoids the necessity to place a bar code on each individual tube. Rather, the process allows one to use a single code for each multi-tube configuration or multi-well plate, thus simplifying obtaining data for large numbers of compounds. The devices include a multi-tube configuration, a chromatographic or other purification device, means for transferring the contents of the tubes to the purification device, a solvent evaporator, optionally a means for weighing the evaporated samples, a means for adding solvent to the solvent-evaporated tubes, analytical instrumentation, and a means for transferring some or all of the contents to, and optionally from, the analytical instrumentation. The devices and processes described herein provide for the complete control of the synthesis, purification, and/or analysis of entire libraries of compounds, without the need to identify each test-tube with a bar code. The lack of a bar code as an identifier allows for increased accuracy and decreased likelihood of error. This can be particularly relevant when the amount of the compound to be measured is on the same scale as the amount of adhesive lost to evaporation during the handling of the tubes. Because the contents of each individual tube can be weighed, the amount of each compound which is prepared can be determined. This information can be useful in determining LC 5 0 data as well as in optimizing chemical syntheses. By preparing a solution of the compounds and placing them into separate multi-well plates for subsequent bioassays, the tubes can be reused after cleaning without having to remove bar-codes. The tubes may be cleaned in bulk and re-weighed or it is also possible to clean the tubes individually and return them to their original position on the configuration such that the previously stored tared weight of the tube can be re-used, avoiding a re- measurement of the weight of the tubes. I. Compound Synthesis A. Types of Compounds Which Can be Synthesized Any type of compound can be synthesized according to the processes described herein. In particular, libraries of pharmaceutical compounds and agricultural compounds can be synthesized. Typically, the compounds have a core structure which can be modified in at least one position, preferably two or more positions, with a variety of different functional groups, in order to generate a library, for example, a combinatorial or lead optimization library of compounds. Agricultural compounds which can be synthesized include for example insecticides, pesticides, fungicides herbicides, acaricides and the like. Examples of families of insecticides include 1-aryl pyrazoles, pyrroles, pyrrolidones, and nicotinic acid derivatives. Pharmaceutical compounds which can be synthesized include, without limitation, steroids, hormones, peptides, proteins, oligonucleotides, oligoribonucleotides, enzymes, ligands which bind to various receptors, and the like. Suitable core structures include, but are not limited to: peptides, proteins, oligonucleotides, oligoribonucleotides, oligosaccharides, alkaloids, quinolines, isoquinolines, benzimidazoles, benzothiazoles, purines, pyrimidines, thiazolidines, imidazopyrazinones, oxazolopyridines, pyrroles, pyrrolidines, imidazolidones, guinolones, amino acids, macrolides, penems, saccharides, xanthins, benzothiadiazine, anthracyclines, dibenzocycloheptadienes. inositols, porphyrins, corrins, and carboskeletons presenting geometric solids (e.g., dodecahedrane). The core structures can be derived from naturally occurring compounds, or can include non-natural modifications (i.e., non-naturally occurring amino acids and nucleotides). Suitable modifications for the core structures include: 1) amino acid derivatives, which include, for example, natural and synthetic amino acid residues including all of the naturally occurring alpha amino acids, species having derivatives, variants or mimetics of the naturally occurring side chains; N-substituted glvcine residues; natural and synthetic species known to functionally mimic amino acid residues, such as statin, bestatin, etc. 2) nucleotide derivatives, which includes natural and synthetic nucleotides, such as adenosine, thymine, guanidine, uridine, cytosine, derivatives of these and variants and mimetics of the purine ring, the sugar ring, the phosphate linkage and combinations of some or all of these. Nucleotide probes (between 2 and 25 nucleotides) and oligonucleotides (more than 25 nucleotides) including all of the various possible structural modifications; homo and hetero-synthetic combinations and permutations of the naturally occurring nucleotides; derivatives and variants containing synthetic purine or pyrimidine species, or mimics of these; various sugar ring mimetics; and a wide variety of alternate backbone analogs, including but not limited to phosphodiester, phosphorothionate. phosphorodithionate, phosphoramidate, alkyl phosphotriester, sulfamate, 3'-thioformacetal, methylene(methylimino), 3-N-carbamate, morpholino carbamate and peptide nucleic acid analogs. 3) a carbohydrate derivative, which would include natural physiologically active carbohydrates; related compounds, such as glucose, galactose, sialic acids, beta -D-glucosylamine and nojorimycin, which are both inhibitors of glucosidase; pseudo sugars, such as 5a-carba-2-D-galactopyranose, which is known to inhibit the growth of Klebsiella pneumonia (n = 1); synthetic carbohydrate residues and derivatives of these (n = 1) and all of the complex oligomeric permutations of these as found in nature, including high mannose oligosaccharides. the known antibiotic streptomycin (n > 1). 4) a naturally occurring or synthetic organic structural motif. The term "motif is defined as an organic molecule having or containing a specific structure that has biological activity, such as a molecule having a complementary structure to an enzyme active site, for example. This term includes any of the well known basic structures of pharmaceutical compounds including pharmacophores, or metabolites thereof. These basic structures include beta-lactams. such as penicillin, known to inhibit bacterial cell wall biosynthesis; dibenzazepines. known to bind to CNS receptors and used as antidepressants; polyketide macrolides. known to bind to bacterial ribosymes, etc. These structural motifs are generally known to have specific desirable binding properties to ligand acceptors. 5) a reporter element, such as a natural or synthetic dye or a residue capable of photographic amplification which possesses reactive groups that may be synthetically incorporated into the sulfaminimide structure or reaction scheme, and may be attached through the groups without adversely interfering or affecting with the reporting functionality of the group. Preferred reactive groups are amino, thio, hydroxy, carboxylic acid, carboxylic acid ester, particularly methyl ester, acid chloride, isocyanate alkyl halides. aryl halides and oxirane groups. 6) an organic moiety containing a polymerizable group such as a double bond, or other functionalities capable of undergoing condensation polymerization or copolymerization. Suitable groups include vinyl groups, oxirane groups, carboxylic acids, acid chlorides, esters, amides, azlactones, lactones and lactams. Other organic moiety such as those defined for R and R' may also be used. 7) a macromolecular component, such as a macromolecular surface or structures which may be attached to the sulfaminimide modules via the various reactive groups outlined above, in a manner where the binding of the attached species to a ligand-receptor molecule is not adversely affected and the interactive activity of the attached functionality is determined or limited by the macromolecule. Examples of macromolecular components include porous and non-porous inorganic components, such as, for example, silica, alumina, zirconia, titania and the like, as commonly used for various applications, such as normal and reverse phase chromatographic separations, water purification, pigments for paints, etc.; porous and non-porous organic macromolecular components, including synthetic components such as styrenedivinyl benzene beads, various methacrylate beads. PVA beads, and the like, commonly used for protein purification, water softening; and a variety of other applications, natural components such as native and functionalized celluloses, such as, for example, agarose and chitin, sheet and hollow fiber membranes made from nylon, polyether sulfone or any of the materials mentioned above. The molecular weight of these macromolecules may range from about 1000 Daltons to as high as possible. They may take the form of nano-particles (dp = 1000-5000 Angstroms), latex particles (dp = 1000-5000 Angstroms), porous or non-porous beads (dp = 0.5-1000 microns), membranes, gels, macroscopic surfaces or functionalized or coated versions or composites. Suitable chemical modifications also include