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WO1998033751A1 - Nouvelles techniques de synthese en phase solide permettant de preparer divers composes analogues - Google Patents

Nouvelles techniques de synthese en phase solide permettant de preparer divers composes analogues Download PDF

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Publication number
WO1998033751A1
WO1998033751A1 PCT/US1998/001854 US9801854W WO9833751A1 WO 1998033751 A1 WO1998033751 A1 WO 1998033751A1 US 9801854 W US9801854 W US 9801854W WO 9833751 A1 WO9833751 A1 WO 9833751A1
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WO
WIPO (PCT)
Prior art keywords
phase
solid
cleaving
solution
supported intermediate
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1998/001854
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English (en)
Inventor
John Christopher Phelan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Axys Pharmaceuticals Inc
Original Assignee
Axys Pharmaceuticals Inc
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
Application filed by Axys Pharmaceuticals Inc filed Critical Axys Pharmaceuticals Inc
Priority to AU60519/98A priority Critical patent/AU6051998A/en
Priority to EP98903865A priority patent/EP0960084A1/fr
Priority to CA002279208A priority patent/CA2279208A1/fr
Priority to JP53312798A priority patent/JP2001509809A/ja
Publication of WO1998033751A1 publication Critical patent/WO1998033751A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
    • C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
    • C07C245/08—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene
    • 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

