WO2000003681A2 - Procede de synthese de derives de benzopyrane - Google Patents

Procede de synthese de derives de benzopyrane Download PDF

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Publication number
WO2000003681A2
WO2000003681A2 PCT/US1999/015993 US9915993W WO0003681A2 WO 2000003681 A2 WO2000003681 A2 WO 2000003681A2 US 9915993 W US9915993 W US 9915993W WO 0003681 A2 WO0003681 A2 WO 0003681A2
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Prior art keywords
alkyl
formula
aryl
radical
group
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Application number
PCT/US1999/015993
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English (en)
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WO2000003681A3 (fr
Inventor
James Guy Breitenbucher
Hon C. Hui
Gianine M. Figliozzi
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Axys Pharmaceuticals, Inc.
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Priority to AU49971/99A priority Critical patent/AU4997199A/en
Publication of WO2000003681A2 publication Critical patent/WO2000003681A2/fr
Publication of WO2000003681A3 publication Critical patent/WO2000003681A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to a process for synthesis of compounds having a benzopyran skeleton.
  • benzopyran based compounds seem to possess useful biological activity. Efforts continue to make a wider variety of compounds having a benzopyran nucleus. Current synthetic methods useful in making benzopyran derivatives are slow and time consuming. There is thus a need for a new process that will synthesize a plurality of benzopyran compounds in a short amount to time. Such a library of compounds can then be evaluated for its biological activity.
  • R a and R 1b are independently selected from a group consisting of H, C C 4 alkyl radical, -C C 4 alk-C 6 -C 10 aryl, -C 6 -C 10 aryl, C 4 -C 10 cycloalkyl radical, and C 4 -C 10 branched alkyl radical; or
  • R 1a and R 1b along with the carbon atom that they are attached form an optionally substituted, saturated or partially unsaturated C 4 -C 10 cyclo alkyl or hetero cycloalkyl ring;
  • R 2 is selected from a group consisting of -(CH 2 ) 1 ⁇ -O-C 1 -C 4 alkyl, C C 6 alkyl optionally substituted with C C 4 alkyl radical, C 4 -C 10 cycloalkyl, C 4 -C 10 partially saturated cycloakyl, C 5 -C 10 heterocycloaklyl, -N(C r C 4 ) 2 alkyl, -O-alkyl, aryl, heteroaryl, or
  • R 3 is selected from a group consisting of C,-C 4 alkyl radical, C 4 -C 10 cycloalkyl radical, C 4 -C 10 branched alkyl radical -NH- C r C 4 alkyl, -CH 2 -O-C 6 C 10 aryl, -(CH 2 ) (-S-(CH 2 ) ⁇ -C(O)-O-C alkyl, -(CH 2 ) 1-4 -C 6 -C 10 aryl, C 6 -C 10 aryl, said alkyl groups being optionally substituted with one or more of C ⁇ alkyl, halo, -S-C ⁇ alkyl, -O-C ⁇ alkyl, and -C 6 . 10 aryl;
  • R 4a is selected from a group consisting of H, C 4 -C 6 cyclo alkyl radical, C 1J ⁇ alkyl-O- C ⁇ alkyl, and C C 6 alkyl optionally substituted with C 1 -C 4 alkyl radical, -NH 2 , - N(C 1 -C 4 ) 2 alkyl, OH, -O-alkyl, aryl, heteroaryl, or
  • R 4b represents H
  • R 5 is selected from a group consisting of H, Q, ⁇ alkyl, -O-C ⁇ alkyl,
  • R 6 is selected from a group consisting of H, C,-C 4 alkyl radical, -(CH 2 ) 1 ⁇ -C 6 -C 10 aryl, C 6 -C 10 aryl, C 4 -C 10 cycloalkyl radical, C 4 -C 10 branched alkyl radical, and -O-
  • R 9 independently at each occurrence is selected from OH, heteroaryl, and R 6 ;
  • X is selected from -C(O)-, -NH-C(O)-, NH-C(S)-, and -S0 2 ; and Q is selected from a group consisting of -CH 2 , O, S, SO, S0 2 , -N-heteroaryl,
