GB2338487A - Large porticle size polystyrene support material - Google Patents

Abstract

A process for the production of a particulate polymeric material wherein at least 30% by weight of the material has a particle size greater than 1000Ám, and polymeric material produced thereby, are provided. The polymeric material is produced by a process comprising the suspension polymerisation of a monomer wherein a colloid stabiliser is added to the suspension polymerisation mixture after partial polymerisation of the monomer. Preferably the polymer is a polystyrene or derivative thereof and the colloid stabiliser is polyacrylic acid.

Description

SMC 50313 2338487 PROCESS FOR THE PRODUCTION OF POLYMERIC MATERIALS The

present invention relates to a process for the production of particulate polymeric materials, particulate materials obtainable by the process, the use of the particulate polymeric matedals as supports for chemical synthesis, and chemical libraries synthesised on the particulate polymeric materials.

The technique of combinatorial chemistry is an increasingly important tool for the rapid production of large numbers of chemically diverse molecules. In, for example, the pharmaceutical and agrochemical industries, chemical libraries produced by this technique may be screened to identify new lead compounds having biological activity.

Chemical libraries may be produced by either solution phase or solid phase synthesis, Angew. Chem. Int. Ed. Engl., 1996, 35, 2288-2337, provides a review of combinatorial chemistry using these approaches.

Solid phase synthesis conventionally uses particulate polymeric matemals as solid supports for the synthesised compounds. This approach to the production of chemical libraries has the advantage that it facilitates the physical separation of the compounds produced. In addition, solid supports may be labelled or tagged such that the identity or reaction history of a compound attached to a particular solid support can be elucidated.

Solid phase synthesis performed on discrete supports, such as resin beads, can generate very large numbers of compounds using a "split and mY technique, as described in Int. J. Peptide Protein Res., 1991, 37, 487-493. The supports used in this technique generally have a diameter in the range of from 35 to 500 pm, e.g. from 100 to 200 lim. However, handling supports of this size can be problematic and their size means that on average only about 10-'1 to 10-8 mol of compound can be synthesised per support which may not be a sufficient quantity for some screening operations.

Particulate polymeric supports of the size described above are generally produced by an aqueous suspension polymerisation process, such as that described in Journal of Applied Polymer Science, 1982, 27, 133-138. In this process, suspension polymerisation is carried out by suspending the monomer as droplets (1 pm to 1000 pm) in water (continuous phase). Suspension is maintained by mechanical agitation and the addition of stabilisers. Vahous water insoluble (ionic) inorganic stabilisers (dispersants) may be used to prevent agglomeration of the monomer droplets, for example hydroxy apetite, barium sulphate, kaolin, magnesium sulphate. Polymerisation is initiated by the addition of a monomer soluble free radical initiator. Once the polymerisation is complete the product can be collected by filtration from the continuous phase.

Polymedc supports of the type described above are commercially available, for example, PL-CIVIS resins from Polymer Laboratories Ltd (Essex Rd, Church Stretton, Shropshire SY6 6AX) are available in the size range 75300 pm. Chloromethyl SIVIC 50313 polystyrene resins (1 or 2% divinyl benzene) are available from Senn Chemicals (Industriestrasse 12, CH-8157, Dielsdorf Switzerland) in the size range 35-150 pm.

In order to produce larger quantities of compound per support in solid phase synthesis it would be desirable to use particulate polymer supports having a diameter greater those conventionally available. However it has not proved possible to obtain larger particulate polymer supports using a standard suspension polymerisation process, such as that described above.

We have now found that particularly 'large' particulate polymeric materials which are suitable for use in the solid phase synthesis of chemical libraries can be made by a modified suspension polymerisation process.

Therefore, according to the invention there is provided a process for the production of a particulate polymeric material wherein at least 30% by weight of the material has a particle size greater than 1 000pm, comprising the suspension polymerisation of a monomer wherein a colloid stabiliser is added to the suspension is polymerisation mixture after partial polymerisation of the monomer.

