WO1999058475A2

WO1999058475A2 - Preparation of compounds using polymer supported reagents

Info

Publication number: WO1999058475A2
Application number: PCT/GB1999/001251
Authority: WO
Inventors: Steven Ley; Martin Bolli; Berthold Hinzen; Anne-Geraldine Gervois; Beverley Hall; Jorg Habermann; James Scott; Frank Haunert
Original assignee: Cambridge Combinatorial Limited
Priority date: 1998-05-11
Filing date: 1999-05-11
Publication date: 1999-11-18
Also published as: WO1999058475A3; GB0000469D0; GB2342095A

Abstract

There is described a process for the preparation of a compound which process includes a first reaction and a second reaction, wherein the process uses a first solid supported reagent in said first reaction and a second solid supported reagent in said second reaction. The process may be used to effect multi-step organic synthesis for potential applications in combinatorial chemistry and/or the preparation of chemical libraries.

Description

PREPARATION OF COMPOUNDS USING POLYMER SUPPORTED REAGENTS

This invention relates to the preparation of compounds using polymer supported reagents. Particularly, although not exclusively, the methodology described may have application in the area of pharmaceutical, agrochemical or biotechnology research, process research or fine chemical production (including intermediates for the fine chemical manufacturing sector) .

With the advent of high throughput screening, it became commercially desirable for research organisations in the business sectors mentioned above to be able to access larger numbers of organic compounds than their traditional synthetic chemistry groups could generate. This led to the emergence of parallel synthesis in the form of combinatorial chemistry. Using this approach, it is possible to obtain an order of magnitude increase in the synthetic productivity of the chemists. As a result, this has been an area of intense commercial activity in terms of identifying new chemistries and technologies.

Combinatorial chemistry requires:

1. Access to a diverse set of monomers from which to construct libraries of molecules likely to have the desired biological and physical properties. 2. Clean chemistry that can be applied to the synthesis of molecules with the minimum amount of purification. 3. Automated procedures to give low unit time per synthesis. Process research and manufacturing groups within the chemical industry require:

1. Low unit times of synthesis.

2. Clean chemistry with a minimum of washing and purification procedures.

3. Low cost manufacturing routes with efficient operation parameters such as yield, throughput, minimum waste streams etc.

For this reason, synthetic methodology which meets some or all of the criteria stated above for combinatorial chemistry would be of commercial interest.

It is an object of the present invention to develop and/or apply a methodology to address the needs described above.

1-H-Pyrazoles and 4, 5-dihydro-lH-pyrazoles have found diverse applications in medicine and agriculture. In particular, they are known as potent antibiotic agents. Hence, methods capable of generating libraries of heterocycles of this type are extremely attractive. It is an object of the present invention to provide such libraries.

Thiomorpholine analogues have also found application in medicine and agriculture. Therefore, the development of a simple, fast and flexible method to generate libraries of such compounds is desirable. It is one object of the present invention to provide a route to piperidino- thiomorpholines as potentially interesting chemical scaffolds. According to a first aspect of the invention, there is provided a process for the preparation of a compound which process includes a first reaction and a second reaction, wherein the process uses a first solid supported reagent in said first reaction and a second solid supported reagent in said second reaction.

Said first and second solid supported reagents may comprise respective first and second polymer supported reagents.

The invention extends to the use of polymer bound reagents to effect multi-step organic synthesis for potential application in combinatorial chemistry.

The invention also extends to the use of sequential, multi-step organic synthesis for potential application of a variety of polymer supported reagents to the synthesis of organic compounds.

The invention further extends to the use of a combination of polymer supported reagents in multi-parallel synthesis.

The invention further extends to the use of polymer supported reagents in multi-step syntheses of chemical libraries .

The invention described allows automation, including the opportunity of converting batch-wise procedures into continuous flow processes, giving high throughput in low unit time and, furthermore, purification requirements are minimal . The invention may be applied in the synthesis of monomer sets of building blocks of utility in combinatorial chemistry. These include alcohols, aldehydes, olefins, epoxides, amines and β-unsaturated compounds. These molecules can be further elaborated into structures such as heterocycles, which may have applications in the pharmaceutical, agrochemical or biotechnology sectors. Furthermore, the invention may be used with a packed column or flow reactor. This may see application within the process research and manufacturing areas of the chemical industry.

The following benefits of the use of the invention have been demonstrated:

(i) High yielding reactions;

(ii) A broad range of synthetic chemistry;

(iii) Practically useful reaction times;

(iv) Clean chemistry requiring a minimum of washing and purification of products;

(v) The sequential multi-step application is amenable to automation of the process giving efficiency benefits .

In the following description the term "supported reagent" is used to refer to a solid supported reagent or a polymer bound or polymer supported reagent.

Preferably, in said first reaction a first reactant is contacted with a first supported reagent suitably in the presence of a solvent. The mixture is then subjected to appropriate reaction conditions. Preferably, an excess of said first supported reagent is used. After completion of the reaction, the product may be separated from said first supported reagent by filtration. Said first supported reagent may optionally be washed to make available more of said product. Preferably, separation of said product from said first supported reagent does not involve any solvent extraction technique. Preferably, separation of said product from said first supported reagent involves no chromatographic purification. Preferably, said separation does not involve crystallisation and/or distillation techniques. Advantageously, said product can be separated from said first supported reagent by filtration alone.

