CA2232505A1 - Apparatus and process for multiple chemical reactions - Google Patents

Abstract

Multiple chemical reactions are performed in a plurality of reaction vessels (12) mounted in inlets in a manifold valve block (30). The manifold valve block (30) is connected to a channel block (34) which is utilized in conjunction with a solvent delivery system (21) as part of the reaction cycle.
The solvent fluid is drained from the reaction vessels (12) when valves in the manifold valve block (30) are opened while applying a vacuum thereto.
Optionally, a thermal block (40) may be utilized in conjunction with the manifold valve block (30) and the channel block (34) to facilitate the reaction. Upon completion of the reactant cycle, the manifold valve block (30) is disconnected from the channel block (34) and connected to a cleavage block assembly (120, 121) which contains vials (128) for collecting reaction products. The cleavage product is drained from the reaction vessels (12) through the manifold valve block (30) into the vials (128) upon opening the valves in the manifold valve block (30) and applying a vacuum to the channel block (34).

Description

CA 02232~0~ 1998-03-18 APPARATUS AND PROCESS FOR MULTIPLE CHEMICAL REACTIONS

~ross-Referenc~ to Related ApDlications This application is a continuation-in-part of U.S. Patent Application Ser. No. 08/532,279, filed Sept:ember 22, 1995, and incorporated in its entirety by reference.

Field ~f the Invention The invention relates to an apparatus and process for performing mul-tiple chemical reactions, in particular for performing multiple solid phase chemical synthesis reactions and for isolating and collecting the final products of chemical reactions.

Backqround of the Invention One of the key processes in solid phase chemical synthesis is the washing of the solid support resin which has a chemical template attached thereto. Multiple washing cycles with different solvents ensures that all excess reagents used during reaction cycles are washed from the resin. A
typical protocol involves addition of a wash solvent, shaking the resin with the solvent for five minutes and then removing the wash solvent from the reaction vessel. In many instances, the wash solvent is drained from the bottom of the reaction vessel by applying a vacuum, i.e., filtering the resin free of the waste solvent. The task is further complicated when multiple solid phase syntheses are simultaneously carried out.

CA 02232~0~ 1998-03-18 For example, if each reaction vessel is to be subjected to a filtration step, performing separate filtration on each individual reaction vessel can be very time consuming. Alternatively, if filtering is to be performed on all of the reaction vessels simultaneowsly, this can lead to a very complicated and awkward arrangement of apparatus with, for example, each individual reac-tion vessel being connected to a vacuum source by a separate vacuum hose.
As described above, the vvaste liquid is flushed out during the wash-ing cycles typically by vacuum filtration. During reaction cycles, however, the solvent and the reagents are to be retained in the reaction vessel which by design has a filter at the bottom. Previously, when batch filtering from several sources, each source was connected to the filter by a line with each line having a stop-cock or valve to regulate drainage.

Sl~ &-./ of the Invention Thus, an object of this invention is to provide a reaction apparatus for performing multiple chemical reactions on solid support in a parallel fashion which provides stable support for multiple reaction vessels and permits such tasks as washing and filtering to be performed simultaneously on all the reaction vessels in a simple and easy manner through a manifold design. A
further object is to provide an apparatus to be used in association with the reaction apparatus, for cleaving reaction products from the solid support and separately collecting the reaction products from each of the individual reac-tion vessels.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
These objects are achieved at least in part in accordance with the in-vention by a reaction grid apparatus that can be used to perform multiple separate chemical reactions, the reaction grid comprising:
a first retaining member with a plurality of openings therethrough, each opening having an inlet and an outlet connected through a valve;
-CA 02232~0~ 1998-03-18 a separate reaction vessel for mounting in the inlet of each opening;
~ a drainage member havin0 draina~e channels therein ali~7ned with the outlets of the bores; and a valve operator for operating at least several of the valves simul-taneously to drain fluids from the reacLion vessels into the drainage member.
Also, in accordance with the invention, a cleava~e block assembly is provided for separately collecting reaction products from multiple separate reactions, the cleavage block assembly comprisin~:
a vial rack capable of supporting an array of separate vials;
a cleava~e block section having a chamber therein for receiving the vial rack and a vacuum port for applying a vacuum to the chamber;
a reaction grid section having an array of openings there-through, each opening corresponding in position to a position in the vial rack, the reaction grid section including a valve associated with each 1 5 opening;
an array of reaction vessels mounted in the openings in the reaction grid and having reaction products therein; and members for securin~ the reaction grid section to the cleavage block section in sealed relation t[-erewith.
In accordance with the invention, the reaction reagents and solvents are contained within each of the reaction vessels.
Further, in accordance with a process aspect, the invention provides a process for performing multiple~eactions and separately collecting reaction products, the process comprisin~:
connecting reaction vessels to valved openings through a manifold block of a reaction grid;
Ioading each of the reaction vessels with solid support beads and attaching chemical templates to the solid support beads via linkers;
performing chemical synthesis reactions for the preparation of organic molecules within each of the reaction vessels;

g~ A-UL~.~C'HF\, (;~ CA 022i2505 1998-03-18 ~ 39~ 3 removin~ ~luid from the r~ction vessels ~y openin~ the valved open-in~s to drain the fluid to a channeled block by applyin,~ ~ v~cuum to the ~hanneled ioiock;
Yvashin~ the solid support beads with wash solvent and removing the wash solvent from the rea~tion vessels by drainin~ the wash solYent to a charlnel i~lock;
removing the manifold block fr~m c~ nnection with the channele~
block and connectir-~ the rn~nifold block to a cleava~e sectTon, the cleavage section comprisin~a a cham~er con~ainin,~ a plurality of vial ports e~ch hold-0 in,3 a sep~r~te vial, each of th~ viai ports communicatin~ h an inlet po~t~f the manifold block, the cleav~ge sec~ion further comprising an outlet for c~nnecting the chambef to a vacuum supply;
cleavin~ desired organic product from each of the reaction vessels an~
c~llectin~ the organic product w;thin the individual vial.
The reaction ~rid in accordance with the inventiRn ena~les the user to simultaneously carry out multiple chemi~l synthesi~ of desired molecule~
using solid phase ehemic~l synthesis. Eaeh of the multiple connec:tion ele-mermc attached to the inlet port:s of the fe~ation ,~ri~ provide means for ri~idand st~ble a~ta~ hment of a reacti~an vessel such as a syrin~,3e barrel.
~0 The reaction grid also allows the user to carry out several different steps in a chemical synthesis process in an integra$ed manner. Usin~ stan-dard prS2~ocols for solid phase synthesis, the reaction ~ ri~ permits a user to simultaneously rinse or vacu~sm filter all of the rea~tion vessels. In addition,the user can per~orm different reactions simul~aneously by utilizin,~ different rea~ents in ~ch of the reactiorl vessels durin~ the synthesis mode. Further-more, the reaction grid pro~rides easy manipulation with r~spect t~ a~itation.
The reaction grid can ~e ~onvel1ierltly attached to a a~itation device su~:h as a wrist action shaker, vortexer or orbit~l shaker.
The plurality of inlet ports in the top sur~ace of the reaction ~rid can be ~rr~n~ed in any suitable desi~n. ~referably, the inlet ports are arran~ed in the form of a square o~ r~Pn~l~r array having a certain number of rows SUBSTITUTE; PAGF

CA 02232~0~ 1998-03-18 and columns. A square or rectangular array is preferred for ease of format-ting and tabuiating individual chemical products obtained from a matrix synthesis.
The reaction grid can be ~lesigned to provide any desired number of inlet ports for attachment of reaction vessels. In a preferable arrangement, the reaction grid has 96 inlet ports in a 1 2x8 array, this being the standard microtiter plate format used in industry for hi~h throughput screenin~ of compounds and biological assays. It is emphasized that other arrays, such as the smaller 5x8 array of parent application SN 08/532,279, filed September 22, 1995, incorporalted herein by reference, may be used in the practice of this invention.
Of course, even larger arrays, for example, a 1 OOx100 matrix, can be provided in accordance with the invention. However, such large arrays re-quire a large reaction grid which may require specialized agitation equipment and accessories for addition of solvents and reagents.
Each of the inlet ports is preferably equipped with a connection ele-ment that provides rigid and stable attachment of a reaction vessel to the inlet port.
In accordance with the preferred embodiment, the reaction vessels are syringe barrels with a male Luer connection tip and a filter positioned at the end of the barrel. The connection element is preferably a female Luer-type connection element unitary with a valve insert in an opening through a first block of the reaction grid. Thus, when a reaction vessel is inserted into an inlet port, the male Luer connection tip of the syringe engages the female Luer-type connector of the valve insert to provide a stable, rigid connection.
Preferably, the Luer connections are unitary with the valve inserts in the manifold plate with the syringes of the reaction vessels being separate therefrom.
Preferably, valves are disposed between each of the male and female connectors, with at least several of the valves being interconnected to operate simultaneously.

