JP2001527025A - Solid support material - Google Patents

Abstract

(57) Abstract A series (2) of sachets (4), each containing a tag (14), is made of a monomer and post-exposure grafted fine fibrous polypropylene fabric. The monomer contains functional groups arranged to covalently bond with other compounds or sites. As a combinatorial technique, a method using a series of sachets to create a library of compounds is also disclosed.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a solid support material, a method for its use and / or a method for its manufacture and an apparatus therefor. In particular, the invention relates to, but not limited to, solid support materials for solid phase synthesis and for supporting other materials, compounds or sites that can be used for solid phase or solution phase synthesis.

[0002] The use of solid support materials in solid-phase chemical and biochemical synthesis, immunoassays and hybridization reactions to support reagents (eg, catalysts or enzymes) is well known, including solid support materials, Many prior arts describing the preparation method have been published. Hereinafter, the selected prior art contents will be described.

[0003] International Patent Application Publication No. WO 96/16078 (Pfizer) describes the use of paper that has been treated to allow binding of reagents. For example, if the reagent is an amino acid or peptide fragment, the paper can carry an anchoring group and releasably bind the carboxylic acid of the amino acid. This publication also describes the use of a laminate comprising a solid material (eg, a crosslinked polystyrene resin containing amino groups) sandwiched between fabric sheets (eg, a polypropylene nonwoven sheet).

[0004] International Patent Application Publication No. WO90 / 02749 (Forsnings Center Litho) discloses a solid support for use in peptide synthesis, comprising an alcohol solution of a styrene monomer optionally substituted with a polyethylene sheet or film. A solid support comprising a thin polyethylene sheet or film grafted with polystyrene chains in a free-radical initiated method, immersed therein and subjected to gamma irradiation, is described. Such a grafting method in which the material to be grafted is irradiated in the presence of the monomer is described as an "alternating" grafting method.

[0005] International Patent Application Publication WO 91/04266 (Roseco) describes the preparation of solid surfaces for peptide synthesis by an alternating grafting method using acrylic acid solution as monomer.

[0006] International Patent Application Publication WO 98/31732 (Iroli) states that the resulting grafted polymers are suitable for use as supports in synthesis and screening, especially for use in combination with synthesis and high throughput screening protocols. A method of radiation grafting to a polymer surface is described that addresses the problem of providing a graft polymer that is sufficiently highly grafted to be suitable.
The solution to this problem, in one aspect, involves chemically polishing the surface with an acid (eg, sulfuric acid or nitric acid) before grafting in an alternating grafting method. In another aspect, this problem is described as being solved by physically polishing the polymer to be grafted before grafting.

One of the problems with the alternating method that we have recognized is that it is difficult to control the length of the grafted chain due to monomer self-polymerization, and that the It is difficult to control the chain density. as a result,
Difficulty in maximizing the number of positions to which the site to be supported can be attached, and furthermore, long grafted chains can cause entanglement, thereby reducing the space for supporting the site . Another problem with the alternating method is that the relatively long grafted chains increase the melt flow index of the molten material making it difficult to predict and control the reshaping of the grafted material ( For example, it is difficult to heat and mold or reshape the (grafted) grafted material.

[0008] In general terms, the solid support materials used in the synthesis and screening methods preferably have one or more of the following properties: (a) It is not brittle, but is preferably flexible so that it can be formed into a sheet. (b) inert to solvents and / or reagents that can be used in downstream synthesis or screening methods. (c) It is thermoplastic and can be processed by extrusion or other methods so that it can be molded into the desired shape. (d) Since the portion to be supported has a relatively large number of positions that can be bonded, the amount of material that can be supported per unit mass or unit area is relatively large. (e) It has a large surface area to support the material. (f) Because it is thermally stable, it does not melt, deform, or become brittle upon heating.

Various methods have been provided that provide a means of creating libraries of compounds on solid supports and / or uniquely identifying and tracking the same attributes of solid supports during a series of manufacturing steps. I have. The following is a further description of selected prior art disclosures.

International Patent Application Publication No. WO 96/16078 (Pfizer) describes a method for preparing a library of compounds using a three-dimensional stack of independent sheets in which a reaction region is indicated on each sheet. The stack of sheets is cut into strips and the strips are subjected to separate reactions. Unfortunately, when the stack is cut into strips, almost all of the original order in the stack is lost, so the same attributes of each reaction zone and the process to be applied must be recorded at each stage. This makes it difficult to track the process to which each reaction zone is attached.

International Patent Application Publication No. WO 98/15825 (Iroli) describes a “sort classification” method for solid-phase combinatorial chemistry using a matrix containing a memory microreactor. In this method, each microreactor is assigned to one particular compound and the microreactor is stored in a suitable reaction vessel. After appropriate reaction and / or washing, each microreactor is individually identified and then distributed to the next reaction vessel. This method will disadvantageously turn out to require a very large number of microreactor identifications during the preparation of the library of compounds.

It is an object of a preferred embodiment of the present invention to address the above problems.

According to a first aspect of the present invention, there is provided a method of supporting a compound or other site, the method using a fabric containing a plastic material.

The fabric has a diameter of at least 5 μm, preferably at least 10 μm
m, more preferably at least 15 μm filaments. The filament has a diameter of 500 μm or less, suitably 200 μm or less, preferably 100 μm or less.
μm or less, more preferably 60 μm or less, preferably 30 μm or less.

[0015] The density of the fabric may be at least 20 g / m ² , suitably at least 40 g / m ² , preferably at least 60 g / m ² , more preferably 80 g / m ² . The density may be less than 250 g / m ² , suitably less than 200 g / m ² , preferably less than 150 g / m ² , more preferably less than 120 g / m ² .

The fabric is preferably in a thin layer. The fabric may have a thickness as described below.

[0017] The fabric may or may not be woven. The fabric is preferably not woven.

[0018] The fabric, especially a non-woven fabric, may include an array of fine fibers suitably welded in place (preferably a random array). Structures can be formed that have relatively gaps (so that liquids used in downstream manufacturing processes can easily penetrate). The fine fibers are preferably not embedded in the binder material or are not associated with the binder material. The fabric preferably contains endless filaments that are thermally bonded.

[0019] The fabric is preferably thermoplastic.

[0020] The fabric preferably includes a first polymer material that may have the characteristics of the first polymer material described below. The first polymer material may be a graft polymer. The graft polymer may be prepared by any method. The graft polymer preferably comprises one or more monomers that may have the characteristics of one or more monomers described below.
It is prepared using more than one. Preferably, the graft polymer is prepared by a radiation grafting method, such as an alternating radiation method. The graft polymer is more preferably prepared as described for the seventh aspect below.

Preferably, the fabric does not contain any functional groups capable of forming hydrogen bonds (eg, with another functional group of the same type).

[0022] The fabric preferably has reactive sites, through which compounds or other sites may be associated with the fabric. The reactive site is preferably capable of covalently attaching the compound or site to the fabric. Preferably, the reaction site does not include the sites necessary for hydrogen bonding within the fabric. Preferably, the reaction site is not a hydroxyl group. Preferably, the binding of the reactive site to the compound or other site does not significantly reduce the physical strength of the fabric.

The fabric is preferably covalently linked to other compounds or sites and / or
Or it contains a linker site suitably arranged so that it can be cleaved therefrom when necessary. The linker site may be as described herein.

The method preferably comprises forming a covalent bond between the compound or other moiety and the fabric. Preferably, an intermediate site is located between the fabric and the supported compound or site, and preferably, the compound or other site is covalently linked to the intermediate site. The intermediate site is preferably covalently bonded to the fabric. The intermediate site may include a linker site described herein.

Preferably, the fabric is at least 70%, suitably at least 80%, preferably at least 90%, more preferably at least 70% by weight of the solid support material used in the method for supporting a compound or other site. Accounts for 95% by weight or more. Preferably, the solid support material used in this method consists essentially of a fabric.

According to a second aspect of the present invention, a fabric, in particular a nonwoven, is used as a solid support for supporting a compound or other site.

According to a third aspect of the present invention there is provided a solid support for supporting a compound or other moiety, the solid support comprising a fabric, especially a nonwoven.

[0028] The solid support preferably has a linker moiety as described herein positioned such that the compound or other moiety can be covalently attached to the support and / or can be separated therefrom when necessary. Including.

[0029] The solid support is preferably represented by a plurality of independent regions for supporting a compound or other moiety.

The fabric may include associated identification means. The identification means distinguishes a part of the fabric (preferably, a part capable of supporting a first compound) from another part (preferably, a part capable of supporting a second compound different from the first compound). It is preferably arranged as possible. Identification means include, for example, numbers, letters, symbols, colors in an encrypted combination, smileys, bar codes, chemical structures, stamped or printed stamped card formats, and UV-readable devices (eg, , Magnetic strip). Preferably, the identification means comprises an electromagnetically readable device (eg, a device arranged to be read by an Rf transmitter or a magnetically readable device). The identification means preferably comprises an encrypted identifier arranged to be read by a reader. The encrypted identifier preferably contains a unique code. Preferably, the same attribute of the encrypted identifier and / or information associated with the identification means is predetermined and preferably cannot change after the identification means has been associated with the fabric. For example, the identification means is preferably not re-programmable after being coupled with the fabric and / or is otherwise not arranged to accept new data.

According to a fourth aspect of the present invention there is provided a solid support for supporting a compound or other site, the solid support being a means that is flexible and represents an enclosed area. (Hereinafter referred to as "enclosure means").