The product of said first reaction (or a derivative thereof) , suitably in a solvent, may be contacted with a second supported reagent (suitably different to said first supported reagent) , optionally in the presence of a second reactant (suitably different to said first reactant) . The mixture may then be subjected to appropriate reaction conditions. Preferably, an excess of said second supported regent is used. After completion of the reaction, the product may be separated from said second supported reagent by filtration. Said second supported reagent may optionally be washed to make available more of said product. Preferably, separation of said product from said second supported reagent does not involve any solvent extraction technique. Preferably, separation of said product from said second supported reagent involves no chromatographic purification. Preferably, said separation does not involve crystallisation and/or distillation techniques. Advantageously, said product can be separated from said second supported reagent by filtration alone. ^mM,S - 6 - PCT/GB99/01251

Third and subsequent reactions may be effected using supported reagents in a similar manner to said first and second reactions described above.

Advantageously, a multiplicity of different products may be produced using said first and/or second reactions in a parallel array or combinatorial chemistry technique, suitably under automatic control, for example using a robot or the like. In this case, a multiplicity of different first reactants may be individually reacted with said first supported reagent as described. The respective products may be separated from said first supported reagent as described. Thereafter, said respective products (or derivatives thereof) may be individually reacted with said second supported reagent as described. Products of this reaction (or derivatives thereof) or subsequently prepared products may be reacted further using supported reagents in a similar manner.

Unless otherwise stated in this specification, preferred cyclic, heterocyclic, aromatic and heteroaromatic groups have 5 or 6 ring atoms.

Unless otherwise stated in this specification, where any group is stated to be optionally-substituted, optional substituents may be selected from halogen (preferably fluorine, chlorine or bromine) atoms and optionally substituted, preferably unsubstituted, alkyl, acyl, nitro, cyano, alkoxy, alkoxyalkyl, hydroxy, amino, alkylamino, sulphinyl, alkylsulphinyl, sulphonyl, alkylsulphonyl, sulphonate, amido, alkylamido, alkoxycarbonyl, halocarbonyl (especially chlorocarbonyl) , haloalkoxy, and haloalkyl (especially fluoroalkyl or chloroalkly) , groups. Unless otherwise stated, where any group is stated to be optionally substituted, it may be substituted by up to 4, preferably up to 3, more preferably up to 2, especially 1 substituent.

Unless otherwise stated in this specification, an alkyl group may have up to 12, suitably up to 10, preferably up to 8, more preferably up to 6, especially up to 4 carbon atoms, with methyl and ethyl groups being preferred.

A first embodiment of a reaction which may be carried out in accordance with the invention is the oxidation of an alcohol, preferably to an aldehyde. In this case, a polymer supported oxidising agent, for example a perruthenate may be used. Preferred alcohols are of general formula R¹⁰-Q^x wherein R¹⁰ represents an optionally-substituted alkyl, cyclic or heterocyclic group (preferably an optionally-substituted aromatic or heteroaromatic group, with optionally-substituted phenyl, pyridyl and furanyl being especially preferred) ; and wherein Q¹ represents an optionally-substituted hydroxyalkyl group, preferably an optionally-substituted Cι-₄ hydroxy alkyl, especially an optionally-substituted hydroxymethyl group, for example a group -CHR^uR¹²OH wherein R¹¹ and R¹² independently represent a hydrogen atom or an optionally-substituted, especially an unsubstituted, alkyl group. Preferably, R^u represents a hydrogen atom and R¹² represents an alkyl group, for example a methyl group, or a hydrogen atom. Where group R¹⁰ is substituted it may be substituted by a halogen atom especially a fluorine or bromine atom or an amino, nitro, alkoxy (especially lower alkoxy for example methoxy) , or an optionally-substituted alkyl (especially lower alkyl which may be optionally-substituted by a halogen, especially a fluorine atom), group.

Where group R¹⁰ is substituted it may be substituted by 1- 3, especially 1-2 groups. It may, however, be unsubstituted.

Especially preferred alcohols may be selected from one or more of the alcohols show in Figure 1; or from alcohols corresponding to the aldehydes shown in Figure 8.

A second embodiment of a reaction which may be used in accordance with the invention is the reductive amination of carbonyl, especially aldehyde, compounds. In this case, a polymer supported reducing agent, for example a cyanoborohydride may be used. Preferred amines for use in said second reaction are either primary or secondary amines, suitably of general formula R¹³R¹NH wherein R¹³ and R¹⁴ may be independently selected from a hydrogen atom or an optionally-substituted alkyl group or R¹³ and R¹⁴ may together form an optionally-substituted ring structure, provided that both R¹³ and R¹⁴ do not represent a hydrogen atom.

Especially preferred amines may be selected from one or more of the amines shown in Figure 2.

A third embodiment of a reaction which may be used in accordance with the invention is the sulfonylation of an amine. In this case, a polymer supported sulfonyl chloride may be used. Preferred sulphonyl chlorides are of general formula R¹⁵S0₂R¹⁶ wherein R¹⁵ is a polymer bound moiety and R¹⁶ is a optionally-substituted alkyl, cyclic, heterocyclic, aromatic or heteroaromatic group. Preferably, R¹⁶ is an optionally-substituted alkyl, aromatic (especially optionally-substituted phenyl), or heteroaromatic (especially a sulphur containing aromatic) group. Especially preferred groups R¹⁶ are shown bound to the right hand end of the -S0₂- moiety in figure 3. R¹⁵ preferably includes a pyridinium moiety, especially an amino pyridinium moiety bound to a solid polymer.