r~A~ E~C~IE~ 1~'? :'7~- ~ C~7 '~ 70;~ 3 ~410- +19 ~'~ 't3(3~ "~, # 4 In accordance with a pre~erred ~m~odiment, the reaction ~rid has an overall scluare or rect~n~ul~r sh~pe, nn~ comprises two rectangular secti~ns;
a top section ar~d a bottom section. ~he inlet pc~r~s pass through the en~ire thickness of th~ top section ~rom its top surfa~e, ~hich ;s als~ the top s~r-5face Of the grid, to itS ~otton~ s~r~ce. The bottom se~tion, on the other hand, is provide~ with the substanti~lly horizom~l ch2nnels. ~3y substantially horizomal, it is meant tha~ the channels ~re oriented to provide draina~e ev~nly from all of ~he reaction vessels without ca~sin~ cross-contamina~ion.
Betw~en the two square or rectangular sections a ~asket i~ positivned tO
10provide a vacuum seal between the lop ~nd ~ottom sections. Preferably, groove ~or the gasket is machined into ~ither the bottom s~face of the top e~tion, or the ~op sur~ace of th~ bottom se~ti~n. The 3as~e~ is then posi-tion~d within this ~roove. The top and bottom sections ~n b~ connecte~
to eaoh other by any suitable fastenin~ means, for example, ~olts or clamps.
15After cc~mpletion of the multiple reaetions, a fur~her development of the invention, the cleava~ bloclc assem~ly, can be used to separatsly col-lect the products frorn the individual reaction vess~ls. The cleavage ~lock ~ssembly comprises the top section or manifol~ section of th~ reactlon grid, a vial rack capable of supportin~ multiple viais, and a cleava~e bTock seGtion 20h~rin~ a charn~er for h~ldinç~ the vial r~k.
The vial rack supports sn ar~ay of collection vials, whieh array oorre-sponds t.~? the array af inlet port:~ and reaction vess~ls of the top section ~fthe reaction ~rid. The vials are held in a v~rtical orientation whereby fiuid from each reacticn vessel can flow throu~h an inlet port into the rnouth opening at the top of a vial.
In the clea~ e btock s~c-tion, an internal chamber is provided which is ad~pted to hol~ the vial rack. On~e the vial r~ck cc~ntainin~ an array of vi~ls is positioned wilhin the internal chamber, the top section of ~he rear~-~ion ~rid is then positioned on top of the cleavage sec:tion and at~ached 30thereto by suitable fastening rnf~ans, e.~., bolts or cl~mps. To facilit~te draina~e of the reaction ~esse!s and c~llection of re~ction products within SU~S~ TE PA~E

_ CA 02232~0~ 1998-03-18 WO 97/10896 PCT/US96/lSlZ4 the individual vials, the cleava~e section is provided with a vacuum port that communicates with the internal chamber. The vacuum port can be con-nected to a vacuum source to thereby apply a vacuum to the internal cham-ber. As a result, fluid is withdrawn from each of the reaction vessels and collected in the vials.
In accordance with a further aspect of the invention, the aforemen-tioned objects, advantages, methods, systems and apparatus are further en-hanced by performing fluid dispensing operations for washing and cleaving by employing a fluid dispensing system for simultaneously dispensing pro-cess fluids.
In accordance with still a further aspect of the invention, the afore-mentioned objects, advantages, methods, system and apparatus are further enhanced by heating or cooling the reactions.

Brief Des~ ution of the Drawings Various other objects, fealtures and attendant advantages of the pre-sent invention will be more fully appreciated as the same becomes better understood when considered in conjunction with the accompanying draw-ings, in which like reference characters designate the same or similar parts throughout the several views, and wherein:
Figure 1 is a side perspective view of an apparatus configured accord-ing to the present invention for supporting ninety-six reaction vessels, one of which is shown in enlarged isolation, in order to practice the process of the present invention;
Figure 2 is a perspective view of a valved manifold plate or block used with the apparatus of Figure 1;
Figure 3A is a side elevation of one of ninety-six valve inserts mounted in the manifold plate or block of Figure 2;
Figure 3B and 3C are side views of a valve stem used with an aligned array of valve inserts in the valved manifold plate of Figure 2;

CA 02232~0~ 1998-03-18 Fiçlure 4 is a top view of a valve manifold asserrlbly with a multi-valve operator;
Fi~aure 5 is a side view of the valve manifold assembly of Figure 4;
Figure 6 is an end view of the valve manifold assembly of Figures 4 and 5;
Fiç~ure 7 is a top view of a channel block used in conjunction with the valve manifold assembly of Figures 2-6 in the manner shown in Figure 1 and in FiQures 32-34;
Figure 8 is a side view of the channel block of Fi~ure 7;
Fi~ure 9 is an end view of the channel block of Figures 7 and 8;
Fi~ure 10 is a top view of a cap system plate assembly used with the manifold assembly of Figures 2-~i and the channel block assembly of Fi~ures 7-9;
Figure 11 is a side view of the cap plate assembly of FiQure 10;
Figure 12 is an end view af the cap plate assembly of Fiç~ures 10 and 1 1 ;
Figure 13 is a top view of a vortexer mounting plate upon which the manifold assembly of Figures 2-6, channel block assembly of Figures 7-9 and cap system of Figures 10-11, when assembled with one another, are mounted for agitation or stirring;
Figure 14 is a side view of the vortexer mounting plate of Figure 13;
Fi~ure 15 is an end view of the vortexer mounting plate of Figures 13 and 14;
Figure 16 is a bottom view of a thermal block used with a reaction grid assembly shown in Fi~ure 1;
Figure 17 is a bottom view of the thermal block assembiy of Figure 16;
Figure 18 is an end view of the thermal block assembly of Figures 16 and 17;
Figure 19 is a side view~of the reaction ~rid assembly ready for loading by a robotic loader;

-CA 02232~05 1998-03-18 PCT~US96~ 24 WO g7/1(1896 _ 9 _ Figure 20 is a side view of the reaction grid assembly with a wash system mounted thereon;
Fiç1ure 21 is a side view showing the reaction grid assembly mounted on a vortexer;
Fi~ure 22 is a side view showing the reaction grid assembly and wash system mounted on the vortexer;
Figure 23 is a side view showing the cleavage system mounted on the vortexer;
Figure 24 is a top view of a vial rack assembly utilized with a cleavage system employed to coOlect reaction products after the reaction in the reaction vessels is complete;
Figure 25 is a side view of the vial rack assembly;
Figure 26 is an end view oF the vial rack assembly of Figures 16 and 17;
Figure 27 is an exploded view, in perspective, of a preferred ernbodi-ment in which a composite vial rack having four sections mounted in the cleavage block;
Figure Z8 Is an exploded vlew showing the four vial rack section and a rack mounting tray of Figure 27;
Figure 29 is a top view of a cleavage system assembly which is com-prised of the valve manifold assennbly of Figures ~6, and a cleavage block of Figures 35-37 which receives the vial rack assembly therein and the channel system assembly thereon;
Figure 30 is a side view of the cleavage system assembly of Figure 29;
Figure 31 is an end view of ~he cleavage system assembly of Figures 29 and 30;
Figure 32 is a top view of a reaction grid assembly which comprises the valve manifold assembly of Figures ~6 and the channel block assembly of Figures 7-9 retained together with fasteners;
Figure 33 is a side view of the reaction grid assembly of Figure 32;

KC~ . ~O,~,:F.~ 'E~\:CIII,~ ' CA 02232~0~ 1998-03 i(8'3 '-'~ 3 t;3 IC), +~ 3 .~ ;, ,;, 5 F~ur~ 34 is an end view of the reaction grid ~ssembly of Fisure~ 32 and 33~
Fi~ure 35 is a top view of a clea~ e block used with ~he ass~mbly of Figur~s 29~
Fi~ure 36 is a side view of the cle~a~e bk~ck of Fi~ure 3~;
Figure 37 i.~ an end view of the cl~avage bl~k of Fi~llres 3~ and 36;
Fi~ure 38 is a top view o. a ro~ot de~k mo~ntin~ p~a~e u~e~ t~ rnount the reaction ~rid assem~ly w~ile loading the viais o~ the reactien gri~;
Fis~ure 39 Is a front ~ vv o~ the robot ~eck rncunting plate of 0 Fi~ure ~8;
Fi~ure 40 i~ an end vievv o-~ the ro~ot deck mountin~ platP of ~igures 3~ and 39i Fi~ure 41 is ~ top view o~ ~ wash system manifold assembiy u~ed with the system of Fi~re 1;
Figure 42 is a side view of the wash ~ystem rnanifol~ assembly o~
Fi3;~ur~ 41;
Fi~re 43 is an end view o~ lhe wssh syst~m manifold assemb-y of Fi~ure~ 41 and 42;
Fiç~ur~ 44 is a diagramrraltical ~rlew of a ~ash dispr~nsin~ system, Figure 45 is a ~i~grammatical view of a suc~ian system ~OF rernoving liquid from th~ assem~ly of FiS~ure l; ~nd F;~ure 46 is a diagr~mm~tir~al yiew c~f a v~'ve ~ctuating syst~m.