The enclosure means preferably comprises two layers of laminar material. The lamellar material is preferably porous. The lamellar material has a thickness of at least 100 μm, suitably at least 200 μm, preferably at least 3 μm.
It may be 00 μm, more preferably at least 400 μm, especially at least 500 μm. The thickness of the laminar material is less than 5000 μm, preferably 4000 μm
Less than 2000 μm, more preferably less than 1000 μm. The two layers are preferably adhered to each other along at least part of this area to represent at least part of the border of the enclosed area. The lamellar material may include a woven or non-woven fabric described herein. The laminar material preferably comprises a nonwoven.

The enclosed areas preferably have different volumes and / or different three-dimensional shapes. The enclosed area preferably has a substantially quadrilateral shape, more preferably a substantially rectangular shape in plan view. The width of the enclosed area (in plan view) may be at least 5 mm, preferably at least 10 mm, more preferably at least about 15 mm. The width of the enclosed area (in plan view) is 1
Less than 00 mm, preferably less than 50 mm, more preferably less than 40 mm, especially 3
It may be less than 0 mm. The length of the enclosed area (in plan view) may be at least 5 mm, suitably at least 10 mm, preferably at least 15 mm, more preferably at least 20 mm, especially at least 25 mm. The length of the enclosed area (in plan view) may be less than 100 mm, suitably less than 80 mm, preferably less than 60 mm, more preferably less than 50 mm, especially less than 40 mm.

For a particular loading of nonwoven or woven material, variations in the physical dimensions of each enclosure means will lead to an increase or decrease in the amount of product supported on each support in subsequent manufacturing steps. You will see that.

If the enclosed area is a quadrilateral, at least one side of the quadrilateral (hereinafter referred to as “first side”) is a fold of a material (preferably a thin layer material) forming the solid support. May be represented. Preferably, the side opposite to the first side of the quadrilateral (hereinafter referred to as “opposite side”) is represented by two layers of material that are physically adhered to each other. This may preferably be accomplished by welding (eg, heat welding) the two layers together such that the heat welded lines represent the boundaries of the enclosed area. Heat welding
This can be achieved by using direct heat or by using alternative forms of energy that generate heat to the materials to be joined (eg, ultrasonic means). The first side and the second side are preferably longitudinal sides of the enclosure means. A boundary extending across the enclosure means may be represented by physically joining the two layers of material together (eg, by heat welding).

[0036] The enclosure means is preferably substantially completely enclosed. Preferably, the enclosure means is capable of being contained therein (eg, 1
It has no gaps smaller than the physical dimensions of the resin beads (100-200 mesh resin). Preferably, the enclosure means does not include gaps of a size larger than 1 mm, more preferably larger than 0.5 mm, especially larger than 0.25 mm.

[0037] The enclosed area preferably contains, for example, a confined member or material.
Hold (confine). The confined material may be a resin (or the like), for example, a resin bead, and may position itself to support a compound or other site. Preferably, however, the enclosed area retains the identification means as described herein. The dimensions of the identification means may suitably be less than 30 mm, preferably less than 20 mm. Its dimensions may suitably be 1 mm or more. Preferred identification means are elongate.

The solid support preferably includes a plurality of enclosure means representing a plurality of enclosed areas, each as described herein, and preferably (if included) ) It is substantially the same except for the same attribute of the code combined with the identification means. Preferably, adjacent enclosure means of the solid support have a boundary line extending generally therethrough, representing a portion of the adjacent enclosure means.
The solid support may comprise an elongate continuum, wherein the encapsulated regions are preferably aligned with and adjacent to each other, preferably at least 10,
Preferably it has at least 100, more preferably at least 500, especially at least 1000. Preferably, the enclosed areas are located apart from each other.
Thus, the solid support can be split (eg, cut) between adjacent enclosed areas. The enclosure means is preferably arranged such that the split has little effect on the integrity of the enclosed area.

[0039] The solid support is preferably non-self supporting. The solid support may be flexible enough to be formed into a roll.

According to a fifth aspect of the present invention there is provided a method of manufacturing a solid support according to the fourth aspect of the present invention, the method comprising defining a region enclosed by a flexible material. Including doing.

Preferably, the flexible material is initially in the form of an elongate strip, preferably containing one layer of material, preferably a fabric as described herein. The method preferably comprises folding the elongate strip around a fold, which preferably extends substantially parallel to the longitudinal direction of the strip, and preferably extends in the middle along the longitudinal direction. Preferably, the strip is folded along its center. Preferably, the strip is only folded over along a part of its length. Preferably, the strip is folded from an extension point from its free end. After folding, the strip represents a container that opens upward because the other portion of the strip is preferably folded down.

The method preferably includes securing the opposing portions of the folded strip together. Preferably, the opposing portions, which initially extend transversely, are fixed to one another, preferably by heat welding.

The method preferably includes the step of coupling another member (eg, identification means) to the enclosed area. More preferably, the method comprises placing the identification means in said folded strip. The method preferably then comprises arranging the strip such that the identification means is enclosed in the enclosed area. The method may include securing the remaining opposing portions of the folded strip together. The method may also include securing opposing portions spaced apart from the fold and extending substantially parallel to the fold, preferably free ends of adjacently disposed strips, to one another. Good. The method may also include securing the opposing portions that are spaced from the opposing cross-extending portions and that preferably extend substantially parallel thereto.

In this way, a continuous strip containing a continuous volume of the enclosed area can be produced. For this purpose, after forming the above-mentioned encapsulated area, the enclosed area (
The enclosed area adjacent to the "first enclosed area" is hereinafter referred to as upstream of the first enclosed area, preferably by means of identification therebetween, of the folded area of the strip. It can be manufactured by fixing the facing parts together.

According to a sixth aspect of the invention, there is provided an apparatus for use in the method of the fifth aspect, comprising: feeding means for feeding an elongate strip of material; An apparatus is provided that includes folding means and securing means for securing portions of the strip together to define the area.

The supply means preferably supplies the strip towards the folding means. The securing means is preferably arranged to heat weld the parts together to define the enclosed area.

The apparatus preferably secures dispensing means for dispensing another member (eg, identification means) to the elongate strip for encapsulation in the enclosed area, and secures a portion of the strip to one another. Included before the fixing means.

The apparatus preferably includes reading means for reading the same attribute of the identification means, and information relating to the same attribute is preferably recorded electronically. Solid support (
If (optionally) the variety of the enclosed area is involved, the identification means are each preferably read and by recording the same attributes, the order of the identification means along the solid support is recorded.

According to a seventh aspect of the present invention, there is provided a method for synthesis or for use in screening (
Provided is a method of making a solid support (e.g., to support a compound or other moiety), which comprises irradiating a first polymeric material and then one or more monomers to prepare a graft polymer. Including contacting with.

Solid supports can be used in solid-phase chemical and biochemical synthesis, immunoassays and hybridization reactions, or to support reagents and scavengers. Preferably, a solid support is used in synthesis (eg, chemical synthesis) or as a reagent support. More preferably, the solid support is used in synthesis, especially in conjugation chemistry.

In the present specification, unless otherwise specified, when a group is described as being optionally substituted, the optional substituent may be a halogen (preferably, fluorine, chlorine or bromine,
Especially chlorine) atoms and alkyl, acyl, nitro, cyano, alkoxy, alkoxyalkyl, hydroxyl, amino, alkylamino, sulfinyl, alkylsulfinyl, sulfonyl, alkylsulfonyl, sulfonate groups, It can be selected from an amide group, an alkylamide group, an alkoxycarbonyl group, a halocarbonyl group (especially a chlorocarbonyl group, a haloalkoxy group) and a haloalkyl group (especially a chloroalkyl group).

Unless otherwise specified herein, an alkyl group has up to 12, preferably up to 10, preferably up to 8, more preferably up to 6, and especially up to 4, carbon atoms.
May be present, and methyl and ethyl groups are preferred.

Unless otherwise specified, preferred aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl groups have six membered ring atoms.

[0054] The first polymer material is preferably a thermoplastic polymer. The first polymer material may be a copolymer. The first polymeric material has a melt flow index (MFI) measured according to ASTM D1238 of at least 0.5 g / 10 min, suitably at least 2 g / 10 min, preferably at least 5 g / 10 min, more preferably at least 10 g / min. It can be 10 minutes. This MFI may be less than 50 g / 10 min, suitably less than 40 g / 10 min, preferably less than 30 g / 10 min, more preferably less than 20 g / 10 min, especially less than 15 g / 10 min.

[0055] The first polymer material is preferably hydrophobic. The first polymeric material is preferably thermoplastic.

The first polymer material may be a material that can be grafted in the method.
Such materials may include optionally substituted polyolefins, silicone polymers, natural or synthetic rubbers, polyurethanes, polyamides, polyesters, formaldehyde resins, polycarbonates, polyoxymethylenes, polyethers, epoxy resins, or copolymers thereof.

Optionally substituted polyolefins include polyethylene, polypropylene, polyisobutylene, acrylic polymers (eg, polyacrylates, polymethacrylates, polyethylene acrylates), halogenated vinyl polymers (eg, polyvinyl chloride), fluoropolymers (polytetraethylene). Fluoroethylene, chlorotrifluoroethylene and fluorinated ethylene-propylene), polyvinyl ether (for example, polyvinyl methyl ether), polyvinylidene halide (for example, polyvinylidene fluoride and polyvinylidene chloride), polyacrylonitrile, polyvinyl ketone, and polyaromatic And vinyl ethers (eg, polyvinyl acetate).

Suitably, the optionally substituted polyolefin is selected from polyethylene, polypropylene, partially fluorinated or perfluorinated polyolefin, and copolymers comprising any of the foregoing. Preferably, the optionally substituted polyolefin is selected from polyethylene, polypropylene and partially or perfluorinated polyethylene or polypropylene. More preferably, the optionally substituted polyolefin is a polyethylene and polypropylene polymer, with unsubstituted polyethylene and polypropylene being particularly preferred. Unsubstituted polypropylene is most preferred.