In one embodiment described hereinafter, said first embodiment of a reaction described above may be followed by said second embodiment of a reaction described above and, optionally, by said third embodiment of a reaction described above, suitably to prepare a library of compounds .

A fourth embodiment of a reaction which may be used in accordance with the invention is a polymer supported Mukaiyama aldol condensation, suitably using silyl enol ethers which are coupled with aldehydes to generate α,β- unsaturated ketones. Such ketones may subsequently be treated with selected hydrazines to produce 4,5-dihydro- lH-pyrazole compounds. Advantageously, the aldehydes used in the process may be prepared from alcohols as described above according to said first embodiment. Preferred enol ethers for use in the process are shown in Figure 6. Hydrazine compounds used in the process may be optionally- substituted by one or more, preferably only one, alkyl group, especially a methyl group. Especially preferred hydrazines are shown in Figure 7. A fifth embodiment of a reaction that may be used in accordance with the invention is the preparation of alkenes from aldehydes, suitably using a polymer supported Wittig reagent. The alkenes prepared may be converted to epoxides which, in turn, may be converted to β- hydroxyamines . Advantageously, the aldehydes used in the process may be prepared from alcohols as described above according to said first embodiment. Preferred aldehydes may be as described in any statement herein. Especially preferred aldehydes are shown in Figure 8.

The polymer supported Wittig reagent may be of general formula R¹=CR¹⁸R¹⁹ wherein R¹⁷ is a polymer bound phosphonium moiety and R¹⁸ and R¹⁹ are independently selected from a hydrogen or halogen atom, a cyano (or other substitutent group as described in any statement herein) or an optionally-substituted alkyl, cyclic, heterocyclic, aromatic or heteroaromatic group. Preferred groups R¹⁸ and R¹⁹ can be ascertained from groups included in the specific Wittig reagents described hereinafter. Preferably R¹⁷ represents a polymer bound -PR₂ ¹⁶= moiety wherein R¹⁸ represents an optionally-substituted, preferably an unsubstituted, phenyl group.

Preferably, said process of the first aspect includes at least two reactions selected from said first to fifth embodiments described above.

One or more of the sixth to the ninth embodiments described hereinafter may be used as component parts of a reaction scheme for preparation of piperidino- thiomorpholine compounds, especially a library of such compounds, prepared using a range of polymer-supported reagents .

In the sixth embodiment, the nitrogen atom of a piperidone, especially a 4-piperidone, may be derivatized using sulphonyl chlorides to give corresponding sulphonamides . The reaction may be carried out using a polymer supported base, suitably a dialkylaminopyridine. Excess amine may be removed using a solid supported sequestrating agent.

In a seventh embodiment, a polymer supported brominating agent may be used (e.g. pyridinium bromide perbromide) .

In an eighth embodiment, α-bromoketones may be reacted with protected aliphatic l-amino-2-thiols in the presence of a polymer supported base.

In a ninth embodiment, polymer supported cyanoborohydride is reacted with an imine to produce a thiomorpholine derivative. Such derivatives may be reacted further to give a diverse range of products.

According to a second aspect of the invention, there is provided a method of producing a library of compounds, the method comprising contacting a plurality of respective first compounds with a first solid supported reagent and carrying out a first reaction and contacting respective products of said first reaction or derivatives thereof with a second solid supported reagent and carrying out a second reaction. The method may include contacting said plurality of respective first compounds or derivatives thereof with a second compound, suitably in the presence of said first solid supported reagent.

The method may use an array of reaction sites, for example reaction receptacles. Reagents and/or products for use in said first and/or said second reactions may be transferred into and/or from said sites by a robot (or the like) in an automated process.

The method of the second aspect may include a plurality of processes, for example parallel processes, according to said first aspect.

The library produced in a method according to said first aspect may have at least 10, suitably at least 20, preferably at least 30, more preferably at least 40, especially at least 50 members.

According to a third aspect of the invention, there is provided a library of compounds produced as described according to said first or said second aspect.

According to a fourth aspect of the invention, there is provided any novel library of compounds described herein.

A library of the third or fourth aspects may include a plurality (suitably 4, preferably 8, more preferably 12) compounds selected from either the aldehydes shown in Figure 5; the enones shown in Figure 6; the 4,5-dihydro- pyrazoles shown in Figure 7; the carbonyl compounds shown in Figure 8; the olefins shown in Figure 9; the olefins WO 99/58475 „,,,--,_-.

- 13 - PCT/GB99/01251

shown in Figure 10; the epoxides shown in Figure 11; products of the reaction shown in scheme 7; products of the reaction shown in scheme 8; products of the reactions shown in scheme 9; or products of the reaction shown in scheme 10.

According to a fifth aspect of the invention, there is provided any novel compound or intermediate described in any statement herein.

Any feature of any aspect of any invention or embodiment described herein may be combined with any feature of any aspect of any other invention or embodiment described herein.

