JP2002512878A - How to synthesize multiple products - Google Patents

Abstract

(57) Abstract A method is described for synthesizing multiple products using a process. The process is a multi-stage process. The product formed through the process is applied to an article known as beads (20). The method includes the steps of separating the individual beads (20) and labeling them with a laser to provide a unique identification code at the penultimate stage of the process. This code makes it possible to record the chemical synthesis route taken by the individual beads (20) and the chemical synthesis to which the beads (20) are to be subjected in the final stages of the process. The product can therefore be easily identified.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for synthesizing a plurality of products using a process.

BACKGROUND combinatorial chemistry invention, whereby a technique of chemical compounds so many different are produced by complex (multiple) chemistry. Libraries of chemical compounds can be formed on solid supports. Solid supports are commonly known as beads. Beads with a size of approximately 1/10 millimeter in diameter are typically used in such reactions. Molecules can be attached to beads via chemical hooks.

[0003] In order to form a library of chemical compounds, it is usual to start with a large number of beads. To illustrate the combinatorial process, assume that the beads are divided into three groups. Different reagents (A, B and C) can then be added to groups of individual beads. At this time, there are three types of molecules attached to the beads: beads in group 1 have molecules of compound A attached to them, beads in group 2 have molecules of compound B, and The beads have Compound C molecules. Next, the three groups of beads are pooled, mixed well, and again divided into three groups. Then 3 more
Another reaction takes place. This results in the production of nine different molecular species in a combination of three reactions in the first stage of the process and three reactions in the second stage. If the groups of beads are pooled again, mixed well and divided into three further groups, 27 different compounds are produced.

A library of compounds created by the above steps is known as a 3 × 3 × 3 library. Nine (3 + 3 + 3) individual reactions are performed, producing 27 different (3 × 3 × 3) compounds. Other size libraries can be made by changing the number of reaction steps and by changing the number of groups of beads. (50 × 50 × 50) or (20 × 20 × 2
A library containing thousands of compounds (0x20) is envisaged (envisaged)
.

[0005] It is preferable to label individual chemical compounds of such libraries. Until recently, this was a very difficult task; an additional elaborate chemical processing step was typically undertaken to add a “chemical tag” to the beads.
Such chemical tags have proven difficult to identify and, in addition, limit the chemical processes available in forming the desired compound.

[0006] International Patent Application No. WO-A3-97126680 (IRORI) discloses a method of data storage and retrieval technology for use in molecular tracking and identification.
Products for such tracking and identification have been described, along with screening protocols, assays, and diagnostics using the products. UK Patent Application GB-A-2 306 484 discloses a method of labeling beads by applying a barcode to each bead to identify the particular reaction that the bead has undergone. The chemical compound of interest can be identified by reading the bar code on the bead. However, a disadvantage of this method is that at each stage of the combinatorial process, individual beads must be labeled. This can be a time consuming and therefore expensive operation.

Another method for forming a library of compounds is to keep the beads in a container having porous walls. Chemical reagents can penetrate the walls of the container and interact with the beads. Each container has a unique tag, which can be used to identify the container and the reactions in which it participated. Such a container is generally known as a microreactor. An advantage of using microreactors in complex chemistry is that by encapsulating them within the microreactor, large volumes of beads can be processed more conveniently.

One such type of container is now known as the “MICROOKAN” trademark
Sold under. Microcan ™ is well known in combinatorial chemistry as a means involving a set of beads as they pass through various stages of the combinatorial chemistry process. The Microcan ™ microreactor is designed to be loaded with solid phase resin beads. By allowing reagents to flow through the outer mesh wall, chemical synthesis takes place in the microreactor. "
In a method known as "direct sorting" (rather than individual solid resin beads)
By combining and separating multiple microreactors, one individual compound is synthesized within each individual reactor.

[0009] Small radio frequency (RF) tags are included within individual microreactors. RF
The tag is a unique label used to identify the microreactor during the sorting process that occurs between chemical synthesis steps. RF tags are placed in glass and give each microreactor, and thus each compound, a unique ID. This unique ID allows the identification of individual microreactors during the combinatorial “direct sorting” process.

However, one disadvantage of the Microcan ™ microreactor is that
That is expensive. When synthesizing a library containing thousands of compounds,
This is restrictive. Another disadvantage is that the beads used in the Microcan ™ microreactor are not individually identified or labeled. Therefore, there is no easy way to subdivide such a library of beads and maintain knowledge about the chemical compounds attached to each individual bead.