[0059] Optionally substituted silicone polymers include polydimethylsiloxane.

[0060] Natural or synthetic rubbers include butadiene-styrene copolymer, polyisoprene, polybutadiene, butadiene-acrylonitrile copolymer, polychloroprene rubber, polyisobutylene rubber, ethylene-propylene diene rubber, isobutylene-isoprene copolymer and polyurethane rubber.

[0061] Preferred polyamides are nylon 66 and poly or prolactam.

A preferred polyester is polyethylene terephthalate.

[0063] The first polymeric material is preferably isotactic.

[0064] The first polymeric material is preferably substantially insoluble in water at 25 ° C. The first polymer material typically has lower solubility in organic solvents (eg, dichloromethane) than polymers made from one or more monomers. The graft polymer is preferably 1
Combined with the combined chemistry of the above monomers, it has a low solubility of the first polymeric material.

The first polymeric material is preferably an optionally substituted polyolefin, polyamide, polyurethane, polyester or ethylenically unsaturated comonomer (eg,
(Olefin and vinyl acetate). More preferably, the first
The polymeric material is an optionally substituted polyolefin as described above.

[0066] The first monomer used in this method is preferably unsaturated, more preferably ethylenically unsaturated. The monomer is preferably reacted (suitably,
It contains a functional group that can cause an electrophilic or nucleophilic reaction, such as a substitution reaction. This preferably allows the other groups or sites to react with the sites derived from the monomers after the polymer has been prepared in a particular way. The first monomer comprises an optionally substituted aryl and heteroaryl group, a carboxylic acid group, a carboxylic acid derivative,
It may contain an amine group, an amine derivative, an inorganic acid, a sulfate group, a hydroxy group and a substituted alkyl group, a cycloalkyl group and a silk heteroalkyl group, and a functional group selected from any of the above protected forms.

[0067] Protected forms of the functional groups are well known to those skilled in the art. Details of protecting groups can be found in Protective Groups in Organic Synthesis, Theodora Greene and Peter Watts (1991) John Wiley and Sons, Inc., which is incorporated herein. I do.

A preferred aryl group is phenyl. A preferred heteroaryl group is pyridyl. Preferred carboxylic acid derivatives include ester groups, amide groups (including cyclic amides such as pyrrolidine moieties), and acid halide groups. Particularly preferred amides are carboxylic acid derivatives. Preferred functional groups based on inorganic acids include sulfur-oxo acids, especially sulfonic acid groups, and sulfur-oxo acid groups, especially phosphoric or phosphonic acid groups. Preferred alkyl groups are C _1-6 , more preferably C _1-4 , and especially C _1-2 alkyl groups. A preferred cycloalkyl group is cyclohexyl. Preferred cycloheteroalkyl groups have 5- or 6-membered ring atoms and include oxygen or nitrogen ring atoms.

Any substituents of an aryl or heteroaryl group can react, preferably in a substitution reaction (eg, a nucleophilic or electrophilic substitution reaction). This optional substituent is
It may be an optionally substituted alkyl group. Preferably, this optional substituent is
An optionally substituted haloalkyl group. More preferably, the optional substituent is a haloalkyl group, preferably a mono-halogenated group. A chlorine atom is a preferred halogen atom of a haloalkyl group. Preferred haloalkyl groups have 1 to 1 carbon atoms.
It has four, especially one or two. A chloromethyl group is a particularly preferred haloalkyl group.

The substituted alkyl, cycloalkyl, and cycloheteroalkyl groups preferably include a substituent that can react in a substitution reaction (eg, a nucleophilic or electrophilic substitution reaction). Examples of the substituent include a halogen atom, particularly a chlorine atom. Preferred alkyl, cycloalkyl and cycloheteroalkyl groups are monohalogenated.

Preferred functional groups of the first monomer include carboxylic acids, carboxylic acid derivatives, optionally substituted phenyl, and organic basic groups based on pyrrolidine or pyridine. Preferred functional groups are polar.

The functional group of the first monomer may be linked to the C ＝ C site of the monomer by any suitable means. Preferably, this functional group is a vinyl group or an allyl group. Vinyl groups are most preferred.

Preferably, the first monomer is an ethylenically unsaturated carboxylic acid (eg, an alkyl-substituted ethylenically unsaturated acid such as acrylic acid or methacrylic acid), an ethylenically unsaturated carboxylic acid amide (eg, acrylamide), ethylene Ethylenically unsaturated carboxylic amines (eg, alkylamine acrylates such as butylamine acrylate), ethylenically unsaturated organic bases (eg, vinylpyrrolidine or vinylpyridine), and ethylenically unsaturated, optionally substituted phenyl compounds (styrene) Or substituted styrene).

Preferably, the first monomer is selected from the ethylenically unsaturated acids, the ethylenically unsaturated carboxylic amides, and the ethylenically unsaturated, optionally substituted phenyl compounds.

Preferably, the first monomer does not include a functional group capable of hydrogen bonding with another functional group of the same type.

[0076] The first monomer is preferably a vinyl monomer.

[0077] The method can cause the first polymeric material to contact the second monomer. The second monomer may have any of the characteristics of the first monomer described in the present invention. However, preferably, the first and second monomers have different functional groups. Preferably, the first monomer is the first monomer after preparing the graft polymer.
Since the functional group carried by the monomer is selected to be capable of reacting with the compound (eg, a linker), the compound can contact the first polymeric material via the first monomer, but under the reaction conditions The compound does not contact the first polymer material via the second monomer because the functional groups carried by the second monomer do not react. Thus, preferably, the second monomer is substantially non-reactive under the reaction conditions, but the functional groups of the first monomer can react. Thus, in the graft polymer, the second monomer may help dilute the amount of the first monomer on the surface of the first polymer. As a result, the functional groups of the first monomer (and / or the sites that bind to it in downstream manufacturing steps), and thereby the sites that come into contact with the functional groups, are further apart. Therefore, the spacing between each purified side chain of the first monomer can be minimal.

Preferably, the second monomer does not contain any displaceable chlorine atoms (preferably no chlorine atoms). More preferably, it does not contain a halogen atom. Preferably, the second monomer does not contain a carboxylic acid group.

The second monomer may contain a functional group selected from an amide group, especially a primary amide group, an ether group or a polyether group, or an optionally substituted aryl group, especially a phenyl group. A phenyl group may be substituted or unsubstituted. Preferably, the phenyl group is unsubstituted.

[0080] The substituents of the second monomer may be bonded directly or by any suitable means to the C = C site of the monomer. Any type or length of site may be provided between the C = C site and the functional group. Preferably, the functional groups are vinyl or allyl groups. Vinyl groups are most preferred.

[0081] Preferably, the second monomer is an ethylenically unsaturated carboxylic amide (eg,
Acrylamide) and an ethylenically unsaturated, optionally substituted (preferably unsubstituted) phenyl compound (eg, styrene).

The volume ratio of the first monomer to the second monomer (if a second monomer is used) may range from 9: 1 to 1: 9. Preferably, the volume ratio is between 3: 1 and 1
: 3.

[0083] In the method of the seventh aspect, the first polymer material may be irradiated using a suitable light source. Irradiation is preferably performed in the presence of oxygen, preferably in air. Irradiation is believed to cause free radicals generated by hydrogen extraction in the polymer backbone of the first polymer material. The free radicals combine with oxygen to form a peroxide species on the polymeric material that is stable at ambient temperature (eg, 22 ° C.). Thus, a peroxided first polymeric material is prepared as a result of the irradiation. The irradiation used in this method is preferably ionizing radiation and may include gamma rays, electron beams, X-rays, ultraviolet rays, ozonizing radiation or plasma radiation. The use of gamma rays is preferred.

The irradiation dose is at least 1 kGy, suitably at least 2 kGy, preferably at least 3 kGy, more preferably at least 4 kGy, especially at least 5 kGy.
may be y. The irradiation dose may be less than 100 kGy, suitably less than 50 kGy, preferably less than 40 kGy, more preferably less than 30 kGy, especially less than 20 kGy. The irradiation measure may be at least 0.25 kGy / h, preferably at least 0.5 kGy / h, more preferably at least 0.75 kGy / h. The irradiation measure may be less than 10 kGy / h, preferably less than 5 kGy / h, more preferably less than 2.5 kGy / h, especially less than 2 kGy / h.

In this method, preferably, there is an interval after irradiation and before contact with the monomer. The irradiated first polymeric material may be stored during the interval, preferably at or below ambient temperature.

[0086] Graft polymerization can be achieved by contacting the irradiated first polymer material with the monomer in a solution, which can be in the form of a liquid, a partial solution or an emulsion. The monomer is suitably provided in a solvent, which is preferably an aqueous solution, more preferably water. In particular, when the monomer does not dissolve in water, a surfactant (for example, an emulsifier) may be contained in the solvent. Homopolymerization initiator (
For example, iron (II) sulfate may be contained. The reaction between the monomer and the peroxided material is preferably in the absence of oxygen, suitably inert (eg, nitrogen)
It is performed in an atmosphere.

The concentration of the monomer in the liquid is at least 5% by weight, preferably at least 1%.
It may be 0% by weight, more preferably at least 15% by weight. This concentration is 5
It may be less than 0% by weight, preferably less than 40% by weight, especially less than 30% by weight.