chemical bonds to a suitable organic moiety, a radioactive moiety, a hydrogen atom, an organic moiety which contains a suitable electrophilic group, such as an aldehyde, ester, alkyl halide, ketone, nitrile, epoxide or the like; a suitable nucleophilic group, such as a hydroxyl, amino. carboxylate, amide, carbanion, urea or the like; or one of the other structural diversity elements defined below. In addition, the chemical modifications can be in the form of a ring, bi-cyclic or tri-cyclic ring system; or structure which connects to the ends of the repeating unit of the compound defined by the preceding formula; or may be separately connected to other moieties. B. Types of Reactions Which Can be Performed Virtually any type of reaction commonly performed in conventional combinatorial chemistry processes can be performed using the devices and processes described herein as well as air sensitive reactions. The scale of the synthetic reactions is preferably in the range of greater than about 200 μg, more preferably between one and 100 mg, although the scale can be modified depending on the amount of compound necessary for the particular application. The chemistry can be performed using solid phase or solution phase chemistry. Solution phase chemistry is advantageous because it is typically more amenable to scaleup than solid phase chemistry. Further, a wider variety of reactions and reaction conditions can typically be used with solution phase chemistry. Nevertheless, solid phase chemistry can be used to synthesize the compounds of interest. Examples of reactions which can be done in either solid or solution phase include, for example, air sensitive reactions, condensation reactions for preparing amides, esters, ureas, imines. and phosphorous compounds. Various carbon-carbon bond forming reactions can be performed using solid and solution phase chemistry. Examples include Suzuki reactions, organozinc reactions, Stille coupling reactions. Heck reactions, enolate alkylations, Wittig reactions. Homer-Wadsworth-Emmons reactions, metathesis reactions, such as ruthenium- catalyzed metathesis of polymer-bound olefms, Mitsunobu reactions, nucleophilic displacement of support-bound a-bromoamides in the submonomer preparation of peptoids, thiol alkylation, anilide alkylation with primary alkyl halides, one pot cyclization and anilide alkylation in the solid-phase synthesis of 1.4-benzodiazepine-2,5-diones, successive amide alkylations (generating new combinatorial peptide libraries from existing combinatorial peptide libraries), benzophenone imine X-carbon alkylation, alkylation or sulfonylation of a support-bound phenol, enolate monoalkylation, alkylation of support-bound 1,3-diketones in the solid-phase synthesis of pyrazoles and isoxazoles. tosyl displacement with primary or secondary amines, grignard reactions. SNAr reactions. Michael additions, iodoetherification reactions, oxidations, reductions, such as reductive alkylation, Pictet-Spengler reactions, and the like. The types of reactions used to generate particular libraries will be expected to vary according to the types of compounds in the libraries as well as the types of substitutions which will be made. Those of skill in the art can readily determine appropriate sets of reactions and reaction conditions to generate the libraries of interest. C. Organization of Compound Modifications in Multi-Tube Configurations The compounds can be laid out in any desired fashion in multi-tube configurations or multi-well plates, in the form of configurations of chemical compounds. For example, the compounds can be laid out in such a manner as to maximize structural diversity. P. Performing the Reactions To perform the chemical reactions needed to synthesize a library of compounds, a compound with one or more reactive sites for carrying out chemical reactions is placed in a number of tubes. Appropriate reagents for carrying out the desired chemistry are added to the tubes, and the reactions allowed to take place. Robotic arms and multi-pipet devices can be used to add the appropriate reagents to the appropriate tubes. When appropriate, the chemistry can be performed in an inert atmosphere. The tubes can each be covered with a rubber septum to avoid contamination, and the reagents added via injection. Preferably, the synthesis is carried out via computer control, where the location of each tube in a multi-tube configuration or each well in a multi-well plate is stored in a computer, and the identity of the compound to be synthesized is stored in the computer in a "memory map" or other means for correlating the data for the compound to the position of the tube or well. Alternatively, the chemistry can be performed manually, preferably in multi-tube racks or multi-well plates, and the information stored on a computer. The compounds in the tubes can be purified, chemically analyzed, and optionally submitted for bioassays, in subsequent stages. Preferably, the number of tubes in the multi-tube configuration or the number of wells in the multi-well plate in the synthesis stage is the same as the number of tubes in the multi- tube rack used in the purification stage and all subsequent stages, including chemical analysis and optionally bioassay. However, in one embodiment, the number of tubes in each stage can be different, as long as a correlation between the orientation of the tubes from one stage is made with the orientation of the tubes in each subsequent stage. This correlation is typically performed using relational database software, where various information regarding the contents of each tube is stored in a database. II. The Device A. Multi-well Plate or Multi-Tube Configuration Any type of multi-well plate or multi-tube configuration commonly used in combinatorial chemistry can be used. Preferably, the number of wells or tubes is in excess of 30, and there is a tube in at least 60 percent of the positions in each multi-tube configuration. Preferably, the rack is square or rectangular and the tubes are identified using a Cartesian coordinate system. The tubes can be made, for example, from plastic, polymers, glass or metal, such as stainless steel, depending on the type of chemical reactions which are to take place in the tubes. The tubes can optionally be covered, for example, with a septum, which permits reagents to be added via a syringe, and also minimizes loss of product should the tube be jostled or otherwise mishandled, short of actually breaking the tube. In one embodiment, the multi-tube configuration(s) include a cover, which can be placed on or removed from the configuration by computer control. The cover preferably includes a plurality of holes or other spaces which correspond to the tubes in the configuration. The holes are preferably not large enough for the tubes to be accidentally removed, but are large enough to allow for sample removal and solvent addition. In this manner, the computer can control the addition and removal of reagents from the tubes. The application or removal of the cover may be achieved, for example, by inserting and removing a screw locking the cover in place, or using other locking mechanisms. This permits the computer to move tubes from the multi-tube configuration to other locations, such as a weighing station, and also protects the tubes from being moved manually. This overcomes the need to place a bar code on each tube to minimize the types of human error which result in misplaced tubes. When a cover is placed over the configuration and septums are placed over each tube, it is possible to control the addition and removal of reagents from the tubes, as well as the removal of tubes from the configuration, using a computer. The possibility of human error is significantly minimized. B. Means for Transferring the Contents of the Tubes Any type of robotic arm which can transfer the tubes and the contents of the tubes to from one stage to the next, for example, from the purification device to the analytical device, can be used. Suitable robotic arms and robotic devices are well known to those of skill in the art of combinatorial chemistry, and include those by Zymart, Gilson, Hamilton, Bodhan and Tecan. A preferred robot is the Gilson 215 robot. The use of robotic arms to move tubes in combinatorial chemistry is known to those of skill in the art. C. Purification Devices Any device which can take the samples from the individual tubes and purify the resulting compounds can be used. Preferably, the device is a chromatographic device, such as a preparative scale HPLC, GC, preparatory supercritical fluid chromatography, or column chromatography, although other devices can be envisioned, depending on the chemistry performed. Preferably, in those embodiments in which a chromatographic column (HPLC, GC or column chromatography) is used, the device has the ability to identify when the compound of interest is eluting from the column. Various