Abstract:
A cover assembly of the type disposed over a reaction block for preparing reaction mixtures and, in particular, for enabling reflux condensation of the mixtures is provided. The cover assembly includes a cover assembly having a cover housing with a gas inlet adapted to receive a cooling gas from an external source and an internal cavity through which the reaction vials extend. The cover assembly also includes at least one gas port in communication with the internal cavity and through which the cooling gas from the gas inlet flows to cool portions of the reaction vials which are distal their lower ends.

Description:
FIELD OF THE INVENTION 
     This invention relates to a reaction block and cover to prepare reaction mixtures. 
     BACKGROUND OF THE INVENTION 
     In recent years, methods for simultaneously preparing large numbers of chemical compounds have attracted increasing interest. One approach for preparing the compounds is to arrange individual reaction vials within a single reaction unit or block. 
     A reaction block generally includes a large number of reaction vials, each of which corresponds to a reaction vial for containing a reaction mixture. The reaction block provides a spatially-addressable approach for analyzing the synthesis of a family or library of chemical compounds. Using reaction blocks in this way allows larger number of compounds to be generated and screened more quickly. Thus, reaction blocks are valuable in reducing, for example, the time necessary in bringing new pharmaceutical drugs to market. 
     Although different reaction blocks are known in which the temperature of the block, and thus the reaction mixture within the vessel, can be controlled, it is difficult to carry out a reflux reaction in a simple, reliable way using known reaction blocks. 
     SUMMARY OF THE INVENTION 
     The invention is based on the discovery that a cover assembly that directs a stream of cooling gas (e.g., air) to the middle or upper ends of reaction vials nested in a reaction block is effective to cool the vials sufficiently to carry out a reflux reaction without the need for cooling the ambient air around the reaction block and without the need for a sophisticated and possibly complex cooling system. 
     In one aspect, the cover assembly includes a cover housing having a gas inlet adapted to receive a cooling gas from an external source and an internal cavity into which the reaction vials extend during operation. The cover assembly also includes an inlet port, positioned between the gas inlet and the internal cavity, through which the cooling gas from the gas inlet flows to cool upper ends of the reaction vials; a movable vane disposed within the internal cavity and configured to be positioned and secured over a portion of the inlet port; and an outlet configured to allow the cooling gas to exit the internal cavity after cooling the upper ends of the reaction vials. 
     In another aspect, the cover assembly includes a cover housing having a gas inlet adapted to receive a cooling gas from an external source; an internal cavity into which the reaction vials extend; and a plurality of inlet ports, positioned between the gas inlet and the internal cavity and through which the cooling gas from the gas inlet flows to cool upper ends of the reaction vials. The cover assembly also includes an outlet configured to allow the cooling gas to exit the internal cavity after cooling upper ends of the reaction vials. 
     In still another aspect, the cover assembly includes a gas inlet adapted to receive a cooling gas from an external source; a top wall and a plurality of sidewalls which together define an internal cavity adapted to receive upper ends of each reaction vial during operation; and a plurality of outlet ports formed within at least one of the sidewalls to allow the cooling gas to exit the internal cavity after cooling the upper ends of each reaction vial. 
     Embodiments of these aspects of the invention may include one or more of the following features. 
     The cover housing defines a plenum chamber positioned between the gas inlet and the inlet port (or plurality of inlet ports); a plenum member having the inlet port formed therein, an upper surface, and a bottom surface; and a top cover disposed over the plenum member and having a bottom surface which together with the upper surface of the plenum member define the plenum chamber. The gas inlet can be provided within the top cover. The cover assembly can also include a spacer positioned between the plenum member and the reaction block. The spacer has an upper surface which together with the bottom surface of the plenum member defines the internal cavity and the gas outlet. 
     In other aspects of the invention, a reaction block includes one of the above described cover assemblies and further includes a base including an array of first holes formed therein. Each of the first holes are sized and configured to receive a lower end of a reaction vial. With this arrangement, the array of holes defines a pattern of rows and columns so that the upper ends of the reaction vials themselves form channels to allow the cooling gas to exit the cover through exit openings positioned at an end of the cover assembly and between adjacent rows or columns of the reaction vials. 