I;)eeailed ~es~riotion of th~ ~r~win~s.
R~actic~n ~rid Structure :25 Referrin~ n~w to Fi~ure ~, there is shown a reaction station sys~em 10, in accordance with the present invention, ha~in~ ~n ~3x12 array of reac-~ion statlons arra~g~d in twelve columns and ei~ht row~ with ~ach reaction station associatecl with a sin~le re~tion vessel 1~ havin~ a syrinç~e tip 13.
E~ch of the reacTk~n v~ssels 12 i of a generaliy known confi~uration ~nd includes e~ filter 12~ at ~ syringe tlp 1~ above ~,vhich i5 a fritt 12~ is con-SUBS'rITUTE F'A~E

RC~ E~ M~F~C~ ()<~ __6- ~-~7 ~ 4(! _ 70~ ~4~ f;41(~ 3~3 ~39944~i5:~
CA 0223250s 1998-03-18 ~i~ured ;~s solid support beads uporl which chemical templates are attached via appropriate linkers. The filter 1 2a normally holds liquid~ such as solventsand reaction products in the rea~ti~n Yessel 12. As will ~e explainPd herein-a~ef~ ~pplication ~ a parti~l v~cuum to the syringe tip 13 evacuates th~se li~uids from the plurali~y of reaotion vess~ls 12 simultaneously.
Generally, the reaction statior- system 10 Zs comprise~ of ~ re~ction grid i~ssembly 14 which is fixed to a universal mo~Jntin~ plate 16 that is in turn att~ched to a vortexer 18. The vor~exer 18 stirs the contents of the reactor vessels 12 by imparting ;3 oircular motion to the reaction ~rid 14.
Abo~e the reaction ~rid 14 is a fiuid delivery manifold ~0 fnrming pa~t of a liquid delivery system ~1 which has an array of ninety-six injection probes in the forrn of needlss 2~ each of which is ali~ne~ with a separate reaction station for ~ispensing washin~ solvent from reser~oirs 24 and 26 to ~he reaclion ves~s 12. ~:)pera~ion of the liquid deliv~ry sys~em 21 is controlled by a PLC con~loller 27. The reaction ~rid 14 and fluid delivery manifold 20 are covered by an exhaus~ hood 28.
The fluid delivery manifold Z0 is pref~r~3bly mour~ted on a wall or other slJpport by an elevator system 2~ which IQwers and raises the fluid deli~erY
rnanifold ~o deliver fluid to ~he reac~ion vessHls vi~ the needles 22. While the vor~exer 1~ is agitating the corlterits within the re3ction ~essel~ 12, the nee~les 22 are withdrawn from the reac~ion vessels 12 and spaced from the reacti~n~rid 14.
The feaction ~rid 14 includes ~ manifol~ v~ e block 30 with the rows of v~lve operators :~2 theFein ali~ned with separate rows of valves for each ~5 reaction ves~l so that the reaction vessels can b~ closed to retain solvents therein durin~ the r~a~tion stage of the process. The manifold valve block 30 also receives the syringe tip 13 of each reaction vessei ~2. Beneath manlfold ~IOCk 30 is a channel bk~;k 34 whiGh has ch~nnels therein for ~rainin~ fluid out of the systenn via a draina~ system 35. The draina~e 3~ system 35 includes an exhaust line 36 connec~ed to a waste vessel 38 and vac~um pump which draws 11~id from the reaction vessels ~ 2 ~er the SUBSTI~UT~; PAGE

I~C~ . ~<)~ Il E!~C~IF.~ ()~ . ~>a- ~3-97 . ~ t ~ _ ~ -~~ ~ ~ CA 0223i505 1998-03-18 ~ C~ 3 ~e'3~7~46~ 7 -valves in ~he m~nifo~d ~/al~re ~lock 30, opera~ed by t~e Yalva oper~t;~rs 32, have been opened. The contr~ller 27 which operates the w~hln~ sy~t~m 21~ may also ~e ~sed to opel~te the ~raina~e sys~Jn 3 A thern~al contl ol block 40 wi~h ninety-six ~pert~res ther~throu~h slJr~
ro~n~s e~ch onB of the reaction vessels ri ~ ~o control the ~emperature of the re~ti~n ~y ~ither he~ting the cont~nts of the rea~tion ves~eis or c~oiin~ th~
~ontents of the re~tion vessels durin~ the re3ction.
A cappin~ plate 42 overlies the open ~:ops of the re~cti~ ~essels 17 and seals each reaction vessel. Th~ c~pping plate 42 is p~rt o~ a cappîng ass~mbly 43 ~nd in~ludes nin~ty-six ho~es 44 there~hrough, eaeh of which h~les is se~le~ by a stiicon rubber septum sheet which is dispose~ between the capping plate 42 and the open tops of the rBactk~n v~sseis 1:~. The neeciles ~2 e~c~h simultane~usly puilcture the se~ling mat~ri21 ~ ned with the holes 44 to deliver s~lvent to ~he reacti~n vesse5s. After the sol~ent h~s been delivered to the re~&tion vessel~ 12, the fluid dellwery m~nifol~ :~0 is rai~ed and the vortexer 18 agi~ates the nine~y-six solutio~s in the ninety-six reaction ve~sels 1~ ~or a select~d period of time. ~Ipon conclusion of the a~it~tion, the valves operated ~y ~h~a valve operators 32 are opened and the washin~ flui~ Is drawn off through ~in~ 36. Fluid treatment may be repeate~

2~ a nun~b~r of times with the same or different fluids, dep~n~ing on the r~ac-tion sou~ht in the reaction vessels 12 whether the reaction is anticipated or unfintici,~ated. The reaction blo~k 14 i~ disposed betw~en ~he fl~id dispens-ins sys~em 21 ~nd the drainag~ ~iystem 35 which are cQnfigure~ ~o faGiiitate rapid ~nd convenient ~luid tr~atment and processin~ c~f the contents in the ~5 reacti~n vessels 12. The re~c~ion sta~ion concept havin~ ~een ~hus far d~-scribed ~roadly, the following description sets f~r~h in ~reater detail the stmcture and fun~tion of ~he various con~ponents shown in Fi~3ur~ 1.
Referrin~ now to Fi~tres ~ and 3A-C, where the mani~ld valve block ~0 ~nd associa~ed insert v~lves ~re shown, it is ~een that the m~nifold plate i~ in ~he form of a f~rst polypl~pylen~ b~r~ck havin~ an upper surface ~15, a lower surfa~ 4~ and sicle ~r~es ~7 wi~h in'ets ~ throu~h ~he upper SUBST~rTE PAGE

RC\. ~Oi~:Er>A~ CIJF~ CA 02232505 l998-03-l8 -~- 4l +~9 ~ 99~5:~ 8 ~ - 13-surface 45 and outlets 4g through the lower surface 4~. The inlets and OUt-lets ~ and 4g are each connected by first pas~a~es 50, each of which first pass~es 50 receives a valve ins0rt 51 (Figure 3A). Each valv~ insert 51 has a female Luer connector ~2 at the top and a male Luet connector ~3 ~t the bottom. Ea~h female Luer ~onnector 52 serves as an inlet int~ the m~ni-f~td v~lve block :~0 and rec~i~es t~le syrin~e tip 13 of one reac:tion ~fessel 1~. Ea::;h male Luer connector 53 serves as an outlet for flu;d passa~e from the manifoi~ valv~ blo~k 30. E~ch valve insert 51 further includes a lateral bore 5~ therethrou~h which receives a valve stem 55 (see Figures 3B ~nd 3C~. The ~Jalve stem ~5 is ~ rod haYing transverse holes 56 therethrough which are ali~ned with the axe~ c~f the female and m21e 1 uer connectors to allow for liq~ to ~rain throu~h the valve inserts 51 and are misali~ned with the Luer connectors by rG~tion <~f the valve stems 55 to block the flow of li~uid throu~h the va~ve inserts. By rotatin~ the vaive stems ~5, ei~ht of ~he vatYe inserts 51 can be opened and closed stmultaneousty. The vaiv~ stems are ~e~eived in second passa~es 57 through the block whi~h inters~ct the first passages 5CI and allow ~ccess to a plulality of first passa~es by a v~lve stem 55.
Referrin~ now to Fi~res 4-6, there is shown an arran~ement fo~
operating all twelve of the valve stems 55 simultaneously s~ ~s to simLJlta-neousiy block drain~e frclm or allow dr~in~e from the nirlety-six r0~ction vessels~2 slmult~neously. This is accomplished by fixing ~ link 60 non-rol~tably ~o ~3ach ~alve rod 55 and ~onne~ting the lirlks 60 to an act-lator link 61. When o~e of the links 60 is opened or closed by rotating a handle 2~ ~i2, ~hen the actu~tor link 61 ca~ses ev~ry link 6~ to rctate, Gl~sing or open-ing ea~h of the ninety-six valve inserts 51 simultaneol~sly.
R~ferring now to Fiaures 7-9, a second poly~ropylene block in tl e form of the channel block 34 is shown. The char\nel block 34 is a drainage ~lock which is assem~led to~ethef with ~he manifold valve blc>ck 30 for col-~scting waste fluid drained from the reaction v~3sseis 12. The channel block 34 has a cavity th~ le~ned ~y ~ se~les ~f intelcor-nected channels 65 SUE~STITUTE3 PAGl~:

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aliQr7ed with the rn~le Luer connoctors ~3 Of the ~a~re ins~erts 51 in the manifold valve block ~0 so that when thc v,~lve inserts are openedr the lia,uid therein simultaneously drains into the ~rray Of inl~conr~ec:t~d chan-nels. Thete is a ~rain hc~le 6~i in the arr3y of inter~onnecte~ ch~nnels whii~h is connect~d by fluld pas~a~es in the ~hannel biock 34 to a ~ulck connect ~rain fittlng 68 that is in turn con~e~ted by the iine 3~ ~see Figur~ 1 ) to a waste colle~tor 6~3~ Li~uids, su~h as s~llvents in the reaction ~essels 12 are puiled throu~h the filtets 1 2a in the reaction v~ssels 12 ~e Figure 1 ) by a vacuun~ pump 3~ ~see Fi~ure 1~.
1~ The ch~nnel block 34 has a face 69 with z surface ~roo~e ~herein which surrounds the area ~c)ntainin~ the open intefconn~cted ch~nnels 65.
The ~roove retains ~ ~asket 72 therein. The ~3asket 72 se~ls with th~ bot-torn surfa~e of the n~anifold valve block 30 S0 that ~hen liquld is drained ~rom the reaction vessei~ 12 through the valve inserts 51, i~ does not teak t 5 outside of the system 10. The channel i~l~ck in~ludes ei~ht post~ 70 which extend therefr~m and pass thro~gh hsoles in the manifoid v~ e ~lo~lc 30 to property position the manifold valve plate with l'e!Sp~C:t tO the ~hannel block.The assemi~ly of th~ nnanifold valve block 30, o~ first block, and the chann~
block 34, or secon~ blo~k, is he~d ti~htly enga~ed ~y ~ick ti~h~ene~s 71 ;~0 ~hich are received ove~ ~n~ ti~h~ened, b~ut the posts 70. The face 69 is a c~upiin~ face allowinç~ rapir~ assembly with the bottom surface 46 of the manifol~valv~ hlock 3Q which, in essence, provides a couplin~ face fc~r the vessel retaining member ~the manifold block 30) that mounts the reaction vessels 1~.
2~ P~efs~in~3 now tO Fi~ures 10-12 where the c~ppin~ assem~ly 43 is shown, it is seen tha~ the ~appin~ asseml~ty 43 inclL~d~s a r5~id metal pl~te 74 and a pol~meric system she~t 7~; of non-chemically rcactive, elas~ic, polymeric material. The polymsric: ma~erial 76 underlies an array of ninety-six holes 7~ in the plate 74, which holes aiign with the open tops of ~he vials 1~ in the as~embly of Fiyure 1. The polymeric septum she~t provides a closure f~r the vpen top of each reaction Yessel 12. When the needles SUBST~IUTE PAGE

-CA 02232~0~ 1998-03-18 (Figure 1) are lowered with the washing manifold 20, the needles pass - through the holes 78 and penetrate the polymeric septum sheet 76 so that fluid from the reservoirs 24 or 26 can be injected into the reaction vessels 12. When the needles 22 are withdrawn, the material of the polymeric sep-tum sheet seals the open tops olF the reaction vessels 12 so that vapors are contained within the reaction vessels when the reaction vessels are a~itated by the vortexer 18.
Referring now to Figures 13-15 where the vortexer 18 mounting plate 16 is shown, the vortexer mounting plate 16 is used to rigidly restrain the reaction grid assembly 14 (Fi~ure 1) to the moving portion of the vortexer as the reaction grid assembly is agitated. The vortexer mounting plate 16 includes a base 80 with a back flange 81 and a pair of side flanges 82 and 83 which cooperate to hold the reaction grid assembly 14 (see Figures 1, 7-10) which is slid onto the base 80 from an open front 84 of the mounting plate 16.
Referring now to Figures 116, 17 and 18, there is shown the thermal control system 40 (see Figure 1 ) which is used to either heat the contents of the reaction vessels 12 or to cool the contents. The thermal control system comprises a bottom plate 90 and a top plate 91, the bottom plate 90 having ninety-six apertures 92 therein which align with ninety-six apertures 93 in the top plate 91. A silicon heating pad 95 is sandwiched between the top heater block 91 and the bottom heater block 90 and is connected by leads 96 to a heater control 41 (see Figure 1 ) which maintains the desired heat level. Four spacers 97 project from the bottom block 91 to keep the heater assembly slightly spaced from the manifold plate 30 in order to raise the thermal block assembly 40 to the level of the fritt 1 2b in the reaction vessels 12. While the heating pad 95 is preferred, other heat approaches may be employed such as wrapping a heating plate, such as the plate 91, with wire to provide electric resistance heating 82 or circulating heated fluid through channels in the plate.

CA 02232~0~ 1998-03-18 lf it is desired to cool, rather than heat the reaction, the top block 91 has an indentation 98 therein for containing a cooling material such as, for example, dry ice. In another approach, cooled ethylene glycol may be circu-lated through channels in the top block 91. It is emphasized that the reac-tion system 10 of Fi~ure 1 need neither be heated or cooled if the reactions in the reaction vessels 12 are to occur at room temperature, or if tempera-ture control is not critical, in which case, the thermal block system 40 need not be used.
The reaction procedure is perhaps best understood in the context of Figures 19-22. In Fi~ure 19, the reaction vessels 12 are assembled with the manifold valve block 30, the channel block 34 and capping plate assembly 20. This arrangement of parts is mounted on a robot deck mounting plate 100 for the loading phase of the procedure in which the reaction vessels 12 are loaded with fritts 12b and chemical linkers at a robotic loading site different from the site shown in Figure 1.
As is seen in Figure 20, the arrangement of Figure 19 is brought into contact with the fluid delivery system 21, which includes the needles 22 (Figure 1). In the fluid delivery system 21, a plurality of valves 110 in a manifold 1 12 are simultaneously opened by hydraulic cylinders 1 14 and 1 16 positioned on opposite sides of the manifold 112 to cause washing fluid or solvent from the container 24 (Figure 1 ) to flow into the ninety-six reaction vessels 12. While fluid is flowing into the reaction vessels 12, the ninety-six valve inserts 51 connected to each reaction vessel are held closed bythe links 60 and operating handle 62 (also see Figures 4-6).
Referring now to Figure 21, after the reaction vessels 7 2 have been filled, the assembly of Figure 19 is disconnected from the washing manifold assembly 20 of Figure 20 and agitated by the vortexer 18.
Referrin~ now to Figure :22, after agitation by the vortexer 18 has stopped, the valves 51 in the rnanifold valve block 30 are opened and the liquid in the reaction vessels 12 is drawn through the filters 12a in the reaction vessels and into the channel block 34 by suction applied to line 36 I~C~ P.~ 'CI~E?~. U~ 1 ] . _ 7()~ f't'i. c~ 39944 ~see Fi~ures 7~ by the vacuum pump 39 lsee Figure 1~. Dependin~ on ~he chemical pro~essin~ bein~ pe~formed, th~ w~shing and e~racuating step may be performed once or repea~d a nun~er of times with various flui~s.
The reactiun phase of the method employin~ the system of the pr~-sent inv~ntion is now complete with the sought after rea~tion p~oducts bonded t~ the fritts 12~ in the ninety-six reaction vessels 12. ~t is now necessary t~ cle~ve the r~ctic)n products from the fritts 1 2b and to sollect the re~ction products in vials. ~his is accompllshed by ~he components of the ~leava~e system set forth in the following descript;on.