means have commonly been used to identify when compounds of interest are eluting from a column, including UV, IR, TLC, GC-MS, FID, NMR, ELSD, nitrogen detection and the like. Any of these means, and others known to those of skill in the art, can be used, alone or in combination. When UV-active compounds are being prepared, the entire eluent from a chromatographic column is sent through a UV detector and then to a mass spectrometer. Sample collection can begin when the UV or mass spectrometry signal indicates the presence of the eluting compound, and can end when the UV signal indicates that the compound has finished eluting from the column. Mass spectrometry can verify that the eluted compound is really the compound of interest. In one embodiment, the position of the tube prior to purification can be correlated to multiple tubes following purification, which permits the analysis of various different reaction products from a single reaction. Accordingly, the database can store information related to the reaction conditions used, the weight of each of the products obtained, the chemical analysis of each of the products, and, optionally, the bioactivity of the products as well. If a chromatographic support is equipped with molecules which bind specifically with a component of the reaction mixture, that component will be separated from the mixture and can be released subsequently by changing the experimental conditions (e.g., buffers, stringency, etc.) This type of separation is known as "affinity chromatography" and is an effective and widely used separation technique. Accordingly, when it is possible to design appropriate conditions for performing affinity chromatography, it is preferred that affinity chromatography is used to separate the compounds. Automatic sample collection is used to collect eluent fractions which include the compound of interest. Using the robotic arm, those fractions containing the compound of interest can be transferred to a second multi-tube configuration, wherein there is a correlation between the position of the tube in the original multi-tube configuration and the tube in the second multi-tube configuration. Purification devices are used to automatically rinse the column of all impurities following elution of the compound of interest. Those of skill in the art can readily determine means for cleaning a purification device between runs. Further, it is also routine in the art for such devices to re-establish the appropriate solvent system for purifying the next type of compound being purified. It is preferred that the purification device have the ability to perform automatic sample collection, rinse the column of impurities after the compound of interest has eluted, and re-establish solvent equilibrium before the next sample is purified. Preferably, two or more purification devices can be run in series or parallel, such that while one column is being cleaned, the other column or columns can be purifying a reaction mixture. The use of multiple purification devices advantageously speeds up the purification stage. One commercially available high throughput purification apparatus is the Biotage Parallex High Throughput Purification Station. This apparatus includes four preparative scale HPLC columns which are run in parallel. There are four pumps and a single injector which is valved to four sample loops. The pumps can be run, for example, with gradient solvent mixtures, for a first time period, a wash cycle for a second time period, and a solvent equilibration cycle for a third time period. The Biotage system includes an intelligent fraction collector which is triggered by signal to noise slope and threshold. The apparatus allows for collection of more than one compound from each tube following chromatographic separation. P. Solvent Removal Apparatus The multi-tube configuration containing the eluted fractions containing the various compounds of interest can be subjected to simultaneous solvent removal by subjecting the entire multi-tube configuration(s) to conditions which remove the solvent. In a preferred embodiment, the solvent is removed using a centrifuge which has the ability to receive a plurality of multi-tube racks. Additional means for removing solvent from the tubes include placing the multi-tube rack(s) in a vacuum oven, or placing a device with a plurality of blowers designed to fit over the individual tubes, and blowing an inert gas over the contents of the tubes until the solvent is substantially removed, or can involve other means known to those of skill in the art for removing solvent. E. Means for Weighing the Fractions In some embodiments, it is desirable to weigh the individual tubes to determine the amount of material obtained in each synthesis. This can be readily accomplished by transferring the (preferably pre-weighed) tubes to a balance, and then back to the original place in the multi-tube rack. The information can be stored, for example, in a computer database. Any balance accurate enough for the scale at which the compound is present can be used. Preferably, a balance is used which is compatible with the robotic arms used to move the tubes from each stage to the next. F. Means for Re-dissolving the Eluted Fractions A robotic arm or other suitable means can be used to add an appropriate solvent to the solvent-evaporated tubes to re-dissolve the evaporated fractions in a solvent suitable for subsequent chemical analyses. In one embodiment, the means includes multi-pipet containing arms, each of which is capable of distributing an appropriate amount of solvent to each tube in the multi-tube rack. The selection of solvent is dependent, in part, on the type of analyses to be performed on the compounds of interest. For example, if the compounds are to be analyzed by NMR, for example, Η NMR or 13 C NMR, then a deuterated solvent can be used. Some NMR instruments have the ability to substract solvent peaks, and the use of deuterated solvents is not a requirement with these instruments. However, this is not a requirement if the compounds are only to be subjected to GC-MS, IR, UV or other analyses. Those of skill in the art can readily determine an appropriate solvent or solvent system for use in a particular chemical analysis. Preferably, the compounds of interest are dissolved in a deuterated solvent, and a fraction containing approximately 1 mg or less is analyzed by Η NMR. When extremely powerful NMR instruments are used, even less sample can be evaluated. Optionally, following NMR analysis, the sample can be removed from the NMR tube or flow cell and returned to the original tube, thereby minimizing product loss. Preferably, the NMR has the ability to transfer solutions of the compounds of interest to an NMR tube, ran the NMR. transfer to the solution of a compound out of the NMR tube, clean out the tube automatically, and transfer a solution of the next compound to be evaluated to the NMR tube. This capability is present in at least one commercially available NMR instruments from Varian®. Preferably, the compounds are analyzed by NMR, GC-MS, LC, ELSP and UV. Following chemical analysis, the racks of compounds can be transferred to a storage facility until bioassays are performed. In one embodiment, the chemicals are stored at a sufficiently cold temperature, for example, -15 to -20" ® C, that the compounds do not degrade significantly prior to the bioassay. G. Bioassavs Following the chemical analyses, it can be desirable to evaluate the bioactivity of the compounds of interest. Methodology exists for performing multi-tube rack bioassays. Accordingly, the compounds of interest, in the multi-tube racks identified, for example, with a single bar code for the plate, can be sent off for bioassay and each tube in the rack identified by its position on the plate. This information can be stored electronically, for example, in a computer system. Bioassays useful for a particular class of compounds are either well known or can be readily developed depending on the particular intended use of the compounds. When compounds are developed for binding to various receptors, numerous binding studies have been developed and described in the literature, which can readily be adapted to a combinatorial approach. H. Computer System and Related Software The device includes a computer system capable of storing the relative positions of the tubes in the multi-tube racks or wells in multi-well plates, as well as the data obtained for each tube. Software for managing the data is stored on the computer. Relational database software can be used to correlate the position of the tubes at each stage of the process with the identify of the individual compounds, the analytical data from each compound, the percent yield of the chemical reactions used to obtain the compounds, and the optional bioassay data for each compound. Numerous commercially available relational database software