WO1999058475A2 - Preparation de composes utilisant des reactifs a support polymere - Google Patents

Preparation de composes utilisant des reactifs a support polymere Download PDF

Info

Publication number
WO1999058475A2
WO1999058475A2 PCT/GB1999/001251 GB9901251W WO9958475A2 WO 1999058475 A2 WO1999058475 A2 WO 1999058475A2 GB 9901251 W GB9901251 W GB 9901251W WO 9958475 A2 WO9958475 A2 WO 9958475A2
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
use according
supported
reagent
products
Prior art date
Application number
PCT/GB1999/001251
Other languages
English (en)
Other versions
WO1999058475A3 (fr
Inventor
Steven Ley
Martin Bolli
Berthold Hinzen
Anne-Geraldine Gervois
Beverley Hall
Jorg Habermann
James Scott
Frank Haunert
Original Assignee
Cambridge Combinatorial Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9810073.8A external-priority patent/GB9810073D0/en
Application filed by Cambridge Combinatorial Limited filed Critical Cambridge Combinatorial Limited
Priority to GB0000469A priority Critical patent/GB2342095A/en
Publication of WO1999058475A2 publication Critical patent/WO1999058475A2/fr
Publication of WO1999058475A3 publication Critical patent/WO1999058475A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
    • C07C1/34—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen reacting phosphines with aldehydes or ketones, e.g. Wittig reaction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/28—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of CHx-moieties
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C07D307/44—Furfuryl alcohol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B99/00—Subject matter not provided for in other groups of this subclass
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • 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) .
  • 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.
  • 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 ⁇ -unsaturated compounds. These molecules can be further elaborated into structures such as heterocycles, which may have applications in the pharmaceutical, agrochemical or biotechnology sectors.
  • 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.
  • supported reagent is used to refer to a solid supported reagent or a polymer bound or polymer supported reagent.
  • 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.
  • an excess of said first supported reagent is used.
  • 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.
  • separation of said product from said first supported reagent does not involve any solvent extraction technique.
  • separation of said product from said first supported reagent involves no chromatographic purification.
  • said separation does not involve crystallisation and/or distillation techniques.
  • 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.
  • an excess of said second supported regent is used.
  • 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.
  • separation of said product from said second supported reagent does not involve any solvent extraction technique.
  • separation of said product from said second supported reagent involves no chromatographic purification.
  • said separation does not involve crystallisation and/or distillation techniques.
  • said product can be separated from said second supported reagent by filtration alone.
  • Third and subsequent reactions may be effected using supported reagents in a similar manner to said first and second reactions described above.
  • 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.
  • 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.
  • cyclic, heterocyclic, aromatic and heteroaromatic groups have 5 or 6 ring atoms.
  • 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.
  • halogen preferably fluorine, chlorine or bromine
  • 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.
  • a polymer supported oxidising agent for example a perruthenate may be used.
  • Preferred alcohols are of general formula R 10 -Q x wherein R 10 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 Q 1 represents an optionally-substituted hydroxyalkyl group, preferably an optionally-substituted C ⁇ - 4 hydroxy alkyl, especially an optionally-substituted hydroxymethyl group, for example a group -CHR u R 12 OH wherein R 11 and R 12 independently represent a hydrogen atom or an optionally-substituted, especially an unsub
  • R u represents a hydrogen atom and R 12 represents an alkyl group, for example a methyl group, or a hydrogen atom.
  • group R 10 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.
  • a halogen atom especially a fluorine or bromine atom or an amino, nitro, alkoxy (especially lower alkoxy for example methoxy)
  • an optionally-substituted alkyl especially lower alkyl which may be optionally-substituted by a halogen, especially a fluorine atom
  • group R 10 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.
  • 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 R 13 R 1 NH wherein R 13 and R 14 may be independently selected from a hydrogen atom or an optionally-substituted alkyl group or R 13 and R 14 may together form an optionally-substituted ring structure, provided that both R 13 and R 14 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.
  • a polymer supported sulfonyl chloride may be used.
  • Preferred sulphonyl chlorides are of general formula R 15 S0 2 R 16 wherein R 15 is a polymer bound moiety and R 16 is a optionally-substituted alkyl, cyclic, heterocyclic, aromatic or heteroaromatic group.
  • R 16 is an optionally-substituted alkyl, aromatic (especially optionally-substituted phenyl), or heteroaromatic (especially a sulphur containing aromatic) group.
  • Especially preferred groups R 16 are shown bound to the right hand end of the -S0 2 - moiety in figure 3.
  • R 15 preferably includes a pyridinium moiety, especially an amino pyridinium moiety bound to a solid polymer.
  • 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 ⁇ , ⁇ - unsaturated ketones. Such ketones may subsequently be treated with selected hydrazines to produce 4,5-dihydro- lH-pyrazole compounds.
  • 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.
  • 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 ⁇ - hydroxyamines .
  • 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.
  • 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 .
  • the nitrogen atom of a 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.
  • a polymer supported brominating agent may be used (e.g. pyridinium bromide perbromide) .
  • ⁇ -bromoketones may be reacted with protected aliphatic l-amino-2-thiols in the presence of a polymer supported base.
  • 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.
  • a method of producing a library of compounds 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.
  • a robot or the like
  • 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.
  • Figure 1 showns a set of alcohols oxidized by polymer supported perruthenate (PSP) in a multi-parallel fashion to the corresponding aldehydes;
  • PSP polymer supported perruthenate
  • 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.
  • Figure 12 provides a summary of polymer supported reactions referred to in schemes 7 to 10.
  • 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.
  • PSCBH was prepared by filtering a solution of NaBH 3 CN 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 NaBH 3 CN. It was then dried in vacuo . The loading of the resin was estimated to be approximately 2 mmol BH 3 CN-ion per gramme of resin.
  • Scheme 2 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) .
  • PSP polymer supported perruthenate
  • a polymer supported Mukaiyama aldol condensation is used, using silyl enol ethers which are coupled with the synthesised aldehydes to generate ⁇ , ⁇ -unsaturated ketones that on subsequent treatment with hydrazines lead to the desired 4 , 5-dihydro-lH-pyrazole scaffold.
  • the Nafion-TMS allowed the clean coupling of silyl enol ethers to aldehydes to yield aldol products which reacted further to lead directly to ⁇ , ⁇ -unsaturated ketones.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)).
  • the examples describe an efficient procedure for the clean preparation of ⁇ -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.
  • reaction 1 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
  • 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).
  • aromatic 2-amino thiophenols were compatible with the reductive amination conditions to give the thiomorpholine derivatives (e.g. 5) .
  • 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.
  • 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.
  • 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
  • reaction 8 a solution of dimethyl dioxirane in acetone
  • reaction 8 a solution of dimethyl dioxirane in acetone
  • 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
  • the di ethyldioxirane was evaporated together with the solvent to afford the pure products.
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Structural Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