In this method, the temperature is preferably raised (preferably to at least 40 ° C., more preferably to at least 50 ° C.) after irradiation and when the peroxided first polymeric material is in the presence of the monomer. The temperature rises preferably in the range of 40-60 ° C, more preferably in the range of 40-80 ° C. It is believed that at elevated temperatures, the peroxide species decomposes, thereby obtaining peroxy radicals that can initiate the reaction of the grafted side chains with the monomer. The side chains are considered to be covalently linked to the main chain of the first polymer material by -O- bonds. This fact distinguishes materials prepared according to the first aspect from materials prepared by the alternating irradiation step, as the side chains are attached to the main chain by carbon-carbon bonds in the materials prepared by the alternating irradiation step. Can be used for

[0089] The first polymeric material used in the method may be in any suitable form. For example, the first polymeric material may include powder or pellets (or the like) after preparation of the graft polymer, which may be reshaped, for example, by melting, extraction, blow molding or other molding methods. Accordingly, the method of the first aspect may include the additional step of changing the physical form of the graft polymer and molding it into a form for use as a solid support. Alternatively, the first polymeric material may be in a form that can be used as a solid support.

Preferably, the first polymeric material is in the form of a fabric, which may or may not be woven. The fabric may be as described herein.

[0091] The fabric is preferably not woven.

The one-dimensional dimension of the graft polymer prepared in this way is at least 1 cm
, Preferably at least 2 cm, the two-dimensional dimensions being at least 10 cm.
cm, suitably at least 50 cm, preferably at least 100 cm, more preferably at least 200 cm, especially at least 300 cm, the three-dimensional dimensions being at least 0.1 mm, suitably at least 0.3 mm, preferably at least 0.3 mm. It may be 4 mm, more preferably at least 0.5 mm. The three-dimensional dimensions may be less than 1 cm, suitably less than 0.5 cm, preferably less than 0.2 cm, more preferably less than 0.1 cm, especially less than 0.08 cm.

The degree of grafting may be at least 5% by weight, preferably at least 8% by weight, in particular at least 10% by weight. The degree of grafting may be up to 50% by weight, preferably up to 45% by weight, in particular up to 40% by weight. The degree of grafting is calculated from the original weight of the first polymer material and the monomer according to the following equation.

[0094]

(Equation 1) (Where wf is the final weight of the graft polymer and wi is the initial weight of the first polymer material.)

The melt flow index (MFI) of the graft polymer, when measured according to ASTM D1238, is in the range of 0.5 to 15 g / 10 min, preferably 0.5 to 5 g / min.
It can be 10 minutes.

[0096] The method of the seventh aspect may include providing a linker site on the graft polymer. The linker moiety is suitably arranged so that other compounds or moieties can be covalently linked to the linker moiety and / or separated therefrom when necessary.
The linker moiety can be synthesized on the graft polymer in a series of steps. Or,
Suitably, the linker compound is a moiety derived from one or more monomers, or
The graft polymer may be treated with a linker compound to form a covalent bond with another site linked to a site derived from the above monomer. (However,
The linker moiety (to be formed) is preferably covalently linked to a moiety derived from or bonded to a functional group of the monomer.

[0097] Methods for providing linker sites are well known. For example, tetrahedron No. 51
Vol. 30, No. 8, pp. 8135-8173 (1995), and commercially available "Wang (W
ang), "Rink" and "Trityl" linkers.

[0098] The solid support prepared by the method of the seventh aspect may be of any known type. For example, International Patent Application Publication No. WO 98/31732 (Iori) describes a particular range of supports, including walls, trenches, containers, beads, pins, crowns and shafts. However, preferably, the solid support is one described by the invention or embodiment described herein.

According to an eighth aspect of the present invention, as a solid support for use in synthesis or screening, a graft polymer prepared by irradiating a first polymeric material and then contacting with one or more monomers The use of is provided.

According to a ninth aspect of the present invention there is provided a solid support for use in synthesis or screening, wherein the solid support is prepared or prepared as described in the seventh aspect. be able to.

The method of the seventh aspect preferably results in the monomer being covalently linked to the first polymeric material via an ether group. Thus, in a tenth aspect, there is provided a solid support for use in synthesis or screening, the solid support comprising a polymer backbone containing a first polymer material and a pendant side chain derived from one or more monomers. And the side chain is covalently bonded to the first polymer material by an ether bond.

[0102] The presence of an ether linkage may be indicated by conventional analytical techniques. Furthermore,
The solid support may be treated with undiluted HI or HBr to separate sites derived from the monomers from the first polymeric material.

The solid support may include the above-described linker moiety covalently linked to the polymer backbone, preferably via a pendant side chain derived from the monomer. The linker site suitably provides a point of attachment to which other compounds and / or materials can be covalently bonded. For example, the compound may be a starting material in a series of synthetic steps to produce a chemical compound.

For release, the solid supports described herein support relatively many added materials.
There are things that can be done. The amount added is at least 0.01 mmol / g, preferably
Has at least 0.1 mmol / g, preferably at least 1 mmol / g,
More preferably at least 2 mmol / g, especially at least 3 mmol / g.
May be. Depending on the case, 4 mmol / g or 5 mmol / g can be supported. Ah
Under certain circumstances, it may be possible to support about 10 mmol / g. "
The term "mmol / g" refers to the first polymer used to make the solid support.
-Note that the amount of material that can be separated from the solid support per gram of material
It is. Stated another way, the amount added is 1 cm of material^TwoPer micromole (and this is the case when the solid support is a laminar material).
Especially suitable). In this case, the amount of addition is at least 0.1 micromol / cm. ^Two , Preferably at least 1 micromol / cm^Two, Preferably at least 2 microphones
Romole / cm^Two, More preferably at least 3 micromol / cm^TwoEspecially less
Both 4 micromol / cm^TwoIt may be. 10 micromol / cm^TwoUp to
The quantity is fulfilled.

According to an eleventh aspect of the present invention, there is provided a method of generating a library of compounds, the method beginning with an arrangement of an x × y array of independent reaction regions, each arrangement of a reaction region , Each of which comprises a combined identification means for uniquely identifying each. Here, adjacent reaction regions in the arrangement of the sequence are properly connected to each other,
The order of the identification means in the arrangement of the array is predetermined (hereinafter, referred to as “predetermined order”). This method comprises the steps of: (a) dividing the arrangement of the sequences into a plurality of subsequence arrangements; (b) subjecting some of the arrangements of the subsequences to a different chemical process than others; By identifying the identification means coupled to the reaction region in the sub-array arrangement that is less than the total number of identification means coupled to the reaction area in the arrangement of the arrays, (D) determining (when necessary), (d) repeating the above step (c) to identify the arrangement of other subsequences, and (e) arranging each of the subsequences in a plurality of further subsequences. Arbitrarily, and repeating steps (b) to (d) in this further arrangement of subsequences, wherein the reference to `` arrangement of subsequences '' in steps (b) to (d) is made. Is treated as a reference to "arrangement of additional subsequences". As different chemical processes is apparent that each reaction zone is subjected, different chemical processes each reaction region is subjected is recorded.

The library of compounds has at least 500, preferably at least 1000,
More preferably it may have at least 5000, especially at least 1000 members. However, there is no practical limit on the method or the number prepared in the library.

The ratio between x and y is at least 50, suitably at least 100, preferably at least 500, more preferably at least 1000, especially at least 5000
It may be.

Y is suitably 10 or less, preferably 7 or less, more preferably 5 or less, especially 2
It is as follows. Most preferably, y is 1, so that the arrangement of said sequence is a primary sequence. x may have any value up to infinity. x is suitably at least 100, preferably at least 1000, more preferably at least 5000, especially at least 10,000.

The independent reaction zones may be represented by any suitable means. For example, it may be in the form of a container, such as a microtiter dish or a hole, even if it is a particle, or an induced glass slide, a silicon chip with a surface suitable for binding biologic particles or molecules, nitro, Cellulosic sheets, nylon mesh or other such materials, or pores or solid surfaces that bind molecules or biologic particles (eg, microtube micros marketed under the trade name “Pin” by Airoli and Keiron) (Reactor).
Examples of suitable means are described in WO 98/15825 (Iroly).

Preferably, the independent reaction zone is represented by a laminar material. The reaction zone is
It may be represented by any of the materials described herein.

The identification means may be as described herein.

[0112] Coupling of adjacent reaction regions within the arrangement of the sequences can be achieved by suitable means. For example, the granular reaction regions or reaction regions connected to the vessel may be in a bead with respect to each other. Particles or containers can be manufactured by extrusion or other suitable techniques, using a bonded web (such as) between adjacent particles / containers.

Preferably, the coupling means for coupling adjacent reaction regions is an integral part of the means for supporting independent reaction regions (eg, a unit including the means). The coupling means is preferably made of substantially the same material as part of the means for supporting the independent reaction zone. If the independent reaction zone is represented by a laminar material,
Bonding of adjacent reaction zones can be achieved by portions of laminar material extending between adjacent reaction zones.

The recording means is preferably provided for recording a predetermined order, preferably electronically. The recording means preferably comprises a computer.

In step (a), preferably, the arrangement of the sequences is divided at a part of the adjacent reaction region. Splitting may simply involve cutting the arrangement of sequences at adjacent reaction regions to separate adjacent reaction regions from each other.

Preferably, when separating adjacent reaction zones, indicator means are arranged to distinguish between the ends of the part formed thereby. The indicator means is preferably a visible indicator. It may include only a visible indicator (eg, a notch) at or adjacent one end of the portion to be formed. Preferably, the indicator means is arranged to indicate whether one end is the upstream end or the downstream end of the secondary arrangement (or the right end or the left end).