It is an object of the present invention to provide a method for synthesizing a large number of different chemical compounds that can be easily identified. SUMMARY OF THE INVENTION According to the present invention, there is provided a method of synthesizing a plurality of products using a process, comprising: 1) providing a plurality of articles on which the products are to be formed; Dividing the articles into a plurality of article groups and introducing the individual groups of articles into respective microreactors; 3) subjecting the articles therein to the first synthesis step of the process; and 4) Subjecting to at least a second synthesis step of the process, and in a penultimate synthesis step at least some of the articles are removed from the at least one microreactor, and wherein A method is provided, wherein the article is labeled with an identification code indicating the history of the composition received.

After they have been labeled, the articles can be returned to the same or different microreactors, which can be subjected to the final synthesis step of the process. Alternatively, the articles may be retained so that chemical compounds formed on (or attached to) them can be analyzed. The microreactor can then participate in further synthesis steps of the process.

The identification code preferably also indicates the final synthesis step of the process in which the article is to be provided. Preferably, the process has at least three synthesis steps. For example, 3
In staged synthesis, some of the articles are removed when the second stage of the process is completed. These articles are then labeled with an identification code. The identification code also records the synthesis steps that the articles have undergone in steps 1 and 2, and the synthesis steps that the articles will undergo in the final step. Thus, in a three-stage synthesis, the labeling of the article (or a subset of the articles) is performed only once, ie, at the completion of the second synthesis stage.

[0014] The process may be a combinatorial process. Preferably, the microreactors are grouped together and then, prior to the individual synthesis steps of the process, are divided into groups, as in a conventional combinatorial process. Some or all of the articles can be marked with a code before the first stage of the combinatorial process, ie, before they are introduced into the microreactor (or microreactors). These marked articles can be removed from the microreactor (or microreactors) and the code is read in the penultimate synthesis step. After this is done, the goods will be transferred to the microreactor (or multiple microreactors)
Or can be reserved for future use.

[0015] The microreactor can be a container having porous walls. The container may for example be similar to a tea bag. The container can have an identification label or tag. Preferably, the identification code is applied to the article using a laser. in this way,
A "physical" tag is formed on the article. The use of such tags does not limit the chemical processes that may be used in forming the desired chemical compound.

Preferably, the identification code includes an alphanumeric code. The alphanumeric code makes it easy to record both the chemical synthesis steps that the article has undergone while being encapsulated in the microreactor and the subsequent synthesis steps. Thus, the chemistry performed on the article
Can be identified. According to another aspect of the present invention, there is provided an apparatus for labeling an article. The apparatus includes a laser beam positioned to direct the article to label the article, a means for separating the individual articles, and a surface on the article to form the label thereon. Means for directing the beam at the beam.

[0017] The article may also be known as beads. Ideally, beads labeled using this system are standard beads known in the field of combinatorial chemistry. However, non-standard beads or other solid supports can be used. Beads can be formed from highly cross-linked, lightly derivatized resins. It can be used as a laser marked bead, so that the label is retained throughout all processing steps. As unlabeled beads during the combinatorial process, a lesser crosslinked, highly derivatized resin can be used.

According to a further aspect of the present invention there is provided a product synthesized by the method described above. The product is preferably a chemical compound. Numerous embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings described below. DESCRIPTION OF THE PREFERRED EMBODIMENTS Referring to FIG. 1, one embodiment of a microreactor is shown. Microreactor 24 includes a mesh wall that allows reagents to flow into (and out of) microreactor 24 to interact with beads 20.
Microreactor 24 includes solid phase resin beads 20. Typically about 30m
g resin beads 20 can be included in the microreactor 24. The microreactor 24 has a tag 22 that is used to identify the chemistry of the beads 20 contained therein. Tag 22 can be a handwritten label, barcode, RF tag or other identifying mark.

Individual beads from the microreactor can be labeled using a laser system. The label forms a record of the synthesis received by the bead and the next step in the synthesis to which the bead would be subjected. Beads can then be easily identified by reading the laser-marked label. The label can be, for example, an alphanumeric code, or any other identifier. As the synthesis that the beads received (and would undergo in a further synthesis step) is recorded on individual beads, the library can be subdivided to give more sublibraries. The microreactor is then available for reuse.