Definitions

  • Solid-phase synthesis techniques are used in preparing peptides (Merrifield, J. Am. Chem. Soc. 85:2149-2154 (1963)), oligonucleotides ⁇ Oligonucleotide Synthesis: A Practical Approach, Gait, ed. IRL Press, Oxford (1964)) and small organic molecules (Leznoff, Ace. Chem. Res., If, 327 (1978); Hermkins, Tetrahedron, 52, 4527-4554 (1996)).
  • Solid-phase synthesis techniques are powerful methods for the combinatorial synthesis of large libraries (Bunin et al., J. Am. Chem. Soc. 114, 10997-10998 (1992)), which libraries are in themselves powerful tools in pharmaceutical research (U.S. Patent No. 5,506,337; Terrett et al, Tetrahedron, 51, 8135-8173 (1995)).
  • solid-phase techniques One of the advantages of solid-phase techniques is that reactions can be driven to completion by using reagents in large excess, whereupon the excess reagent is removed simply by filtration.
  • the solid-phase supported product is then released from the solid support by a cleaving reagent, whereupon the solution-phase product is separated from the solid-phase by filtration.
  • the final step reaction in the solid-phase synthetic scheme is coupled with the cleavage reaction resulting in the formation of final product and a concomitant release of the product into the solution-phase (Dewitt and Czarnik, Ace. Chem. Res., 29, 114 (1996)).
  • solid-phase synthetic methods afford a single solution-phase product from each aliquot of solid-phase supported starting material or intermediate. Techniques are needed that will allow for the preparation of multiple compounds from one aliquot of solid-phase supported intermediate.
  • step (b) separating the solution-phase condensation product formed by step (a) from the solid-phase;
  • step (c) reacting remainder solid-phase supported intermediate with a cleaving/condensing reagent distinct from the cleaving/condensing reagent applied in step (a) to give a solution-phase condensation product analogous to the solution-phase condensation product formed by step (a);
  • step (d) separating the solution-phase condensation product formed by step (c) from the solid-phase;
  • a second aspect of this invention relates to a process for synthesizing multiple analogous compounds, which process comprises:
  • step (b) separating the solution-phase condensation product formed by step (a) from the solid-phase;
  • step (f) separating the solution-phase condensation product formed by step (e) from the solid-phase;
  • a third aspect of this invention relates to a combinatorial library comprising multiple analogous compounds prepared by the processes of this invention.
  • Alkyl as in 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfmylalkyl, 4-hydroxyphenylsulfonylalkyl, 4-aminosulfonylbenzoylaminoalkyl, and 3-aminosulfonylpropionylaminoalkyl, means a straight branched, saturated, aliphatic hydrocarbon radical having from 1 to 6 carbon atoms.
  • linking group means a divalent radical which links an intermediate compound to the solid support.
  • linking groups are referred to in the specification and the claims as the monovalent precursor radical is attached to the solid support.
  • SS is the solid support
  • 4-hydroxyphenylthioalkyl which includes, for example, 4-hydroxyphenylthiomethyl.
  • Remainder solid-phase supported intermediate means solid-phase supported intermediate that remains unreacted and attached to the solid-phase support after a portion of the solid-phase supported intermediate has been subjected to a cleaving/condensation reaction and the resulting solution-phase condensation product has been separated from the solid-phase.
  • Substoichiometric amount means a molar amount which is less than one molar equivalent. Thus, when referring to substoichiometric amounts of cleaving/condensing reagents in describing or claiming the process of this invention, it is intended that the molar amount of reagent present in the reaction medium is a fraction of the molar amount of solid-phase supported intermediate present.
  • the process of this invention relates to the synthesis of multiple analogous compounds by the sequential treatment of a solid-phase supported intermediate by a means that results in the formation of a solution-phase condensation product and affords an amount of the solid-phase supported intermediate in remainder sufficient to perform subsequent cleavage/condensation reactions with other cleaving/condensing reagents.
  • the process of this invention can be depicted by the following reaction scheme:
  • SS is a solid support
  • X is a the linking group between the solid support and the solid-phase supported intermediate
  • Y is any moiety capable of causing a cleavage/condensation reaction
  • R 1 , R a , R b and R" are each any non-reactive moiety
  • Z is a connecting moiety formed by the condensation reaction.
  • the process of this invention comprises reacting a solid-phase supported intermediate (Formula 1) with an appropriate cleaving/condensing reagent (R ⁇ ) by any means whereby the solid-phase supported intermediate is cleaved from the solid support and concomitantly condensed with the cleaving/condensing agent to form a first solution-phase condensation product (Formula 2(a)) and some fraction of the solid-phase supported intermediate remains unreacted, separating the first solution-phase condensation product from the solid-phase, reacting the remainder solid-phase supported intermediate (Formula 1(a)) with a second distinct cleaving/condensing reagent (R b Y) to give a second solution-phase condensation product (Formula 2(b)); and then separating the second solution-phase condensation product from the solid-phase.
  • a solid-phase supported intermediate Formmula 1
  • R b Y second distinct cleaving/condensing reagent
  • Remainder solid-phase supported intermediate present after separation of the second solution-phase condensation product (Formula 1(b)) or after any subsequent condensation/cleavage reaction and separation steps (Formula ⁇ nj) is optionally further reacted with an appropriate cleaving/condensing reagent (R"Y) to give additional analogous solution-phase condensation products (Formula 2( «)).
  • Remainder solid-phase supported intermediate can be afforded by any means which results in an incomplete reaction relative to the amount of solid-phase supported intermediate used.
  • an incomplete reaction can be effected by varying the reaction conditions (e.g., reaction temperatures or pressures, solvents, etc.) to slow the rate of reaction or by limiting the reaction times.
  • a convenient means for providing that an incomplete reaction occurs is by using a substoichiometric amount of the cleaving/condensing reagent relative to the amount of solid-phase supported intermediate used.
  • Suitable solid supports include polymers (e.g., polystyrene, poly(ethylene glycol) grafted polystyrene, poly(ethylene glycol) grafted polyacrylamide, etc.), cellulose, derivatized silica gel supports, derivatized controlled-pore glass, and the like.
  • Suitable linking groups can comprise any chemical functionality or bond that is capable of reacting with the cleaving/condensing reagent.
  • suitable linking groups for carboxylic acid intermediates include 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfinylalkyl, 4-hydroxyphenylsulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, and the like, wherein an ester linkage is formed between the intermediate and linking group, or 4-aminosulfonylbenzoylaminoalkyl, 3-aminosulfonylpropionylaminoalkyl, and the like, wherein an amide linkage is formed.
  • Other suitable linkers for various intermediate compounds are known to those of ordinary skill in the art.