The splitting of the sequence arrangement according to steps (a) and / or (e) can be determined when the sequence / subsequence arrangement is to be split during the construction of the compound library, Preferably, each division of the arrangement of the sequence / subsequence is determined in advance as described below.

Similarly, the chemical process for subjecting the arrangement of sub-sequences and / or the arrangement of further sub-sequences to steps (b) and / or (e) may comprise the arrangement of sub-sequences / addition of further sub-sequences After being subjected to the process, the same attributes of each of the arrangement of the sub-sequences / the arrangement of the further sub-sequences (or more preferably the same attributes of each of the independent reaction regions in the arrangement) and their (or more preferably You can choose when you want to record the reaction to which the reaction region (each of the reaction regions) is attached, but the chemical process that is to be applied to the arrangement of subsequences / further subsequences (or more preferably each of the independent reaction regions). Is preferably determined in advance as described below.

Preferably, the position at which the arrangement of the sequence is divided in step (a) is determined in advance. Preferably, a computer is arranged to instruct the operator to divide the array. Preferably, the arrangement of the sequences is divided into the same number of subsequences, since there are different chemical processes in step (b).

Preferably, in this method, adjacent reaction zones are fixed in relation to each other (preferably directly) until they are subjected to a different process, and when subjected to a process, the reaction regions described in step (a) are described. They are suitably split as described above. This is in contrast to the method described in WO 96/16078 (Pfizer) in which adjacent reaction areas in the starting sequence (eg, a three-dimensional stack of independent sheets) are initially not fixed at all to one another. It is a target.

In step (b), preferably, the configuration of each subsequence is subjected to a different chemical process than the configuration of the other subsequence. The different chemical processes preferably involve reactions with different compounds and / or different reagents.

Preferably, each step to which the arrangement of each sub-sequence is added in step (b) is predetermined. Preferably, the computer is arranged to instruct the operator to go to the process to which each of the sub-array arrangements is applied.

In the step (c), the same attribute of the arrangement of the sub-array can be determined as described above, except that the same attribute of the arrangement of the sub-array is not known. For example, if the array arrangement is divided at the start of the method to represent the arrangement of two sub-arrays, the arrangement of each sub-array can be known without having to be determined in step (c) to be performed . However, after a subsequent step, the attribute will need to be determined as described in step (c).

In step (c), if the same attribute of at least one reaction region is determined, less than 50%, preferably less than 25%, preferably less than 10% of the total number of reaction regions in the arrangement of subsequences
The same attribute of less than%, more preferably less than 5% is determined. Suitably, in step (c), 1 to 10, preferably 1 to 5, more preferably 1 to 2 and especially only 1
The same attribute of one reaction area is determined.

Preferably, in the step (c), the same attribute of each of the independent reaction regions in the arrangement of each subsequence is determined by associating a predetermined order with the same attribute of the identification means.

Preferably, the method of step (c) includes the following steps. (i) selecting a reaction region identified in the arrangement of the selected subsequence (hereinafter referred to as “identified reaction region”); and (ii) a position of the reaction region identified in the arrangement of the selected subsequence. (Iii) determining the same attributes of the identified reaction areas, (iv) associating the information identified in steps (ii) and (iii) with a predetermined order, Determining the same attributes for each reaction region in the arrangement of the sequence.

As shown in this method, the different chemical processes to which the reaction zones are assigned are recorded. The recording is made when or at about the time the reaction zone is subjected to a particular process (eg, immediately before or immediately after the process), but preferably, a different chemical process to which the reaction zone is applied, preferably It is determined and recorded before performing with the chemical process, more preferably before dividing the arrangement of the sequences in step (a) and / or subjecting it to a chemical process, for example in step (b).

In a preferred embodiment, the method of constructing a library of compounds begins with the arrangement of an x × y array of independent reaction regions (ie, a one-dimensional array), starting with each reaction region in that arrangement and adjacent reaction regions. The combined identification means for uniquely identifying the regions are each fixed to one another in the order of the identification means in a predetermined arrangement of arrangements, and are preferably stored electronically, for example in a computer. Here, each process to which each reaction zone is to be applied is predetermined and preferably recorded electronically, for example in a computer. The method includes the following steps. (A-1) dividing the arrangement of the arrangement in a predetermined manner so as to provide an arrangement of a plurality of predetermined sub-arrays, and (B-1) pre-determining the arrangement of the sub-arrays. (Preferably, chemistry) process, (C-1) Subsequence arrangement is selected, and the next step to assign the selected subsequence arrangement (for example, (B-1) In order to enable the determination of the subsequence of the subsequence, only one reaction region of the arrangement of the subsequences (preferably the reaction region at one end of the arrangement of the subsequences) is identified so as to enable its determination. Determining attributes.

Step (C-1) may be performed before step (B-1) to ensure that the arrangement of the subsequences is subjected to a suitable predetermined chemical process. . Step (C-1) is a step
It may be repeated for each arrangement of the sub-arrays subjected to the chemical process in (B-1). Step (C-1) may be repeated after performing the following procedure described in step (C-1).

The arrangement of sub-arrays may be stored for cleaning purposes (or other procedures common to the arrangement of multiple sub-arrays). For release, the arrangement of the subsequences may be selected and identified after such a common procedure, as described in step (C-1).

In a less preferred embodiment, the method of creating a library of compounds begins with the arrangement of an xx array of independent reaction regions. Each of the independent reaction regions includes a combined identification means for uniquely identifying each region, and adjacent reaction regions are coupled to each other with a predetermined order of the same attribute means in the arrangement of the sequence, It is preferably stored electronically, for example in a computer. The method includes the following steps. (A-2) dividing the arrangement of the sub-sequences into arrangements of a plurality of sub-sequences, (B-2) subjecting the arrangement of the sub-sequences to a process, preferably a chemical process, (C-2) (step (B By selecting a subsequence configuration (before or after -2) and identifying only one reaction region of the subsequence configuration (preferably, a reaction region at one end of the subsequence configuration). The attributes are determined and each reaction region in the sub-sequence is identified using available information (eg, the order of the identification means, the location of the reaction region to be identified and / or the number of reaction regions in the arrangement of sub-sequences). (D-2) Recording each process to which each reaction zone is applied, preferably immediately before or immediately after applying the reaction zone to the process.

In the method according to the eleventh aspect, after performing all relevant process steps,
A library of compounds associated with each independent reaction region may be provided. This compound can then be separated from the independent reaction zone. At the end of the method, it will be appreciated that the process to which each reaction zone is assigned can be determined, thereby determining the same attributes of each of the compounds separated from each reaction zone.

According to a twelfth aspect of the present invention, there is provided a library of compounds created using the method of the eleventh aspect.

The method according to the eleventh aspect used to identify each reaction region within the arrangement of subsequences is considered to be novel. Thus, in a thirteenth aspect, the present invention provides a method for determining the same attribute of each of the reaction regions in a sub-array arrangement including a known number of reaction regions. Here, the arrangement of the sub-sequence is separated from the arrangement of the parent sub-array, and the same attribute and position of each reaction region in the arrangement of the parent sequence are determined in advance. The method includes the following steps. (a) selecting a reaction region to be identified in the arrangement of the subsequences (hereinafter referred to as “identified reaction region”); and (b) writing down the position of the identified reaction region in the arrangement of the subsequences. (C) determining the same attribute of the reaction region to be identified; (d) determining the information confirmed in the above steps (b) and (c) by determining the information of each reaction region in the arrangement of the parent sequence. Associating with the same attribute and position, thereby determining the same attribute of each reaction region in the arrangement of the subsequence.

The reactions extend to methods of creating libraries of chemical compounds that can be synthesized on a much larger scale than previously used techniques, and materials in the range of 1-5 mg are easily handled. The present invention provides a method for producing a lamellar material suitable for creating a combinatorial library, wherein the material can be added in large amounts and is easily handled. The reaction may use a laminar material with a fine fibrous structure that derives new and previously unapproved advantages. For example, the surface area of the microfibrous lamellar material is so large that the available chemical functional groups available per unit surface area are greatly increased. This allows for the preparation of large amounts (mg) on small areas of laminar material, for example, a combined product set of 50 mg can be prepared for about 2 cm ² of material. In this method, a sample of a suitable type of polyethylene, polypropylene or other polyolefin in solid powder form is irradiated with a ⁶⁰ Co source and then separately functionalized by suitable graft copolymerization with a monomer. The chemical functionality that can be imparted to the solid powdered graft copolymerized polyolefin is then accessed in a manner well described in the chemical literature. Functionalized solid powder graft copolymerized polyolefin is melted into the required physical form, extruded, blow molded,
It can be molded and formed. This is a small porous container, tape. It can take the form of a strip or a streamer.

Features of any aspect of the invention or embodiment described herein may be combined with features of any other aspect of the invention or embodiment described herein.

Specific embodiments of the present invention will be described by the following examples with reference to the accompanying schematic diagrams.

Example 1 Polypropylene nonwoven fabric (Freudenberg-Spinfriedoffe-Comandit Gesellshaft, marketed under the trade name LUTRASIL; density 100 g / m ² ; thickness 550-650 μm) A sample (3 cm × 10 cm) was exposed to a cobalt 60γ-ray source in air at a total dose of 2.5 kGy to 1 kGy.
Irradiation was performed at 0 kGy at an irradiation rate of 1 kGy / hour. After the irradiation, the accurately weighed sample was treated with methacrylic acid (MAA) and dimethylacrylamide (DAM) having a volume ratio of 10/0 to 1/9% by volume and iron (II) sulfate as a homopolymerization initiator.
Was placed in a glass container together with 100 mL of an aqueous solution containing The mixture was deoxygenated by bubbling with oxygen-free nitrogen and the glass container was placed in a thermostated water bath at 70 ° C. under nitrogen for 3 hours. The grafted fabric is filtered from the grafting solution and thoroughly washed with warm deionized water,
Dried to constant weight. The degree of grafting was calculated by the following equation.