Any conventional colloid stabiliser may be used in the process of the invention, examples of suitable colloid stabilisers include polyacrylic acids, polyvinyl alcohols, polyvinyl pyrrolidones, polyalkoxylates (PEGs and PEGIPPG block copolymers), xanthan gums and cellulosics.

Polyacrylic acids are particularly preferred colloid stabilisers for use in the process of the invention. In some cases the level of polyacrylic acid required to give particulate polymeric materials of the desired size may be insufficient to maintain stability of the suspension throughout the polymerisation. In such cases it is desirable to add an additional stabiliser, e.g. a polyvinyl alcohol, during polymerisation. The timing of the addition of additional stabiliser has been found to be of importance to the size of the particulate polymeric material obtained. If it is added too early in the polymerisation the additional stabiliser may stabilise and encourage the formation of smaller monomer droplets and if it is added too late the polymerisation may become unstable as partially polymerised particles may stick together and flocculate.

In the process of the invention preferably at least 50% by weight of the material has a particle size greater than 1000pm. Preferably at least 50%, and more preferably at least 75%, of the material by weight has a particle size in the range 500 to 1700 pm.

The particulate polymeric materials produced by the process of the invention are novel.

Therefore, according to a further aspect of the invention, there is provided a particulate polymeric material wherein at least 30% by weight of the material has a particle size greater than 1 000pm, obtainable by a process comprising the suspension polymerisation of a monomer wherein a colloid stabiliser is added to the suspension polymerisation mixture after partial polymerisation of the monomer.

SIVIC 50313 A further aspect of the invention is to make larger particulate materials by taking the existing particulates and swelling more monomer onto them, followed by a further polymerisation process.

The particulate polymer materials produced according to the invention have various advantages over particulate polymeric materials known from the prior art for use in the synthesis of chemical libraries. These include improved handling properties, such as flowability and visualisation. Since the particulate polymeric materials are larger than conventional supports they allow greater quantities of members of a chemical library to be synthesised. Furthermore, since the polymeric materials are not composites they offer various manufacturing advantages over both composite supports and grafted supports, including greater flexibility in the choice of polymer. Grafting, such a radiation grafting, imposes restrictions on the choice of polymer since it must not decompose during exposure to gamma radiation, thus, for example, pre-functionalised monomers such as chloromethyl styrene cannot be used.

The monomer used in the process of the invention preferably contains between 0.1 and 5.0 % w/w of a linear polymer, more preferably between 0.3 and 1. 0 % w/w of a linear polymer, for example about 0.75 % w/w of a linear polymer.

Any linear polymer may be used provided it is soluble in the monomer phase and remains there during suspension polymerisation rather than partitioning into the water.

The linear polymer may also contain functionality, e.g. unsaturation, which would cause it to become chemically grafted into the bead during the polymerisation. Examples of suitable polymers include polystyrene, polyethylene, polypropylene, polymethyl methacrylate, polytetramethylen glycol, polybutadiene and styrene butadiene copolymers. However, the linear polymer is preferably polystyrene.

Monomers which may be used in the process of the invention include monomers which have appropriate functionality, or may be functionalised, to render the resulting polymer suitable as a support for chemical synthesis. Suitable monomers include styrene and substituted styrenes, for example alkyl, halo, haloalkyl, amino, hydroxy, acetoxy or carboxy styrenes, such as chloromethylstyrene and 4-bromostyrene; and styrenes and substituted styrenes modified with polyethylene glycol. The resulting polymers may contain a multi functional vinyl species, e.g. divinyl benzene or diltri (meth)acrylates, to act as a crosslinker. Other suitable monomers include (meth)acrylates andlor (meth)acrylam ides, and (meth)acrylates andlor (meth)acryfam ides together with styrene type monomers, for example methacrylic or acrylic acid and their alkyl esters such as glycidyl methacrylate, hydroxy ethyl methacrylate, beta carboxy ethyl acrylate etc., crosslinked with 1,6-hexane diol dimethacrylate etc. Examples of suitable (meth)acrylamide monomers, are N-acryloyl sarcosine methyl ester, cross-linked with N,Wbis-acryloyl ethylene diamine.