programs are available, for example, from Oracle, Tripos, MDL. Oxford Molecular ("Chemical Design"), IPBS ("Activity Base"), and other software vendors. Relational database software is a preferred type of software for managing the data obtained during the processes described herein. However, any software that is able to create a "memory map" of the positions of the tubes at each stage of the process and correlate that information with the information obtained at the other various stages can be used. This type of software is well known to those of skill in the art. III. Methods of Identification and Analysis The multi-tube racks or multi-well plates including a plurality of different compounds, located in individual tubes or wells, is subject to purification and analysis as described below. A. Compound Purification Using the computer software and hardware described above, the relative positions of the individual tubes, and therefore, the compounds within each tube, are stored in a database. The robotic arms, with the means for transferring the contents of each tube, are used to individually, and in a stepwise manner, transfer the contents of the tubes, one by one, to the device used for purifying the compounds. Following purification, the eluent fractions containing the compounds of interest are transferred from the purification device to the tubes in a second multi-tube configuration which correlates the position of the tubes in the second multi-tube configuration to the position of the tube or well in the first multi-tube configuration or multi-well plate. Preferably, the weight of each of the tubes in the second multi-tube configuration has been previously recorded in the database so that the weight of the compound, and, accordingly, the chemical yield, can be determined following removal of the solvent and subsequent weight of the solvent-evaporated tube. Once the compounds in the tubes in the first multi-tube configuration have been purified and transferred to the second multi-tube configuration, the second multi-tube configuration can then be subjected to a solvent evaporation step. Following solvent removal, the purified compounds, preferably with a purity exceeding about 80%, can then optionally be weighed, and then subjected to chemical analyses. The weight of the material and the results of the chemical analysis is preferably stored in the database. B. Chemical Analyses The contents of the tubes in the second multi-tube configuration, following solvent removal, can be re-dissolved in a suitable solvent, and subjected to chemical analyses by transferring the contents of the tubes to various devices for analysis, such as NMR, UV, IR, GC, GC-MS, and the like. The analytical data thus obtained can be stored by the computer and correlated to the compound of interest to which it pertains. C. Bioassays The compounds of interest, in the second multi-tube configuration, or in a third multi- tube configuration to which a portion of the compounds have been transferred, can be analyzed in bioassays to determine their bioactivity for a particular indication. In one embodiment, the assays involve binding affinity studies, wherein the ability of the compounds to bind to a particular site are evaluated. Such studies are routine in the art, and typically do not involve a large amount of material. Using these studies, and correlating the results of the studies with the compounds using the same database used to identify and characterize the compounds, one can generate a large amount of bioactivity data in a relatively short amount of time using a relatively small amount of material. Generally, bioassays involve in- vitro and in-vivo screening tests of the compounds so generated, eg., insecticidal. fungicidal, herbicidal, pharmaceutical, or veleunary tests. The apparatus and methods described herein will be better understood with reference to the following non-limiting example. Generic Synthesis, purification, analysis and distribution procedure: A library of 96 individual compounds is synthesized by chemical reactions in a 96- well plate, the wells of which are arranged in an abscissa and ordinate two dimensional configuration. The contents of each well is submitted individually to a preparative high pressure liquid chromatography (HPLC) system. 96 purified products (as detected by a mass spec detector) are collected into a series of tubes in racks each rack of which is labeled with a bar code for identity. The identity of the contents of each tube, its position in the rack and the rack's bar-code are recorded in a database on a computerized database. The racks are transferred to an analytical HPLC and the bar-codes read. An analytical HPLC trace is recorded using ultraviolet (UV) and electron light scattering detector (ELSD) detectors and this data recorded in the database. The racks are transferred to a centrifugal evaporator and the solvent removed from all the tubes at once. The racks are then transferred to a system equipped with a robotic arm, a bar-code reader and a balance so that the weight of each tube can be recorded. In another embodiment, the evaporation step may be followed by weighing each tube to determine the weight of product in each tube and the weight recorded in a database; thereafter the contents of each tube are diluted to a predetermined concentration; and the contents of each tube are analyzed by appropriate analytical means including nuclear magnetic resonance spectroscopy, analytical HPLC and mass spectral analysis. This information is transferred to the central server where the tare weight of each tube had already been recorded and thus the weight of material in each tube can be calculated. The racks are transferred to a liquid handler, the bar-code is read and the contents of the tubes are diluted to a predetermined concentration using the weight of material recorded on the central server. The rack is transferred to an NMR, the bar-code is read and the Η NMR is recorded and stored on the central server. All of the analytical data is viewed and a decision regarding what biological testing is required is made and recorded on the central server. The racks are transferred to a distribution device, the bar-code is read and samples for testing are prepared based on the decisions recorded on the central server. Any excess material is transferred to a storage vessel. The tubes in the rack are replaced with fresh tubes and the rack recycled through the process. In all transformations, the computer database tracks the movement of the compound so synthesized from the 96-well plate to the end of the process. The racks are the only devices that are bar-coded for identity. Second and Third Embodiments - Interface and Multi-tube Rack Automated synthesizers commonly used in automated synthesis, for example, combinatorial chemistry, typically include liquid handlers, which include a deck for receiving a multi-tube rack and also include robotic arms which can perform a variety of applications, including adding and removing components to and from the individual tubes, adding and removing tubes from the rack, and adding and removing racks from various components used in automated chemical synthesis. When all of the components in the automated synthesizer are from the same manufacturer, the deck of the liquid handler and the bottom of the rack include matching parts, typically a male and female part, positioned in such a way that the rack can be placed on the deck and physically held in place by the interconnection of the male and female parts. However, it is often desirable to use multi-tube racks from a different vendor than the one who manufactured the liquid handler or other components used in the automated chemical synthesis. The result is that multi-tube racks from one vendor do not match the other components. An advantage of fitting the rack with an interface as described herein is that the interface can be standardized with the other components used in automated chemical synthesis. The interface described herein permits one to use racks from one vendor and other components from other vendors. Generally, the interface functions to allow a rack to be moved from different pieces of equipment without manual displacement of the individual tubes. Such function precludes any error in the weight, position, and accidental breakage of the tubes. I. The Rack The rack described herein is a multi-tube rack for holding tubes, which includes a block which has a top and bottom surface. The block includes a plurality of voids in the top surface extending along a longitudinal axis toward but not penetrating the bottom surface. The voids form a substantially round opening at the top surface of the block, which opening does not extend through the bottom surface of the block. The voids include a top portion, a bottom portion and a bottom surface. The top portion is connected to the bottom portion which is in