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WO2000039055A1 - Purification rapide par reactifs de refroidissement brusque polyaromatiques - Google Patents

Purification rapide par reactifs de refroidissement brusque polyaromatiques Download PDF

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WO2000039055A1
WO2000039055A1 PCT/US1999/030470 US9930470W WO0039055A1 WO 2000039055 A1 WO2000039055 A1 WO 2000039055A1 US 9930470 W US9930470 W US 9930470W WO 0039055 A1 WO0039055 A1 WO 0039055A1
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compound according
quenching
pah
compound
reagents
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Marianne Da Silva
Dennis Michael Downing
Joseph Scott Warmus
Lu-Yan Zhang
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D211/84—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 two 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 directly attached to ring carbon atoms
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    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • 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
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Definitions

  • the present invention relates to novel polyaromatic quenching reagents, to methods for their preparation, and to methods for their use in the rapid purification of synthetic intermediates and products in the practice of organic synthesis, combinatorial chemistry, and automated organic synthesis.
  • Combinatorial chemistry and automated organic synthesis have proven to be highly effective means for the generation of multiplicities of novel molecules known as libraries. As the size of such a library grows, so does the likelihood that it will contain individual molecules with useful biological activities which may be employed in the treatment of human, animal, and plant diseases. Research organizations that can prepare and screen a large number of diverse compounds efficiently, have an increased likelihood of discovering and optimizing new products. For recent reviews in the use of combinatorial chemistry in pharmaceutical discovery see Gallop M.A., et al., J. Med. Chem.,
  • EDC N-ethyl-N'-dimethylaminopropylcarbodiimide
  • DCC N-ethyl-N'-dimethylaminopropylcarbodiimide
  • Polymer-supported reagents and byproducts derived therefrom are likewise easily separated by filtration of the polymeric materials from a crude reaction mixture.
  • An example of a polymer-supported reagent is poly(styrene-divinylbenzene)-supported triphenylphosphine which may be used in Wittig olefination reactions.
  • the byproduct of this transformation polymer-supported triphenylphosphine oxide, is easily removed by filtration which simplifies purification greatly compared to the solution phase reagent.
  • the use of triphenylphosphine in solution phase Wittig reactions gives triphenylphosphine oxide as a byproduct which is difficult to completely remove except by time consuming chromatography or repeated crystallization.
  • Polymer-supported synthesis minimizes time spent on purifications by attaching a starting material to a polymer. Subsequent synthetic transformations are carried out in such a manner that desired reactions are driven to completion on the polymer-supported material and excess reagents and byproducts in solution are subsequently removed by filtering the polymer and rinsing with solvent(s). At the end of the synthesis, the desired product is chemically cleaved from the polymer. The resulting product is typically obtained in greater purity than would be possible if all of the steps were carried out in solution with no chromatography or crystallization of synthetic intermediates.
  • a purification process known as covalent chromatography has been described in the scientific literature.
  • covalent chromatography a desired material is isolated from a complex mixture by selective reaction with a polymeric reagent, followed by filtration, and rinsing. The desired material is then liberated from the polymer by a chemical cleavage. Typically this process is applied to proteins and other macromolecules as a way of isolating them from complex mixtures of cellular components.
  • This technique has also been applied in the separation of low molecular weight allergens from plant oils as described by Cheminat A., et al., in Tetr. Lett.. 1990;617-619.
  • Covalent chromatography differs from the instant invention in that the polymeric materials used must be both capable of covalently reacting with a desired material in a solution containing impurities and capable of subsequent cleavage of said covalent bond during the retrieval of the desired material.
  • Polymer-supported quench methods rely on chemically robust and ideally irreversible attachment of undesired materials that are found in the crude product of an organic reaction to a polymeric support, leaving the desired product in solution.
  • dendritic polyamides on polymeric supports has been described by Ulrich K.E., et al., Polymer Bui.. 1991;25:551-8.
  • polymer-supported dendritic polyamines are described which, by virtue of the fact that they contain an easily cleaved linker, are structurally distinct from those of the present invention which contain chemically robust linkers.
  • Polymer-supported quench reagents have been used in the generation of compound libraries, e.g., Kaldor S.W., et al., Tetrahedron Lett., 1996;37:7193- 7196; Kaldor S.W., et al., Curr. Qpin. Chem. Biol..