SIVIC 50313 In the process of the invention the monomer is preferably styrene, a substituted styrene, or a mixture thereof.

During the suspension polymerisation process the suspension is preferably agitated, e.g. by stirring. It has been found advantageous to reduce the shear rate of the agitation in the process of the invention compared to that used in conventional suspension polymerisation processes, e.g. by optimising the stirrer speed, the shape of stirrer blade, the size andlor shape of the reaction vessel.

The particulate polymeric materials produced according to the invention may be functionalised so as to render them suitable for solid phase chemical synthesis.

Functionalisation of the polymeric materials allows the attachment of chemically reactive ligands to the polymer which can then be used in the synthesis of chemical libraries. The monomer from which the polymeric material is formed may be pre-functionalised, or the resulting material may be post-functionalised. Pre-functionalisation is preferable to postfunctionalisation since it allows higher levels of functionality to be introduced into the polymer and avoids the batch variation often exhibited in post-functionalised polymers. The ability to use pre- functionalised monomers gives the particulate polymeric materials of the invention advantages over e.g. grafted polymer composites which are not amenable to pre-functionalisation.

Typically the monomer will be mixed with an initiator to initiate polymerisation.

The initiator used will depend on the monomer, and examples of initiators include free radical initiators such as 2,2'-azobisisobutyronhrile, 2,2'azobis (2,44m ethyl valeronitrile), dioctanoyl peroxide and tert-amyl peroxyneodecanoate. The monomer may also be heated to assist polymerisation, the temperature to which it is heated will depend on the particular monomer(s) and initiator(s), however suitable temperatures are in the range 15 to 160%, more preferably 50 to 80%, for example 60%.

Following polymerisation of the monomer the polymeric material is preferably washed with solvent to remove any monomer, low molecular weight polymer and initiator fragments. Suitable solvents for the washing procedure include THF, alcohols such as methanol and ethanol, DIVIF, toluene, ethyl acetate, and ethers such as diethyl ether and butyl methyl ether, or mixtures thereof.

As mentioned previously the particulate polymeric materials of the invention find application as supports for the synthesis of chemical libraries, the supports are of particular use in synthesis of chemical libraries by a "split and mW technique. Other applications include general solid phase synthesis, peptide synthesis, the immobilisation of reagents or catalysts, immobilisation of enzymes and use as scavengerlsequestering resins.

Thus, according to a further aspect of the invention, there is provided the use of a particulate polymeric material according to the invention as a support for chemical library synthesis.

SIVIC 50313 There is also provided a chemical library comprising a plurality of different chemical compounds bound to a plurality of discrete particulate polymeric materials according to the invention.

Chemical libraries according to this aspect of the invention will generally comprise at least 10 different compounds, and preferably contain at least 50 different compounds, for example between 102 and 1010 compounds.

The chemical libraries produced using the particulate polymeric materials of the invention may comprise a wide variety of chemically diverse compounds. The polymeric materials may be used as solid supports for any type of solid phase synthesis which is io conventionally performed on resin beads. The chemical libraries produced may comprise any compounds which can be synthesised using, for example, the stepwise addition of a number of building blocks andlor reagents. Examples of compounds which may be synthesised in this manner include peptides, oligonucletoides and synthetic small molecules.

The particulate polymeric materials of the invention may be used in the synthesis of chemical libraries by either manual or automated techniques Chemical compounds synthesised using the particulate polymeric materials of the invention, will generally be attached to the polymeric material by means of a linking group. The linking group will be provided with appropriate functionality to enable it to bind at one end to the polymeric material and at the other end to the precursor of the compound to be synthesised. Cleavable linkers may be used to facilitate removal of the compounds from the polymeric materials prior to screening andlor identification. Suitable linking groups include those present in, for example, trityl chloride resin, Rink amide resin, Wang resin and Kaiser oxime resin.