Specific embodiments of the invention will now be described, by way of example, with reference to the accompanying figures, wherein:

Figure 1 showns a set of alcohols oxidized by polymer supported perruthenate (PSP) in a multi-parallel fashion to the corresponding aldehydes;

Figure 2 shows a set of amines used in a polymer supported cyanoborohydride (PSCBH) effected reductive amination;

Figure 3 shows polymer bound amino pyridinium sulfonyl chlorides;

Figure 4 provides a summary of product purities of an automated sequential application of PSP and PSCBH; Figure 5 provides a summary relating to the oxidation of certain alcohols to aldehydes using PSP;

Figure 6 provides a summary relating to Nafion-TMS mediated Mukaiyama aldol reactions of aldehydes and silyl enol ethers yielding enones;

Figure 7 provides a summary relating to the synthesis of 4, 5-dihydro-lH-pyrazoles starting from enones;

Figure 8 provides a summary of carbonyl compounds subjected to polymer supported Wittig olefination;

Figure 9 provides a summary of polymer supported Wittig olefinations;

Figure 10 provides examples of epoxidation with DMDO of olefins obtained from polymer supported Wittig reactions;

Figure 11 provides details on aminolysis reactions of various epoxides; and

Figure 12 provides a summary of polymer supported reactions referred to in schemes 7 to 10.

Example 1

In this example, there is described the combination of polymer supported perruthenate (PSP) and polymer supported cyanoborohydride (PSCBH) making use of readily available alcohols as a primary feedstock which after oxidation and further coupling by reductive amination affords a wide range of secondary or tertiary amines. Some of those may be further sulfonylated using a third polymer system to give a more complex array of products. Scheme 1 summarises the process involved.

NMe₃ ^* BH₃CN eOH

Polymeric reagents PSP and PSCBH may be prepared as described in B.Hinzen and S.V Ley, J.Chem. Soc. Perkin Trans 1, 1997, 1907 and R.O. Hutching, N.R. Natale and I.M. Taffer, J. Chem. Soc. Chem. Comm. 1978, 1088, respectively. However, in the example, PSCBH was prepared by filtering a solution of NaBH₃CN through an ion exchange resin (Amberlyst A-26) containing quaternary ammonium groups. The resin was then washed with water, methanol and finally briefly with acetone to remove excess NaBH₃CN. It was then dried in vacuo . The loading of the resin was estimated to be approximately 2 mmol BH₃CN-ion per gramme of resin.

In the example, the chemistry using PSP oxidant and PSCBH was conceived to run in parallel using robotic synthesis methods to achieve overall oxidation and reductive amination. To this end an 8x12 array of secondary and tertiary amines was prepared using an ACT496 Multiple Organic Synthesizer. Twelve alcohols (compounds 1-12 shown in Figure 1) were firstly oxidized using PSP and were subsequently reacted with eight amines A-H (Figure 2) and reduced with PSCBH as shown in scheme 1.

The products were characterised by LC-MS which indicated that 88 out of 96 two step syntheses had been successful with product purities in the range of 35-92%. These results are illustrated in figure 4.

The electron rich amine F gave a significant proportion of bis-alkylated product. However reaction of the piperazine B afforded only a small amount of the double-alkylated product.

The procedures for the syntheses of the amines of Figure 2 involved each alcohol (0.26 mmol) of Figure 1 being dissolved in toluene (5 ml) and PSP (1.3mmol g^"1, 200 mg, 0.26 mmol) added. The mixtures were stirred at 80°C for two hours and then the PSP resin was filtered off and washed with toluene (3 ml) . The filtrate and washings were combined to afford the aldehyde solutions which were dispensed into 96 wells each containing PSCBH (1.0 mmol g^-1, 35 mg, 35 μ ol) . Each amine was dissolved in methanol (10 ml) and the robot used to dispense these such that each well contained 32 μmol of amine. The resulting mixtures were shaken at room temperature for 72 hours. The PSCBH resin was removed by filtration and washed with methanol (1 ml) . The filtrate and washings were collected and evaporated in a Genevac centrifugal evaporator to afford the product amines. This two step automated polymer bound reagent synthesis was unoptimised yet the success rate was considered to be very acceptable for combinatorial chemistry.

In order to extend this process further just one combination of benzylalcohol with benzylamine which yielded dibenzylamine after sequential reactions with PSP and PSCBH was selected. The yield at this stage was estimated to be 91%. Next the amine was dissolved in CH₂C1₂, partitioned and reacted with four different polymer bound amino pyridine sulfonyl chlorides (compounds 13-16 shown in Figure 3) . These all reacted well (i.e.>90%) to give the corresponding sulfonated products showing that a further level of diversity is possible using additional polymer bound reagent systems.

Compounds 13-16 were prepared by adding 0.3 g of commercial dimethylaminopyridine on polystyrene (more particularly, N-methyl-N- (4-pyridyl) aminomethyl polystyrene cross-linked with divinylbenzene purchased from Fluka Chemie AG) to 0.33 mmol of the sulfonyl chloride. The mixture was suspended in dry CH₂C1₂ (4 ml) . After stirring for half an hour 0.03 mmol of dibenzylamine was added. The reaction mixture was stirred at room temperature for 0.5-6 hours and the progress of the reaction was monitored by tic. Eventually, the resin was removed by filtration and washed with further CH₂C1₂ (4 ml) . The filtrate and washings were combined and evaporated. GLC and ^XH-NMR analysis revealed that the crude products were of high purity (>90%) . Example 2

In this example, there is described how the Nafion-TMS mediated Mukaiyama aldol reaction of silyl enol ethers w th aldehydes, obtained from mild oxidation of alcohols with polymer supported perruthenate (PSP) as described m Example 1, yields α, β-unsaturated ketones which, upon treatment with hydrazines, allow the clean synthesis of 4 , 5-dihydro-lH-pyrazoles

Scheme 2 below summarises a route used to prepare 4,5- dihydro-lH-pyrazoles . This starts with alcohols which are firstly oxidised to the corresponding aldehydes in si tu using polymer supported perruthenate (PSP) . Next a polymer supported Mukaiyama aldol condensation is used, using silyl enol ethers which are coupled with the synthesised aldehydes to generate α, β-unsaturated ketones that on subsequent treatment with hydrazines lead to the desired 4 , 5-dihydro-lH-pyrazole scaffold.

