WO2000053545A1 - Procede de synthetisation de dihydropyridones - Google Patents

Procede de synthetisation de dihydropyridones Download PDF

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Publication number
WO2000053545A1
WO2000053545A1 PCT/US2000/005922 US0005922W WO0053545A1 WO 2000053545 A1 WO2000053545 A1 WO 2000053545A1 US 0005922 W US0005922 W US 0005922W WO 0053545 A1 WO0053545 A1 WO 0053545A1
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WIPO (PCT)
Prior art keywords
formula
phenyl
alkyl
compound
aryl
Prior art date
Application number
PCT/US2000/005922
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English (en)
Inventor
Barry A. Bunin
Steven P. Tushup
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Axys Pharmaceuticals, Inc.
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Publication date
Application filed by Axys Pharmaceuticals, Inc. filed Critical Axys Pharmaceuticals, Inc.
Priority to AU35157/00A priority Critical patent/AU3515700A/en
Publication of WO2000053545A1 publication Critical patent/WO2000053545A1/fr

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    • 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
    • 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
    • C07D211/80—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
    • 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
    • C07D211/86—Oxygen atoms
    • 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

  • the present invention relates to a process for the synthesis of dihydropyridone compounds of Formula I.
  • a variety of small organic molecules are of interest since they can have potentially useful pharmacological activity.
  • nitrogen heterocycles hold a special place as historical pharmacophores.
  • Combinatorial library i.e., a library containing a large number of small organic molecules is useful as a research tool.
  • use of such libraries allows determination of biological binding properties of a large number of molecules.
  • the present invention provides a process for the synthesis of dihydropyridone compounds of Formula I.
  • the process of the present invention can also be used to synthesize combinatorial libraries of dihydropyridone compounds of Formula I.
  • the present invention thus provides a process for the synthesis of a compound of Formula I:
  • R 1 represents H, an amino acid side chain, (CH 2 ) 0-4 - ⁇ henyl, (CH 2 ) ⁇ . 6 -NH-C(O)-O-alkyl,
  • R 2 represents C ⁇ -4 -alkoxyphenyl, di-C 1-4 -dialkylphenyl, C ⁇ -8 -alkylphenyl, halophenyl, halo-C 1-4 -alkyl phenyl, benzyl, cyanophenyl, -Cs-io-cycloalkyl, biphenyl, or C ⁇ - -alkyl;
  • R represents C 1-14 -alkyl, C 2- ⁇ 4 -alkenelene, aryl, substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalkyl, or -Ci-g alkyl-R 5 ;
  • R 4 represents H or alkyl
  • R 5 represents aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, C 1-8 -alkylethers, -C 1- -alkyltertiaryamines, or
  • X represents O, NH or S; the process comprising the steps of:
  • step(i) comprises reacting a compound of Formula A with a compound of Formula B in the presence of a coupling agent selected from DIC, PyBOP, DCC and EDC, and a dialkyl amino pyridine catalyst; and step (ii) comprises treating a compound of Formula C with a compound of Formula D in the presence of an amine base.
  • a coupling agent in step(i) is DIC
  • the catalyst is dimethyl amino pyridine(DMAP); and the amine is triethyl amine.
  • R 1 represents CH 2 -Ph, Ph, (CH 2 ) 4 -NH-C(O)-C ⁇ -4 -alkyl
  • R represents p-Cj -4 -alkoxy phenyl, 3,5-dialkyl phenyl, C ⁇ -4 -alkyl phenyl, p-halophenyl, 3,5-trifluoromethyl phenyl, benzyl, 4-cyanophenyl, 4-alkyl-phenyl, cyclohexyl, biphenyl, or alkyl; and R 3 represents C 2 H 5 ,
  • a further preferred embodiment is one wherein R 2 represents p-methoxy phenyl, 3,5-dimethyl phenyl, p-bromo phenyl or 4-methyl phenyl.
  • an amino ester 1 In a reaction vessel was placed an amino ester 1, and from about 0.5 to about 1.6 mole equivalents of an aldehyde 2, both preferably as inert solvent solutions, for example THF solutions. To this mixture was added about 1.5 to about 2 mmol of magnesium sulfate, as a drying agent. This resulting mixture was mixed and was then combined with additional magnesium sulfate (0.8 to 2 equivalents). After cooling this mixture to low temperatures, preferably from about 10°C to about -78°C, one mole equivalent of zinc chloride was added, while maintaining the reaction mixture at a temperature of about 0°C.