By way of example only, a typical sequence of events for labeling beads 20 will be described. Consider a three-step synthesis (eg, a 3 × 3 × 3 library of 27 chemical compounds). Forming such a library on beads contained in microreactor 24 (or any other type of microreactor) would require 27 such microreactors and would be very expensive Will be. In this method, the first two steps of the synthesis are performed using nine microreactors, giving a set of 3 × 3 compounds on the beads. Step 1 of the synthesis is illustrated by FIG. 2 and step 2 is illustrated by FIG.

FIG. 2 shows reaction vessels 30, 32 and 34, each containing three microreactors. The reaction vessel 30 includes the microreactors 40, 4
1 and 42. The reaction vessel 32 is provided with the microreactor 4
3, 44 and 45. Reaction vessel 34 includes microreactors 46, 47 and 48 that come into contact with reagent C. Prior to the second synthesis step, the microreactors are pooled and separated, as shown in FIG. Now, the reaction vessel 30 contains the reagent A
The reaction vessel 32 includes microreactors 40, 43 and 46 that are in contact with
Reaction vessel 3 including microreactors 41, 44 and 47 that come into contact with reagent B
4 comprises microreactors 42, 45 and 48 that come into contact with reagent C.

The beads contained in the microreactor, after a two-step synthesis, have the chemistry shown in the table below.

[0023]

[Table 1] Prior to the third synthesis step, a number of beads were extracted from each of the nine microreactors and labeled with a laser (not shown). Laser marking indicates the processing performed in the microreactor and the processing to be performed in the next stage of the synthesis. For example, beads from the microreactor 40 can be marked with 1 _A 2 _A 3 _B. This label indicates that the beads receive synthetic type A in the first step, type A in the second step (both while contained within the microreactor 40), and, for example, 1 _C 2 _B 3 _{B and the} like. Indicate that in the microreactor with the other beads should undergo synthetic type B in the final step. This step is performed for all of the beads participating in the third stage synthesis. Screening for compounds of interest attached to individual beads then follows.

The above aspects can be modified without departing from the scope of the invention. For example, a MicroTube (trademark) microreactor can be used.

[Brief description of the drawings]

FIG. 1 shows a diagrammatic cross-section through one embodiment of a microreactor.

FIG. 2 shows a schematic representation of the first stage of a combinatorial process according to the invention.

FIG. 3 shows a schematic representation of the second stage of the combinatorial process according to the invention.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) G01N 37/00 103 G01N 37/00 103 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, S, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU , LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZWF Term (Reference) 4G068 AA03 AA04 AA06 AB21 AB22 AC20 4G075 AA01 AA22 AA65 BA10 BD16 DA02 EB01 EE15 FA03 FC01 4H006 AA05

Claims (12)

[Claims] 1. A method of synthesizing a plurality of products using a process, comprising: i) providing a plurality of articles on which the product is to be formed; ii) dividing the articles into a plurality of article groups; Introducing an individual group of articles into a respective microreactor; iii) subjecting the articles therein to a first synthesis step of the process; and iv) subjecting the articles to at least a second synthesis step of the process. And in a penultimate synthesis step, at least some of the articles are removed from the at least one microreactor and labeled with an identification code indicating the synthesis history received by the articles in the microreactor. A method comprising: 2. The method according to claim 1, wherein the articles are returned to the same or different microreactors after they have been labeled, and the microreactors are subjected to a final synthesis step of the process. 3. The method according to claim 2, wherein the identification code also indicates the final synthesis step of the process in which the articles are to be provided. 4. The method according to claim 1, wherein the microreactors are grouped together and divided into a plurality of groups of microreactors before the individual synthesis steps of the process. 5. The method according to claim 1, wherein said process has at least three synthesis steps. 6. The process according to claim 1, wherein said process is a combinatorial process.
5. The method according to any one of 5. 7. The method according to claim 1, wherein the identification code is applied to the article using a laser. 8. The method according to claim 7, wherein said identification code comprises an alphanumeric code. 9. An apparatus for labeling an article, comprising: a laser having a beam arranged to be directed onto the article to label the article; a means for separating individual articles; Means for directing the beam against the surface of the article to form a label thereon. 10. The device according to claim 9, wherein said article is a bead. 11. A product synthesized using the method according to claim 1. 12. The method substantially as described herein with reference to FIGS. 2 and 3 of the accompanying drawings.