3a,

Scheme 2 Figure 5 summarises the aldehydes used which were prepared from alcohols as described in Example 1. Referring to the figure, the general reaction conditions were: 3 equivalents of PSP, CH₂C1₂, room temperature; ^bGLC yield was judged by NMR analysis of crude product; the purity in all entries was >95%. In a typical experiment, the alcohol (0.2 mmol) was added to a mixture of PSP (0.6 mmol) in 2.5 ml dichloromethane at room temperature. Work-up consisted of filtration followed by evaporation in vacuo without any further chromatographic purification. In general, the alcohols were converted quantitatively into their corresponding aldehydes within 16 hours. These aldehydes were then used directly in Nafion-TMS mediated Mukaiyama aldol reactions with silyl enol ethers to yield the corresponding unsaturated carbonyl compounds.

The Nafion-TMS allowed the clean coupling of silyl enol ethers to aldehydes to yield aldol products which reacted further to lead directly to α, β-unsaturated ketones. In the process, an aldehyde (0.2 mmol) was added to a mixture of Nafion-TMS (0.6 mmol) and 4A-molecular sieves as dehydrating agent, in dichloromethane (3 ml) at -78°C followed by addition of the trimethylsilyl enol ether (0.2 mmol) which was then allowed to slowly warm to room temperature. The work-up consisted only of filtration followed by evaporation in vacuo. No further purification was needed. The results of a number of these reactions are summarised in Figure 6. Referring to the figure, the general reaction conditions were: 3 equivalents Nafion- TMS, CH₂C1₂, -78°C to room temperature; ^bEnones were satisfactorily identified by their ^XH- and ¹³C- NMR spectra and where possible by comparison with authentic samples; ^cAs judged by NMR analysis of the crude product the purity was >85%. Using 2- (trimethylsilyloxy) propene 3a the aromatic aldehydes were cleanly transformed into the corresponding enones overnight. No other product could be detected by GLC analysis. In general, the coupling with 1- (trimethylsilyloxy) cyclopentene 3b proceeded slightly less efficiently and some cyclopentanone was observed as decomposition product. While the yield for the aldol condensation was generally around 95% in many cases, electron withdrawn aldehydes coupled slowly. No attempt was made to optimise these reactions.

Eventually, the above α, β-unsaturated ketones were treated with hydrazine (as described in CH. De Puy and R.J. Van Lanen, J. Org. Chem., 1974,39,3360) or methylhydrazine to give the final products. The crude enone (0.2 mmol) was dissolved in absolute ethanol (2 ml) and 1.0 equivalent of hydrazine or methylhydrazine was added. Upon consumption of the starting material, as indicated by GLC, the solvent was removed by evaporation in vacuo and the products were analysed by NMR spectroscopy. All 4, 5-dihydro-lH- pyrazoles synthesised were obtained in good yields and high purities (see Figure 7) . Referring to the figure, the general reaction conditions were: 1 equivalent hydrazine in absolute ethanol, room temperature; 4,5- dihydropyrazoles were satisfactorily identified by their ^lH- and ¹³C-NMR spectra and where possible by comparison with authentic samples: ^cAs judged by NMR analysis, the purity in all entries was >85%.

Due to the high yielding nature of both the solid support processes (oxidation and aldol coupling) as well as the condensation with hydrazine reagents in the final step, the synthesis sequence proceeds without any intermediate tedious cleaning procedures. Between the individual steps throughout the whole process, the only purification step needed to afford pure products consists of a mere filtration of the reaction mixture in order to remove the functionalised polymers.

Thus, in summary, this example describes a clean multi- step preparation of 4, 5-dihydro-lH-pyrazoles starting from alcohols which is believed to be suitable for robotic synthesis procedures. The route clearly demonstrates the considerable potential the orchestrated combination of several polymer supported reagents has for the preparation of chemical libraries. The methods described may be combined with polymer supported sequestration and capture, as described in S.W. Kaldor, M.G. Siegel, B.A. Dressmann and P.J Hahn, Tetrahedreon Lett., 1996, 37, 7193; R.J. Booth and J.C. Hodges, J.Am Chem. Soc, 1997, 119, 4882; M.W. Creswell, G.L. Bolton, J.C. Hodges and M Meppen, Tetrahedron, 1998 54, 3983 and M.G. Siegel, P.J. Hahn, B.A. Dressman, J.E. Fritz, J.R. Grunwell and S.W. Kaldor, Tetrahedron Lett., 1997, 38, 3357 respectively, to provide further opportunities.

Example 3

In this example, there is described a polymer bound Wittig reaction and its use in multi-step organic synthesis for the overall conversion of alcohols to β-hydroxyamines .