  • SS is a solid support and halo represents Cl, Br, F, or I, with a compound of Formula B
  • Another aspect of the present invention provides a compound of Formula E which is useful in synthesizing benzopyran compounds of Formula 1 :
  • SS is a solid support
  • R 1a and R 1 are independently selected from a group consisting of H, C C 4 alkyl radical, -(CH 2 ) 1-t -C ⁇ -C 10 aryl, -C 6 -C 10 aryl, C 4 -C 10 cycloalkyl radical, and C 4 -C 10 branched alkyl radical; or R 1a and R 1b along with the carbon atom that they are attached to form an optionally substituted, saturated or partially unsaturated C 4 -C 10 cyclo alkyl or hetero cycloalkyl ring;
  • R 5 is selected from a group consisting of H, C lJt alkyl, -O-C ⁇ alkyl,
  • R 6 is selected from a group consisting of H, C r C 4 alkyl radical, aryl, C 6 -C 10 aryl, C 4 -C 10 cycloalkyl radical, C 4 -C 10 branched alkyl radical, and -O-
  • R 1a and R 1b are independently selected from a group consisting of H, C r C 4 alkyl radical, aryl, -C 6 -C 10 aryl, C 4 -C 10 cycloalkyl radical, and C 4 -C 10 branched alkyl radical; or
  • R 1a and R 1 along with the carbon atom that they are attached to form an optionally substituted, saturated or partially unsaturated C 4 -C 10 cyclo alkyl or hetero cycloalkyl ring;
  • R 2 is selected from a group consisting of -(CH 2 ) 1 ⁇ -O-C 1 -C 4 alkyl, C,-C 6 alkyl optionally substituted with C,-C 4 alkyl radical, C 4 -C 10 cycloalkyl, C 4 -C 10 partially saturated cycloakyl, C 5 -C 10 heterocycloaklyl, -N(C 1 -C 4 ) 2 alkyl, -O-alkyl, aryl, heteroaryl, or
  • R 3 is selected from a group consisting of C C 4 alkyl radical, C 4 -C 10 cycloalkyl radical, C 4 -C 10 branched alkyl radical -NH- C,-C 4 alkyl, -CH 2 -O-C 6 C 10 aryl, -(CH 2 ) M (-S-(CH 2 ) M -C(O)-O-C alkyl, -(CH 2 ) ⁇ -C 6 -C 10 aryl, C 6 -C 10 aryl, said alkyl groups being optionally substituted with one or more of C ⁇ alkyl, halo, -S-C M alkyl, -O-C ⁇ alkyl, and -C 6 . 10 aryl;
  • R 5 is selected from a group consisting of H, C 1-4 alkyl, -O-C ⁇ alkyl,
  • R 6 is selected from a group consisting of H, C C 4 alkyl radical, -(CH 2 ) 1 ⁇ -C 6 -C 10 aryl, C 6 -C 10 aryl, C 4 -C 10 cycloalkyl radical, C 4 -C 10 branched alkyl radical, and -O-
  • Z is selected from H, -C(O)-, -H-C(O)-, -NH-C(S)-, and -SO 2 ; with the proviso that when Z represents H, R 3 does not exist.
  • Preferred embodiments of the present invention provide a process wherein the titanium alkoxide reagent in step (iii) is Ti(O-iPr) 4 , Ti(OEt) 4 , Ti(OMe) 4 , or mixtures thereof.
  • Another preferred embodiment provides a process wherein the borohydride reagent in step (iii) is Na(OAc) 3 BH, Na(CNBH 3 ), NaBH 4 , BH 3 .pyr, or mixtures thereof.
  • a further preferred process is one wherein, R 1a and R 1 are independently selected from C C 2 alkyl radical, or R 1a and R 1b along with the carbon atom that they are attached to forms
  • R 2 is selected from a group consisting of -C 2 . 3 alk-O-CH 3 , and C ⁇ alkyl substituted with
  • R 3 is selected from -CH 3 ,
  • R 4a is selected from a group consisting of C 4 -alkyl, benzyl,
  • R 1a and R 1 are independently selected from C C 2 alkyl radical, or R 1a and R 1b along with the carbon that they are attached to forms
  • R 5 is selected from a group consisting of H, and C ⁇ alkyl; and R 6 is H, or -CH 3 .
  • a third aspect of the present invention provides a preferred embodiment of a compound of Formula 3 wherein, R 1a and R 1b are independently selected from C C 2 alkyl radical, or R 1a and R b along with the carbon that they are attached to forms