  • the magnesium sulfate was separated from the reaction mixture and the magnesium sulfate was washed with DCM.
  • the DCM washings were mixed with the filtered reaction mixture and this new reaction mixture was extracted, in succession, with an inorganic acid, preferably 2N HC1, NaHCO 3 (x 2), dried (Na 2 SO ) and concentrated under reduced pressure to yield a compound of Formula 3 as an oil.
  • the hydrolysis procedure converting a compound of Formula 3 to Formula B, comprises combining an alcohol and an inert solvent, preferably a mixture of methanol- THF solution of a compound of Formula 3 with from about 2 to about 6 mole equivalents of NaOH and stirring this mixture for 8-16 h.
  • This reaction mixture was then diluted with ether and extracted with water (x2).
  • the aqueous layers were combined and further washed with ether (xl), and acidified (preferably with HC1) to a pH of about 0.5 to about 2.5.
  • This acidic mixture was then extracted with DCM (x3), dried with sodium sulfate and concentrated to yield a compound of Formula B.
  • amino esters 1 with side chain protecting groups can be used in Scheme I, step A for the hetero-Diels Alder reaction with Danishefsky's Diene.
  • Hydrophobic aminoesters are preferred.
  • Illustrative examples of the hydrophobic aminoesters are tryptophan methyl ester (Trp-OMe), lysine (epsilon Boc-amine) methyl ester (Lys(BOC)- OMe), and tyrosine (benzyl ether) methyl ester (Tyr(Bz)OMe).
  • Table I are additional examples of the amino esters, compounds of Formula 1 that can be used in Step A of Scheme I.
  • cleaving nucleophiles R 3 -X-H, Formula D
  • Preferred cleaving nucleophiles are low boiling, low molecular weight primary alcohols.
  • Table LLI lists alcohols (compounds of Formula D) that are useful as cleaving nucleophiles in the novel process of the presently claimed invention.
  • the process of the present invention can also be used to synthesize a library of compounds of Formula I.
  • the following experimental procedure outlines a general procedure for the synthesis of such a library.
  • Dihydropyridone scaffolds (compounds of Formula 3) were prepared in sets of 30, by reaction between two free amino esters (compound 1) and fifteen different aldehydes (compound 2).
  • an amino ester 1 50 mmol each, in its free base form following extraction with bicarbonate
  • an aldehyde 2 50 mmol each
  • Approximately 9.0 g (75 mmol, 1.5 equiv) of magnesium sulfate was added to each reaction mixture in the individual pyrex jars.
  • Danishefsky's diene (l-methoxy-3-trimethylsilyl-oxy-l,3-butadiene) (1.2 equiv, 60 mmol, 12.5 mL total) was added to each reaction mixture in four 3.15 mL portions over a four hour period (once/hour). In between additions the reaction mixtures were stored at 0°C. After the addition of Danishefsky's diene was completed the resulting reaction mixtures were maintained at 0°C for 8-16 hours.
  • reaction mixtures were then individually decanted in to a mixture of 100 mL 2N HC1 and 25 mL DCM in separatory funnels leaving the magnesium sulfate behind. After extraction and separation, the aqueous layer was rinsed twice with 15 mL DCM. The combined organic layers were backwashed with about 100 mL (+ 10 mL) saturated aqueous sodium bicarbonate (NaHCO 3 ). After collecting the organic layer, approximately 2.5 g of sodium sulfate (Na s SO ) was added as a drying agent, followed by 1.0 g of decolarizing carbon.
  • Na s SO sodium sulfate
  • the resulting solutions were filtered through fritted syringes (catalog #2456, Applied Separations, ca. 1 inch diameter) packed with 0.75 inches of silica gel topped with 0.75 inches of Celite (the silica gel was primed with 10 mL DCM).
  • the eluents were individually collected in respective appropriately labeled 50 mL Falcon Tubes (two Falcon Tubes per product to keep the volume in each Falcon tube below 35 mL and avoid bumping in the Savant vacuum centrifuge).
  • the solvent from the samples in the Falcon Tubes was concentrated in parallel with a commercially available Savant vacuum centrifuge fitted with an adapter for Falcon Tubes to yield an oily residue.