The Cieavage System As is seen in FiQure 23, after the washing step ~f Figllre 22, the manifold valve block 30 is separated from the channel ~lock 3~ and mounted on a cleava~e block 120 to form a cleava~e assenn~!y 121 in whieh a viai tr~y rack 122 ~sh~wn in dotted iines~ is mounted in a cavity 1~3 of the cieavage block 1~0. 1, he ~leava~e block 120 i5 in turn retained on th~ universal moun~ing plate 16 moun~ed on the ~ortexer 18. The vial rack 1~2 is loaded With ninety-siX one dram vi31s 128 for re~ei~rin~ the reaction products fron~ the reaction vess~ls 1~ upon simult~neo~sl~ opening the val~res 51 in the manifoid v~lve block ~ see Figures 3-6).
Referrin~ now ~o Fi3ures 24-:2B where the vial rac~ 122 is shown re-m~?ved from the clea~ra~e ~lock 120, it-is seen that th~ ~,al tray has a top pl~te 130 wi~h ninety-six holes 1:~1 ther~through and a b~ttom plate 132 with ninety-six indentations 133 therein. The ninety-six Yials 128 ar~
m~unted in the holes 131 with the bottoms of the vials resting in the inden-tations 1 33. Since it is necessary to ha~,re the Yial rack 1 2~ recessed with~nth~ cavity 12:~ sa as to provid~ c~earan~e for the male L-ler cs~nnectors 5:~
of the valve ;nserts 51 l~ee Fi~ure 3), lifting pins '~36 are provided which facilitate removal of thP valve ral~k 122 frorn the ca~ity.
Referrin~ now ~o Figures 27 and 2~, where a secc~nd em~odiment for s~pportin~ the ~i~ls 128 in the Gleavage b~ock 120 is shown, it is seen that SUBSTITI~E P~GE

I~C~ E~PA ~ E~:I ll'~ o the second embodiment is a c~rnposit~ vial tr~y ~40 havinç~ four ~e~ nts ~41, 142,143 and 144. Thefourse~ments 1~1-144aremourltedona~/ial rack mountiny tra~/ 145. As is seen in Fi~ure ~Q, the fc~ur via~ mo~ntin~
r~ks 141-144 are separable Into r3~ks that hol~ tw~nty-~our one dram ~ials 128 each. The vial ra~k~ ~41-144 each ~i~ in ~ speed ~,ac which spins fo.lr rscks per c:y~ie.
The r~k mountin~ tray 145 includes ~n array of pin holes 14~ which ~rray is unique for each of the racks 141-144 so that the rack~ have ~
uniq~e loc~tion to facilitate identi~y;n~ the reaction pro~lcts in ~he vi~;ls 128. Pin holes 14~ receive pins throu~h holes 150 in the separate Yial racks 141-144 to accumplish the aliçlnment. Lar~er ho~es 15Z in the vial rack mauntin~ tra~ 145 can receive proieetin~ knobs 156 to ~acilitate pulling the en~ire vial rack assembly from the caYity 1~3 in the c:leavas3e block 1~0.
tn order tO fac~lita~e h~ndling an~ identifyin~ the reacticsn products in the ~lals 148, separa~e b~r codes 158 are located on each of the vi~l racks 141~144 and a bar coda 15~3 is on the rack mo~ntiny tray 145 to iden~ify the batch of ninety-six vials 128 cont3inTn~ r~action products cleaved in one operation .
Referrin~ now to Fi~ure~ 2g-31 and Fi~LIres 32-~4, i~ is seen that the cleava~H block 1~0 re~,ves ~he vial raçk 122 of Fi~ures 24-26 or the com-posite vial rack 140 of Fi~ures ~7 anrJ 28 ~only the vi~l rack 122 is shown).
As is s~n in Figures ~9-31, in the ~leavage operatlon, it is the cieaYage block 1~0 which is sttachsd to the rnanifold vaive block 30, r~ther than the channel block 34 bein~ at~ached to the manifold valve block 30, as is the 2~ case in Figures 3~-34~ Th~ ~ubstitution o~ the cleavage block 120 for the ehannel block 34, is rapidly and conveniently a~çomplished by rerno~in~ the quick conne~t fasteners 71 ~also se~ Fi~ure 8). From comparin~ Figures ~-31 ~o Fi~ures 32-34, it is readily apparent that changln~ from the reactit~n phase tO ~he cleavag~ ph~se is rap~dly acc:omplished by simply substituting the ~leava~e biock 120 ~or the c:h~nnel black ~4 by loosening and fastening the quick connect fasteners 71.

SuBsTITtJTE PAGP.

.
~C~ ~'O'~ ~f'A~ E~HL~ : 7~'3 ~ 3~ 8~ .- J

~9 Further in this re~rd ~n~ fe~erring to Fi~ures 35-37, it is seen that the eleavag~ blo~k 120 has a top str~cture whieh pro~ides a ~oupl;n~3 fa.e 1~0 which is substan~ially Ldentical to the t~p s~ructur~ whi~h provides the cr~uplin~ face 69 of the channel ~lo~k 34 shown in Figures 7-9 in that it h~s identic~lly spaced at~ached att~chment pin~ 7~', as well as an identic~lly placed ~asket 7-r~ ~he couplir~ ~lock 120 is, tt~erefore, ~s stated, rapiàiy interchan~eabl~ with the ch~nnel block 34. Ac~ordingly, it is rea~ily ~ppa rent that th~ interface between the manlfoid Yalv~ bloGk 3C~ an~ ~he channel ~lock 34 is substanti~lly ide~ti~al to the interface ~etween the m~n~fold valve blo~k 30 and the cleava~e blo~k 120. The cleavag~3 block ~20 a~so includes a quick ~onnect fi~ins~ 162 for atti3chment to ~acuum llne 36 ~see Fi~ure 1 ), Referrin~ a~ain to the ~ssembly of Fi~ure 23, after the rea~ent vessels 1~2 ha~e bsen agitated ~r the vs~rt~xer 18, the ninely-six vRlves 51 in the valve manifold 30 are opene~ simult~neously ~y operatin~ the h~ndl~ 62 Which rot~tes ~he link~es ~0 l:o rotate ~he vaJve stems 55. With the openin~ of the insert valves 51, a v~cuum is applied 'C3 the quick conn~ct fittin~ 60 by the va uum pump 39 which causes the solvent in th{~ reaction v~.ssels 12 v~hich has cleaved the rea~ion products from the frirts 12b in ~0 the reaction ~.ressels to flow with those reaction produGt~ into the array of ninety-six YialS 128. The vlals 128 ~re then removed frc~m the sa~ity 123 in the chava~c block 12~ and processed tO s~parale ~h~ reaction products fram the solvent.

~--hcomponents and System~
~5 Figures 38-45 are direct~d ~o su~omponents and system which facili-tate the op~ration of the ~foredescribed rea~ion ~rid system and cleava~e systern.
Fi~ures 38~40 are views of the robot deck mol~ntinE3 plate 1~0 shown in Fi~ures ~g ~nd 20 which is used t~ mountthe reac~ion ~rid assembly 14 3G on a roboti~ machine which loa~,~ chemic~l a~ents in the reac~ion vessels 12 SUB ST T TUTE PAGE

F'A~ E,.~;C~ 37: ~ 703 ~'4~3 f~411~-- +~ 53 '7~94~ ;:f~1'3 . - 2~ ~

prior tc~ moun~ing the reaction ~ri~ assernbly on the vortexer 18 shown in the reaction station system 10 ol Fiyure 1.
Referrin~ now to Figures 41-43 where the fluld dispensing manifold 20 is shown in ~reater detail, it is seen t~a~ the washin~ m~3nifold 20 in-cludes 2 plurality of the val~es 1 10 operate~ by valYe stems 1 7Z positioned on opposite sides ~f the manifold ~0 to release simult~neously fluids ~or the fluid trsatn~en$ steps of Figures :Z0 and ~!2, upon a~t;vating the h~draulic cylinders l 14 and 1 16 shown in F:i~ures ~0, 22 ~nd 46 ta release the wash-in0 ~n~ re~ction fl~ids in cont~in~rs 24 an~ 26 of Figures 1 ~nd 44.
11:) Re~errin~ now to Fi~ure 44, there is shown a washin~ fluid bottle 2~
and a solvent bottle ~4 ~also see Fi~ure 1 ) whir h are connected by valves 180 and 182 for selective dispensing of these liquids through a lin~ 1~4 to the w~shing m~ni~ol~ 20 of Fi~ures 1, 20, ~!2 and 41-43.
Referrin~ now to Fi~u~e 45, there is 6hown the vacuum systern for appiying a vacuum ~o either ~he channel block :~4 or cleavage b~ock 120 via vacuum line 36 ~ith waste washing fluid from the channel block 34 being accumulated in a waste container 3~.
The resultin~ fl~i~ dispensin~ apparatus, systems and methods result-ing from combinin~ the features o~ Fi~ures 1, 20, ~2, 44 and 4~ enables ~0 r~pid, simultanec~us washin~ and trPatin~ of the contents in the ninety-six rva~tion Yessels 12 whil~ the e~acuatin~3 system of FiE3ur.s 45 cooperates with botb the channel block 34 and ~he cleava~e ~lock 120 to remove the fluids from the reaction vessels '12 to the v~aste cantainer 3~ o~ the vi~ls 128, respectively.
By utilizing the manifold ~ralve block 30 to retain and release ~~rious washin~ fluids and the reactio~ products within and from the reaction ~ressels 12, as well as the s~lected fluid collection arran~emen~ provided by channel block 34 anc7 cleavage ~lock 1Z0, the convenience, sp~e~ and efficiency of simultaneous7~y ~eneratin~ new compounds is further ~acilitated 3~ by empl~ying the fluid handlin~ system of Fi~res 1, 20, 2~ and 41-46 therewlth .