  • R 2 is selected from -C ⁇ alk-O-CH 3 , and C ⁇ alkyl radical, said alkyl radical optionally substituted with
  • R 3 is selected from -CH 3 , -C ⁇ alk-C 6 aryl, -CH[C 2 H 5 -O-C(O)]-(CH 2 ) 3 -S-CH 3 , and C 6 aryl, said aryl groups substituted with at least one of H, F, Cl, -CH 3 , -C 2 H 5 , -C 6 aryl, -O-CH 3 , and -SCH 3 ;
  • R 5 is selected from a group consisting of H, and C, ⁇ alkyl; and R 6 is H, or -CH 3 .
  • Compounds of Formula E were generally prepared by coupling a benzopyran carboxylic acid (Formula D) to the thiophenol resin of Formula C. To a solution of DIC, and the benzopyran carboxylic acid (Formula D) in methylene chloride was then added a methylene chloride solution of the thiophenol resin (Formula C). To this mixture was further added a base, preferably NMM, and pyridyl base, preferably DMAP, and the resulting mixture was then mixed with shaking for up to 24 hours. The resin thus obtained was washed with methylene chloride, DMF, MeOH, and dried in a vacuum oven for 24 hours at temperatures ranging up to 60°C to yield a compound of Formula E.
  • a base preferably NMM
  • pyridyl base preferably DMAP
  • the general procedure for preparing compounds of Formula G involved reductive amination of a compound of Formula E.
  • the resin of Formula E was swollen with a hydrocarbon based solvent, preferably toluene, to which was then added a titanium alkoxide, and R 2 -NH 2 , an amine of Formula F.
  • This reaction mixture was agitated by bubbling nitrogen gas for up to four hours.
  • the reaction mixture was then diluted with AcOH, and anhydrous THF.
  • a borohydride reducing agent To the diluted mixture was then added a borohydride reducing agent and this resulting mixture was further agitated by bubbling nitrogen gas through it for up to two days.
  • the resin from the reaction mixture was then washed with MeOH, THF, Pyridine, MeOH, and DCM. The washed resin was dried under reduced pressure.
  • the general synthetic procedure is as described below.
  • the first step involved the synthesis of the 3-hydroxymethyl-4-hydroxy benzoic acid, followed by the synthesis of compounds of Formula D.
  • N-Acetyl-piperidone (78.5 mL, 640 mmol) was added to toluene (700 mL) and stirred under anhydrous conditions.
  • Pyrolidine (18.0 mL, 212 mmol) was then added over 15-30 min via an addition funnel.
  • the 3-carboxymethyl-4- hydroxy benzoic acid, above, (77 g, 425 mmol) was then added in one portion.
  • This reaction mixture was refluxed with a Dean-Stark trap for 3-4 hr. Upon cooling to RT the solid product was separated from the solution by decanting.
  • HCI 800 mL, 1.0N was added to the solid and stirred to provide a fine powder.
  • the resin was analyzed by elemental analysis for chlorine and sulfur content to determine loading. Anal. Calculated: S 3.97%, Found: S 3.96%.
  • the resin was then washed using the following solvent sequence: (CH 2 CI 2 , DMF, MeOH)x4; (MeOH, CH 2 CI 2 )x2.
  • the resin was then dried in a vacuum oven for 24 hr. at 40°C to yield a compound of Formula E.
  • Illustrative examples of the amines used in the reductive amination step above are: benzyl amine, methoxypropylamine, tetrahydrofurfurylamine, N- aminopropylpyrolidine-2-one, 2-fluorophenethylamine, and 3,4- dimethoxyphenethylamie.