  • the solutions can be individually concentrated in round-bottom flasks using a rotary evaporator.
  • reaction mixtures were individually added to a mixture of ether (150 mL) and water (100 mL) in separatory funnels. Following extraction, the aqueous layer was collected in appropriately labeled containers and was washed two more times with ether (150 mL). The combined aqueous layer was acidified to a pH of 1 using hydrochloric acid. The acidified aqueous layer was extracted with 3 x 10 mL of DCM. The combined organic layers (ca.
  • scaffolds (compounds of Formula 3) were reliably obtained in sufficient purity and quantity (as determined by in-process analysis) for further use. Specifically, every scaffold that was selected to load onto resin (compound of Formula A) was identified by LC-MS and was present as greater than 50% AUC at 214 nm. The mass balance of each selected scaffold also correlated to greater than 0.8 molar equivalents relative to resin (loading 1.0 mmol/g). Enough resin was used with all scaffolds to provide 100 mg of resin (1.0 mmol/g)/well for a yield of 0.1 mmol well of final products.
  • the selected scaffolds derived from each amino ester were acylated onto a thiophenol resin (Formula A) according to the following procedure.
  • a 0.1 M solution of DIC and the appropriate scaffold, of Formula 3, (5-10 mmol, depending on the mass balance of the particular scaffold) in 50-100 mL in DCM was allowed to react for 15 min.
  • 5.0 g (5.55 mmol based on theoretical loading 1.11 g/mol) thiophenol resin was added followed by 63 mg (0.5 mmol) of DMAP catalyst.
  • the reaction mixtures in the jars were sealed and shaken for 18 h.
  • the derivatized thiophenol resin was transferred into clamped Polyfiltronics plates (2.7 ⁇ ) either as slurries in dioxane or as dry samples with shallow well ( ⁇ 0.5 cm high) microtiter plates.
  • Polyfiltronics plates 2.7 ⁇
  • Robbins Scientific Hydra 96 automated parallel syringes in a microtitor plate format, Robbins Scientific, Sunnyvale, CA
  • 1.0 mL of a 8:1:1 (v/v/v) mixture of dioxane/triethylamine/alcohols (#1-X) was added to each resin.
  • the top of the plates were clamped shut and the plates were placed in a preheated oven at 40°C for up to 12 h.
  • the plates were removed from the oven and the products were collected in a pretared 2 mL Beckman microtitor plate by gravity filtration followed by positive nitrogen pressure.
  • the plates were rinsed in parallel with 0.7 mL of dioxane employing an ATR moduline apparatus (ATR Biotech, Inc., Emeryville, CA).
  • ATR Biotech, Inc. Emeryville, CA
  • the resulting dioxane solutions were placed in a -78 °C freezer until frozen.
  • the solvent was removed in parallel via lyophilization at 5°C with a tray lyophilizer (Virtis, Gardiner, NY).
  • the plates were then removed from the tray lyophilizer and placed in a desiccater under high vacuum overnight prior to quality analysis of the resulting library products.
  • Library products were identified by Mass Spectroscopy (MS).
  • the derivatized resin, compound of Formula C above, was mixed with 1.0 mL of a 8:1:1 (v/v/v) mixture of dioxane/triethylamine/alcohol. This reaction mixture was maintained at about 40°C for 12 hours. The product formed was then collected by filteration and diluted with about 1 mL dioxane. The dioxane solution was lyophilized at about 5°C over 12 hours, the product thus obtained was dried and identified by mass spectroscopy
  • Solvent A 99% water + 1% methanol + 0.1% acetic acid
  • Solvent B 99% methanol + 1 % water + 0.1% acetic acid
  • HPLC HPLC data was obtained using the following instruments and conditions.
  • Solvent B 99.9% methanol + 0.1% trifluoroacetic acid
  • Library of compounds This term indicates a collection of independent (individual) compounds that are synthesized by the process of the present invention. Generally the term library of compounds indicates a collection of individual compounds distinct from one another. Also included in the library of compounds is a mixture of the individual compounds.
  • Alkyl or “alkyl radical” is meant to indicate a hydrocarbon moiety of up to 8 carbon atoms. This hydrocarbon is generally attached to at least one other atom, and can be straight chain, or branched, or cyclic.