S~TBsTIT[~TE PAGE

WO 97J10896 PC'r~US96/~5~Z~

Referring now to Figure 46, there is shown a valve actuating system for gang actuating the valves of the washing manifold 112 shown in Figures 20, 22 and 41-43, wherein pneumatic cylinders 1 14 and 1 16 open valves 1 1 O.

CA 02232~0~ 1998-03-18 E X A M P L E

Example 1 - Solid Phase Chemical Synthesis (General) The reaction grid is used to perform multiple solid phase chemical syn-thesis of organic molecules in a matrix format. The reaction vessels 12 are filled with solid support resins and chemical templates are attached thereto via appropriate linkers. Subseql~ently, chemicals are added to the reaction vessels through the top of the xyringe barrel, thereby permitting chemical transformations and reactions to occur on the templates attached to the solid support beads. The sealed reaction grid and filters used in the reaction vessels 12 prevents chemical reagents from leaking out of the reaction ves-sels during the reaction cycles.
After a desired chemical transformation has been performed, the beads are rinsed free of excess chemicals in a wash cycle by the application of vacuum to the block. The vacuum source is connected to the block through the outlet port. This allows liquid waste to drain from each of the reaction vessels through the inlet holes into the drainage channel and then to the main channel and finally into a waste trap. Subsequently, the beads are then washed repeatedly with wash solvent and again the waste removed by suction via the outlet connection port connected to the vacuum source.
Following completion of the transformations in each of the reaction vessels 12 and the washing and rinsing of the solid support resin, the manifold valve plate or block 30 is removed from the channel block 34.
Thereafter, the manifold valve plate or block 30 is connected to a second block which is the cleavage block 120. In this assembly, the cleavage block 120 has individual receptacles or vials 128 corresponding to the number of reaction vessels/inlet ports in the array in the top section. Thus, in an 8x12 matrix design, there are ninety-six individual vials 128 or test tubes posi-tioned within the cleavage block 120.
In comparing the cleavage block 120 to the channel block 34 of the reaction grid, the cleavage block is a hollow block containing individual _ CA 02232~0~ 1998-03-18 receptacles or vials 128 for the chemical products either in a tray or as a molded microtiter plate. The top section of the cleava~e block 120 is the same as the top section of the cl1annel block 34. In the cleavaç~e block, the top sections and bottom sections are sealed to one another usin~ an 0-ring positioned therebetween just as in the reaction ~rid assembly 14. The male Luer connectors 53 of the valve inserts 51 (see Fi~ure 3A) function as spouts to the cleavage block 120, drainin~ into individual chambers (vials 128) rather than into connected channels 65 as in the case of the channel block 34.

ExamDle 2 - Solid Phase Chemical Synthesis ISPecific Example) The followinq is a solid phase synthesis procedure for the synthesis of a library of 96 quinazoline analo~s. These analo~s are synthesized in an 8x12 matrix startin~ from a common anthranilic acid precursor. Treatment with 12 unique isocyanates and 8 unique alkylatin~q a~ents provides 96 unique compounds.

-Solid Phase Organic Svnthesis of 1,3-Dialkvl-2,4-Quinazoline Diones Example of Solid Phase Synthesis of Quinazoline Analogs Using the Reaction Grid Assembly o ~solid support ,b~

1. pipendine DMF 1 h ~ o ~NHFmoc 2 20 eq~ R1NC~.CH2CI2, 18h ~ j~,R~ 1 M KOH in EtOH, 2h O COOC~3 COOCH3 02 g resin - 0.06 mmol per well ~H 1.15eq. L~ " ~,1 h ~N
2. 40 eq. R2X, THf/DMF, 18 h ~ R2 ~OJ~ NR ~ ~3 TFA ,~ O

3 4 40 unique cornpounds Polymer (Tentagel-S NH2) supported anthranilic acid derivative 1 is slurried in dimethyl formamide (DMF) and transferred to 96 individual reac-tion vessels 12 in an 8x12 matrix format 10.20 9, 0.06 mmol per vessel in 2 mL DMF). Piperidine (0.5 mL) is added to each vessel and the vessels are shaken for 1 h. The reaction gricl assembly 14 is connected to a vacuum source via line 36 and the reaction solution is filtered away. DMF (2 mL) is added to each vessel 12 by using the washing system 21 of Fi~ures 1, 20, 22, 41-44 and 46, and the vessels are shaken for 5 min., then drained via vacuum as described above using the drainage system of Figure 45. This rinsing step 35 is repeated three tirnes. Methylene chloride (2 mL) is added to each vessel 12 and the vessels are shaken for 5 min., then drained via vacuum as described above. This rinsing step is repeated three times again , CA 02232~0~ 1998-03-18 WO 97/10896 PCT~US96nSlr24 using the washing system 21 and the drainage system 35 provided by th - manifold.
Methylene chloride (2 mL) is added to each vessel 12 and individual isocyanates (R,) are then added to each vessel (8 different reagents, 1.16 mmol, 20 equivalents). The reaction grid assembly 14 is shaken for 18 hours to carry out the chemical transformation. Then the agitation is stopped, the vacuum port 68 of 1:he reaction grid assembly 14 is connected to a vacuum source and the reaction solution filtered. Methylene chloride (2 mL) is added to each vessel 12 using the fluid handling manifold 20. The reaction grid assembly 14 is shaken for 5 min. and then drained via vacuum as described above using the drainage system 35. This rinsing step is re-peated three times. Ethanol (2 mL) is added to each vessel 12 and the assembly 14 is shaken for 5 mill., then drained via vacuum as described above. This rinsing step is repeated three times using the washing and drainage system 27 and 35. This operation now provides 8 unique urea derivatives 2.
1 M Potassium hydroxide in ethanol (2 mL) is added to each vessel 12 and the assembly 10 shaken for 1 hour. The assembly 14 is connected to vacuum and the reaction solution is filtered away. Ethanol (2 mL) is added to each vessel 12 and the reaction grid assembly 14 is shaken for 5 min., then drained via vacuum as described above. This rinsing step is repeated three times using the washin3 and drainage systems 27 and 35, respectively. Tetrahydrofuran (2 mL) is added to each vessel 12 and the reaction grid assembly 10 is shaken for 5 min., then drained via vacuum as described above. This rinsing step is repeated three times. This operation now provides 8 unique monoalkylquinazolines 3.
Tetrahydrofuran (1 mL) is added to each vessel 12 followed by lithium benzyloxazolidinone (3 mL), 0.3 M in tetrahydrofuran, 0.90 mmol, 15.5 equivalents). The vessels are shaken for 1.5 hours. A different alkylating reagent (R2) is now added down each of the 12 columns of the 8x12 grid. (12 different alkylating reagents, 2.32 mmol, 96 equivalents).

CA 02232~0~ 1998-03-18 DMF (1 mL) is added to each vessel 12 and the vessels are shaken for 18 hours then the reaction grid assembly 14 is connected to vacuum via port 68 and the reaction solution is filtered away. The addition of lithium benzyloxazolidinone and alkylation agents is then repeated as described above. Tetrahydrofuran (2 mL) is added to each vessel 12 and the vessels are shaken for 5 min., then drained via vacuum as described above. This rinsing step is repeated three times. 50% Tetrahydrofuran in water ~2 mL) is added to each vessel and the vessels are shaken for 5 min., then drained via vacuum as described above. This rinsing step is repeated three times.
Tetrahydrofuran (2 mL) is added to each vessel 12 and the vessels are shaken for 5 min., then drained via vacuum as described above. This rinsing step is repeated three times. This operation now provides 96 unique dialkyl quinazolines 4, one in each reaction vessel 12, attached to the solid support.
The manifold valve block 30 with the attached reaction vessels 12 is separated from the channel block 34 and attached to cleavage block 120 to form the cleavage block assennbly. A vial rack 122 or 140 is positioned within chamber 123 of cleavage block 120. 95% Trifluoroacetic acid in water (2 mL) is added to each vessel 12 using the fluid handling system 21 and the reaction vessels 12 are shaken for 3 hours. A vacuum source 38 is attached to vacuum port 160 of the cleavage block and the vessels 12 are filtered into 96 separate vessels, diluted with water and Iyophilized to provide 96 unique dialkyl quinazolines 5.
Throughout this example, the washing and drainage systems 27 and 35, respectively, the reaction grid assembly 14 and the vortexer 18 are utilized to form the reaction products in the reaction vessels 12.
The preceding examples can be repeated with similar success by sub-stituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing descrip,tion, one skilled in the art can easily ascer-tain the essential characteristics of this invention, and without departing from the spirit and scope thereo~, can make various changes and modifica-tions of the invention to adapt it to various usages and conditions.