turn connected to the bottom surface. The top portion is of a substantially cylindrical shape with a substantially constant diameter. The bottom portion is of a substantially cylindrical shape wherein the diameter narrows in a substantially linear fashion as it approaches the bottom surface. The bottom surface is either substantially flat or is curved to receive the bottom of a tube. The rack described herein can be used as a component in an apparatus for conducting parallel synthesis to prepare combinatorial libraries of compounds, preferably in an automated fashion. The parallel synthesis can be done either on a solid support or in solution, but is preferably done in solution. The rack can have any of a variety of shapes, but is preferably rectangular or square. It can have any of a number of voids for receiving tubes, but preferably, the number of voids per rack exceeds thirty. A preferred number of voids is ninety six, as this is a common number of tubes in conventional multi-tube racks used in combinatorial chemistry. The size of the voids can vary, depending, among other factors, on the scale of the chemistry to be performed. Those of skill in the art can readily determine an appropriate void size depending on the tubes to be used in the synthesis. The voids are designed such that the wall of the voids is a relatively snug fit with the tubes to be inserted in the voids. A cross section of the voids is shown in Figure 1. Of course, the actual void is more or less cylindrical in shape, with the lower end of the void (the area detailed by the taper) forming a tapering cylinder, which leads to a flat or, in one embodiment, curved bottom, where the curve is designed to receive the bottom of the tube. The angled lower end of the void provides the tube with some freedom of movement. This can be important when a robotic arm lifts the tube out of or places the tube into the rack. The presence of the additional freedom of movement lowers the incidence of tube breakage. A cross section of a tube present in a void is shown in Figure 2. As shown in Figure 2, there is a significant amount of contact between the walls of the tube and the walls of the void which can be used to provide adequate heat transfer to the contents of the tube, but there is also a sufficient amount of free space between the wall and the tube near the bottom of the void such that errors in robotic arm movement are less likely to result in tube breakage relative to a void that is designed to receive a tube without having such free space (i.e., the void is designed to exactly fit the tube). A. Establishing an Inert Atmosphere or Vacuum Certain processes and chemistries require that the chemical reagents (which may be reactants, solvents, or reactants dissolved in solvents) be kept under an inert or anhydrous atmosphere to prevent reactive groups from reacting with molecular oxygen, water vapor, or other agents commonly found in air. Examples of atmosphere or moisture sensitive chemistries include peptide chemistry, nucleic acid chemistry, organometallic, heterocyclic, and chemistries commonly used to construct combinatorial chemistry libraries. Accordingly, such reagents must be stored and used under an anhydrous or inert atmosphere, such as one of argon, nitrogen, or other gases or mixtures of gases. When the combinatorial chemistry requires the use of an inert atmosphere, the racks can be adapted to provide such an atmosphere. One means for keeping the tubes sealed from outside air is to cover each of the tubes with a gas impermeable septum. Another means is to provide the entire rack with a cover which is designed to keep out atmospheric gases, and also to provide an intert atmosphere (and/or to provide vacuum). The cover (or use of septum) can also protect the tubes such that the contents of the tubes are not spilled if the rack is jostled. When maintaining an inert atmosphere, it is important to create an effective seal. To create such a seal, the cover can be fitted with a rubber gasket, and clamped onto the rack. When inert atmospheres or vacuum are required, the cover preferably includes inlet and outlet ports for establishing an atmosphere of a gas, for example, an inert gas, or for establishing a vacuum. A pressure port can be coupled to both a regulated inert gas source and a means for controlling pressure within the covered rack, and a vacuum port coupled to a means for controlling vacuum within the covered rack. The pressure control means may be manually operated but, preferably, an electronic pressure control device will be disposed to control the pressure in the cover. The vacuum control means may either be operated manually or be self regulating. B. Controlled Heating and Cooling Automated sample preparation and on-line analysis often requires controlled sample heating and cooling for optimal results. Thermoelectric units are available for controlled heating and cooling of samples and analytes stored in the tubes located in the voids in the rack. For example, Gilson® offers a peltier (thermoelectric) unit for such a use. In one embodiment, the rack includes a means for attachment to a heating or cooling block. Suitable heating and cooling blocks are well known to those of skill in the art. In another embodiment, the rack can include gas or liquid ports. The interior of the rack can be machined to include passages in which heating or cooling gas or liquid can flow if desired (but not through the voids intended to receive tubes). If the rack is made of material having high thermal stability or thermal mass such as 6061 aluminum, this arrangement allows the rack to be quickly and efficiently heated or cooled for chemistries that require such heating or cooling. The rack is preferably prepared from a material which conducts heat sufficiently well that solvents can be evaporated from the tubes by heating the walls surrounding the voids, and, accordingly, heating the tubes and their contents through heat transfer. Metals and glasses are examples of suitable materials. In another embodiment, the rack includes means for inducing heat via electrical resistance. C. Means for Identifying Racks The racks may be color coded for ease of identification, may have identification numbers machined into or printed on the sides, and may also have a bar code printed on the side for identification by machine. Use of the Racks The racks are advantagously used in combinatorial chemistry to receive tubes in which synthetic reactions are run. The resultant products in the tubes may subsequently be taken to dryness by removal of volatile components either under a stream of inert gas or by concentration under vacuum. In one embodiment, solvents are removed from the tubes by centrifugation, which typically occurs under vacuum. In this embodiment, the rack is designed to be received by a centrifuge. Those of skill in the art know how to adapt a rack to be received by centrifuges. The racks described herein can be used as part of a device which automatically performs many or all of the steps required to generate combinatorial and/or lead generation libraries. Any commercially available automated combinatorial chemical library synthesizer which can receive the racks described herein can be used. Such synthesizers are well known to those of skill in the art. To facilitate use in a synthesizer, the racks preferably have fittings that facilitate robotic manipulation. Such fittings are well known to those of skill in the art. For example, the ends of the rack can be fitted with pins or other suitable means to facilitate handling by a robotic gripper. Each side of the rack can be fitted with a pin to facilitate securing the rack onto a docking station. Robotic manipulation of the rack can facilitate automation of the synthetic process. For example, reagents can be introduced into tubes disposed in the voids in the rack when the rack is locked onto a docking station or a pipetting work station. The rack can subsequently be moved to a separate docking station, vortexing shaker table, heating or cooling chamber, or any other location or device useful in synthesis or the collection of material. For reactions that take a considerable amount of time, it can be advantageous to manually or robotically move the rack to another docking station, or to some other location while the reactions are taking place. An example of an automated combinatorial chemical library synthesizer is the Model 396 MPS fully automated multiple peptide synthesizer, manufactured by Advanced ChemTech, Inc. ("ACT") of Louisville, Ky. The Model 396 MPS is capable of generating up to 96 different peptides or other small molecules in a single run, where the syntheses occur simultaneously. In the commercially available model, the syntheses occur in an ACT proprietary plastic reaction block having 96 reaction chambers. The racks described herein can be substituted for the reaction block. At least