  • PAH quench reagents do not describe or suggest the polyaromatic hydrocarbon (PAH) quench reagents disclosed herein, nor do they teach methods of preparation of PAH quench reagents disclosed herein, nor do they teach the rapid purification utility of PAH quench in the practice of automated organic synthesis and combinatorial chemistry as described in the present invention.
  • PAH polyaromatic hydrocarbon
  • PAH reagents can be added at the conclusion of an organic reaction to covalently react with excess reagents and/or unwanted byproducts.
  • the PAH impurities are then easily removed by addition of charcoal and conventional solid-liquid phase separation techniques leaving a solution of the desired synthetic intermediate or product which is enhanced in purity relative to the crude reaction mixture.
  • Purification by PAH quench is mechanically simple and rapid compared to conventional means of purification such as column chromatography, distillation or crystallization. This means of purification is readily applied to large variety of organic reactions and is amenable to both manual and automated organic synthesis environments. Hence, it is of tremendous value in the preparation of large libraries of organic molecules by automated parallel synthesis and by automated or manual combinatorial synthesis.
  • a first aspect of the present invention is a compound of Formula I,
  • P is a polyaromatic hydrocarbon of low chemical reactivity which is soluble
  • Q is one or more quenching reagents, or an acid or base addition salt thereof, that are capable of selective covalent reaction with unwanted byproducts, or excess reagents
  • L is one or more chemically robust linkers or dendritic linkers that join P and Q.
  • a second aspect of the present invention is a method for enhancing the purity of a desired compound which comprises:
  • Step (a) treating a crude reaction product which contains at least one desired compound, unreacted starting materials and/or byproducts with at least one polyaromatic hydrocarbon quenching reagent of Formula I,
  • P is a polyaromatic hydrocarbon of low chemical reactivity which is soluble
  • Q is one or more quenching reagents, or an acid or base addition salt thereof, that are capable of selective covalent reaction with unwanted byproducts, or excess reagents
  • L is one or more chemically robust linkers or dendritic linkers that join P and Q.
  • Step (b) allowing the polyaromatic hydrocarbon quenching reagent to covalently react with unreacted starting materials and/or byproducts to afford a derivatized reagent of Formula II,
  • X is unreacted starting material and/or byproduct and P, L, and Q are as defined above.
  • Step (c) absorb P-L-Q-X to charcoal; and Step (d) separation of the reagents of Formula I and Formula II from the solution and removal of solvent to afford a compound of enhanced purity.
  • a third aspect of the present invention is a process of preparing a compound of Formula I,
  • P is a polyaromatic hydrocarbon of low chemical reactivity which is soluble
  • Q is one or more quenching reagents, or an acid or base addition salt thereof, that are capable of selective covalent reaction with unwanted byproducts, or excess reagents
  • L is one or more chemically robust linkers or dendritic linkers that join P and Q, which comprises:
  • Step (a) reacting P and L to afford a compound of P-L; and Step (b) reacting P-L with Q to afford a compound of Formula I.
  • inorganic acids such as, for example, hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like
  • water soluble organic acids such as, for example, aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic, and aromatic sulfonic acids and the like.
  • Dendritic molecule A subset of polyfunctional molecules which have two or more equivalent arm-like structures with functional groups at the ends emanating from a central core structure. For example, tris(2-aminoethyl)-amine, ethylenediaminetetraacetic acid, tris(hydroxymethyl)- aminomethane, and 1,3,5-benzenetricarboxylic acid are dendritic molecules.
  • Dendritic linkers A subset of polyfunctional linkers which have two or more equivalent arm-like structures with functional groups at the ends emanating from a central core substituent. For example, N'-(3-aminopropyl)- N'-(3 - ⁇ 3 - [bis-(3 -aminopropyl)-amino] -propylamino ⁇ - propyl)-propane- 1 ,3 -diamine.
  • Enhancing purity A For a single desired compound, enhancing purity means the process of removing excess or unreacted starting reagents to the limit of detection by TLC or by NMR spectroscopy and/or reducing the content of any single byproduct to less than ten molar percent, exclusive of solvents.