L'invention concerne un procédé de préparation d'un composé, ledit procédé consistant en une première et une seconde réactions. Le procédé utilise un premier réactif à support solide dans la première réaction, et un second réactif à support solide dans la seconde réaction. Le procédé peut être utilisé pour effectuer une synthèse organique multi-étape pour des applications potentielles en chimie combinatoire, et/ou dans la préparation de bibliothèques chimiques.
PCT/GB1999/001251 1998-05-11 1999-05-11 Preparation de composes utilisant des reactifs a support polymere WO1999058475A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB0000469A GB2342095A (en) 1998-05-11 1999-05-11 Preparation of compounds using polymer supported reagents

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9810073.8 1998-05-11
GBGB9810073.8A GB9810073D0 (en) 1998-05-11 1998-05-11 The sequential use of polymer supported regeants, their application to the construction of monomer sets, heterocyclic compounds in a continous flow procedure
GBGB9819402.0A GB9819402D0 (en) 1998-05-11 1998-09-04 Clean six-step synthesis of a piperidino-thiomorpholine library using polymer-supported reagents
GB9819402.0 1998-09-04

Publications (2)

Publication Number Publication Date
WO1999058475A2 true WO1999058475A2 (fr) 1999-11-18
WO1999058475A3 WO1999058475A3 (fr) 2000-06-15

Family

ID=26313647

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1999/001251 WO1999058475A2 (fr) 1998-05-11 1999-05-11 Preparation de composes utilisant des reactifs a support polymere

Country Status (2)

Country Link
GB (1) GB2342095A (fr)
WO (1) WO1999058475A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1997796A1 (fr) * 2007-06-01 2008-12-03 DSMIP Assets B.V. Réaction de condensation d'aldol et catalyseur correspondant
WO2009138488A1 (fr) * 2008-05-15 2009-11-19 Novo Nordisk A/S Purification de peptides préparés par synthèse en phase solide