[0139]

(Equation 2) Where wi is the initial weight of the pre-irradiated sample and wf is the resulting weight of the grafted sample. )

Table 1 shows the degree of grafting (% by weight) obtained at different irradiation doses and with different monomer ratios.
).

[0141]

[Table 1]

Example 2 The polypropylene fabric described in Example 1 was preliminarily irradiated with gamma rays at a total irradiation dose of 25 kGy and an irradiation speed of 1 kGy / hour in the same manner as in Example 1, and then the emulsifier [sodium dodecylbenzenesulfonate] was used. Salt (manufactured by BDH)] containing 0.1% styrene / 4-chloromethylstyrene aqueous emulsion (styrene: chloromethylstyrene volume ratio of 8: 2, 7: 3, 6: 4, 5: 5 (vol%)) Changed by
Was reacted at 80 ° C. for 5 hours for grafting. Grafted Fabric Samples were filtered from the grafting solution and thoroughly washed with warm deoxygenated water before Soxhlet extraction in acetone. When the samples were dried to constant weight, the degree of grafting was 10.2%, 8.8%, 8.3% and 9.4% by weight.

Example 3 The polypropylene fabric described in Example 1 which had been peroxided under the same conditions as described above was used as an emulsifier in a 10% by volume aqueous solution containing methyl methacrylate / dimethyl acrylate in a volume ratio of 6: 4. ) Using X-114 [octylphenoxypolyethoxyethanol (manufactured by BDH)], the mixture was graphitized at 80 ° C for 5 hours. The grafted fabric was washed with warm deionized water and extracted with acetone to give a degree of grafting of 30.4% by weight.

Example 4 A polypropylene powder which had been peroxided under the same conditions as described above was mixed with acrylic acid / dimethylacrylamide (volume ratio 6: 4) and 5.56 g / L of iron (II) sulfate as a homopolymerization initiator. Grafting was carried out at 80 ° C. for 5 hours in the contained 10% by volume aqueous solution. The grafted polypropylene powder was filtered from the grafting solution, thoroughly washed with warm deionized water until neutral and dried to constant weight.
The degree of grafting was 38.33% by weight.

Example 5 Polypropylene pellets (NOVOLEN) 2800J (manufactured by BASF) were molded into plaques having a thickness of 1500 μm by compression molding, cut into small dumbbells of 33 mm × 3 mm, and subjected to a total irradiation with a γ-ray source. Peroxidation was performed at 25 kGy at an irradiation rate of 1 kGy / hour. The peroxidized polymer was grafted in a 10% by volume aqueous solution containing acrylic acid / dimethylacrylamide (volume ratio of 6: 4) at 80 ° C. for 5 hours using iron (II) sulfate as a homopolymerization initiator. . The resulting grafted polymer was thoroughly washed and dried to a constant weight. The degree of grafting is 29.
It was 57% by weight.

Example 6 Preparation of Long Chain Grafted Materials In general, the procedures of Examples 1 to 3 can be used to provide long chain grafted materials. For this, the strip (which can be up to 6 m long and up to 30 cm wide) was wound up on a roll and irradiated to peroxideize.
The peroxided material is stable at ambient temperature (about 22 ° C.) for up to about 3 months. The roll of material was rewound and re-wound in contact with the nonwoven interlayer material.
Next, the reaction can be carried out in the same manner as in Example 1 by immersion in a monomer solution. The supply of the intermediate layer comprises contacting the monomer solution with peroxided propylene,
Helps penetrate into it.

Examples 7-19-Reactions Arising on Grafted Materials The following reactions were performed to demonstrate that the materials prepared as described herein can be used as solid supports. The following abbreviations are used below. Boc-tert-butyroxycarbonyl DIC-diisopropylcarbodiimide HOBt-N-hydroxybenztriazole TFA-trifluoroacetic acid DCM-dichloromethane Fmoc-9-fluorenylmethoxycarbonyl DMF-N, N'-dimethylformamide

Example 7 Production of Acrylic Acid-Grafted Material An acrylic acid-grafted material [2 m, 0.75 Mrad, grafted product of methacrylic acid: dimethylacrylamide = 6: 4] was treated with Boc-NH— (CH ₂ ) in dichloromethane. _{) 2 -NH 2 / DIC-HOBt} (10 equivalents) was 48 hours. After the normal wash cycle described in Example 19 below, the Boc group was replaced with TFM5 in DCM.
Removed using 9%. The amino compound was then prepared from 3,6,
Reaction with 9-trioxaundecandioic acid (20 eq) in DCM for 48 hours. The resulting carboxy derivative, then, Boc-NH- and _{(CH 2) 2 -NH 2 /} D IC-HOBt (10 equivalents), during DCM, and coupled for 48 hours. Then, the Boc group was removed as described above, and the ninhydrin quantitative test was performed to determine the substitution rate of 2.
35 micromoles / cm ² were obtained. The material (2.35 micromoles ^{/ cm 2) 200cm 2 Fmoc-} Gly /
The reaction was performed with DIC-HOBt in DMF for 1 hour. The resin is then dried in DCM for 2 hours.
Allowed to react for hours and capped with Ac ₂ O / pyridine. By performing a quantitative test of Fmoc, a substitution rate of 1.42 μmol / cm ² was obtained. The resulting material was treated with 20% piperidine in DMF for 20 minutes. The free amino derivative was then converted to p-[(R, S) -κ- [1- (9H-fluoren-9-yl) -methoxyformamide] -2,4-dimethoxybenzyl] -phenoxyacetic acid (Fmoc-Rink linker , 1.5 equivalents)
, DIC (1.5 eq), HOBt (1.5 eq) in DCM and the resin was shaken overnight. The remaining free amino sites were removed by adding excess acetic anhydride / DCM in DCM.
Capped with pyridine.

Example 8 Preparation of Tripeptide Fmoc-Ala-Phe-Gly-NH ₂ 90 cm ² of the Fmoc-Rink linker material prepared in Example 7 was treated with 20% piperidine for 20 minutes. The obtained amino compound was converted to Fmoc-Phe-G
Treated with a solution of ly-OH (4 eq), HOBt (4 eq) and DIC (4 eq) in DCM for 24 h. Thereafter, the Fmoc group was removed and Fm was removed using the same procedure.
Coupling oc-Ala to Fmoc-Ala-Phe-Gly-Rink
A linker material was obtained. Next, the tripeptide was separated from the resin by shaking with 95% TFA, 5% H ₂ O for 1 hour. The crude material was purified first on silica and then by secondary purification HPLC to give 1.7 mg of pure tripeptide (38% yield).
). This tripeptide was identified by NMR data, ES MS (MH) 415. Eluted with authentic samples prepared on regular polystyrene beads.

Example 9-Oxidation Experiment Fmoc-Rink linker material (0. 0) prepared as described in Example 7.
316 μmol / cm ² ) 50 cm ² with 20% piperidine in DMF
Minutes. Fmoc-phenylalanine (5 equivalents), HOBt (5 equivalents),
DIC (5 eq) was added and the coupling reaction was performed in DCM for 6 hours. 25 cm ² of this material was treated with 20% piperidine in DMF for 20 minutes to remove the Fmoc group before coupling 4-hydroxymethylbenzoic acid using the same coupling procedure described above. The 4 cm ² of the test piece 25 cm ² of this material, 95%
Treatment with TFA provided the starting material. The remainder of the resin was suspended in dry DMSO (10 mL) and pyridine sulfur trioxide (10 equivalents), triethylamine (10
Was added and the reaction was shaken for 18 hours. Separation with 95% TFA, HPLC
Analysis confirmed complete conversion to the aldehyde product (ES MS, MH2
Identified at 97 and eluted with the authentic sample (purity 51%, impurity is HOBt).

Example 10-Reduction Experiment 25 cm ² of the Fmoc-Phe-Rink linker material prepared in Example 9 was treated with 20% piperidine in DMF for 20 minutes to remove the Fmoc group. The resulting amino product is then converted to 4-formylbenzoic acid (5 equivalents), DIC (5 equivalents),
HOBt (5 eq) was coupled in DCM for 2 h. The 4 cm ² was separated with 95% TFA to give a starting standard. The remaining resin was suspended in MeOH (10 mL) and treated with sodium cyanoborohydride (10 eq). (A small amount of bromocresol green was added to monitor the pH and the pH was adjusted to 1 in methanol.
0% HCl was added and maintained periodically (one or two drops at a time). 16) After 16 hours, the resin was washed as described in Example 19, separated with 95% TFA and verified by HPLC analysis for complete conversion to the alcohol product. ES
The alcohol product was identified by MS (MH299) and elution with authentic samples (39% purity, HOBt impurity).

[0152]Example 11-Suzuki experiment The Fmoc-Phe-Rink linker material prepared above (0.316 microphone
Romole / cm^Two) 30cm^TwoWas treated with 20% piperidine in DMF for 20 minutes
. The resulting amino compound was then combined with Fmoc-glycine (5 equivalents), DIC (5
Eq.), HOBt (5 eq.) In DCM for 3 h. Ninhydrite
The test was negative. The Fmoc group is then removed as described above to give
The amino product was treated with 4-iodobenzoic acid (5 eq), HOBt (5 eq) and DIC
(5 equiv.) In DCM. The reaction was shaken for 16 hours. this
4cm^TwoWas treated with 95% TFA to give a starting standard. After swelling the remaining resin in DMF (20 mL), phenylboronic acid (1.5 equivalents), Pd @ P (Ph) _Three ｝_Four(0.1 equivalent) and K_TwoCO_Three(2 equivalents) was added. 6 hours at 60 ° C
For a while. The reaction medium became black, but the resin was used according to the procedure described in Example 19.
And thoroughly washed. Thereafter, this was separated by 95% TFA for 1 hour to obtain a crude material.
Was analyzed by HPLC (35% conversion, ES MS 255, depending on the long reaction time).
Increased).