  • Polyfunctional A compound which contains two or more functional molecule groups attached to a carbon framework or interspersed with more than one carbon framework are polyfunctional molecules.
  • 2,6-diamino-hexanoic acid, 1,8-diamino- 3,6-diazaoctane, and 2,6-diisocyanatohexane are polyfunctional molecules.
  • Quenching reagent A molecule that covalently combines with a reactant to make it less reactive or a molecule that covalently combines with a byproduct.
  • Polyaromatic Polyaromatic hydrocarbon is defined as a substantially hydrocarbon (PAH) planar ring system. This should consist of three or more rings, of which one or more may not be aromatic, such as, for example, naphthalene, anthracene, pyrene, phenanthrene, 3,4-benzofluoranthrene, tetrabenzo- [a,c,g,i]-fiuorene, fluorene, 5H-dibenz[b, jazepine, and the like.
  • PAH substantially hydrocarbon
  • EDC N-Ethyl-N'-Dimethylamino propylcarbodiimide
  • the first aspect of the instant invention is a compound of Formula I,
  • P is a polyaromatic hydrocarbon of low chemical reactivity including naphthalene, anthracene, pyrene, phenanthrene, 3,4-benzofluoranthrene, tetrabenzo-
  • Q is one or more quenching reagents which contain at least one functional group, or an acid or base addition salts thereof, that is capable of selective covalent reaction with unwanted byproducts, or excess reagents such as, for example, primary amine, secondary amine, tertiary amine, isocyanate, isothiocyanate, carboxylic acid, acid chloride, ketone, aldehyde, cyclic imide, cyclic anhydride, hydroxyl, diol, aminoalcohol, thiol, dithiol, aminothiol, thioether, thiourea, chlorosilane, diene, dienophile, dipole, dipolarophile, enolate, enol ether, alkylsulfonate, alkyl halide, aryl halide, arylsulfonate, arylboronic acid, hydrazine, semicarbazide, acyl hydrazide, hydroxylamine
  • the second aspect of the present invention is a method for the preparation of novel polyaromatic hydrocarbon quenching reagents from known polyaromatic hydrocarbons.
  • Polyaromatic hydrocarbon quenching reagents are made in one to four synthetic steps from readily available starting materials, such as for example, pyrene or derivatives thereof which contain convenient linker functionality, and one or more polyfunctional quenching reagents which bear a compatible connecting functionality and one or more functionalities used in the quenching process.
  • Preferred polyaromatic hydrocarbon starting materials are pyrene and tetrabenzo-[a,c,g,i]-fluorene.
  • Preferred solvents used in the chemical transformations of preferred starting polyaromatic hydrocarbons which lead to novel polyaromatic hydrocarbons quenching reagents include, for example, DMF, DMA, NMP, DCM, dioxane, THF, benzene, and the like.
  • a PAH chloro or bromo methyl compound can be treated with a suitably protected amine in toluene, or other non-nucleophilic solvent in the presence of triethylamine, pyridine, N-methyl morpholine or other lower alkylamine base provides the protected PAH polyamine.
  • Deprotection with acid (TFA, H 2 SO 4 , CSA, etc.) for Boc protected amines, or other suitable deprotection method for various protective groups affords the polyamine PAH.
  • a PAH methyl amine can be treated with phosgene, triphosgene, thiophosgene or synthetic equivalent to prepare the isocynate or thioisocynate. Addition of a suitable protected polyamine followed by deprotection provides the polyamine PAH.
  • a PAH methyl alcohol can be treated with phosgene, triphosgene or synthetic equivalent to prepare the chloroformate. Addition of a suitable protected polyamine followed by deprotection provides the polyamine PAH.
  • reaction of a PAH methyl amine with a suitably protected monoamino isocynate, deprotection of the amine and treatment with phosgene, thiophosgene or equivalent provides a PAH isocynate or thioisocynate quench reagent.
  • PAH methyl chloride or bromide Treatment of a PAH methyl chloride or bromide with a monoprotected diamine in the presence of triethylamine, pyridine, N-methyl morpholine or other lower alkylamine base, deprotection of the amine and treatment with phosgene, thiophosgene or synthetic equivalent gives the PAH isocynate or thioisocynate quench reagent.