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
BOLLI M. H. AND LEY S. V.: "Development of a polymer bound Wittig reaction and use in multi-step organic synthesis for the overall conversion of alcohols to beta-hydroxyamines" J. CHEM. SOC., PERKIN TRANS. 1,1998, pages 2243-2246, XP002121625 *
CORNELIS A. AND LASZLO P.: "Oxidation of alcohols by clay-supported iron (III) nitrate; a new efficient oxidizing agent" SYNTHESIS,1980, pages 849-850, XP002121622 *
FRECHET J. M. J. ET AL.: "Poly(vinylpyridinium dichromate): an inexpensive recyclable polymeric reagent" J. ORG. CHEM, vol. 46, 1981, pages 1728-1730, XP002121618 *
HAUNERT F. ET AL: "Clean three-step synthesis of 4,5-dihydro-1H-pyrazoles starting from alcohols using polymer supported reagents" J. CHEM. SOC., PERKIN TRANS. 1,1998, pages 2235-2237, XP002121623 *
HINZEN B. AND LEY S. V.: "Polymer supported perruthenate (PSP): a new oxidant for clean organic synthesis" J. CHEM. SOC., PERKIN TRANS. 1,1997, pages 1907-1908, XP002121616 cited in the application *
HINZEN B. AND LEY S. V.: "Synthesis of isoxazolidines using polymer supported perruthenate (PSP)" J. CHEM. SOC., PERKIN TRANS. 1,1998, pages 1-2, XP002121617 *
KANEMOTO S. ET AL.: "Cr(III) or Ce(IV) impregnated perfluorinated resin-sulfonic acid catalyst for the oxidation of alcohols" TETRAHEDRON LETTERS, vol. 25, no. 31, 1984, pages 3317-3320, XP002121621 *
LEY S. V. ET AL.: "Use of polymer supported reagents for clean multi-step organic synthesis: preparation of amines and amine derivatives from alcohols for use in compound library generation" J. CHEM. SOC., PERKIN TRANS. 1.,1998, pages 2239-2241, XP002121624 cited in the application *
NEUMANN R ET AL: "SELECTIVE AEROBIC OXIDATIVE DEHYDROGENATION OF ALCOHOLS AND AMINES CATALYZED BY A SUPPORTED MOLYBDENUM-VANADIUM HETEROPOLYANION SALT NA5PMO2V2O40" JOURNAL OF ORGANIC CHEMISTRY, vol. 56, no. 19, 13 September 1991 (1991-09-13), pages 5707-5710, XP000226294 ISSN: 0022-3263 *
NISHIGUCHI T. AND ASANO F.: "Oxidation of alcohols by metal nitrates supported on silica gel" TETRAHEDRON LETTERS, vol. 29, no. 48, 1988, pages 6265-6266, XP002121620 *
PARLOW J J: "Simultaneous Multistep Synthesis Using Polymeric Reagents" TETRAHEDRON LETTERS, vol. 36, no. 9, 27 February 1995 (1995-02-27), page 1395-1396 XP004028583 ISSN: 0040-4039 *
TAYLOR R. T. AND FLOOD L. A.: "Polystyrene-bound phenylseleninic acid: catalytic oxidations of olefins, keones, and aromatic systems" J. ORG. CHEM., vol. 48, 1983, pages 5160-5164, XP002121619 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1997796A1 (fr) * 2007-06-01 2008-12-03 DSMIP Assets B.V. Réaction de condensation d'aldol et catalyseur correspondant
WO2008145350A1 (fr) * 2007-06-01 2008-12-04 Dsm Ip Assets B.V. Réaction de condensation d'aldol et catalyseur associé
JP2010528998A (ja) * 2007-06-01 2010-08-26 ディーエスエム アイピー アセッツ ビー．ブイ． アルドール縮合反応とそのための触媒
WO2009138488A1 (fr) * 2008-05-15 2009-11-19 Novo Nordisk A/S Purification de peptides préparés par synthèse en phase solide

Also Published As

Publication number Publication date
WO1999058475A3 (fr) 2000-06-15
GB0000469D0 (en) 2000-03-01
GB2342095A (en) 2000-04-05

Similar Documents

Publication Publication Date Title
Ley et al. Use of polymer supported reagents for clean multi-step organic synthesis: preparation of amines and amine derivatives from alcohols for use in compound library generation
JP6554180B2 (ja) Ｄｎａコード化化合物ライブラリーの固相合成方法
EP0734398B1 (fr) Composes et procedes
JP2000511949A (ja) ポリマー支持クェンチによる迅速精製
CN113214129B (zh) 一种磺酰自由基引发的1,6-二烯类化合物碘化/磺酰化反应方法
CN113200933B (zh) 不对称加成反应合成光学活性苯并羧酸酯类化合物的方法
WO1999058475A2 (fr) Preparation de composes utilisant des reactifs a support polymere
US5773512A (en) Compounds and methods
WO2001023352A9 (fr) Preparation de composes de sulfonylimine
JP6980269B2 (ja) キラルロジウム錯体、及び光学活性β−置換カルボニル化合物の製造方法
US7183367B2 (en) Vinyl sulphone modified polymer
CN111960975A (zh) 一种烯丙基硫醚类化合物及其制备方法
JPH11180974A (ja) ビニレンカーボネートの製造方法
CN113024342B (zh) 一种区域和立体选择性合成(e)-2,4,4-三取代共轭二烯烃的方法
WO1998017695A1 (fr) Composes et procedes
CN110467613B (zh) 一种镍催化亚胺阳离子分子内酰胺烷基化的反应方法
Rossé et al. A Novel Synthesis of β-Sulfinyl-and β-Sulfonyl-Hydroxamic Acids via CsF-Mediated Ring Opening of Substituted β-Lactones
US20020025507A1 (en) Polymers as a support for combinatorial synthesis
JP2001525866A (ja) 固相有機合成のためのクロライドリンカー
EP0934345A1 (fr) Composes et procedes
Bartolozzi et al. Advances in the applications of polymer-supported reagents for organic synthesis
CN115246807A (zh) 一种含有(异)色满结构的硫酯化合物的制备方法
AU736585B2 (en) Polymers as a support for combinatorial synthesis
CN116589388A (zh) 一种β-酮砜类化合物的制备方法
JP2002523512A (ja) エン−イン反応によるビニル置換環状生成物

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): GB US

ENP Entry into the national phase

Ref country code: GB

Ref document number: 200000469

Kind code of ref document: A

Format of ref document f/p: F

AK Designated states

Kind code of ref document: A3

Designated state(s): GB US