in some embodiments, use of the racks described herein is advantageous because the voids can be heated and cooled, whereas such heating and cooling might otherwise damage the plastic reaction block in the conventional device. Another example of a suitable automated pipetting work station is the TECAN 5032 automated pipetting work station (Manufactured by TECAN AG, Feldbachstrasse 80, CH-8634 Hombrechtikon, Switzerland) which includes one or more robotic arms. The arms can be used to remove the tubes from the racks, and the racks, having the advantageous shape described herein, protects the tubes from damage when they are placed into and taken out of the racks by robotic arms such as those in the TECAN work station. Preparation of the Racks The racks are preferably machined out of a metal such as 6061 aluminum (which is easily machinable and has good corrosion-resistance) and then anodized for additional corrosion protection. The racks can also be hard coat anodized followed by teflon impregnation. Additionally, the racks can be machined or molded from any suitable metal, engineering plastic, filled plastic, crystalline plastic, ceramic, machinable ceramic, or any other material that can withstand the temperature, pressure, and chemical environment to which the rack will be exposed. If non-metallic materials are used, product reaction can be enhanced by the application of microwaves. If materials transparent to ultraviolet (UV) light are used, reactions catalyzed by UV light can be performed in the racks, and products can be cleaved (when applicable) from a solid support using UV light, without the need for acidic or basic reagents. The voids in the racks described herein can be prepared, for example, by drilling holes in a block using a drill bit shaped such that it has a top portion with a substantially constant thickness, and a bottom portion which is shaped such that it has a narrowing thickness, tapering off to the final thickness of the desired bottom surface of the void. Depending on whether the void is to have a substantially flat bottom surface or a curved bottom surface, the drill bit can be designed accordingly. Means for drilling and cutting non-uniform shapes are well known to those of skill in the art. The racks can also be prepated by injection molding or extrusion, when the rack is to be prepared from a polymer such as polypropylene, polyethylene, teflon, glass, or any other inert material able to withstand the temperature, pressure, and chemical environment to which the rack may be exposed. While the present invention has been described with reference to one or more particular embodiments, those skilled in the art will recognize that many changes may be made thereto without departing from the spirit and scope of the present invention. Each of these embodiments and obvious variations thereof is contemplated as falling within the spirit and scope of the claimed invention, which is set forth in the following claims. II. The Interface The interfaces include a top and bottom side, where the top side attaches to the bottom of a multi-tube rack and the bottom side attaches to the top of a deck of a liquid handler or other component used in automated chemical synthesis, for example, combinatorial chemistry. The attachments (or "interconnections") between the rack, interface and automated synthesizer keep the rack firmly mounted on the deck. As used herein, a "deck" is any part of a component used in automated chemical synthesis which is designed to receive a multi-tube rack. The size of the interface is generally the same as or less than the footprint of the deck of the liquid handler or other component used in automated synthesis to which the rack is attached by means of the interface. Generally, the interface has a rectangular shape such that it may abut on edge another plate which is engaged with the studded deck. In one embodiment, the size of the interface is between 330 and 340 mm in length and between 120 and 130 mm in width. Preferably, the thickness of the interface is between 2 mm and 20 mm, preferably between 3 and 10 mm. The plate may be constructed from any known material and in use is generally rigid. Suitable materials include plastics, metal, composite material or other materials capable of withstanding the physical and chemical conditions associated with automated chemical synthesis. The material is preferably chemically resistant to most organic solvents and water. Various means can be used for interconnecting the rack with the interface, and the interface with the deck on a liquid handler or other component used in automated chemical synthesis. The means for attaching (interconnecting) the rack are configured such that the rack engages the plate in an overlying relationship or a transverse relationship, preferably in overlying relationship. The means for attaching the component used in automated synthesis are similarly configured. A. Male Female Connections In a preferred embodiment, the means for attaching to the liquid handler and rack involve using male/female connections, for example, a round peg fitting in an equally sized round hole. In those embodiments in which the attachment is made using male and female parts, whether the top and or bottom side include male or female parts depends in large part on whether the multi-tube rack and deck have male or female parts. An example of a suitable interface is shown, for example, in Figure 1. Figure depicts an rectangular interface plate with sides A, A', B and B'. Passing through the plate from the top side to the bottom side are a plurality of holes 1-9 which provide a means to grip the deck of the liquid handler. The holes are engaged by male projections extending from the deck of the liquid handler. Projections 10-12 form an asymmetric gripper means extending from the top side of the plate to engage female voids in another plate. The projections are preferably between approximately 0.3 and 1.0 cm in height from the top side of the plate. The thickness of the plate, that is the generally uniform distance from the top to the bottom sides of the plate, is preferably between about 0.3 to 1.0 cm. In a preferred embodiment, male parts are studs, and the means for receiving the studs are holes in the plate or concave indentations in the plate which are on the opposite side of the plate from the means for engaging the rack or component used in automated synthesis. Other such means known to those of ordinary skill in the art include all types of male and female connectors, for example, slots, groves, pins, etc. There are generally from 2 to 20 holes and/or indentations in the plate, preferably from 3 to 15 holes and/or indentations, most preferably from 5 to 12 holes and/or indentations. When engaged with the studs or other male part on the deck of liquid handler or other component used in automated synthesis, the plate is immobile across the face of the handler. Generally the means to attach the rack include between 1 and 10 posts, preferably between 2 and 4 posts, which are inserted into corresponding apertures in the bottom plate of the rack. Preferred racks are obtained from Gilson Inc. (Middleton, WI ). In a highly preferred embodiment, the male parts on the interface are oriented such that the rack overlies the plate in one overlying relationship. An optional embodiment is that the rack may overlie the plate in two overlying relationships, but one is highly preferred such that there is less error introduced when a rack is transferred from one component to another. B. Magnetic Connections In another embodiment, the attachment is made by means of a magnetic linkage, preferably an electromagnetic linkage which can be eliminated by shutting off the electromagnet. This embodiment can be preferred where the rack and or deck is made of a metal. C. Vise In yet another embodiment, the attachment is made by means of a vise. Preferably, at least one end of the vise is transparent to permit one to view a bar code or other means for identifying a multi-tube tack through the vise. This embodiment can be preferred where the rack is significantly smaller than the deck on the liquid handler or other component used in the automated synthesis, or where multiple racks of different sizes are used. The use of a vise can offer more flexibility with respect to rack size than the use of a male/female connection. P. Bench Dog In still another embodiment, limited to use on the top side of the interface, the attachment is made using bench dogs adapted to fit into holes in the interface and clamp down on the multi-tube rack. This embodiment offers many of the same advantages as the use of a vise. E. Other Embodiments In yet another embodiment, the interface includes a top side and a bottom side, the top side having a first asymmetrical gripper means for accepting a multi-well plate or multi tube configuration, the bottom side having a second asymmetrical