  • the resin (Formula G) from the reductive amination was distributed into polyfiltronics plates (2.7 m) using the Falcon Plate Method (85 mg/well). Using SOP "Resin transfer via Falcon plates”. The plates were then clamped with an open top clamp. The appropriate acylating agent (compound of Formula H) was then added as a solution in DCM (330 mL/well; 1.0 M) using the Robins Hydra (see library layout). The wells were then diluted with DCM (800mL/well) followed by the addition of DIPEA (70 mL). The plates were then shaken for 3.0 h, and washed using the following sequence: (DCM, DMF, MeOH)x4; Pyridine x3. Precaution was exercised since some of the acylating agents were lacromators.
  • acylating agents used to prepare compounds of Formula G are p-toluyl chloride, methyl thioisocyanate, acetyl chloride, benzyl isocyanate, and 3-methylthio phenylisocyanate.
  • Illustrative examples of (cleaving) amines (compounds of Formula K) used to cleave the compounds of Formula 1 from the solid support are butylamine, 1- aminoethyl morpholine, aminopropyl pyrolidine-2-one, piperidine, benzyl amine, and 3,4-dimethoxyphenethylamine.
  • Example 2 (MJH2-B): ⁇ 8.1 (s, 1 H), 7.5 (s, 1 H), 7.2 (m, 3H), 7.0 (m, 1 H), 6.8 (d, 1 H), 6.0 (bs, 1 H), 4.1 (m, 3H), 3.5 (s, 3H), 3.4 (m, 4H), 3.0 (m, 2H), 2.5 (s, 3H), 2.0-1.6 (m, 10H), 1.4 (s, 3H), 1.3 (s, 3H).
  • 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 a divalent hydrocarbon having from 1 to 10 carbon atoms. Illustrative examples are methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), and propylene (-CH 2 -
  • alkelene 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 2 , O , S(O), S(O) 2 and S, wherein R 12 is (C 1-6 )alkyl, hetero(C 2 . 6 )alkyl or hydrogen.
  • R 12 is (C 1-6 )alkyl, hetero(C 2 . 6 )alkyl or hydrogen.
  • Illustrative examples of the term heterocyclo(C 5.14 )alkyl are morpholinyl, indolinyl, piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.). As used in the present invention, the illustration:
  • the term “Ph” represents an optionally substituted phenyl radical or group.
  • aryl means an aromatic monocyclic, bicyclic, or a fused polycyclic hydrocarbon radical containing from 4 to 14 carbon atoms indicated. Thus a C 6 - C 14 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.
  • S can exist as a sulfide, sulfoxide, or sulfone.
  • Each heteroaryl ring comprises from five (5) to fourteen (14) atoms.
  • Illustrative examples of heteroaryl groups are thienyl, furyl, pyrrolyl, indolyl, pyrimidinyl, isoxazolyl, purinyl, imidazolyl, pyridyl, pyrazolyl, quinolyl, and pyrazinyl.
  • R 7 and R 8 Optional substituents for aryl, hetero aryl, and Ph groups are R 7 and R 8 .
  • R 7 , and R 8 substituents at each occurrence are independently selected from a group consisting of H, -NH 2 , halo, -0-C lJt alkyl, , -NHC 1 -C 4 alkyl, , -N(C r C 4 ) 2 alkyl, and CF 3 ; while R 8 is selected from H, and C ⁇ alkyl.
  • halo or halogen represents at least one of chlorine, bromine, iodine, and fluorine radicals.
  • solid support (SS), as used in the present invention, signifies polymeric material for supported synthesis. A detailed description of the terms linker molecule, and solid support can be found in The Combinatorial Index, B. A. Bunin, 1998, which is incorporated herein by reference.
  • Inert solvent as used herein represents solvents which do not react with the reagents dissolved therein.
  • Illustrative examples of inert solvents are tetrahydrofuran (THF), methylene chloride, dichloro methane (DCM), ethyl acetate (EtOAc), dimethyl formamide (DMF), diaoxane, chloroform, and DMSO.
  • THF tetrahydrofuran
  • DCM dichloro methane
  • EtOAc ethyl acetate
  • DMF dimethyl formamide
  • diaoxane chloroform
  • DMSO diaoxane