The particuiate polymeric materials supports may be labelled or tagged prior to, or during, chemical synthesis, such that at least part of the reaction history of a particular particle of polymeric material can be elucidated. Information about the reaction history provided by the label or tag can be used to identify, in part or full, the structure of the compound synthesised on a particular particle of polymeric material. Labelling of the particles of polymeric material may comprise marking with indica individual particles of polymeric material, suitable indica include visible indica such as numbers, letters, symbols or colours which may be printed onto the particulate polymeric material prior to library synthesis. Such indica may be 2- or 3-dimensional. The particles of polymeric material may also be labelled with chemical structures e.g. as described in WO 94/08051.

Alternatively, portions of the polymeric material comprising a plurality of particles may be contained within foraminous containers and a tagging system such as a bar code or electromagnetic tag inserted into each container, e.g. as described in WO 97112680 and WO 96136436.

SIVIC 50313 In a preferred aspect of the invention particles of polymeric materials comprising discrete reaction zones for chemical synthesis are labelled, such that at least part of the reaction history of a particular particle of polymeric material can be elucidated following said chemical synthesis.

As an alternative, or adjunct, to labelling, analytical methods such as mass spectrometry andlor nuclear magnetic resonance spectrometry may be used to identify compounds synthesised on a particular particle of polymeric material.

Following library synthesis the compounds making up a chemical library may be cleaved from the particles of polymeric material prior to screening for biological activity, or they may be screened in situ whilst still linked to the particles of polymeric material. The screening method used will depend on the composition of the chemical library and the nature of the screen.

The invention is illustrated by the following non-limiting examples:

Example 1

Polystyrene/DV13 Particles (0.5% Polystyrene, 1.5% DV13) Distilled water (1 130g), sodium sulphate (0.39g) and 3.9g of a 12.5% polyacryiic acid solution Neocryl HX-72 (Neocry] is a trade name of Zeneca Limited) were heated to 800C in a cylindrical 21---glass reactor and stirred with a stainless steel paddle shaped stirrer blade at 300 rpm.

Polystyrene (10g, melt index = 3.4) was dissolved in styrene monomer (90g) and this mixture (9.20g) was added to a mixture of styrene (174.3g), technical grade divinyl benzene (2.8g) and benzoyl peroxide (5.9g). This monomer mixture was poured into the reactor vessel, the whole mixture stirred at 300 rpm and the temperature maintained at 80%. After 45 minutes from the addition of the monomer to the aqueous phase a 2.5% aqueous solution of polyvinyl alcohol (29g) (Airvol 540 - Airvol is a trade name of Air Products) was added to the reactor. After a further 5 hours the reaction was cooled and poured into a 50pm mesh top hat filter and washed with tap water for 30 minutes. The particulate polymeric material was transferred to a beaker and allowed to stand for 16 hours in a 111 mixture of THFIdistilled water (approx. 2 litres) before being filtered on a Buchner using a P2 sintered glass filter. The polymeric material was then washed 3 times with THF and filtered as before. Finally the polymeric material was were washed with 2 different mixtures of THF/MeOH 11, then 12, followed by 3 methanol washes before being dried in a vacuum oven to constant weight.

The particulate polymeric material was classified by sieving, as shown in Table 1.

SIVIC 50313 Example 2 Polystyrene/DVI3 Particles (0.75% Polystyrene. 3.0% DVI3) The title material was prepared according to the process of Example 1 but using a mixture of styrene (169.7g), technical grade divinyl benzene (5. 7g) and benzoyl peroxide (5.9g) The particulate polymeric material was classified by sieving, as shown in Table 1.

Example 3 Polystyrene/DVI3 Particles (0.85% Polystyrene, 2.0% DVI3) The title material was prepared according to the process of Example 1 but using a mixture of styrene (167.9g), technical grade divinyl benzene (3.7g) and benzoyl peroxide (5.9g).

The particulate polymeric material was classified by sieving, as shown in Table 1.

Example 4

4-Chloro methyl styrene/Polystyrene/DVB Particles (4 mmol/q chloro methyl styrene.