  • alkylene represents an alkyl group, as defined above, except that it has at least one center of unsaturation, i.e., a double bond.
  • Illustrative examples are butene, butadiene, propene, and pentene.
  • cycloalkyl indicates a saturated or partially unsaturated three to ten carbon monocyclic or bicyclic hydrocarbon moiety which is optionally substituted with an alkyl group.
  • straight chain alkyl is meant to represent an unbranched hydrocarbon moiety of up to 8 carbon atoms.
  • An example of a straight chain alkyl is a n-pentyl group.
  • hetero cycloalkyl or “hetero cycloalkyl radical” means cycloalkyl, as defined above, except one or more of the carbon atoms indicated are replaced by a hetero atom chosen from N, NR 12 , O , S(O), S(O) 2 and S, wherein R 12 is (C,. 6 )alkyl, hetero(C 2-6 )alkyl or hydrogen.
  • R 12 is (C,. 6 )alkyl, hetero(C 2-6 )alkyl or hydrogen.
  • Illustrative examples of the term heterocyclo(C 5- ⁇ 4 )alkyl are morpholinyl, indolinyl, piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).
  • aryl means an aromatic monocyclic, bicyclic, or a fused polycyclic hydrocarbon radical containing the number of carbon atoms indicated.
  • a C 6 -C ⁇ 4 aryl group includes phenyl, naphthyl, anthracenyl, etc.
  • heteroaryl means aryl, as defined above, wherein one or more of the carbon atoms is replaced by a hetero atom chosen from N, O, and S.
  • the hetero atoms can exist in their chemically allowed oxidation states.
  • Sulfur (s) can exist as a sulfide, sulfoxide, or sulfone.
  • Each heteroaryl ring comprises from five (5) to fourteen (14) atoms.
  • heteroaryl groups are thienyl, furyl, pyrrolyl, indolyl, pyrimidinyl, isoxazolyl, purinyl, imidazolyl, pyridyl, pyrazolyl, quinolyl, and pyrazinyl.
  • amino acid side chain represents a natural or unnatural amino acid.
  • natural amino acid as used herein is intended to represent the twenty naturally occurring amino acids in their L' form, which are some times also referred as 'common amino acids', a list of which can be found in Biochemistry, Harper & Row Publishers, Inc. (1983).
  • unnatural amino acid as used herein, is intended to represent the 'D' form of the twenty naturally occurring amino acids described above. It is further understood that the term unnatural amino acid includes homologues of the natural amino acids, and synthetically modified form of the natural amino acids.
  • the synthetically modified forms include amino acids having alkylene chains shortened or lengthened by up to two carbon atoms, amino acids comprising optionally substituted aryl groups, and amino acids comprised halogenated groups, preferably halogenated alkyl and aryl groups.
  • R 7 and R 8 Optional substituents for aryl, hetero aryl, and Ph groups are R 7 and R 8 . These R , and R substituents at each occurrence are independently selected from a group consisting of H, NH 2 , halo, O-C ⁇ -4 alkyl, NHC 1 -C 4 alkyl, N(C ⁇ -C 4 ) 2 alkyl, and CF 3 ; while R 8 is selected from H and C 1-4 alkyl.
  • amine base as used herein is intended to represent a tertiary amine, preferably having a low boiling point. Illustrative examples of an amine base are triethyl amine and trimethyl amine.
  • alkyl amine is intended to represent an amino compound wherein the nitrogen atom is substituted with at least one alkyl group (alkyl as defined earlier).
  • cleaving nucleophile represents a molecule containing a hydroxy, thiol or a primary or secondary amine group capable of functioning as a nucleophile.
  • Preferred cleaving nucleophiles are compounds containing a hydroxy group, i.e., compounds generally referred to as alcohols.
  • inert solvent represents solvents which do not react with the reagents dissolved therein.
  • inert solvents are tetrahydrofuran (THF), methylene chloride, dichloro methane (DCM), ethyl acetate (EtOAc), dimethyl formamide (DMF), diaoxane, chloroform, and DMSO.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
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  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de synthétisation de composés de dihydropyridone de formule (I). Le procédé de la présente invention peut également être utilisé pour synthétiser une banque de composés de dihydropyridone représentés par la formule (I).
PCT/US2000/005922 1999-03-10 2000-03-07 Procede de synthetisation de dihydropyridones WO2000053545A1 (fr)