In Examples 1 and 2 above, there is described the use of a combination of polymer supported reagents to effect clean multistep organic synthesis leading to products with potential application in combinatorial chemistry. In the current example, polymer supported Wittig reagents are used which, when reacted with aldehydes, produce alkenes. The aldehydes may be derived from alcohols by oxidation with polymer supported perruthenate, as described in Example 1. The alkenes are prepared in excellent yields and require only simple filtration to obtain pure products which are useful for further synthetic transformations. In order to exemplify potential applications many of these alkenes were converted in essentially quantitative yields to epoxides using dimethyldioxirane, as described in R.Curci, M. Fiorentino, L. Troisi, J.O. Edwards and R.H. Pater, J. Org. Chem., 1980. 45, 4758; W. Adam, R. Curci and J.O. Edwards, Ace. Chem. Res., 1989, 22, 205; W. Adam, J.Bialas and L. Hadjiarapoglou, Chem. Ber., 1991, 124, 2377. Once again pure products were obtained only by removing solvent by evaporation. Likewise these epoxides were themselves excellent precursors for further steps such as the reaction with amines to produce β- hydroxyamines since these are considered as key intermediate towards privileged structures in many pharmaceutical and agrochemical products. Scheme 3 (below) summarizes the reaction processes:

R⁴NH₂

The car_bonyl compounds that were subj ecte^d to the polymer supported _Wittig olef ination are given in Figure 8 . _Genera_lly, they can be prepared from their corresponding alcoho_l precursors in excellent yields an^d high purities _by oxidation (as described in Examp^le ^{1 )} .

The procedure used is described in detail below.

A set of six Wittig reagents (8.1 to 8.6⁾ was prepared as described in M. Bernard, W.T. Ford, J. Org. Chem,

1983,48,326, starting from commercial diphenylphosphine derivatised polystyrene (see scheme 4 below⁾. To the support ₍l-2g, 3-6 mmol phosphine) suspended in dry DMF

₍10-20ml₎ was added 2-4 equivalents of the alkyl halide.

The slurry was stirred for 48 hours at 50-70°C. Eventually the suppor _<t- _ww_aas, rcaarreefiuulnly^γ filtered off under argon and extensively was _.h_e_di _wwiitthn d^ur_.y^y toluene (40 ml⁾, dry dichloromethane (4i_n0 m_ml-n) _aann_da darrvy d^uiethyl ether (60 ml^{) ,} The grey to brown po ,w,^d_e_r_r-s_; uwperree d^Qrie^.Ud in vacuo . According to the increase of weight the loading was estimated to be in the range of 1.8-3.0 mmol phosphonium salt per gramme support. The choice of the base and the solvent for the deprotonation of the phosphonium salt as well as the subsequent olefination step was evaluated and the procedure was carefully optimised. With a view to automating the process all steps were carried out in a column technique manner. Hence in a typical experiment a syringe equipped with a sintered Teflon frit was charged with the polymer supported phosphonium salt (300 mg, 0.54- 0.9 mmol phosphonium salt). The support was placed under argon and washed with dry THF (8 ml)). Addition of a 1 M solution of sodium bis (trimethylsilyl) amide (NHMDS) in THF (1.8 ml) at room temperature effected the generation of the ylid within less than 30 minutes. Excess base was carefully removed by extensive washing of the reddish brown to black support with dry THF (25 ml) . Eventually the support was resuspended in dry THF (3 ml) and the carbonyl compound (0.25 - 0.3 mmol) was added at room temperature. According to GLC analysis the olefination reaction was generally complete within 20-40 minutes (conversion >95%) . The olefin containing solution was collected together with additional support washings (15 ml of dry THF) and filtered over a small amount of silica gel (0.5 - 1 g) . Evaporation in vacuo furnished the crude olefins. Some examples are summarised in Figure 9. Referring to the figure, all olefins were satisfactorily identified by their ^XH- and ¹³C-NMR spectra and where possible by comparison with authentic samples; ^aGLC- conversions determined after 20 minutes reaction time; ^byields not determined due to partial loss of the volatile product during evaporation; ^cThe crude product consisted of 73% of 4-methoxy-iodovinylbenzene, 7% of 4- methoxyvinyl-benzene and 21% of presumably 4-methoxy- ethinylbenzene . While aliphatic and benzylic aldehydes as well as phenones were rapidly converted to furnish olefins of high purity (>90%) and in good to excellent yields (70- 100%), 3-pentanone reacted only very slowly. In general, the cis : trans ratios were as expected. However, some examples with the phosphonium salt 8.1 (see scheme 4) showed a slightly enhanced trans- selectivity. The olefination with the cyanomethylene ylid was slow yet very clean. Neither the use of a larger excess of ylid nor elevated temperatures affected the rate of the reaction considerably. In the case of the polymer supported iodomethylphosphonium salt 8.6 (scheme 4) the olefination proceeded less cleanly. In all experiments, the isolated iodoolefin contained various amounts of the corresponding deiodinated Wittig product together with another side product which is considered to be the corresponding acetylene.

ScΛ ovi. i

β 1 9. 2 9. 2

f . i 1. 5 *^s Epoxidation of some of the olefins (0.1 mmol) described in Figure 9 was achieved by the addition of an approx 0.075 M solution of dimethyldioxirane (DMDO) in acetone (2 ml) at room temperature, as shown in scheme 5. In general, within two hours, conversion was complete according to GLC analysis. Stilbenes reacted slightly slower than styrene derivatives. 4-Nitro-stilbene was the slowest, needing 18 hours for complete conversion. Work up simply consisted of evaporation of excess reagent and solvent. Pure epoxides were obtained in nearly quantitative yields. A summary is provided in Figure 10. Referring to the figure, all epoxides were satisfactorily identified by their ^lR- and ¹³C-NMR spectra and where possible by comparison with authentic samples; ^aReaction condi tions : approx 2 eq. of DMDO in acetone, rt ; ^bGLC-conversions determined after 40 minutes reaction time; ^cAfter 120 minutes (approx -80% after 40 minutes); ^d4 eq. DMDO, 24 h.