     In embodiments of these reaction blocks, the spacer can include an array of second holes located in a pattern corresponding to the array of first holes. The array of first holes defines a pattern of rows and columns. The base is formed of a first material having a first thermal conductivity characteristic and the spacer is formed of a thermally insulative material having a second thermal conductivity characteristic less than the first thermal conductivity characteristic. In essence, the spacer serves as a thermal isolating barrier between the upper and lower ends of the reaction vials, thereby enhancing reflux condensation. A thermal conductivity characteristic (or coefficient of conductivity) is a measure of the time rate of transfer of heat by conduction through a unit thickness across a unit area for a unit difference of temperature. 
     In the embodiment in which the cover assembly includes a plurality of gas inlet ports, these ports are formed in the plenum member and are located to direct flow of the cooling gas between adjacent rows of reaction vials. 
     In embodiments where the outlet ports are formed within one of the sidewalls, the outlet ports are located to direct flow of the cooling gas between adjacent rows of reaction vials. 
     In another aspect, the invention provides a method of preparing a reaction mixture within a plurality of reaction vials. The method includes positioning the new cover assembly over the reaction vials in a block; providing a cooling gas from an external gas source to the internal cavity via the gas inlet to cool upper ends of the reaction vials; and heating the reaction vials to a predetermined reaction temperature by heating the base of the reaction block. 
     In certain embodiments, this method further includes positioning each of the plurality of reaction vials within a corresponding one of an array of first holes formed within a base of the reaction block. 
     A reaction mixture is added to each of the reaction vials prior to positioning the cover assembly over the reaction block. 
     As used in this method, the base can be formed of a first material having a first thermal conductivity characteristic and a spacer that includes an array of second holes located in a pattern corresponding to the array of first holes can be formed of a second material having a second thermal conductivity characteristic less than the first thermal conductivity characteristic. 
     In this method, the spacer can be a separate member and can be positioned between the base and cover prior to providing the reaction mixture within each of the reaction receptacles. 
     The reaction block allows reflux condensation to be performed independently within a large number of individual reaction vials or other receptacles, all of which are supported within the same reaction block. Different reaction mixtures can therefore be dispensed within the individual reaction receptacles and processed simultaneously. Thus, throughput in synthesizing reaction mixtures is increased. 
     The reaction block also provides a relatively simple, easily manufactured and assembled apparatus for performing reflux condensation reactions. The cover provides a single, open (i.e., no obstructing channel members) internal cavity through which the cooling gas is provided, e.g., through a single inlet. 
     Although methods and materials of the invention similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. 
     Other features and advantages will be apparent from the following detailed description and drawings, and from the claims. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is an exploded perspective view of a reaction block and cover assembly in accordance with the invention. 
     FIG. 2 is a cross-sectional side view of the reaction block and cover assembly along line  2 — 2  in FIG.  1 . 
     FIG. 3 is a side view, partially in cross section, of the reaction block and cover assembly along line  3 — 3  in FIG.  1 . 
     FIG. 4 is an exploded perspective view of an alternative embodiment of a reaction block and cover assembly. 
     FIG. 5 is a cross-sectional side view of the reaction block and cover assembly along line  5 — 5  in FIG.  4 . 
     FIG. 6 is an exploded perspective view of another alternative embodiment of a reaction block and cover assembly. 
     FIG. 7 is a cross-sectional side view of a reaction block and cover assembly similar to that in FIG. 6, including a fan. 
     FIG. 8 is a perspective view of the embodiment of the reaction block and cover assembly (without top cover) of FIG.  6 . 
    
    
     DETAILED DESCRIPTION 
     Referring to FIGS. 1-3, a reaction block  10  supports an array of reaction vials  12  (FIG. 2) within which individual reflux condensation reactions are to be carried out. Each vial contains a reagent, which can be a solid, e.g., a powder, or a liquid. If a powder, a liquid is typically added to carry out a chemical action. For example, a reagent solution or mixture  14  can be formed. As will be discussed in greater detail below, many chemical reactions require heat to proceed. 
     Reaction block  10  includes a base  16  having a two-dimensional array of support holes  18  sized to receive reaction vials  12  containing reagent solution  14 . The reaction block can accommodate a relatively large number of reaction vials. In the embodiment shown, 96 holes are provided in base  16 . Other arrangements and numbers of holes (e.g., 384 holes) can be provided to suit particular needs. After the reagent solution is dispensed within vials  12 , a cap may be placed over the open end of the vials to avoid possible contamination of the solution (or vapor products of the solution), thereby ensuring the integrity of the solution. In general, and in many applications, caps are not required to seal the vials if the reflux condensation process is carried out properly. Base  16  is preferably fabricated from a metal or other material having a relatively high thermal conductivity characteristic and capable of being heated to reaction temperatures of reagent solutions  14 . For example, the base can be machined from 6061 aluminum and then anodized to provide corrosion protection. Other metals including copper and brass can be used to fabricate base  16 . Support holes  18  are sufficiently deep to support reaction vials  12  at their lower ends while being sufficiently shallow to allow their upper ends to extend above the upper surface of base  16 . By upper ends it is meant those ends excluding the lower ends received within the holes of base  16 . The lower ends of reaction vials  12  are in intimate contact with base  16  when seated within support holes  18 . Thus, when base  16  is heated, as will be discussed below, heat is efficiently and effectively transferred to the vials. 