1.4% DV13) Distilled water (1 130g), sodium sulphate (0.39g) and 3.9g of a 12.5% polyacrylic acid solution Neocryl HX-72 (Neocry] is a trade name of Zeneca Limited) were heated to WC in a cylindrical 21- glass reactor and stirred with a stainless steel paddle shaped stirrer blade at 300 rpm.

4-Chloro methyl styrene (1 17.4g) was added to a mixture of styrene (73g), technical grade divinyl benzene (2.7g) and 2,2'-azobis(2,4-dimethyl valeronitrile) (1.9g).

The monomer mixture was poured into the reactor vessel, the whole mixture stirred at 300 rpm and the temperature maintained at 65%. After 60 minutes from the addition of the monomer to the aqueous phase 29g of a 2.5% aqueous solution of polyvinyl alcohol (Airvol 540 - Airvol is a trade name of Air Products) was added to the reactor. After a further 5 hours the reaction was cooled and poured into a 50pm mesh top hat filter and washed with tap water for 30 mins. The wet particulate polymeric material was transferred to a beaker and allowed to stand for 16 hours in a 111 mixture of THFIdistilled water (approx. 2 litres) before being filtered on a Buchner using a P2 sintered glass filter.

The polymeric material was then washed 3 times with THF and filtered as before. Finally the polymeric material was washed with 2 different mixtures of THF/MeOH 2:1 then 1:2 followed by 3 methanol washes, before being dried in a vacuum oven to constant weight.

SIVIC 50313 Example 5 Comparative Example - normal suspension recipe to make 4-Chloro methyl styrenelstyrene/DVB Beads 150-300pm (4 mmolq chloro methyl styrene, 1.4% DVI3) Distilled water (1 130g), sodium sulphate (0.77g) and 29g of 2.5% Airvol540 (polyvinyl alcohol) were heated to 65% in a cylindrical 21- glass reactor and stirred with a stainless steel paddle shaped stirrer blade at 400 rpm.

4-Chloro, methyl styrene (1 17.4g) was added to a mixture of styrene (73g), technical grade divinyl benzene (2.7g) and 2,2'-azobis(2,4dimethyi valeronitrile) (1.9g). This monomer mixture was poured into the reactor vessel, the whole mixture stirred at 400 rpm and the temperature maintained at 65C. After 5 hours the reaction was cooled and poured into a 50pm mesh top hat filter and washed with tap water for 30 minutes. The wet beads were transferred to a beaker and allowed to stand for 16 hours in a 111 mixture of THFIdistilled water (approx. 2 litres) before being filtered on a Buchner using a P2 sintered glass filter. The beads were then washed 3 times with THF and filtered as before. Finally the beads were washed with 2 different mixtures of THF/MeOH 2:1 then 1:2 followed by 3 methanol washes before being dried in a vacuum oven to constant weight.

The beads were classified by sieving, as shown in Table 1.

Sieve Analysis % Example >1.7mrn 1.4-1.7mm 1.0-1.4mm 0.5-1.Omm<0.5mm 1 0.9 9.2 50.0 36.0 2 9.7 15.7 35.1 35.7 3 2.1 4.4 29.9 56.1 4 0.34 0.84 70.25 24.72 - - - 21 Example 6

Preparation of Benzvioxvbenzhvdrile (BOBA) linker on Chloromethyl Polystryrene a) 4-Hydroxybenzophenone was added to a solution of potassium t-butoxide (1.3g) in DIVISO (15 m]), after 50 minutes chloromethyl polystyrene beads produced according to the invention (1.02g, 1-1.4 mm diameter, 4 meg) were added and the mixture shaken on an orbital shaker for 16 hours. The beads were filtered and washed with DMF (x4), THF (x2), 1:1 THF: water (x3), THF (4) and finally MeOH (x3) before being dried in a vacuum oven at 500C. This gave 1.74g of a buff coloured resin.