  • Suitable cleaving/condensing reagents include nucleophilic amines, organometallic reagents (e.g., Grignard reagents, organolithium reagents, etc.), alcohols, anilines, phenols, thiols, activated carbon nucleophiles (e.g., beta keto esters, beta diesters, beta cyanoesters, nitroalkanes, etc.), and the like.
  • organometallic reagents e.g., Grignard reagents, organolithium reagents, etc.
  • alcohols e.g., anilines, phenols, thiols
  • activated carbon nucleophiles e.g., beta keto esters, beta diesters, beta cyanoesters, nitroalkanes, etc.
  • linking group is selected from 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfmylalkyl, 4-hydroxyphenylsulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, 4-aminosulfonylbenzoylaminoalkyl and 3-aminosulfonylpropionylalkyl.
  • the cleaving/condensing reagent is selected from amines and organometallic reagents or in which the linking group is 4-aminosulfonylbenzoylaminoalkyl or 3-aminosulfonylpropionylaminoalkyl and the cleaving/condensing reagent is selected from alcohols, anilines, thiols and carbon nucleophiles. More particularly preferred is a process in which the solid support is selected from polystyrene and poly(ethylene glycol) grafted polystyrene. Most preferred is a process in which the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the cleaving/condensing reagent is an amine.
  • SS is a solid support and R 2 , R a , R b and R" are each any non-reactive moiety.
  • the process of this invention in which the solid-phase supported intermediate forms an ester linkage with the linking group and the cleaving/condensing reagent is an amine can be carried out under standard acylation reaction conditions and using typical separation techniques.
  • the cleavage/condensation reaction can be carried out in the presence of a suitable base (e.g., triethylamine, diisopropylethylamine, l,4-diazabicyclo[2.2.2]octane, N-methylmorpholine, etc., preferably triethylamine) in a suitable solvent (e.g., 2,6-lutidine, pyridine, toluene, tetrahydrofuran, etc., preferably 2,6-lutidine or pyridine) at 0 to 70°C, preferably at approximately ambient temperature, and requires 1 to 100 hours.
  • a suitable base e.g., triethylamine, diisopropylethylamine, l
  • the solution-phase condensation product can separated from the solid-phase by filtering and washing the solid support with suitable solvents (e.g., dichloromethane, methanol, tert-butyl methyl ether, toluene, tetrahydrofuran, diethylether, etc.).
  • suitable solvents e.g., dichloromethane, methanol, tert-butyl methyl ether, toluene, tetrahydrofuran, diethylether, etc.
  • Certain solid supports e.g., polystyrene
  • separation can be facilitated by washing the solid support alternately with a solvent that produces a large amount of swelling (e.g., dichloromethane, toluene or tetrahydrofuran) and a solvent that produces a small amount of swelling (e.g., tert-butyl methyl ether, diethyl ether or methanol).
  • a solvent that produces a large amount of swelling e.g., dichloromethane, toluene or tetrahydrofuran
  • solvent that produces a small amount of swelling e.g., tert-butyl methyl ether, diethyl ether or methanol
  • solid-phase supported intermediates used in the process of this invention can be prepared by methods known in the art.
  • solid-phase supported intermediates which form an ester linkage with the linking group, wherein the linking group is
  • 4-hydroxyphenylthioalkyl can be prepared by reacting an appropriate carboxylic acid or activated ester (e.g., carboxylic acid halide), or protected derivative thereof, with an appropriate 4-hydroxyphenylthioalkylpolystyrene.
  • the reaction can be effected in the presence of a suitable coupling agent (e.g., diisopropylcarbodumide, benzotriazole-1-yloxytrispynolidinophosphonium hexafluorophosphate (PyBOP ), bromotrispyrrolidinophosphonim hexafluorophosphate, 0-benzotriazole-N,N,N 'N -tetramethyluronium hexafluorophosphate, NTVN'N-tetramethylfluoroformamidinium hexafluorophosphate, etc.) a suitable base (e.g., triethylamine, N-methylmorpholine, diisopropylethylamine, etc.) and a suitable catalyst (e.g., 4-dimethylaminopyridine, 1-hydroxybenzotriazole, l-hydroxy-7-azabenzotriazole, etc.) at 20 to 60 °C, preferably at approximately ambient
  • An alternative process of this invention comprises reacting a solid-phase supported intermediate by any means whereby a first solution-phase condensation product and some fraction of the solid-phase supported intermediate remains unreacted, separating the first solution-phase condensation product from remainder solid-phase supported intermediate, modifying the remainder solid-phase supported intermediate to give a second solid-phase supported intermediate (Formula 3) and then reacting the second solid-phase supported intermediate with a cleaving/condensing reagent to give an analogous solution-phase condensation product Formula (4(a)).
  • the 4-tert-butoxycarbonylaminoacetoxyphenylthiomethylpolystyrene was treated with dichloromethane/trifiuoroacetic acid/anisole (50:48:2 by volume) for 0.5 hours at ambient temperature. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and then methanol (3x) to give 4-aminoacetoxyphenylthiomethylpolystyrene.
  • the 4-(3-tert-butoxycarbonylaminopropionyloxy)phenylthiomethylpolystyrene was treated with dichloromethane/trifluoroacetic acid/anisole (50:48:2 by volume) for 0.5 hours at ambient temperature. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and then methanol (3x) to give 4-aminopropionyloxyphenylthiomethylpolystyrene.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Structural Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne un procédé permettant la synthèse de divers composés analogues comportant les étapes suivantes: (a) faire réagir un produit intermédiaire sur phase solide avec un réactif de clivage/condensation grâce à un moyen qui provoque la formation d'un produit de condensation en phase solution et permet de disposer d'un produit intermédiaire sur phase solide restant; (b) séparer de la phase solide le produit de condensation en phase solution formé au cours de l'étape (a); (c) faire réagir le produit intermédiaire sur phase solide restant avec un réactif de clivage/condensation distinct du réactif appliqué lors de l'étape (a) de façon à obtenir un produit de condensation en phase solution analogue au produit de condensation en phase solution formé au cours de l'étape (a); (d) séparer de la phase solide le produit de condensation en phase solution formé en (c); et (e) répéter éventuellement les étapes (c) et (d) du procédé une ou plusieurs fois si le produit intermédiaire sur phase solide restant est toujours présent, en utilisant chaque fois un réactif de clivage/condensation distinct de façon à obtenir une phase solution analogue supplémentaire.
PCT/US1998/001854 1997-01-31 1998-01-29 Nouvelles techniques de synthese en phase solide permettant de preparer divers composes analogues Ceased WO1998033751A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU60519/98A AU6051998A (en) 1997-01-31 1998-01-29 Novel solid-phase synthesis techniques for preparing multiple analogous compounds
EP98903865A EP0960084A1 (fr) 1997-01-31 1998-01-29 Nouvelles techniques de synthese en phase solide permettant de preparer divers composes analogues
CA002279208A CA2279208A1 (fr) 1997-01-31 1998-01-29 Nouvelles techniques de synthese en phase solide permettant de preparer divers composes analogues
JP53312798A JP2001509809A (ja) 1997-01-31 1998-01-29 多くの類似化合物を製造するための新規固相合成法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3489297P 1997-01-31 1997-01-31
US60/034,892 1997-01-31