     A cover assembly  11  includes a cover  22  positioned over base  16  of reaction block  10  and is in the form of a box-like enclosure having a top wall  24  and four sidewalls  26  which together define an internal volume  28  (FIG. 2) surrounding the upper ends of vials  12 . In this embodiment, top wall  24  of cover  22  is spaced from the upper ends of the vials to provide an open area for the cooling gas to circulate. Alternatively, in other embodiments, top wall  24  may contact the upper ends of the vials, thereby securing them in place. 
     At least one inlet fixture  30  is positioned within a hole  31  (FIG. 2) formed in top wall  24  and is configured to be attached to a hose  32  connected to a fluid, such as a pressurized gas source  33 . In many applications, cooling air is provided from gas source  33 , e.g., a standardized pressurized air source at room temperature found in many laboratories which has the advantage of being readily available and inexpensive. However, in other applications, the pressurized gas source can be a specialized gas source that provides other gases or fluids, at room temperatures or at some predetermined cooling temperature. Cover  22  also includes exit openings  34  formed in one of the four sidewalls  26  so that with the cover positioned over base  16 , the exit openings are between adjacent rows of vials  12 . 
     An insulating spacer  36  having an array of thru holes  38  can be optionally placed between base  16  and cover  22 . Spacer  36  can have a thickness, in this embodiment, of about 0.25 inches and can be formed of a thermally insulative material (e.g., polypropylene, polyethylene, teflon, or other inert material) capable of withstanding varying temperatures and chemical environments. Spacer  36  serves as a thermal isolating barrier between the upper and lower ends of vials  12 , and between base  16  and cover  22 . 
     Base  16 , spacer  36 , and cover  22  can be fastened together, for example, using screws  40  (only one being shown in FIG.  1 ), each of which extends through respective holes  42 ,  44  in the spacer and the cover, respectively, and received within threaded holes  46  of base  16 . Alternative fastening approaches, including clamps, pins, etc., can be used as well. 
     In use, reaction vials  12  are placed within support holes  18  of base  16  with spacer  36  positioned thereon. The reaction solution  14  is dispensed into each vial  12 , for example, using a syringe and needle which can be manipulated manually or, preferably, using an automated robotic system. Alternatively, the vials can be preloaded with a reagent or solvent before insertion into the base. Cover  22  is placed over spacer  36  and fastened to base  16  through spacer  36  using screws  40 . 
     Hose  32  is connected to inlet fixture  30  and pressurized cooling gas (designated by arrows  48 , e.g., at room temperature or lower, depending on the particular reaction) is directed into internal volume  28  of cover  22  to cool the upper ends of vials  12 . Internal volume  28  of cover  22  is open and clear of obstructions. Thus, the upper ends of the array of vials form flow channels between the vials through which the pressurized gas  48  passes before exiting cover  22  via exit openings  34 . Exit openings  34  are shown here along a single sidewall  26   a  of cover  22  so that gas  48  which enters internal volume  28  and is initially directed away from sidewalls within which exit openings  34  are formed, strikes the sidewalls  26  and is redirected back into the inner volume to be recirculated before eventually exiting through exit openings  34 . 
     The reaction vials  12  are then heated, e.g., by placing the reaction block  10  on a heating block  50  or other heating device, to a temperature required by a particular reagent solution  14 . Alternatively, base  16  can include electrical resistance heaters or other means of heating, so that base  16  can be heated independently and without the need for additional parts such as a heating block. Vapors released during reaction of the reagent solution rise to the upper end of vials  12 , are cooled by the circulating gas in internal volume  28  and condensed on the inner sidewalls of the vials. The condensate then flows back to the lower end of vials  12  due to gravity. Thus, reaction block  10  enables a reflux condensation to occur during reaction of the reagent solution. 