b) The beads (0.5g) from step a) were swollen in THF (3 mi). To this lithium borohydride (180 mg) was added portion-wise and then the mixture was heated to 550C for 16 hours. The beads were filtered and washed with a mixture of 1: 1 MeOHITHF (x2), I SMC 50313 -g- 3:1 THF: water (x2), THF (x2) and finally MeOH (x2) before being dried in a vacuum oven at 50"C.

c) The reduced beads (0.4g) from step b) were refluxed with toluene (3 mi) containing acetyl chloride (1 m[) for 18 hours. The beads were filtered and washed with toluene (x3) and ether (x2). The resultant beads were suspended in THF (4 mi) then 2 thiophene methylamine was added and the mixture shaken on an orbital shaker for 16 hours. The beads were filtered and washed with 1:1 THF: water (x3), THF (x3), and finally MeOH (x2) before being dried in a vacuum oven at 5M. This gave beads which showed microanalysis of C = 77.23%, H = 6.47%, N = 2.44%, S = 5.84%.

Example 7 Preparation of N-3-trifluoromethy[benzoyi 2thiophenvimethylamine The beads (99 mg) from Example 6c) were swollen in DCM, then pyridine (1 mi) and 3-trifluoromethyl benzoyl chloride (0.1 mi) added and the mixture shaken on an is orbital shaker for 16 hours. The beads were filtered and washed with 1: 1 THF: water (x3), THF (x3) and finally methanol before being dried in a vacuum oven at 5M. The product was cleaved from the resin by the addition of a 1 mi mixture of 90:9A of DCM TFA: water and shaking this for 30 minutes. The filtrate was collected and the resin washed with further DCM, the combined filtrates were concentrated under reduced pressure, the excess TFA was removed by forming an azeotrope with toluene, and finally on the high vacuum. This gave the title product (22 mg, 46% yield) as a white solid.

H NIVIR 8 4.6(2H,d); 6.90(1 H,m); 6.98(1 H,m); 7.34(1 H,m); 7.68(1 H,t); 7.86(1H,d); 8.10-8.20(2H,m); 9.36(1H,t) ppm.

Example 8

Preparation of Hydroxy thiophenol linker (HTP) on Chloromethyl Polystyrene a) 4-Hydroxy thiophenol (1.26g) was dissolved in DMF (5 mi). To this was added over 1 hour a suspension of chloromethyl polystyrene beads (1.05g, 1-1.4 mm diameter, 4 meg) pre-swelled in DIVIF (10 mi). This was shaken on an orbital shaker for 3 days.

The beads was filtered and washed with DIVIF (x4), THF: water 1:1 (A), THF (A), THF:

MeOH 1:1 (A) and finally MeOH (x2) and dried in a vacuum oven at 500C for 16 hours.

This gave a buff resin (1.46g). Microanalysis showed C = 78.25%, H = 6. 98%, S 8.08%.

b) The 'HTF beads (500 mg) from step a) were swollen in 4 mi of a 1:1 mixture of DCM: N-methyl pyrrolidinone (NMP). h[-(teft-butoxycarbonyi)-L-valine (1. 36g) dissolved in 2 mi of a 1: 1 mixture of DCM: NIVIP was added to the beads, followed by diisopropylcarbodiimide (1 mi) and dimethyl amino pyridine (0. 15 g in 1 mi of NIVIP). The reaction mixture was shaken for 16 hours then washed with DCM (x2), THF (x2) and finally methanol (MeOH x2) before being dried in a vacuum oven for 16 hours. The beads SIVIC 50313 were treated with a 1: 1 mixture of DCM and trifluoroacetic acid (TFA 10 mi) and shaken for 2 hours. The beads were washed with DCM (x2) then treated with the DCM: TFA mixture again. After the 2 hours the resin was washed with DCM (x2), THF (x3) and MeOH (x2) then dried in a vacuum oven for 16 hours. This gave 0.741 g (99% yield) of a buff coloured resin, microanalysis showed C = 71.92%1 H = 6.99%, N = 2. 73%, S 5.67%.

c) The beads (250 mg) from step b) were swollen with DCM (4 m[) then 3 trifluoromethyibenzoyl chloride (0.37 mi) was added followed by diisopropyiethylamine (DIPEA 0.39 mi). The reaction mixture was shaken for 16 hours, then washed with DCM (x3), a mixture of 3:1 THFI1 M aqueous HCl (x2), 3:1 THF: water (x2), THF, and finally methanol (x2) before being dried in a vacuum oven at 50C for 16 hours to give the resin as a buff powder (256 mg), microanalysis showed C = 68.88%, H = 5.40%, N = 1.97%, S = 5.10%.