Claims (81)

WHAT IS CLAIMED IS:

1. A reaction grid system for use in performing multiple separate reactions, said grid comprising:
a vessel retaining member with plurality of openings therethrough, each opening having an inlet and an outlet connected through a valve;
a plurality of reaction vessels for mounting individually in the inlets of the openings;
a drainage member associated with the vessel retaining member, the drainage member having a drainage field therein aligned with the outlets of the bores; and a valve operator for operating at last several of the valves simultaneously to drain fluids from the reaction vessels into the drainage member.
wherein the vessel retaining means is a block of material and the openings are passages through the material; and wherein the valve operator includes valve portions in a single rod, wherein when the rod is moved, the valves of a single column or row are opened or closed.

2. The reaction grid system according to claim 1, wherein said plurality of inlets are arranged in an array of at least two columns and at least two rows and the number of channels within said drainage member is equal to the number of rows in said array, wherein each inlet in a given row of said array communicates with a single channel.

3. The reaction grid system of claim 2, wherein the valves are interconnected to open and close simultaneously.

4. The reaction grid system of claim 1, wherein the valve portions are spaced openings in the rods which when aligned with the inlets and outlets allow fluid to pass therethrough and, when misaligned, block passage of fluid therethrough.

5. The reaction grid system of claim 4, wherein the rod is rotated to align and misalign the openings with the passages.

6. The reaction grid system of claim 1, wherein the valves are formed by inserts in each of the passages, the inserts each having radially extending precision bores formed therein for receiving precisely formed valve portions of the rods and having axially extending bores for providing fluid flow through the inserts, the fluid flow being controlled by the valve portions of the rods.

7. The reaction grid system according to claim 2, wherein each of said channels in the drainage member is in fluid communication with a main channel, wherein said main channel provides fluid communication between each of said channels and said at least one outlet port.

8. The reaction grid system according to claim 1 further including a coupling face on the vessel retaining member and a complimentary coupling face on the drainage member for detachably securing the drainage member to the vessel retaining member.

9. The reaction grid system according to claim 1, wherein the reaction grid further includes a capping assembly associated therewith for simultaneously closing each vessel with a closure portion, which closure portionis configured to admit fluid when penetrated.

10. A reaction grid system according to claim 9, wherein the closure portion is an elastomeric material providing an opening therethrough when penetrated by a probe.

11. The reaction grid system according to claim 10 further including a coupling face on the vessel retaining member and a complimentary coupling face on the drainage member for detachably securing the drainage member to the vessel retaining member.

12. The reaction grid system of claim 11 further including a cleavage assembly having a coupling face attachable to the coupling face of the vessel retaining member, the cleavage assembly including a plurality of reactionproduct collection vials aligned with the outlets of the vessel retaining member when the drainage member is detached from the vessel retaining member and the cleavage assembly is attached to the vessel retaining member.

13. The reaction grid system of claim 12 further including a solvent delivery system comprising an array of probes corresponding to the array of closures in the capping system, wherein a probe is aligned with each closure for selectively penetrating that closure to deliver liquid simultaneously to each reaction vessel.

14. The reaction grid system of claim 13 further including a vacuum system connectable to the drainage member for applying a vacuum thereto for evacuating fluids therefrom and for applying a vacuum to the cleavage assembly to cause reaction products in the reaction vessels to drain to the collection vials.

15. The reaction grid system of claim 14 further including a thermal control arrangement juxtaposed with the reaction vessels for heating or cooling the contents of the vessels.

16. The reaction grid assembly of claim 15 further including an agitator for agitating the contents of the reaction vessels.

17. The reaction grid system of claim 14 further including an agitator for agitating the contents of the reaction vessels.

18. The reaction grid system according to claim 1, wherein said vessel retaining member is;
a block of resinous material having an upper surface, a lower surface and side surfaces:
an array of first passages through block from inlets at the upper surface to outlets at the lower surface;
arrarray of second transverse passages extending through the block, each second transverse passage intersecting a plurality of first passages, whereby the inlets of the first passages each receive one of the reaction vessels and the second passages provide access to pluralities of first passages for controlling flow of fluid from the reaction vessels out through the outlets in lower surface of the block,

19. The reaction grid system comprising the manifold block of claim 18 and further comprising:
a capping assembly attached to the manifold block in spaced reaction thereto, the capping assembly sealing inlets of the reaction vessels when the reaction vessels are mounted in the inlets of the manifold block.

20. The reaction grid system comprising the manifold block of claim 18 and further comprising:
a drainage block attached to the manifold block, the drainage block having at least one cavity therein for receiving fluid from the reaction vessels when fluid in the reaction vessels flows from the outlets in the manifold block.

21. The reaction grid system of claim 20, wherein drainage block has interconnected channels therein aligned with the outlets of the manifold block.

22. The reaction grid system of claim 21 further including:
a capping assembly attached to the manifold block in spaced relation thereto, the capping assembly sealing inlets of the reaction vessels when the reaction vessels are mounted in the inlets of the manifold block.

23. The reaction grid system comprising the manifold block of claim 18 and further comprising:
a valve insert in each of the first passages.

24. The reaction grid system of claim 23 further including valve operators extending in each of the second passages to simultaneously operate valve inserts in the first passages.

25. The reaction grid system of claim 24 further including a drainage block attached to the manifold block, the drainage block having at least one cavity therein for receiving fluid from the reaction vessels when fluid in the reaction vessels flows from the outlets in the manifold block.

26. The reaction grid system of claim 25, wherein drainage block has interconnected channels therein aligned with the outlets of the manifold block.

27. The reaction grid system comprises the manifold block of claim 25 and further comprising:
capping assembly attached to the manifold block in spaced relation thereto, the capping assembly sealing inlets of the reaction vessels when the reaction vessels are mounted in the inlets of the manifold block.

28. The reaction grid system comprising the manifold block of claim 18 and further comprising:
a thermal block held spaced from the manifold block for surrounding the reaction vessels when the reaction vessels are mounted in the inlets of the manifold for controlling the temperature of contents within the reaction vessels.

29. The reaction grid system of claim 28 further including;
a drainage block attached to the manifold block, the drainage block having at least one cavity therein for receiving fluid from the reaction vessels when fluid in the reaction vessels flows from the outlets in the manifold block.

30. The reaction grid system of claim 23 further including:

a capping assembly attached to the manifold block in spaced relation thereto, the capping assembly sealing inlets of the reaction vessels when the reaction vessels are mounted in the inlets of the manifold block,

31. The reaction grid system of claim 29 further including:
a valve insert in each of the first passages,

32. The reaction grid system of claim 31 further including valve operators extending in each of the second passages to simultaneously operate valve inserts in the first passages.

33. The reaction grid system of claim 28 further including:
a capping assembly attached to the manifold block in spaced relation thereto, the capping assembly sealing inlets of the reaction vessels when the reaction vessels are mounted in the inlets of the manifold block.

34. The reaction grid system of claim 33 further comprising:
a valve insert in each of the first passages of the manifold block.

35. The reaction grid system of claim 34 further including valve operators extending in each of the second passages to simultaneously operate valve inserts in the first passages.

36. The reaction grid system of claim 33 further comprising:
a drainage block attached to the manifold block, the drainage block having at least one cavity therein for receiving fluid from the reaction vessels when fluid in the reaction vessels flows from the outlets in the manifold block.

37. The reaction grid system of claim 36, wherein drainage block has interconnected channels therein aligned with the outlets of the manifold block.

38. The reaction grid system of claim 36 further including:
a valve insert in each of the first passages of the manifold block.

39. The reaction grid system of claim 38 further comprising:
an agitation device for agitating the contents of the reaction vessels.

40. The reaction grid system of claim 39, wherein the agitation device is a vortexer.

41. The reaction grid system comprising the manifold block of claim 18 and further comprising:
a vial retaining member for coupling to the lower surface of the manifold block and for holding a plurality of vials in alignment with the outlets of the manifold block.

42. The reaction grid system of claim 41, wherein the vial retaining member is a cleavage block having a cavity therein in which the vials are received.

43. The reaction grid system of claim 42 further comprising:
a capping assembly attached to the manifold block in spaced relation thereto, the capping assembly sealing inlets of the reaction vessels when the reaction vessels are mounted in the inlets of the manifold block.

44, The reaction grid system of claim 42, further comprising:

a valve insert in each of the first passages.

45. The reaction grid system of claim 44 further including valve operators extending in each of the second passages to simultaneously operate valve inserts in the first passages.