gripper means for engaging an automated synthesis device. The interface plate may be made of any suitable material and is preferably resistant to solvents typically encountered in automated synthesis. The first and second asymmetrical gripper means are any means that will provide for only a single orientation of the plate or configuration when attached to the plate e.g. interlocking male and female connectors, pins, slots, holes or plates. In a preferred embodiment, the interface includes more than one means for attachment which are compatible with decks of more than one type of component and/or more than one type of rack. For example, the orientation of holes (female parts) on the bottom of the interface (if present) can be made such that the male parts from a variety of components, from a variety of vendors, will match the female parts on the bottom of the interface. Also, the female parts on the top of the interface (if present) can be made such that the male parts from a variety of racks, from a variety of vendors, will match the female parts on the top of the interface. III. Components Used in Automated Synthesis Any suitable component used in automated synthesis can be used with the interface described herein. Examples of suitable components include liquid handlers, such as Tecan® liquid handlers, centrifuges, weighing stations, analytical equipment, including HPLC stations, storage facilities, automatic synthesizers, biological evaluation apparati, evaporators, dessicators, and the like. IV. Controlled Heating and Cooling Automated sample preparation and on-line analysis often requires controlled sample heating and cooling for optimal results. Thermoelectric units are available for controlled heating and cooling of samples and analytes stored in the tubes located in the voids in the rack. For example, Gilson® offers a peltier (thermoelectric) unit for such a use. In one embodiment, the interface includes a means for attachment to a heating or cooling block. Suitable heating and cooling blocks are well known to those of skill in the art. In another embodiment, the interface itself includes means for inducing heat via electrical resistance. In yet another embodiment, the interface includes gas or liquid ports. The interior of the interface can be machined to include passages in which heating or cooling gas or liquid can flow if desired. If the interface is made of material having high thermal stability or thermal mass such as 6061 aluminum, this arrangement allows the interface to be quickly and efficiently heated or cooled, which then heats or cools the multi-tube rack. This can be useful for chemistries which require such heating or cooling. The interface is preferably prepared from a material which conducts heat sufficiently well that solvents can be evaporated from the tubes in the multi-tube racks by heating the walls surrounding the voids, and, accordingly, heating the tubes and their contents through heat transfer. Metals and glasses are examples of suitable materials for preparing both the interface and the rack. V. Means for Identifying Racks The racks and/or interfaces may be color coded for ease of identification, may have identification numbers machined into or printed on the sides, and may also have a bar code printed on the side for identification by machine. Radio frequency chip tracking devices may also be used. VI. Use of the Racks/Interfaces The interfaces are advantageously used to hold multi-tube racks in place on one or more components used in automated chemical synthesis, for example, combinatorial chemistry. The multi-tube racks receive tubes in which synthetic reactions are run to other components used in the automated synthesis. The resultant products in the tubes may subsequently be taken to dryness by removal of volatile components either under a stream of inert gas or by concentration under vacuum. In one embodiment, solvents are removed from the tubes by centrifugation, which typically occurs under vacuum. In this embodiment, the interface may be designed to be received by a centrifuge which includes the appropriate male or female parts or other interconnecting means for attachment to the rack. Those of skill in the art can readily use the teachings herein to adapt a centrifuge to receive the interface, and, therefore, the multi-tube rack attached to the interface. The interfaces described herein can be used as part of a device which automatically performs many or all of the steps required to generate combinatorial and/or lead generation libraries. Any commercially available automated combinatorial chemical library synthesizer which can receive the racks described herein can be used. Such synthesizers are well known to those of skill in the art or can be modified using the teachings herein to receive such a rack. To facilitate use in a synthesizer, the interfaces and/or racks preferably have fittings that facilitate robotic manipulation. Such fittings are well known to those of skill in the art. For example, the ends of the interface and/or rack can be fitted with pins or other suitable means to facilitate handling by a robotic gripper. Each side of the interface and/or rack can be fitted with a pin to facilitate securing the rack onto a docking station. Robotic manipulation of the interface and/or rack can facilitate automation of the synthetic process. For example, reagents can be introduced into tubes disposed in the voids in the rack when the rack is locked onto a docking station or a pipetting work station. The rack can subsequently be moved to a separate docking station, vortexing shaker table, heating or cooling chamber, or any other location or device useful in synthesis or the collection of material. For reactions that take a considerable amount of time, it can be advantageous to manually or robotically move the rack to another docking station, or to some other location while the reactions are taking place. An example of an automated combinatorial chemical library synthesizer is the Model 396 MPS fully automated multiple peptide synthesizer, manufactured by Advanced ChemTech, Inc. ("ACT") of Louisville, Ky. Another example of a suitable automated pipetting work station is the TECAN 5032 automated pipetting work station (Manufactured by TECAN AG, Feldbachstrasse 80, CH-8634 Hombrechtikon, Switzerland) which includes one or more robotic arms. The arms can be used to remove the tubes from the racks, and the racks, having the advantageous shape described herein, protects the tubes from damage when they are placed into and taken out of the racks by robotic arms such as those in the TECAN work station. VII. Preparation of the Interfaces The interfaces are preferably machined out of a metal such as 6061 aluminum (which is easily machinable and has good corrosion-resistance) and then anodized for additional corrosion protection. The interfaces can also be hard coat anodized followed by teflon impregnation. Additionally, the interfaces can be machined or molded from any suitable metal, engineering plastic, filled plastic, crystalline plastic, ceramic, machinable ceramic, or any other material that can withstand the temperature, pressure, and chemical environment to which the interfaces will be exposed. If non-metallic materials are used, product reaction can be enhanced by the application of microwaves. If materials transparent to ultraviolet (UV) light are used, reactions catalyzed by UV light can be performed in the racks, and products can be cleaved (when applicable) from a solid support using UV light, without the need for acidic or basic reagents. The male and/or female parts in the interfaces described herein can be prepared, for example, by drilling holes in a block (female parts) or by attaching suitable male parts to the top or bottom surface of the interface. Alternatively, male parts can be present on the top or bottom surface of the rack or interface by virtue of removing all of the material except for the male part from the appropriate surface of the rack or from the top and/or bottom surfaces of the interface. Means for drilling and cutting these shapes are well known to those of skill in the art. The interfaces described herein can also be prepared by injection molding or extrusion, when the interface is to be prepared from a polymer such as polypropylene, polyethylene, teflon, glass, or any other inert material able to withstand the temperature, pressure, and chemical environment to which the interface may be exposed. While the present invention has been described with reference to one or more particular embodiments, those skilled in the art will recognize that many changes may be made thereto without departing from the spirit and scope of the present invention. Each of these embodiments and obvious variations thereof is contemplated as falling within the spirit and scope of the claimed invention, which is set forth in the following claims.