  • preparation of a PAH dicarboxylic acid can be accomplished by treatment of a PAH methyl amine with acrylic acid, or by treatment of a PAH aldehyde with malonic acid followed by hydrogenation over a palladium catalyst.
  • reaction of a PAH methyl halide with a suitable amino alcohol in toluene, benzene or other non-nucleophilic solvent in the presence of triethylamine, pyridine, N-methyl morpholine or other lower alkyl amine base affords PAH aminoalcohol quench reagent.
  • reaction of a suitable aminoalcohol with a dialkylsilyl dichloride in the presence of triethylamine, pyridine, N-methyl morpholine or other lower alkyl amine base provides a PAH chlorosilane quenching reagent.
  • reaction of a PAH methyl halide with a ⁇ -sulfhydryl sodium thiolate in THF or with thiomorpholine in DMF provides a quenching thiol reagent.
  • Reaction of a suitable PAH amine with 2,2'-bisthioacetic acid in the presence of a suitable coupling reagent, such as DCC, EDC or CDI, followed by reductive cleavage of the dithiane affords a quenching thiol reagent.
  • PAH quenching aryl boronic acids can be prepared by treatment of a PAH methyl halide with 4-iodophenol or 4-bromophenol in a polar aprotic solvent such as THF or DMF with a base, such as potassium carbonate with 18-crown-6. Lithiation of the aryl halide using an organolithium reagent and quenching of the resulting anion with triisopropyl borate gives the aryl boronic ester. Hydrolysis of this with aqueous acid provides the aryl boronic acid.
  • PAH quenching thioureas can be prepared by reaction of a suitable PAH amine with any suitable isothiocyanate or thiocarbamyl chloride, or by treatment of a suitable PAH isothiocyanate with any primary or secondary amine.
  • reaction of a suitable PAH amine with maleic anhydride with removal of water, or a PAH methyl halide with the anion of maleimide provides the dienophile quench agent.
  • Treatment of a suitable PAH amine with 4'-carbomethoxy-3-phenyl- propynoic acid or other similar aryl propynoic acid with an electron withdrawing group in the 4'-position, such as nitro or cyano groups, in the presence of standard peptide coupling reagents provides PAH dipolarophile quenching groups.
  • reaction of PAH methyl halide with the alkoxide form of 2-hydroxymethyl furan or the thiolate of 2-thiomethyl furan in a polar aprotic solvent such as THF or DMF provides the PAH quenching diene.
  • reaction with the anion of methyl vinyl ether of methyl acetoacetate followed by treatment with a trialkyl silyl chloride gives the PAH Danishefsky diene equivalent.
  • PAH guani dines can be prepared either by addition of a suitably substituted guanidine to a PAH methyl halide in a polar aprotic solvent, such as DMF, or by addition of a S-methyl thiourea to a PAH amine.
  • a PAH hydrazine or hydroxylamine can be prepared starting from a PAH aldehyde. Addition of either a monoprotected hydrazine or a suitable hydroxyl amine and reduction of the resulting imine with a reducing agent, such as NaBH 3 CN or
  • Na(OAc) 3 BH provides the protected hydrazine or hydroxylamine, respectively.
  • a silylenol ether quenching agent can be prepared from the PAH methyl halide and an enolate prepared from a ketone, such as acetophenone. Reaction of the resulting homologated ketone with a trialkyl silyl chloride in the presence of a trialkylamine base, such as triethylamine, gives the PAH enol silyl ether.
  • a trialkylamine such as triethylamine, diisopropylethylamine
  • an oxidizing agent such as NaIO 4 , mCPBA or hydrogen peroxide and enolate formation with an alkoxide base affords the carbanion reagent.
  • PAH alcohols, iodides, and sulfonates can be prepared from a PAH methyl halide and a suitably protected 4'- ⁇ -hydroxyphenol.
  • Ether formation using a base such as potassium carbonate and 18-crown-6 and deprotection using standard conditions provides a PAH alkyl alcohol.
  • Oxidation of this intermediate to the aldehyde with an appropriate oxidant, such as PDC, PCC, Swern condition (oxalyl chloride, DMSO) affords the alcohol.
  • an iodination reagent such as triphenylphosphine diiodide produces the alkyl iodide reagent.