ϋ ₊ Scheme 5

Aminolysis of the above epoxides was carried out using either ammonia, cyclohexylamine or piperazine as amine, as summarised in scheme 6 below. Typically the epoxide (0.1 mmol) was dissolved in either methanol or ethanol (1 ml) and a large excess (25-100 eq.) of the amine was added. The reaction mixture was stirred at 75°C. Whilst most of 5 the epoxides were converted into their corresponding β- hydroxyamines within less than 24 hours (as shown by GLC analysis), the sterically hindered 1, l-dimethyl-2- (3, 4- dimethoxyphenyl) oxirane needed considerably longer reaction times. Work up consisted of the evaporation^' of 10 the solvent and the excess of amine, followed by careful drying.

15

Scheme 6

£

25

30

In the case of piperazine, the excess of reagent was removed under high vacuum (0.2 torr) at 40°C within 12 hours. In general, the purity of the obtained amino alcohols exceeded 85%. Some examples are given in Figure

11.

Thus, in summary, the examples describe an efficient procedure for the clean preparation of β-hydroxyamines starting from alcohols using polymer supported reagents in combination with solution chemistry. Throughout the whole process, work-up is achieved by mere filtration and evaporation.

Example 4

In this example, there is described a route to piperidino- thiomorpholines which are fragments of potential pharmaceutical interest.

Starting from commercially available 4-piperidone hydrochloride hydrate 1 (schemes 7, 8, 9 and 10, wherein the key for the schemes is shown next to scheme 7), the nitrogen was derivatised with a range of commercially available sulphonylchlorides to give the corresponding sulphonamides 2a-2d in high yields and purities (reaction 1) . This reaction was carried out using carefully dried polymer supported dimethylaminopyridine in dichloromethane (as described in S.V. Ley, M.H. Bolli, B. Hinzen, A.G. Gervois, B.J.Hall, J. Chem. Soc,. Perkin Trans. 1, 1998, 2239) , with excess of amine being removed by addition of acidic Amberlyst 15 as a sequestering agent.

WO 99/58475 ^{" 3}° ^" PCT/GB99/01251

KEY TO SCHF F 7

i a) R-SO Cl Q- DMAP . Dichloromethane t» Amberlyst l - - S0₃H

2 " Br₂ . Toluene

3 _/V BocZMercaptoamine . Amberlyst A21 O NMe₂ . Tetrahydrofuran < »l 2 . Aminothiophenoi O N Me₃ C BH₃ . Methanol t» Amberlite IRA 420 0" N^*Me₃ ^"OH

5 a) Trifluoroacetic acid. Dichloromethane t»l O- N^*Me₃ CNBΗ₃ Methanol a) Phenyl.NCS - ^-^lι • Dichloromethane b) Q- NH₂ c⁾ Amberlyst 130"" S0₃H a) R . NCO. Dichloromethane b) O NH₂ cl Amberlyst IfQ- SO₃H Dimethyldioxirane . Acetone en υ

E 26

This was followed by a bromination α to the keto-function using polymer supported pyridinium bromide perbromide. (as described in M.J. Frechet, M.J. Farrel, L.J. Nuyens, J. Macromolecular Sci, Chem, 1997, 11, 507), in toluene at 10°C (reaction 2) . This process needed careful control of the reaction temperature, as higher temperatures resulted in the formation of a substantial amount of the undesired dibromination product.

The α-bromo ketones 3a-3d were then reacted with W-Boc- protected aliphatic l-amino-2-thiols in tetrahydrofuran using Amberlyst A21 as base to effect the coupling. Cleavage of the Boc-group using trifluoroacetic acid in dichloromethane yielded the corresponding imine directly which could be reduced with polymer supported cyano borohydride in methanol (as described in R.O. Hutchins, N.R. Natale, I.M. Taffer, J. Chem. Soc, Chem. Common., 1978,1088) to give the corresponding thiomorpholine derivatives 4a-4f (reaction 5) . Alternatively, the Boc- group could be cleaved by shaking a solution of the compound with Amberlyst 15 in dichloromethane (as described in Y.-S. Liu, C. Zhao, D.E. Bergbreiter, D. Romo, J. Org. Chem, 1998, 63, 3471) . The reduction of the imines resulted in the formation of two diasteromers { cis and trans about the ring junction, where the trans-product predominates in approx. 2:1 ratio). It was also demonstrated that aromatic 2-amino thiophenols were compatible with the reductive amination conditions to give the thiomorpholine derivatives (e.g. 5) . In the example attempted (reaction 4), the excess of the 2-amino thiophenol was removed by treatment of the reaction mixture with A berlite IRA-420 to act as a sequestering agent which could be removed by filtration. The amino function of the thiomorpholine unit could be further elaborated with a range of commercial available isocyanates (reaction 7) and isothiocyanates (reaction 6) to furnish ureas 6a-6p and thioureas (e.g. compound 7), respectively. The reaction of the isothiocyanate required the presence of diethylaminomethyl polystyrene (prepared by heating a suspension of chloromethylpolystyrene in N,N- dimethylformamide with diethylamine in the presence of a catalytic amount of tetra-N-butylammonium iodide to 75°C for 20 hrs.) as basic catalyst. The excess quantities of the isocyanates and isothiocyanates were scavenged with aminomethyl polystyrene. This was followed by a brief treatment of the reaction solution with Amberlyst 15 and resulted in pure products being isolated. If desired, the diastereomeric mixture could be separated by classical methods to aid H nmr spectroscopic determination of the products.