Claims: We claim 1. A process for synthesizing, purifying, and analyzing a plurality of compounds in a lead optimization library comprising: a) synthesizing a series of compounds in a first multi- well plate or multi-tube configuration; b) transferring the contents of the wells or tubes to a liquid chromatography purification device and submitting the contents to a purification which produces one or more eluent fractions; c) transferring the eluent fraction(s) to one or more tubes in a second multi-tube configuration, wherein the positions of the tubes in the second multi-tube configuration are correlated to the position of the tubes in the first multi-well plate or multi-tube configuration: and d) analyzing the contents of the tubes; wherein information regarding the synthesis of each compound and analysis of the compounds, the position of each of the compounds in the various multi-tube configurations or multi-well plate, and the analysis data is stored in a database such that said information can be correlated to the position of each tube or well in the first multi-well plate or multi-tube configuration and wherein the liquid chromatography purification device is preparative scale HPLC or column chromatography.. 2. The process of claim 1, wherein the tubes are not individually labeled. 3. The process of claim 1, wherein the solvent is removed from the tubes following purification and transfer of the eluent fraction or fractions to the tubes in the second multi- tube configuration. 4. The process of claim 3, wherein the tubes in the second multi-tube configuration are weighed prior to receiving the eluent fraction and after the solvent has been removed. 5. The process of claim 4, wherein the weight of each purified compound is obtained by subtracting the weight of the empty tube from that of the solvent-evaporated tube in the second multi-tube configuration, and that information is stored in the database. 6. The process of claim 1, wherein the first and second multi-tube configurations are arranged in abcissa and ordinate configurations. 7. The process of claim 1, wherein at least one of the multi-tube configurations includes a cover which is removable using computer control. 8. The process of claim 7, wherein the cover includes a plurality of holes or other openings which correlate to the tubes in the configuration, and wherein the size of the openings is such that the tubes cannot be removed from the configuration without removing the cover, and items can be added to or removed from the tubes without removing them from the rack. 9. The process of claim 1 , wherein the synthesized, purified and analyzed compounds are further subjected to one or more bioassays. 10. The process of claim 9, wherein results of the bioassay of the contents of each tube are correlated with the information. 11. A method of automated chemical synthesis which comprises a) disposing an configuration of tubes, each of which contains at least one core compound, on a rigid support, wherein each tube is in a fixed location in the configuration; b) performing a chemical reaction on the core compounds to form an configuration of reaction mixtures containing an configuration of reaction products, c) purifying the reaction mixtures and isolating the reaction products, d) characterizing the reaction products with one or more analytical instruments, and e) optionally repeating one or more of steps a-d, wherein at least one or more of the steps is effected globally on the configuration, at least one of the steps is effected on each tube individually, and the initial reactant as well as the end products of the syntheses are identified by their position on the configuration, the position being recorded by computerized means using the location of the tube on the rigid support. 12. The method of claim 11 wherein the tubes are not individually labeled. 13. The method of claim 11 wherein the amount of isolated reaction product in each tube is calculated by obtaining a tare weight of the tubes, obtaining the weight of the previously tared tubes after the compounds are isolated in the tubes and all solvent is removed, and subtracting the tare weight of the tubes from the weight of the tubes containing the reaction products. 14. An apparatus for conducting sequential synthesis, purification and characterization of a plurality of compounds, comprising: a) one or more multi-tube configurations, b) a purification device, c) means for transferring the contents of the tubes, d) a solvent evaporator, e) means for adding solvent to the tubes, f) analytical instrumentation, and g) a computer with suitable software control for storing information regarding the contents of each tube in the multi-tube configuration. 15. The device of claim 14, further comprising a weighing instrument. 16. The device of claim 14, wherein the multi-tube configuration includes a cover which is removable by computer control, which locks the tubes in a given configuration or unlocks the tubes by computer control. 17. The device of claim 14, wherein the purification device comprises one or more preparative HPLC columns, wherein when more than one HPLC column is used, they are set up in parallel. 18. The device of claim 14, wherein the means for transferring the contents of the tubes is a robotic arm. 19. The device of claim 14, wherein the solvent evaporator is a centrifuge adapted to contain a plurality of multi-tube configurations. 20. The device of claim 14. wherein the analytical instrumentation comprises one or more analytical instruments selected from the group consisting of NMR instruments. UV spectrometers, and IR spectrometers. 21. An interface for attaching to a multi-tube rack and a deck on a component used in automated chemical synthesis, comprising a top and bottom side, where the top side comprises a means for attachment to the bottom of a multi-tube rack and the bottom side comprises a means for attachment to the top of a deck of a liquid handler or other component used in automated chemical synthesis by using attachment means adapted for use with attachment means present on the deck and the rack. 22. The interface of claim 21, wherein the means for attaching the deck and/or rack comprises male and/or female parts. 23. The interface of claim 21, wherein the means for attaching the deck and/or rack comprises an electromagnet. 24. The interface of claim 21 , wherein the means for attaching the deck and/or rack comprises a vise. 25. The interface of claim 24, wherein the vise comprises a transparent end. 26. The interface of claim 21, wherein the means for attaching the rack comprises one or more bench dogs adapted to fit in one or more holes in the interface. 27. The interface of claim 21. wherein the interface is prepared from a material that comprises a metal. 28. The interface of claim 27. wherein the metal is selected from the group consisting of aluminum and stainless steels. 29. The interface of claim 27, wherein the metal is a metal that resists oxidation in air. 30. The interface of claim 21, wherein the interface is prepared from a material that comprises glass, plastics or polymers. 31. The interface of claim 21, further comprising a means for heating and/or cooling the rack. 32. The interface of claim 21, further comprising a means for identifying the interface. 33. The interface of claim 32, wherein the means is a bar code. 34. The interface of claim 21 , comprising two or more means for attaching racks such that two or more racks with different means for attachment to a deck can be attached to the interface. 35. The interface of claim 21, comprising two or more means for attaching decks of liquid handlers or other components used in automated chemical synthesis such that two or more decks with different means for attachment to a rack can be attached to the interface. \ 36. An interface plate for automated synthesis comprising a top side and a bottom side, the top side having a first asymmetrical gripper means for accepting a multi-well plate or multi tube array, the bottom side having a second asymmetrical gripper means for engaging an automated synthesis device. 37. A multi-tube rack for holding tubes, comprising a block which comprises a top and bottom surface and a plurality of voids in the top surface extending along a longitudinal axis toward but not penetrating the bottom surface, wherein: a) the voids form a substantially round opening at the top surface of the block, which opening does not extend through the bottom surface of the block; b) the voids comprise a top portion, a bottom portion and a bottom surface, wherein: i) the top portion is connected to the bottom portion which is in turn connected to the bottom surface; ii) the top portion is of a substantially cylindrical shape with a substantially constant diameter, ii) the bottom portion is of a substantially cylindrical shape wherein the diameter narrows in a substantially linear fashion as it approaches the bottom surface, and iii) the bottom surface is either substantially flat or is curved to receive the bottom of a tube. 38. The rack of claim 37, wherein the bottom surface is flat. 39. The rack of claim 37, wherein the bottom surface is curved to receive the bottom of a tube. 40. The rack of claim 37, wherein the block comprises a metal. 41. The rack of claim 40, wherein the metal is selected from the group consisting of aluminum, and stainless steel. 42. The rack of claim 37, wherein the block comprises a glass or a polymer. 43. The rack of claim 37, wherein the block comprises a means for attachment to a cover. 44. The rack of claim 37, wherein the cover comprises a means for introducing a gas or a vacuum to the rack. 45. The rack of claim 37, wherein the block comprises a means for heating and/or cooling the voids. 46. The rack of claim 37, wherein one or more of the voids are substantially filled with a tube.

Inventors: ABEDI JALEH AZMI, MCCOMB SUSAN MARIE, MONNET PIERRE, RIBEILL YVES, SMITH HENRY DAVID III, ABEDI, JALEH, AZMI, MCCOMB, SUSAN, MARIE, MONNET, PIERRE, RIBEILL, YVES, SMITH, HENRY, DAVID, III
Applicants: ABEDI JALEH AZMI, AVENTIS CROPSCIENCE SA, MCCOMB SUSAN MARIE, MONNET PIERRE, RIBEILL YVES, SMITH HENRY DAVID III, ABEDI, JALEH, AZMI, AVENTIS CROPSCIENCE S.A., MCCOMB, SUSAN, MARIE, MONNET, PIERRE, RIBEILL, YVES, SMITH, HENRY, DAVID, III
Application year: 2000
Main classification: C07B61
IPC codes: B01J19, C07B61, C40B40, C40B50, C40B70, G01N24, G01N30, G01N35, G01N37