  • PAH amino thiols can be prepared by either addition of 2,2'-dithiobis-ethanamine in a polar aprotic solvent such as DMF and reduction of the dithiane using DTT, NaBH 4 or other reducing agent, or addition of thiazolidine in DMF followed by cleavage with hydroxylamine affords the PAH aminothiol reagent.
  • PAH Polyaromatic hydrocarbon
  • R H or CH 3
  • R* Boc or other protective group
  • R5 Me, CF 3 , C 2 F 5 , Ph, 4-MePh, 4-NO 2 Ph, 4-BrPh, 4-ClPh, 4-FPh,
  • EWG electron withdrawing group such as NO 2 , CO Me, CN, CF 3 , etc.
  • M+ Li+, Na+, K+, MgBr + , Cs+
  • the third aspect of the present invention is the use of PAH quenching reagents, including novel PAH quenching reagents of the present invention, for the rapid purification of crude product mixtures of organic reactions.
  • PAH quench purification is an enabling technology for the preparation of libraries of organic molecules with potential biological activity.
  • PAH quench has utility in reducing purification time associated with automated parallel organic synthesis, manual combinatorial synthesis and automated combinatorial synthesis.
  • Specific types of chemical transformations that benefit from a PAH quench purification procedure include, but are not limited to, O- and N-acylation, O- and N-sulfonylation, O- and N-phosphonylation, O- and
  • Reactant A combines with reactant B to form AB.
  • B is used in excess (Equation 1.0).
  • the excess reactant is quenched by adding a PAH quenching reagent with A-like properties. Once the excess B is attached to the PAH reagent, it is easily and quickly removed by addition of charcoal and a simple filtration.
  • the solution fraction contains AB which is enhanced in purity relative to the crude product.
  • the chemist has a choice of whether to use A or B in excess and subsequently to quench with a PAH quenching reagent with B-like or A-like properties, respectively. Additionally, the chemist may choose to add both A-like and B-like PAH quenching reagents sequentially to ensure that all starting materials have been removed from the desired product in the event that the reaction did not go to completion, despite using an excess of one starting material. Alternatively, a reaction between equimolar quantities of A and B may yield a major desired product, AB, and a minor undesired product, AB' (Equation 1.1).
  • AB' may be removed with a PAH quenching reagent that selectively reacts with this undesired product.
  • One may run analogous combinatorial reactions wherein a diversity of reactants A 1 " ⁇ are reacted with excess of a diversity of reactants B 1_ Y to form all of the possible AB combinations (Equation 1.2).
  • the combinatorial product mixture is separated from the remaining B* ⁇ Y using a single PAH quenching reagent with A-like properties as in the one product case above.
  • the desired product is purified by adding a PAH quenching reagent that selectively derivatives Xj) and removing the PAH by addition of charcoal and filtration.
  • Derivative quench by a PAH quenching reagent may be similarly applied in a combinatorial synthesis mode. Equation 2.0 C + D excess CD + D
  • the desired product, FG is rapidly purified by adding a larger excess of a PAH quenching reagent with F-like properties which consumes the remaining G.
  • Filtration to remove the PAH reactant before adding the PAH quenching reagent is not necessary when insoluble polymers are used but may be required when soluble polymers are employed if a chemical incompatibility exists between the reactant and quench reagent. Filtration of the PAH and addition of charcoal gives a solution of FG which is enhanced in purity relative to the crude product.
  • the use of PAH quenching reagents in conjunction with PAH reactants may be similarly applied in a combinatorial synthesis mode.
  • a reaction which employs multiple reactants (K, L, M, etc.) is run in such a fashion that one of the reactants is limiting.
  • the desired product is rapidly purified from unconsumed reagents by adding PAH quenching reagents; one for each excess reactant.
  • PAH quenching reagents must be added and removed sequentially unless they are chemically compatible.
  • PAH quenching reagents may also be combined with insoluble ion- exchange resins, chelating resins, silica gel, reversed-phase adsorbents, alumina, and the like which make noncovalent interactions with impurities as desired in order to increase the efficiency of the purification step.
  • insoluble ion- exchange resins chelating resins, silica gel, reversed-phase adsorbents, alumina, and the like which make noncovalent interactions with impurities as desired in order to increase the efficiency of the purification step.