The resultant thiomorpholine derivatives could be treated with a solution of dimethyl dioxirane in acetone to give the corresponding sulfones 8a-8p also in a clean reaction process (reaction 8) , (as described in R.W. Murray, R. Jeyaraman, J. Org. Chem, 1985, 50, 2847; W. Adam, Y.-Y Chan, D. Cremer, J. Gauss, D. Scheutzow, M) . After complete conversion the di ethyldioxirane was evaporated together with the solvent to afford the pure products.

Thus, the example describes a clean multi-step preparation of piperidino-thiomorpholines 6 and their corresponding sulphones 8 starting from 4-piperidone 1 by a process which is suitable for automated synthesis. Due to the high yielding nature of all reactions, the process could be carried out without the need for any chromatographic purification. All intermediates were essentially pure according to LC-MS and could be isolated by intercepting part of the reaction streams. Yields and purities of the various products are given in Figure 12.

The reader' s attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All of the features disclosed in this specification (including any accompanying claims, abstract and drawings) , and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, abstract and drawings) , may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

The invention is not restricted to the details of the foregoing embodiment (s) . The invention extend to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel _>f any method or process so combination, of the steps disclosed.

Claims

1. A process for the preparation of a compound which process includes a first reaction and a second reaction, wherein the process uses a first solid supported reagent in said first reaction and a second solid supported reagent in said second reaction.

2. The use of polymer bound reagents to effect multi- step organic synthesis for potential application in combinatorial chemistry.

3. The use of a combination of polymer supported reagents in multi-parallel synthesis.

4. The use of polymer supported reagents in multi-step syntheses of chemical libraries.

5. A process or a use according to any of claims 2 to 4, wherein in a or said first reaction a first reactant is contacted with a first supported reagent.

6. A process or use according to claim 1 or claim 5, wherein after said first reaction, the product thereof is separated from said first supported reagent by filtration.

7. A process or use according to any of claims 1, 5, or

6, wherein a multiplicity of different first reactants is individually reacted with said first supported reagent in a respective first reaction.

8. A process or use according to any of claims 1 or 5 to

7, wherein the or each product of said first reaction (or a derivative thereof) is contacted with a second supported reagent in a or said second reaction.

9. A process according to claim 8, wherein after said second reaction, the product thereof is separated from said second supported reagent by filtration.

10. A process or use according to any preceding claim, wherein a multiplicity of different products is produced using first and/or second reactions in a parallel array or combinatorial chemistry technique.

11. A process or use according to any preceding claim, wherein one reaction carried out is the oxidation of an alcohol to an aldehyde using a polymer supported oxidizing agent.

12. A process or use according to claim 11, using one or more alcohols selected from those shown in Figure 1.

13. A process or use according to claim 11 or claim 12, using one or more alcohols selected from those shown in Figure 8.

14. A process or use according to any preceding claim, wherein one reaction carried out is the reductive amination of carbonyl compounds.

15. A process or use according to any preceding claim, using one or more amines selected from those shown in Figure 2.

16. A process or use according to any preceding claim, wherein one reaction carried out is the sulfonylation of an amine.

17. A process or use according to any preceding claim, wherein one reaction carried out is a polymer supported Mukaiyama aldol condensation.

18. A process or use according to any preceding claim, wherein one reaction carried out is the preparation of alkenes from aldehydes using a polymer supported Wittig reagent.

19. A process or use according to any preceding claim, wherein one reaction carried out uses a polymer supported base.

20. A process or use according to any preceding claim, wherein one reaction carried out comprises a bromination reaction using a polymer supported brominating agent.

21. A process or use according to any preceding claim, wherein one reaction carried out is a reduction reaction using a polymer supported reducing agent.

22. A method of producing a library of compounds, the method comprising contacting a plurality of respective first compounds with a first solid supported reagent and carrying out a first reaction and contacting respective products of said first reaction or derivatives thereof with a second solid supported reagent and carrying out a second reaction.

23. A method according to Claim 22, the method using an array of reaction sites.

24. A method according to Claim 23, wherein reagents and/or products for use in said first and/or second reactions are transferred into and/or from said sites by an automatic means.

25. A library of compounds produced as described in any preceding claim.

26. A library of compounds including a plurality of compounds selected from either the aldehydes shown in Figure 5; the enones shown in Figure 6; the 4, 5-dihydro- pyrazoles shown in Figure 7; the carbonyl compounds shown in Figure 8; the olefins shown in Figure 9; the olefins shown in Figure 10; the epoxides shown in Figure 11; products of the reaction shown in scheme 7; products of the reaction shown in scheme 8; products of the reaction shown in scheme 9; or products of the reaction shown in scheme 10.

27. A novel compound or intermediate described in any of the preceding claims.

28. A novel polymer supported reagent described in any of the preceding claims.