Abstract

La présente invention se rapporte à un procédé de synthèse de composés à base de benzopyrane représentés par la formule (1). Elle se rapporte également à de nouveaux composés à base de benzopyrane représentés par la formule (E) et la formule (3).
PCT/US1999/015993 1998-07-16 1999-07-14 Procede de synthese de derives de benzopyrane WO2000003681A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU49971/99A AU4997199A (en) 1998-07-16 1999-07-14 Process for the synthesis of benzopyran derivatives

Applications Claiming Priority (2)

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US9314298P 1998-07-16 1998-07-16
US60/093,142 1998-07-16

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WO2000003681A3 WO2000003681A3 (fr) 2000-04-20

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010798A1 (fr) * 1999-08-04 2001-02-15 Chemrx Advanced Technologies, Inc. Synthese en phase solide d'oxa- et de thiazoles
WO2007042906A1 (fr) * 2005-10-07 2007-04-19 Glenmark Pharmaceuticals S.A. Dérivés benzofusionnés substitués et leur utilisation en tant que ligands des récepteurs vanilloïdes
WO2007063385A2 (fr) * 2005-12-01 2007-06-07 Pfizer Products Inc. Antagonistes des recepteurs de l'histamine 3 pour des amines spirocycliques
JP2011519343A (ja) * 2007-12-18 2011-07-07 グレンマーク ファーマシューティカルズ， エセ．アー． Ｔｒｐｖ３モジュレーターとしてのクロマン誘導体
US11912693B2 (en) 2017-06-14 2024-02-27 Trevena, Inc. Compounds for modulating S1P1 activity and methods of using the same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5401848A (en) * 1990-11-26 1995-03-28 E. R. Squibb & Sons, Inc. Indane and quinoline derivatives
US5453421A (en) * 1992-09-11 1995-09-26 E. R. Squibb & Sons, Inc. Aryl and heterocyclic substituted propenamide derivatives
US5612370A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phenylglycine and phenylalaninen amido benzopyran derivatives
US5889044A (en) * 1991-06-13 1999-03-30 Smithkline Beecham P.L.C. Benzo- and pyridopyran derivatives having anxiolytic and anti-convulsant activity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5401848A (en) * 1990-11-26 1995-03-28 E. R. Squibb & Sons, Inc. Indane and quinoline derivatives
US5889044A (en) * 1991-06-13 1999-03-30 Smithkline Beecham P.L.C. Benzo- and pyridopyran derivatives having anxiolytic and anti-convulsant activity
US5453421A (en) * 1992-09-11 1995-09-26 E. R. Squibb & Sons, Inc. Aryl and heterocyclic substituted propenamide derivatives
US5612370A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phenylglycine and phenylalaninen amido benzopyran derivatives

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010798A1 (fr) * 1999-08-04 2001-02-15 Chemrx Advanced Technologies, Inc. Synthese en phase solide d'oxa- et de thiazoles
WO2007042906A1 (fr) * 2005-10-07 2007-04-19 Glenmark Pharmaceuticals S.A. Dérivés benzofusionnés substitués et leur utilisation en tant que ligands des récepteurs vanilloïdes
JP2009511465A (ja) * 2005-10-07 2009-03-19 グレンマーク・ファーマシューティカルズ・エスエー 置換ベンゾ縮合誘導体およびバニロイド受容体リガンドとしてのその使用
US7842703B2 (en) 2005-10-07 2010-11-30 Glenmark Pharmaceuticals S.A. Substituted benzofused derivatives and their use as vanilloid receptor ligands
WO2007063385A2 (fr) * 2005-12-01 2007-06-07 Pfizer Products Inc. Antagonistes des recepteurs de l'histamine 3 pour des amines spirocycliques
WO2007063385A3 (fr) * 2005-12-01 2007-10-04 Pfizer Prod Inc Antagonistes des recepteurs de l'histamine 3 pour des amines spirocycliques
JP2011519343A (ja) * 2007-12-18 2011-07-07 グレンマーク ファーマシューティカルズ， エセ．アー． Ｔｒｐｖ３モジュレーターとしてのクロマン誘導体
US11912693B2 (en) 2017-06-14 2024-02-27 Trevena, Inc. Compounds for modulating S1P1 activity and methods of using the same

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AU4997199A (en) 2000-02-07

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