  • Equation 4.0 K + excess (L + M + etc) > ⁇ N + L + M + etc
  • a PAH quenching reagent may perform a dual role in purifying the product of one reaction and causing a subsequent synthetic transformation as a PAH reagent.
  • A reacts with excess B to form C.
  • PAH-D quenches the excess B and also converts product C to product E. This dual role is equally applicable in a combinatorial synthesis mode.
  • the PAH quench reagents and rapid purification methods of the instant invention have, for example, the following advantages over existing methods for automated organic synthesis and combinatorial chemistry:
  • a single PAH quench reagent can remove many different types of reactants and byproducts; hence, customized reagent development time is minimized and quench reagents may be produced in bulk at decreased cost.
  • Reaction progress and product may be analyzed by traditional chromatographic and spectrographic methods.
  • PAH reagent solubility allows simplified robotic delivery of PAH reagents.
  • Alkyl Halides Alkyl sulfonates, Diazoalkanes, ⁇ -Haloketones, Silyl Chlorides, Silyl Triflates, and the like
  • Alkyl Halides Alkylsulfonates, Meerwein Reagent, ⁇ -Haloketones, Silyl Chlorides, Silyl Triflates, Acid Chlorides, Acid Anhydrides, Activated Esters, Imidazolides, Isocyanates, Isothiocyanates, Sulfonyl Chlorides, Phosphonyl Chlorides, Phosphoryl Chlorides, and the like
  • Alkyl Halides Alkylsulfonates, ⁇ -Haloketones, Meerwein Reagent, Silyl Chlorides, Silyl Triflates, Epoxides, Oxidants, Thiols, Dissulfides, and the like
  • Carbanions primary amines, Hydroxylamine, Alkoxyamines, Hydrazines, Glycols, 1,3-Diols, 1,2-Dithiols, 1,3-Dithiols, 1 ,2- Aminoalcohols, 1 ,3 -Aminoalcohols, 1 ,2- Amino thiols, 1,3 -Aminothiols, Hydride Reducing Agents, and the like
  • the pyrene unsaturated acid (1.1 g, 0.004 mol) was taken up in 75 mL THF/DMF 1 :2, and 0.2 g 10% Pd/C was added and the reaction put under H2 at 49 psi for
  • Tetrakis(triphenylphosphine) palladium 13 mg, 0.01 mmol is added, and the reaction is heated at reflux for 3 hours.
  • the black mixture is cooled to room temperature, treated with the aminodiol PAH quench reagent (0.3 mmol), and agitated for 2 hours.
  • Diethyl ether/hexane (1:1, 4 mL) and charcoal is added, and the reaction is shaken for 2 hours.
  • the reaction mixture is filtered, rinsing the solids with Et20/hexane (1 :1, 4 mL). The filtrate is evaporated to give the purified diene.
  • EXAMPLE 17 17H-Cvclopentain.2-l:3.4-ridiphenanthrene-17-ethanol From TBF and 2-(2- Bromoethoxy)tetrahydro-2H-pyran
  • Triethylamine (0.91 g, 9 mmol, 3 eq.) was then added, and the flask was removed from the cold bath. The mixture was allowed to react at room temperature and was sti ⁇ ed for 0.5 hour before addition of water (20 mL). The aqueous layer was extracted with dichloromethane (3x20 mL). The combined organic layer was washed with Na2C ⁇ 3 (sat. aqueous solution) and brine, and dried with anhydrous MgSO The solvent was evaporated under reduced pressure to give the crude product 1.29 g. The crude aldehyde was suitable for use without further purification.
  • the starting material was added to a HCl-gas-saturated ethyl acetate (50 mL) at
  • N-(2-Amonoethyl)-N-[2-(17H-cyclopenta[l,2-v':3,4-7 ldiphenanthrene-17- yl)ethyl]- 1,2-ethanediamine 200 mg was suspended in 10 mL acrylonitrile .and reflux for 12 hours, concentrated and purified (column chromatography on silica gel with ethyl acetate). The tetranitrile was suspended in 5 mL methanol and cobalt(II) chloride hexahydrate (8 equiv.) added. Sodium borohydride (80 equiv.) was added in portions. The resultant mixture was sti ⁇ ed for 12 hours.