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WO1998033751A1 true WO1998033751A1 (fr) 1998-08-06

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EP (1) EP0960084A1 (fr)
JP (1) JP2001509809A (fr)
AU (1) AU6051998A (fr)
CA (1) CA2279208A1 (fr)
HU (1) HUP0003125A3 (fr)
WO (1) WO1998033751A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000053545A1 (fr) * 1999-03-10 2000-09-14 Axys Pharmaceuticals, Inc. Procede de synthetisation de dihydropyridones
WO2001010890A3 (fr) * 1999-08-10 2001-05-17 Chemrx Advanced Technologies I Synthese de substrats a base de protease

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997031880A1 (fr) * 1996-03-01 1997-09-04 Warner-Lambert Company Procede de preparation de molecules aromatiques et hetearomatiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997031880A1 (fr) * 1996-03-01 1997-09-04 Warner-Lambert Company Procede de preparation de molecules aromatiques et hetearomatiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
C. C. LEZNOFF: "The use of insoluble polymer supports in general organic synthesis", ACCOUNTS OF CHEMICAL RESEARCH, vol. 11, 1978, pages 327 - 333, XP002065654 *
S. H. DEWITT: "Combinatorial organic synthesis using Park-Davis's DIVERSOMER method", ACCOUNTS OF CHEMICAL RESEARCH, vol. 29, no. 3, 1996, pages 114 - 122, XP002065653 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000053545A1 (fr) * 1999-03-10 2000-09-14 Axys Pharmaceuticals, Inc. Procede de synthetisation de dihydropyridones
WO2001010890A3 (fr) * 1999-08-10 2001-05-17 Chemrx Advanced Technologies I Synthese de substrats a base de protease

Also Published As

Publication number Publication date
EP0960084A1 (fr) 1999-12-01
CA2279208A1 (fr) 1998-08-06
HUP0003125A2 (hu) 2001-01-29
HUP0003125A3 (en) 2001-07-30
JP2001509809A (ja) 2001-07-24
AU6051998A (en) 1998-08-25

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