Example 9 Preparation of 4-chforobenzviamido-N-(3-triflouromethvibenzovl) valine The beads (200 mg) from Example 8c) in DIVISO (1 mi) were treated with 4chlorobenzylamine (26pl) and heated to 700C for 2 hours. The reaction mixture was filtered and the resin washed with DIVISO and DCM and the filtrate concentrated on a rotovap under high vacuum. This gave the title product (85 mg, 75% yield) as a white solid. The product was recrystalized from a mixture of hexanelchloroform.

H NMR 8: 0.87(61-1, m); 2.09(1 H,m); 4.23(3H,rh); 7.18-7.36(41-1, m); 7. 66(1 H,t); 7.86(1H,m); 8.1-8.2(2H, m); 8.55-8.70(2H,m) ppm; Mass Spectrum Cl 413.

Example 10 a) Polystyrene beads (1.Og of 1-1.4 mm diameter) were swollen in DCM (9.5 mi) to this p-anisoyl chloride (2g) and ferric chloride (0.32g) were added and the mixture stirred with an overhead stirrer for 3 days. The beads were filtered and washed with DCM (A), 1:1 1,4-dioxane: 0.5M HCl aqueous (A), 1:1 THF: water (x3), THF (x3),1A THF: MeOH (x3)) before being dried in a vacuum oven at WC. This gave 1.32g of a buff coloured resin.

b) The beads (0.5g) from step a) were swollen in THF (2 mi). To this lithium borohydride (1.5 mi of a 2M solution in TH17) was added portion-wise and then the mixtur was heated to 600C for 16 hours. The beads were filtered and washed with a mixture of 1:1 THF: MeOH (x2), 1:1 THF: water (x3), water (x2), THF (x3), 1:1 THF: MeOH (x2) and finally MeOH (x2) before being dried in a vacuum oven at 5WC. This gave 0.5g of a light brown resin.

SIVIC 50313 c) The beads (252 mg) from step b) were swollen with CHCL (2 m]) then thionyl chlodde (0.5 mi) was added and the mixture heated to 500C for 16 hours. The beads were filtered and washed with CI-IC13 (x3) and finally THF The beads were re-suspended in THF (1.5 mi) and then 2-thiophene methylamine (0.5 mi) was added and the mixture was shaken for 16 hours. The mixture was filtered and washed with THF, 1: 1 THF: water (x3), THF (x3), 1:1 THF: MeOH and finally MeOH (x2) before being dried in a vacuum oven at 5WC. This gave 0.29g of a light brown resin. Microanalysis showed C = 79.16%, H = 6.90%, N = 2.80%, S = 6.40%.

Example 11 Preparation of N-benzovi 2-thiophenvimethylamine The beads (0. 1 g) from Example 1 Oc) were swollen with DCM (1. 5 mi), filtered and then covered with DCM (1.5 mi). Pyridine (0.5 mi) was added followed by benzoylchloride (0.2 mi). This was shaken for two days after which the beads were filtered and washed with NMP (x2), 3:1 THF: water (x2), water (x2), THF (x3) and finally MeOH before being dried in a vacuum oven at 5M. The product was cleaved from the beads by the addition of a 1 mi mixture of 90:9A of DCM: TFA: water and shaking this for 30 minutes. The filtrate was collected and the resin washed with further DCM, the combined filtrates were concentrated under reduced vacuum the excess TFA was removed by forming an azeotrope with toluene and finally on the high vacuum. This gave the title product (23 mg, 53% yield) as a beige solid.