Priority Applications (1)

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AU35157/00A AU3515700A (en) 1999-03-10 2000-03-07 Process for the synthesis of dihydropyridones

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US12361099P 1999-03-10 1999-03-10
US60/123,610 1999-03-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10159268B2 (en) 2013-02-08 2018-12-25 General Mills, Inc. Reduced sodium food products

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015532A1 (fr) * 1996-10-09 1998-04-16 Novartis Ag Synthese en phase solide de composes heterocycliques
WO1998033751A1 (fr) * 1997-01-31 1998-08-06 Axys Pharmaceuticals, Inc. Nouvelles techniques de synthese en phase solide permettant de preparer divers composes analogues
WO1998045231A1 (fr) * 1997-04-09 1998-10-15 Cadus Pharmaceutical Corporation Supports pour synthese en phase solide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015532A1 (fr) * 1996-10-09 1998-04-16 Novartis Ag Synthese en phase solide de composes heterocycliques
WO1998033751A1 (fr) * 1997-01-31 1998-08-06 Axys Pharmaceuticals, Inc. Nouvelles techniques de synthese en phase solide permettant de preparer divers composes analogues
WO1998045231A1 (fr) * 1997-04-09 1998-10-15 Cadus Pharmaceutical Corporation Supports pour synthese en phase solide

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Title
B.A. BUNIN ET AL.: "Practical methods for combined solution/solid-phase library generation", BOOK OF ABSTRACTS 216TH ACS NATIONAL MEETING AUGUST 23-27 1998 BOSTON *
CHIXU C ET AL: "Solid Phase Synthesis of 2,4-Disubstituted Pyridine and Tetrahydropyridine Derivatives: Resin Activation/Capture Approach/REACAP Technology", TETRAHEDRON LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 39, no. 21, 21 May 1998 (1998-05-21), pages 3401 - 3404, XP004117586, ISSN: 0040-4039 *
CHIXU C ET AL: "Synthesis of Dihydropyridone Scaffolds on Solid Support: Resin Activation/Capture Approach/REACAP Technology", TETRAHEDRON LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 39, no. 3-4, 15 January 1998 (1998-01-15), pages 217 - 220, XP004100925, ISSN: 0040-4039 *
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CRESWELL M W ET AL: "Combinatorial Synthesis of Dihydropyridone Libraries and their Derivatives", TETRAHEDRON,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 54, no. 16, 16 April 1998 (1998-04-16), pages 3983 - 3998, XP004162175, ISSN: 0040-4020 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10159268B2 (en) 2013-02-08 2018-12-25 General Mills, Inc. Reduced sodium food products
US11540539B2 (en) 2013-02-08 2023-01-03 General Mills, Inc. Reduced sodium food products

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