  • the reaction mixture was acidified with concentrated hydrochloric acid and the mixture concentrated. The residue was taken up in concentrated ammonia solution and chloroform. The precipitate was filtered, the aqueous phase extracted with chloroform, and then dried with magnesium sulfate. The crude product was obtained after concentration.
  • TBFCH 2 CHO (crude product) (0.86 g, ⁇ 2 mmol) and N,N,N'N- tetraethyldiethylenetriamine were all dissolved in DCE (35 mL), NaB(OAc)3H was added. The reaction mixture was sti ⁇ ed under an atmosphere of nitrogen at room temperature for 3 hours. TLC showed the product. (Hexanes Ethyl Acetate:2/1, Rf: 0.3) The mixture was concentrated and the residue chromatographed with CHCI3 on Alumina (neutral) to give the product as a brown oil. The yield: 63%.
  • N-[2-(17H-Cyclopenta[l,2-7:3,4-71diphenanthrene-17-yl)ethyl]-N-[2- (diethylamino)ethyl]-NN-diethyl- 1,2-ethanediamine (284 mg, 0.47 mmol) was dissolved in 3 mL C ⁇ 2C-2, N-benzylmethylamine (48.4 mg, 0.4 mmol) and 777-Bromobenzyl chloride (131.7 mg, 0.6 mmol) added, sti ⁇ ed at room temperature overnight, then quench reagent N-(2-amonoethyl)-N-[2-(17H-cyclopenta[l,2- 7:3,4-7 diphenanthrene-17-yl)ethyl]- 1,2-ethanediamine (74 mg, 0.15 mmol) was added, sti ⁇ ed at room temperature for 7 hours, 2 mL reaction solution was taken filtered through charcoal column directly, concentration of the

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Abstract

cette invention concerne de nouveaux réactifs de refroidissement brusque à base d'hydrocarbures polyaromatiques, correspondant à la formule P-L-Q, dans laquelle P représente un hydrocarbure polyaromatique à faible réactivité chimique, et soluble; Q représente un ou plusieurs réactifs de refroidissement brusque, ou des sels d'addition basiques ou acides desdits réactifs, qui sont capables de réactions covalentes sélective avec des produits dérivés non désirés, ou avec un excédent de réactifs; et L représente un ou plusieurs agents de liaison chimiquement robustes ou un ou plusieurs agents de liaison arborescents joignant P à Q. Cette invention concerne également des procédés de préparation desdits réactifs, des procédés d'utilisation desdits réactifs dans la purification rapide d'intermédiaires et de produits de synthèse dans la synthèse organique, la chimie combinatoire et la synthèse organique automatisée.
PCT/US1999/030470 1998-12-23 1999-12-21 Purification rapide par reactifs de refroidissement brusque polyaromatiques Ceased WO2000039055A1 (fr)

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US8466242B2 (en) 2011-02-28 2013-06-18 Midori Renewables, Inc. Polymeric acid catalysts and uses thereof
US8476388B2 (en) 2011-02-28 2013-07-02 Midori Renewables, Inc. Polymeric acid catalysts and uses thereof
US9079171B2 (en) 2011-02-28 2015-07-14 Midori Usa, Inc. Polymeric acid catalysts and uses thereof
US9205418B2 (en) 2011-02-28 2015-12-08 Midori Usa, Inc. Polymeric acid catalysts and uses thereof
US10131721B2 (en) 2011-02-28 2018-11-20 Cadena Bio, Inc. Polymeric acid catalysts and uses thereof
US10787527B2 (en) 2011-02-28 2020-09-29 Cadena Bio, Inc. Polymeric acid catalysts and uses thereof
US9238845B2 (en) 2012-08-24 2016-01-19 Midori Usa, Inc. Methods of producing sugars from biomass feedstocks
WO2022221041A1 (fr) * 2021-04-13 2022-10-20 Huntsman Petrochemical Llc Procédé de production de catalyseurs de morpholine pour systèmes de mousse rigide et leurs utilisations
CN115490860A (zh) * 2022-10-21 2022-12-20 华南理工大学 一种聚硫脲类化合物及其制备方法
CN115490860B (zh) * 2022-10-21 2023-09-26 华南理工大学 一种聚硫脲类化合物及其制备方法

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