Example 12-Derivatization of styrene / chloromethylstyrene grafted material A styrene / chloromethylstyrene (5: 5, degree of grafting 94% by weight) material (30 cm ² ) prepared as described in Example 2 was used. And DMF (50 mL). Potassium phthalamide (10 equivalents) was added and the reaction was slowly stirred at 120 ° C. for 24 hours. This material was combined with hot DMF (5 times), DMF: H ₂ O (1: 1, 5 times), dioxane: H ₂ O (1: 1, 5 times), dioxane (5 times), DCM (5 times) and Washed with ethyl ether (5 times). This material was then suspended in ethanol (50 mL) and hydrazine hydrate (5 m
L) was added and the reaction was refluxed for 4 hours. Washing was performed in the same manner as described in Example 19 to obtain an amino derivative having a substitution rate of 1.9 μmol / cm ² . Using this material, the tripeptide of Example 8 was prepared in the same manner (purity: 95% as quantitative yield).

Example 13-Derivatization of styrene / chloromethylstyrene grafted material Styrene / chloromethylstyrene (5: 5, degree of grafting 20% by weight)
100 cm ² ) was derivatized to an aminomethyl derivative. A substitution rate of 1.9 μmol / cm ² was obtained.

[0155] Preparation of Example 14-Fmoc-Phe-Rink linker material then aminomethyl material 90cm ² of Example 13, in DCM, Fmoc -Rink- linker (1.5 eq), DIC (1.5 Equivalent), HOBt (1.
(5 equivalents) for 16 hours. Nin k hydrin test was negative. Fmoc
The test gave a substitution rate of 1.25 micromol / cm ² . The Fmoc group was removed with 20% piperidine in DMF and the resulting amino product was coupled with Fmoc-phenylalanine (5 eq), DIC (5 eq), HOBt (5 eq) for 4 hours. The ninhydrin test was negative.

Example 15-Reduction Experiment 25 cm ² of the Fmoc-Phe-Rink linker material prepared in Example 14 was treated with 20% piperidine in DMF for 20 minutes to remove the Fmoc group. The resulting amino product was purified in DCM with 4-formylbenzoic acid (5 eq), DIC (
5 eq.) And HOBt (5 eq.) For 2 hours. After the wash cycle described in Example 19, the material was suspended in MeOH (10 mL) and treated with sodium cyanoborohydride (10 equivalents). (A small amount of bromocresol green is added to monitor the pH and the pH is adjusted to 10% HCl in ethanol periodically (
One or two drops at a time) was added to maintain acidity. ) After 16 hours, the resin was washed and separated with 95% TFA to ensure complete conversion to the alcohol product (ES MS, MH299).

Example 16-Suzuki Experiment Fmoc-Rink linker material 25 cm ² was treated with 20% piperidine in DMF for 20 minutes to remove the Fmoc group. The resulting amino compound is then
Fmoc-glycine (5 eq), DIC (5 eq), HOBt (5 eq) and DC
Coupling in M for 3 hours. The ninhydrin test was negative. The above Fmo
After removal of the c group, the amino product was coupled with 4-iodobenzoic acid (5 eq), DIC (5 eq), HOBt (5 eq) in DCM. The reaction was completed in 4 hours. This material is suspended in DMF and phenylboronic acid (1.5 eq), P
Treated with d ｛P (Ph) ₃ ｝ ₄ (0.1 eq) and added K ₂ CO ₃ (2 eq). The reaction was heated at 100 ° C. for 16 hours. After the wash cycle of Example 19, 95% TF
Separation for 1 hour at A, HPLC confirmed complete conversion of starting material to product (ES MS, MH299).

Example 17- Derivatization of Styrene / Chloromethylstyrene Grafted Material with Wang Linker Styrene / chloromethylstyrene (5: 5, degree of grafting about 20% by weight) The material (25 cm ² ) was treated with acetonitrile (30 mL). Suspended in it. Next, 4-hydroxybenzaldehyde (0.5 g, 4 mmol), K ₂ CO ₃ (1.1 g, 8 mmol) was added to sodium iodide (0.6 g, 4 mmol). Mix 1
Reflux for 6 hours. The material was washed as described in Example 19, then reduced with sodium cyanoborohydride in methanol and treated as described previously with Wang.
A linker-derivatized material was produced.

Example 18-Preparation of Fmoc-Phe-Gly-OH The Wang linker prepared above was combined with Fmoc-glycine (0.3 g, 1 mmol), DIC (1 mmol), DMAP (0.1 mmol). , In DCM, 2
The reaction was performed for 4 hours. According to the Fmoc quantitative test, the substitution rate was 2.34 micromol /
cm ² . The Fmoc group was removed with 20% piperidine in DMF and the resulting amino compound was purified in DCM with Fmoc-phenylalanine (0.39 g,
1 mmol), DIC (1 mmol), HOBt (1 mmol) for 4 hours. This material was then treated with 95% TFA and the crude product was
Analysis in C confirmed the desired dipeptide as the only major compound (ES
MS, MH445).

Example 19-Normal wash cycle This cycle was used after every chemical operation on the material: DFM (
5 times), DCM (5 times), MeOH (5 times) and DCM (5 times).

Example 20-Production of a pouch continuum A continuation 2 of pouch 4 is shown in Figs. The pouch 4 is rectangular and has a dimension "x" of about 30 mm and a dimension "y" of about 15 mm, and represents the internal area 6 partitioned by the fold 8, the upper weld 10 and each transverse weld 12 And two layers of material (each layer having a thickness of 550-650 μm). Each common cylindrical Rf tag 14 is carried in each of the inner regions 6.

The Rf tag was a 12 mm RfID obtained from the Selector Tag in Kent, UK
Tag ("Avid tag"). Each tag has a unique code number that cannot be changed. The tags are arranged to be read using a radio frequency emitting reader that activates each tag and communicates the code number to the detector. During or after the manufacturing process, each tag is read,
The code number is recorded on the computer so that the order of the tags along the whole continuum is known.

A continuous pouch can be produced using a machine (not shown) that performs the steps described below in FIGS.

The long strip 20 of grafted polymer prepared as described in Example 6
Feed into a machine (not shown) (see FIGS. 3 (a) and 4 (a)). Its cutting edge 22
The area of the strip extending from is then folded in two (see FIGS. 3 (b) and 4 (b)) and then ultrasonically traversed at the cutting edge (or at the seam), Represents a transverse weld 12 (see FIGS. 3 (c) and 4 (c)). Next, the tag 14 is put into the folded pouch (see FIG. 3 (d)), and then the pouch 8 is completed by ultrasonic welding to show the upper welding portion 10 and the other transverse welding portion 12. (See FIGS. 3 (e) and 4 (e)).
The process then continues from the step shown in FIG. 3 (d) to produce a long continuum containing the desired number of independent sachets, each sachet containing a tag 14.

[0165] Because the transverse weld 12 is of sufficient thickness, the continuum will have a weld integrity and / or
It should also be noted that the pouch positioned adjacent to the cut end can be cut open by cutting in the middle along the weld without affecting the ability to hold the tag in the interior region. When the series is cut open, the cut ends can be distinguished from each other, for example by marking them by suitable means-one can include a cut 13 as shown in FIG.

That is, the above method provides an infinitely long continuous strip of support portions that is independent and uniquely identifiable for solid phase synthesis where the location of each support portion within the strip is predetermined. It can be seen that it provides a simple means to do so.

Example 21-Method for Creating a Library of Compounds The following steps may be involved in creating a library of compounds. (a) The size of the library to be created is predetermined, which predetermines the number of pouches contained in the succession of pouches used in this method. A continuum of sachets of the required length is selected, the tag at the right end of the continuation is read, and the code number by the Rf tag is determined. (The right-most tag may be simply confirmed to be a tag having no cut as shown in FIG. 5.) In the same manner as described in Example 7, by knowing the same attribute of the right-most tag Because the order of the tags along the entire manufactured series is known, the same attributes of each tag and its exact location within the series of selected pouches are known. Further, the same attribute of each compound and a specific pouch when manufacturing each compound are determined in advance. The preparation of the compound in the appropriate sachet is also predetermined. The above information is stored on a computer programmed to provide output to an operator to direct the process of creating the library.

(B) Next, the computer indicates a step to be performed. For example, referring to FIG. 6, in step (i), continuum 2 is reacted with compound A #, and group A is attached to each pouch within the continuum, as represented in step (ii).

(C) Thereafter, the computer indicates a place where the continuum 2 should be cut. It may be cut in half, cut in three, or cut according to any predetermined method as necessary. Determining the exact location for the split can be accomplished by the operator by counting the number of pouches to the split location or measuring the length of the continuum to the prime location. The continuum is cut along the appropriate transverse weld 12, and using an identifier (eg, a notch as shown in FIG. 5), the operator can use the resulting continuum as represented in step (iii). The right and left ends of the can be distinguished.

(D) In step (iii), one of the continuum is reacted with compound B # and the other is reacted with compound C #, as shown in step (iv), to form the groups AB and AC Combine to each succession.

(E) In the step (iv), the continuous substances may be combined and subjected to a washing cycle.