46. The reaction grid system of claim 44 further comprising:
a capping assembly attached to the manifold block in spaced relation thereto, the capping assembly sealing inlets of the reaction vessels when the reaction vessels are mounted in the inlets of the manifold block.

47. The reaction grid system of claim 42 further comprising:
a thermal block held spaced from the manifold block for surrounding the reaction vessels when the reaction vessels are mounted in the inlets of the manifold for controlling the temperature of contents within the reaction vessels.

48. The reaction grid system of claim 47 further comprising:
a valve insert in each of the first passages.

49. The reaction grid system of claim 48 further including valve operators extending in each of the second passages to simultaneously operate valve inserts in the first passages.

50. The reaction grid system of claim 47 further comprising:
a capping assembly attached to the manifold block in spaced relation thereto, the capping assembly sealing inlets of the reaction vessels when the reaction vessels are mounted in the inlets of the manifold block.

51. The reaction grid system of claim 50 further comprising:
a valve insert in each of the first passages.

52. The reaction grid system of claim 51 further including valve operators extending in each of the second passages to simultaneously operate valve inserts in the first passages.

53. The reaction grid system of claim 52 further comprising:
an agitation device for agitating the contents of the reaction vessels prior to transferring the contents to the collection vials.

54. The reaction grid system of claim 53 further including a mounting plate for supporting either the drainage block or the cleavage block on the agitator.

55. A vial retaining block assembly for containing a plurality of vials arranged in an array for receiving reaction products from an array of reaction vessels, the vial retaining block assembly comprising;
a block having a cavity therein and a coupling face, the coupling face including a seal and fastening means;
a vial rack disposed in the cavity, the vial rack including an array of holes for supporting the vials; and a port in the block in communication with the cavity, whereby when a vacuum is applied to the port, a partial vacuum occurs in the cavity to facilitate flow of the reaction products from the reaction vessels to the vials.

56. The assembly of claim 55, wherein the vial rack includes at least one gripping member extending therefrom for facilitating withdrawing the rack from the cavity in the block.

57. The assembly of claim 55, wherein the vial rack is comprised of an upper plate with the arrangement of holes therein and a lower plate spaced from the upper plate, the lower plate having an array of depressions therein aligned with the holes for seating the bottoms of the vials.

58. The assembly of claim 55, wherein the vial rack is a composite rack having more than one vial retaining section, the vial retaining sections being separable from one another when out of the cavity.

59. The assembly of claim 58, wherein each vial retaining section has a separate code marked thereon.

60. The assembly of claim 59 further including a support for the vial retaining sections, the support having a code specific thereto marked thereon.

61. The assembly of claim 60, wherein the codes are bar codes.

62. The assembly of claim 60, wherein the vial retaining sections have location specific couplings thereon which cooperate with location specific couplings on the support wherein each vial retaining section has unique position on the support.

63. The assembly of claim 62, wherein the location specific couplings are arrays of pins on and holes in the support and vial retaining sections which align only when the sections are properly positioned with respect to the support.

64. A liquid delivery system useful for dispensing solvents to a reaction grid system having an array of reaction vessels mounted therein, the solvent delivery system comprising:
a manifold with a plurality of valves arranged therein in an array corresponding to the array of reaction tubes;
an arrangement for delivering solvents to the manifold for release by the valves;
an arrangement comprising a rod with a plurality of openings there-through for opening a plurality of the valves simultaneously; and an array of probes corresponding to the array of valves wherein each individual probe is connected to a specific valve for delivering solvent to one reaction vessel.

65. The liquid delivery system of claim 64, wherein the valves are operated by a pneumatic system in which each valve is connected to a separate link which is in turn connected to a common link with the common link being moved by a piston driven by a pneumatic cylinder.

66. The liquid delivery system of claim 65, wherein one-half of the valves are operated by a pneumatic cylinder located on one side of the manifold and the other half of the valves are operated by a pneumatic cylinder on the other side of the manifold.

67. The liquid delivery system of claim 64 further including an evacuation system for applying a partial vacuum to fluid collection members disposed proximate the reaction grid for withdrawing solvents dispensed by the solvent delivery system from the reaction vessels, the evacuation system including the vacuum pump.

68. The liquid delivery system of claim 67 further including a programmable logic controller for activating the system to deliver solvents and for activating the vacuum pump to remove waste solvents from the system.

69. The liquid delivery system of claim 65 further including an elevator connected to the manifold for raising and lowering the manifold with respect to the reaction grid.

70. The liquid delivery system of claim 65 further including pumps for delivering solvent from reservoirs to the manifold.

71. The liquid delivery system of claim 70 further including a programmable logic controller connected to the elevator and solvent pumps for lowering the manifold to insert the probes into the reaction vessels; the controller being connected to the solvent pumps for activating the solvent pumps to pump solvent into the reaction vessels when the probes are in the reaction vessels and for shutting off the solvent pumps and raising the manifold after the solvent has been dispensed.

72. The liquid delivery system of claim 70 further including an elevator for raising and lowering the manifold.

73. An assembly comprising the solvent delivery system of claim 64 and further comprising:

a manifold valve block associated with the reaction grid system, the manifold valve block including a channel block detachably connected thereto for removing waste solvent from the system after the solvent has flowed through each of the reaction vessels.

74. An assembly comprising the solvent delivery system of claim 64 and further comprising:
a manifold valve block associated with the reaction grid system for supporting the reaction vessels and a cleavage block detachably secured to the valve manifold block, the cleavage block having an array of vials therein corresponding in location to the array of reaction vessels wherein reaction products in solutions within the reaction vessels are dispensed to the vials upon opening valves in the valve manifold block.

75. A thermal arrangement for controlling the temperature of the contents of an array of reaction vessels mounted on a reaction grid, wherein the arrangement comprises:
a first heating block with an array of holes therein corresponding to the array of reaction vessels wherein the reaction vessels are received through the holes;
a second block with an array of holes therein corresponding to the array of holes in the first block also for receiving the reaction vessels therethrough; and an electric heating pad sandwiched between the first and second blocks, the electric heating pad having an array of holes therein corresponding to the arrays of the first and second heating blocks, the pad heating the first and second heating blocks to heat the contents of the reaction vessels.

76. The arrangement of claim 75 further including at least one cooling cavity in the heating blocks.

77. The arrangement of claim 76, wherein the cooling cavity is an indentation in an upper surface of the first block for receiving a cooling medium.

78. The arrangement of claim 77, wherein the cooling medium is dry ice.

79. The arrangement of claim 77, wherein the cooling cavity is a channel which is within the cooling block and receives cooling fluid which circulates through the channel.

80. A process for obtaining reaction products from an array of reaction vessels, the process comprising:
(a) inserting reaction vessels having solid supports therein in a grid having a manifold with an array of valves individually connected to each reaction vessel;
(b) loading the reaction vessels with reagents and solvents at a first site;
(c) simultaneously sealing the reaction vessels;
(d) agitating the reaction vessels to facilitate formation of reaction products within the reaction vessels;
(e) simultaneously delivering a solvent liquid to each of the reaction vessels at a second site to form a suspension;
(f) agitating the reaction vessels while at the second site to facilite homogenization of the suspension;

(g) simultaneously opening the valves in the manifold via a rod having a plurality of valve openings therethrough and applying a partial vacuum to a drainage collection member to remove waste solvents from the reaction vessels;
(h) repeating steps (b)-(g), as necessary, depending on the number of cycles necessary for the reactions;
(i) substituting a vial retaining member for the drainage member to align an array of vials with the array of reaction vessels to form a cleavage grid;
(j) delivering a cleavage fluid to each of the reaction vessels;
(k) agitating the reaction vessels to facilitate cleavage of reaction products from the solid supports in the reaction vessels;
(l) opening the valves in the cleavage grid to allow the reaction products to drain to the vials while apply a partial vacuum to the cleavage grid to facilitate drawing reaction products from the reaction vessels into the vials.

81. A process for carrying out multiple solid phase chemical synthesis reactions in a matrix format comprising:
providing reaction vessels each having filters and outlet ports proximate male end connections;
connecting the reaction vessels to inlets of a reaction grid;
loading each of said reaction vessels with solid support beads and attaching chemical templates to said solid support beads via linkers;
performing chemical synthesis reactions for the preparation of organic molecules within each of said reaction vessels;
removing fluid from said reaction vessels by opening valves of the reaction vessels simultaneously and connecting said outlet port to a vacuum supply;

washing said support solid support beads with wash solvent and removing said wash solvent through said outlet port;
removing a first rectangular section of the reaction grid from connection with a second rectangular section thereof and connecting said first rectangular section to a cleavage section, said cleavage section comprising a chamber containing a plurality of vials, each of said vials communicating with an outlet port of said first rectangular section, said cleavage section further comprising an outlet for connecting said chamber to a vacuum supply means; and cleaving desired organic product from each of said reaction vessels and collecting the organic product within said individual vials.