     Referring to FIGS. 4 and 5, in another embodiment of the invention, a cover assembly  106  is positioned over a base  102  having an array of holes  108  for supporting reaction vials. Cover assembly  106  includes an insulating spacer  104 , a plenum member  112  having a series of gas ports  114  extending therethrough, and a top  116 . When top  116  is placed over plenum member  112  a plenum chamber  118  is provided therebetween. As was the case with spacer  36  of reaction block  10 , spacer  104  is formed of a thermally insulative material such as polypropylene, and includes an array of holes  110  which surround a central portion of the reaction vials. As shown most clearly in FIG. 5, the underside of plenum member  112  includes an array of holes  129  for capturing the upper ends of the reaction vials. 
     Threaded hole  119  of plenum member  112  receives fastening screws (not shown) which extend through holes  121  of top  116  to provide a tight seal around the periphery of plenum chamber  118 . Base  102  similarly includes holes  123  some of which receive fastening screws or alignment pins (neither shown) extending through holes  125  of cover assembly  106 . Base  102  and spacer  104  also include a visual hole, serving as a key  127  to ensure proper registration of cover assembly  106  to the base. Alternatively, a pin,  150 , can be inserted into hole  127  of plate  102  and pass through holes  127  of spacer  104  and into hole  127  of plenum member  112  to provide alignment. A thru-hole  130 , used to receive a temperature measuring device (e.g., a thermometer) extends through top  116 , plenum member  112 , spacer  104  and into base  102 . 
     In operation, a cooling gas is provided within plenum chamber  118  from an external gas source  121  through a gas inlet  120  of top  116 . The pressurized gas exits plenum chamber  118  through gas ports  114  and into a cooling chamber  122  formed by the interface between the bottom surface of plenum member  112  and an outer wall of spacer  104  consisting of sidewalls  124 , an endwall  126  and surface  151 . Pressurized gas entering cooling chamber  122  strikes surface  151  of spacer  104  and endwall  126  and is then redirected toward an opening  128  formed at an end of spacer  104  opposite endwall  126 . As was the case with exit openings  34  of reaction block  10 , gas ports  114  are sized to efficiently distribute the pressurized gas into cooling chamber  122 . 
     Referring to FIGS. 6 and 8, an alternative embodiment of a reaction block  200  includes a mechanism for controlling the volume of air flow used to cool the vials. 
     In this embodiment, a base  202 , spacer  204 , plenum member  212 , and cover  216  are constructed similarly to base  102 , spacer  104 , plenum member  112 , and cover  116  of reaction block  100 , respectively. Plenum member  212 , however, does not include gas ports. Instead, plenum member  212  together with cover  216  defines a plenum chamber  218  having a slot  220  formed along a side wall  221  of the chamber. Disposed on bottom surface  217  of plenum chamber  218  is a relatively thin sliding vane  222  which is positioned to cover no part or some portion of slot  220 , thereby controlling the velocity of the cooling gas flowing into a cooling chamber  228  of spacer  204 . As shown most clearly in FIG. 8, plenum member  212  includes a pair of threaded holes  230  for receiving lock down screws (not shown) to secure vane  222  in place once the desired position of the sliding vane is determined. 
     By providing a mechanism which controls the size of the opening into the slot, greater flexibility is provided to the user. Specifically, by varying the size of the opening into slot  220 , the velocity of the cooling gas is varied, thereby varying the cooling rate of the gas. Among other advantages, the number and size of the vials accommodated in the base can be varied simply by substituting a different base. As a result, a wider variety of reflux condensation processes can be performed with a single reaction block system having, for example, interchangeable bases. 
     It is to be appreciated that the invention encompasses the use of sources other than pressurized cooling gas. Referring to FIG. 7, for example, reaction block  200  includes a cover  216   a  configured to receive a fan  240  (e.g., muffin fan) for cooling the vials. Fan  240  is a single speed fan with the velocity of the air controlled by moving vane  222 . Alternatively, a variable speed fan may be used, for example with the embodiments of FIGS. 1-4 without moveable vanes. 
     Reaction blocks  10 ,  100 , and  200  were described above as being used with separate and removable spacers  36 ,  104 ,  204 , respectively. However, in certain applications, use of a spacer to thermally isolate the upper and lower ends of the vials may not be necessary, and thus the spacer can be removed. Alternatively, the spacer can be permanently affixed as part of the base  12  or cover to form an integral unit. 
     Other Embodiments 
     It is to be understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.