(F) After the wash cycle, each contig is individually selected by the operator and the rightmost tag is read to determine the same attribute of each contig. The computer then directs the next procedure to which each sequence is to be attached.

(G) In step (v), each continuum is reacted with compounds D #, E #, F # and G #, as shown in step (vi), to form groups ABD, ABE, ACF and ACG is associated with each succession.

(H) In step (vi), the batches can be combined and subjected to a washing cycle. Thereafter, all of the continuum was reacted with compound H # and subjected to a wash cycle,
As shown in step (vii), the groups ABDH, ABEH, ACFH and ACGH are attached to each continuum.

(I) Next, the procedure described in the above (f) can be carried out to react with another compound instructed by a computer according to a predetermined method.

(J) At the end of the procedure, each compound is separated from the sachet and assigned to each container containing a marker associated with the Rf tag contained in the sachet from which each compound was separated. Thereby, the operator can identify the marker, and from this the computer is used to determine the same attributes of the compound and / or the process steps used in its preparation.

The prepared compounds can then be tested and / or analyzed and further details associated therewith entered into the computer.

The reader's attention is paid to all papers and papers filed at the same time or earlier in this specification in connection with this application, and all papers and papers that have been submitted to public inspection together with this paper. The contents of all these papers and documents are hereby incorporated by reference.

All features disclosed herein (including the appended claims, abstracts and drawings), and / or all steps of the disclosed method or process,
Unless at least some of the features and / or steps are incompatible with each other, they may be combined in any combination.

Unless stated otherwise, each feature disclosed in the specification (including the appended claims, abstracts and drawings) may be combined with other features providing the same, equivalent or similar purpose. It may be replaced with a feature. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic system of equivalent or similar features.

The present invention is not limited to the details of the above embodiments. The present invention is directed to novel features of the features disclosed herein (including the appended claims, abstracts and drawings),
Or new combinations thereof, or new ones of the steps of the methods or processes disclosed herein or new combinations thereof.

[Brief description of the drawings]

FIG. 1 is a side view of a fragment of a continuous pouch.

FIG. 2 is a sectional view taken along the line II-II in FIG.

FIGS. 3 (a) to 3 (e) show a manufacturing process diagram of a series of small bags including an Rf tag sealed in each small bag.

4 (a) to 4 (d) are cross-sectional views taken along lines AA, BB, CC and DD in FIG. 3, respectively.

FIG. 5 shows the cut end of a continuous pouch.

FIG. 6 shows the sequence of steps using a series of sachets to create a library of compounds.

──────────────────────────────────────────────────続 き Continuation of front page (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, 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, ES, 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, ZW Swindon, Stratton St. Margaret, Nyndham Road No. 29 (72) Inventor Mark Bradley, United Kingdom, S.O.15.5 El Double, Southampton, Shirley, Church Street No. 119 Daniel Cowell UK, CB 1.3H, Cambridge, Coldhams Lane 241 F-term (reference) 4H006 AA05 AC90 4L033 AA05 AB07 C A13 CA18 CA23

Claims (33)

[Claims] 1. A method for supporting a compound or other site using a fabric comprising a plastic material. 2. The method of claim 1, wherein the fabric comprises filaments having a diameter of at least 5 μm. 3. The method according to claim 1, wherein the filament has a diameter of 500 μm or less. 4. The method according to claim 1, wherein the density of the fabric is at least 20 g / m ² . 5. The method according to claim 1, wherein the density of the fabric is less than 250 g / m ² . 6. The method according to claim 1, wherein the fabric is a thin layer. 7. The method according to claim 1, wherein the fabric is a graft polymer. 8. The method of claim 7, wherein the graft polymer is prepared by irradiating the first polymeric material followed by contacting it with one or more monomers. 9. The method according to claim 7, wherein the graft polymer contains a functional group capable of reacting with an electrophilic or nucleophilic site. 10. The method wherein the functional groups are optionally substituted aryl and heteroaryl groups, carboxylic acids, carboxylic acid derivatives, amines, amine derivatives, inorganic acids, sulfates, hydroxy and substituted alkyl groups, cycloalkyl groups and 10. The method of claim 9, wherein the method is selected from a cycloheteroalkyl group and a protected form of any of these groups. 11. The method according to any of claims 1 to 10, wherein the fabric comprises linker sites arranged such that other compounds or sites can be covalently linked and / or split therefrom when necessary. 12. Use of the fabric as a solid support to support compounds or other sites. 13. A solid support for supporting a compound or other site, the solid support comprising a fabric. 14. The solid support according to claim 13, comprising a linker moiety arranged such that the compound or other moiety can be covalently linked to and / or split off from the solid support when necessary. 15. The solid support according to claim 13, wherein the support comprises a plurality of independent regions supporting different compounds or sites. 16. The invention according to claim 1, wherein the identification means is connected to the fabric. 17. A solid support for supporting a compound or other site, comprising means that are flexible and represent an enclosed area (hereinafter “enclosure means”). 18. The solid support according to claim 17, wherein the solid support is a solid support.
A solid support having the characteristics described in any one of the above. 19. The solid support according to claim 17, wherein the solid support is disposed in a region in which the identification means or the resin is sealed. 20. The solid support according to claim 17, wherein the solid support is manufactured from a laminar material having a thickness of at least 100 μm and less than 5000 μm. 21. The solid support according to claim 17, wherein the enclosed areas have different volumes and / or different three-dimensional shapes. 22. The method of claim 13, comprising an elongated series of enclosed areas.
A solid support according to any one of the above. 23. The method for producing a solid support according to claim 17, which comprises specifying the outline of the region enclosed by the flexible material. 24. Supply means for supplying an elongate strip of material, folding means for folding the elongate strip, and securing portions of the strip to one another to define an enclosed area. 24. An apparatus for use in the method of claim 23, comprising securing means. 25. A method of making a solid support for use in synthesis or screening, comprising irradiating a first polymer material and then contacting it with one or more monomers to prepare a graft polymer. A method that includes 26. The method according to claim 26, wherein the first polymer material is an optionally substituted polyolefin;
26. The method of claim 25, wherein the method is selected from a polyamide, a polyurethane, a polyester, or a copolymer of an ethylenically unsaturated comonomer. 27. The method according to claim 25, wherein the first polymer is ethylenically unsaturated and contains a functional group capable of causing an electrophilic reaction or a nucleophilic reaction. 28. A method comprising contacting said polymeric material with both a first monomer and a second monomer, wherein the functional groups carried by the first monomer can react with the compound after the graft polymer has been prepared. The first monomer is selected as described above, so that the compound can contact the first polymer material via the first monomer. However, under the reaction conditions, the compound is not reacted because the functional group supported by the second monomer does not react. 28. A method according to any of claims 25 to 27, characterized in that no contact is made with the first polymer moiety via the second monomer. 29. Use of a graft polymer as a solid support for use in synthesis or screening, prepared by irradiating a first polymeric material followed by contacting it with one or more monomers. 30. A solid support for use in a synthesis or screening prepared or prepareable according to claim 28. 31. An arrangement of xy arrays of independent reaction zones, including identification means coupled to uniquely identify each of the reaction zones, wherein adjacent reaction zones are fixed relative to each other; The order of the identification means in the arrangement of the array is predetermined (hereinafter referred to as “predetermined order”) and the ratio of x to y is 10
A method of creating a library of compounds, starting with an arrangement of xx arrays of larger, independent reaction regions, comprising: (a) dividing the arrangement of the sequences into an arrangement of a plurality of subsequences; b) subjecting some of the arrangements of the subsequences to a different chemical process from the others; (c) the arrangement of the subsequences less than the total number of identification means associated with the reaction regions within the arrangement of the subsequences (D) determining (if necessary) the same attribute of each of the subsequences by identifying the identification means coupled with the reaction region within (d) (if necessary) (E) arbitrarily dividing each of the arrangements of the sub-sequences into a plurality of arrangements of further sub-arrays, and the steps (b) to (d) in the arrangement of the further sub-arrays. Are repeated, and the word regarding “arrangement of sub-sequences” in the above steps (b) to (d) Record the different chemical processes to which each reaction region is assigned, so that the different chemical processes to which each reaction region in the library is assigned can be treated as a reference to "additional subsequence placement" A method for creating a library of compounds, characterized in that: 32. The method of claim 31, wherein the arrangement of the arrays is an x × 1 array of independent reaction regions (ie, a primary array arrangement), wherein each reaction region comprises a respective reaction region. And adjacent reaction areas of said arrangement are fixed to each other in the order of the identification means in a predetermined arrangement of arrangements, each reaction area being labeled (A-1) dividing the arrangement of the arrangement in a predetermined manner so as to provide an arrangement of a plurality of predetermined sub-arrays, wherein (A-1) Subjecting the arrangement of the sub-arrays to a predetermined process; (C-1) selecting the arrangement of the sub-arrays and determining the next step to which the arrangement of the selected sub-arrays should be attached; Identify only one reaction region of the sequence arrangement Comprising the step of determining the same attribute by the. 33. A subsequence comprising a known number of reaction regions, wherein the arrangement of the subsequences is separated from the arrangement of the parent sequence in which the same attributes and positions of the respective reaction regions are predetermined. A method for determining the same attribute of each reaction region in the arrangement, comprising: (a) selecting a reaction region to be identified in the arrangement of the subsequences (hereinafter, referred to as “identified reaction region”); b) writing down the position of the identified reaction region in the arrangement of the subsequences; (c) determining the same attribute of the identified reaction region; (d) confirming in the steps (b) and (c). Associating the determined information with the determined attributes and locations of each reaction region in the arrangement of the parent sequence, thereby determining the attributes of each reaction region in the arrangement of the subsequence.