H NIVIR 3: 4.58(2H,m); 6.90(1H,m); 6.96(1H,m); 7.28-7.50(4H,m); 7.80(2H, d); 9.08(1 H,t) ppm.

Example 12

This example shown in Scheme 1 below illustrates the synthesis of a chemical library using the polymeric material of the invention.

SMC 50313 PS z 0 meoic (1) PS OH MeOic (2) PS 0 N L 1 JY A B MeOi (5) NH2 1 PS c 0 NjYM'C A B MeOi (6) Scheme 1 0 xly L B DY PS cl MeOi( (3) NH2 1 A PS NH A MeOi (4) PS 0 D N, N'Jly 1 c A B MeOji (7) TFA 0 D N, H N "fl'y 1 1 A B (8) SIVIC 50313 The polymeric material was functionalised by treating the polystyrene with a benzoyl chloride, preferably 4-anisoyl chloride, in the presence of a Lewis acid catalyst, for example iron (111) chloride, in a suitable solvent, for example dichloromethane, to give benzophenone (1). The benzophenone (1) was reduced with a suitable reducing agent, for example lithium borohydride, in a suitable solvent or mixture of solvents, e.g. THIF, to give the benzhydryl product (2). Chlorination to give (3) was effected using acetyl chloride in a suitable solvent such as toluene and at a suitable temperature, e.g. WC. Alternatively the chlorination may be effected by treatment with hydrogen chloride or phosgene alternatively with triphenyl phosphine in hexachloroethane.

The first building block or diversity element was put in place by reaction of the chlorohydryl product (3) with an amine (NHA) to give (4).

The amine (4) may now be treated with a variety of reagents in order to build up the target or template.

In this case amine (4) was treated with an acid chloride (9) where X is chlorine, L is a leaving group such as chlorine or bromine and B is, for example, alkyl or ary], to give (5). The leaving group L was then displaced by a nucleophile, such as an amine (NH2C), to give (6). The substrate (6) was treated with a reagent DY, e.g. an acid chloride, isocyanate, isothiocyanate, sulphonyl chloride or an alkylating agent, to give the product (7). The product (7) was then cleaved from the polymeric material by treatment with an acid, for example trifluoroacetic acid (TFA) in dichloromethane with water in the ratio of, for example 90:9:1 to yield the final product (8) a secondary amide. Each of the substrates (5, 6 and 7) may also be treated with an acid to liberate the intermediate products.

SIVIC 50313

Claims (12)

1. A process for the production of a particulate polymeric material wherein at least 30% by weight of the material has a particle size greater than 1 000pm, comprising the suspension polymerisation of a monomer wherein a colloid stabiliser is added to the suspension polymerisation mixture after partial polymerisation of the monomer.

2. A process according to claim 1, wherein the colloid stabiliser is a polyacrylic acid

3. A process according to claim 1 or 2, wherein at least 50% by weight of the material has a particle size greater than 1 000pm.

4. A process according to any one of the preceding claims, wherein at least 50% of the material by weight has a particle size in the range 500 to 1700pm.

5. A process according to any one of the preceding claims wherein the monomer contains between 0.1 and 5.0% w/w of a linear polymer.

6. A process according to claim 5, wherein the monomer contains between 0. 3 and 20 1.0% w/w of a linear polymer.

A process according to claim 5 or 6, wherein the linear polymer is polystyrene.

8. A process according to any one of the preceding claims, wherein the monomer is styrene, a substituted styrene, or a mixture thereof.

9. A particulate polymeric material obtainable by a process according to any one of claims 1 to 8.

10. A polymeric material according to claim 9 wherein particles of the polymeric material comprising discrete reaction zones for chemical synthesis are labelled, such that at least part of the reaction history of an individual particle can be elucidated following said chemical synthesis.

11. The use of a polymeric material according to claim 9 or 10 as a support for chemical library synthesis.

12. A chemical library comprising a plurality of different chemical compounds bound to discrete particles of a polymeric material according to claim 9 or 10.