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WO2006049211A1 - Acide 2 aryl-2-fluoroalcanoique, son ester et methodes servant a preparer ces derniers - Google Patents

Acide 2 aryl-2-fluoroalcanoique, son ester et methodes servant a preparer ces derniers Download PDF

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Publication number
WO2006049211A1
WO2006049211A1 PCT/JP2005/020217 JP2005020217W WO2006049211A1 WO 2006049211 A1 WO2006049211 A1 WO 2006049211A1 JP 2005020217 W JP2005020217 W JP 2005020217W WO 2006049211 A1 WO2006049211 A1 WO 2006049211A1
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Prior art keywords
group
aryl
formula
chemical
fluoro
Prior art date
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PCT/JP2005/020217
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English (en)
Japanese (ja)
Inventor
Yoshio Takeuchi
Hidehito Fujisawa
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University of Toyama NUC
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University of Toyama NUC
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Priority to JP2006542425A priority Critical patent/JPWO2006049211A1/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel 2-aryl-2 fluoroalkanoic acid, its optically active substance and an ester thereof, 2-aryl 2-fluoroalkanoic acid ester, and a method for producing the optically active substance.
  • Non-patent Document 1 There are two types of optical isomers in 2-arylpropionic acids (ibuprofen, naproxen, flurbiprofen, fenoprofen, etc.) that are used as non-steroidal anti-inflammatory drugs. However, since these may be isomerized in vivo [Non-patent Document 1], the pharmacological activity and pharmacokinetics as an optically active substance cannot be strictly investigated. In contrast, attempts have been made to investigate pharmacological activity and pharmacokinetics as optically active substances by preventing in vivo isomerism by using compounds in which 2-position hydrogen of 2-arylpropionic acids is substituted with a fluorine atom. [Non-patent document 2, Non-patent document 3].
  • perchloryl fluoride is used when a fluorine atom is introduced into a compound, and for example, there is a production of fluorosalidomide [Patent Document 1].
  • Examples of the use of perchloryl fluoride to produce fluoralkanoic acids include a-fluoro 1-nitro 1-phenol substituted alkanoic acid esters, specifically a-fluoro-a-tro 13- There is a synthesis of ferrule ethyl pionate [Patent Document 2]. This use example can be applied only to compounds in which a specific substituent such as a -tro group is bonded to the carbon at the ⁇ -position of the carboxylic acid.
  • Patent Document 1 JP 2000-159761
  • Patent Document 2 JP-A 63-79854
  • Patent Document 1 J. Pharm. Pharmacol, 693, 35, 1983
  • Non-Patent Document 2 Tetrahedron, 52 (24), 8257-8262, 1996
  • Non-Patent Document 3 Tetrahedron, 52 (39), 12761-12774, 1996
  • Non-Patent Document 4 Summary of the 25th Fluorination Discussion Meeting, 258-260,2001
  • the photoactive form of the 2-position fluorine-substituted product of 2-aryl alkanoic acids such as 2-aryl propionic acid does not undergo racemization. Therefore, it is a useful compound for investigating the difference in biological activity among stereoisomers and the effect of introduction of fluorine atoms.
  • the necessary 2-aryl-fluoroalkanoic acids are selectively synthesized. It was necessary to establish a method.
  • the present invention provides a general formula
  • Z ring is absent, or represents a benzene ring or a bicyclic heterocyclic ring
  • R a represents a carboxyl protecting group
  • R 1 represents an optionally substituted alkyl group.
  • Ar is a phenyl group that may be substituted, a naphthyl group that may be substituted, or a formula that may be substituted
  • the present invention also provides a general formula
  • Ar a is phenyl, phenol, halogen and phenol, oxocyclopentylmethyl, alkenylamino, or 2_phenyl-1,3-dioxolane.
  • R represents a hydrogen atom or a carboxyl protecting group
  • IT represents an alkyl group which may be substituted, or
  • Ar a represents a phenyl group
  • R represents a hydrogen atom or a carboxyl protecting group
  • R 1 represents a branched alkyl group or an aralkyl group, respectively.
  • a chiral compound in which a fluorine atom is introduced into a structurally important asymmetric center of 2-arylalkanoic acid can be synthesized in a short process.
  • the novel 2-aryl 2-fluoroalkanoic acids produced by the method of the present invention can be expected to enhance the pharmacological action of antipyretic “analgesic” anti-inflammatory drugs and reduce side effects.
  • an aryl group refers to phenol and naphthyl; an aryloxy group refers to funoxy and naphthoxy; and an aryl hydrocarbon group refers to full carbon and naphthyl carbonate.
  • a heteroaryl group is an aromatic cyclic group containing a heteroatom such as pyridyl, fulleryl, chenyl, pyrrolyl, imidazolyl, oxazolyl, pyrazil, pyridazyl, pyrimidinyl; The group is an oxy group to which a heteroaryl group is bonded; the heteroarylcarbonyl group is a bond to a heteroaryl group.
  • An alkyl group is a C alkyl group such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl; an alkoxy group is methoxy
  • alkellyl groups are bur (etul), allyl (2-probe)
  • alkyl group such as pinyl and butynyl
  • alkylamino group means methylamino
  • Mono- or di-C alkylamino groups such as tyramino and methylethylamino
  • -Luamino group means mono C alk eramino such as arylamine, isopropylamine, etc.
  • halogen atom means fluorine atom, chlorine atom, bromine atom, iodine atom
  • V and alkyl groups are branched C-alkyl such as iso-propyl, iso-butyl, tert-butyl, etc.
  • Aralkyl refers to an aryl-C alkyl group such as benzyl, phenethyl, diphenylmethyl, or trityl.
  • Z ring is absent, or represents a benzene ring or a bicyclic heterocyclic ring
  • R a represents a carboxyl protecting group
  • R 1 represents an optionally substituted alkyl group. , Each means.
  • Ar substituents in the general formulas [2] and [3] include alkyl groups, alkenyl groups, Lucinyl, alkoxyl, aryl, aroxy, aryl carbonate
  • Alkylamino group, alkenylamino group, and halogen atomic energy including one or more selected groups, alkyl group, aryl group, aryloxy group, arylcarbonyl group, alkellamino group, and one or more selected groups
  • carboxyl protecting group for R a include C such as methyl group, ethyl group, and t-butyl group.
  • Alkyl group such as benzyl group, diphenylmethyl group, and trityl group
  • the substituent represented by R 1 includes an alkyl group, an alkyl group, an alkyl group, an alkoxyl group, an aryl group. And one or more groups selected from an aryloxy group, an arylcarbonyl group, a heteroaryl group, a heteroaryloxy group, a heteroarylcarbonyl group, a nitro group, and a halogen atom, and an aryl group (particularly a phenol group). I prefer that.
  • the 2-aryl alkanoic acid ester of the general formula [2] is mixed with a base as a solvent in an ether such as tetrahydrofuran (THF) at a low temperature, for example, 20 ° C or lower, preferably 40 ° C to 78 ° C.
  • a metal amide such as lithium dialkylamide (LDA), sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc. (the metal amide may be formed in the reaction solution), and then fluorinated.
  • Perchloryl (FCIO) preferably fluorinated perchlor
  • the 2-aryl alkanoic acid ester as a raw material has a ketone portion
  • a method of fluorinating the ketone portion after ketal protection is more preferred and may be mentioned as a method. .
  • the 2-aryl-2-fluoroalkanoic acid ester of general formula [3] can be hydrolyzed to the corresponding 2-aryl 2-fluoroalkanoic acid.
  • 2-aryl 2 fluoroalkanoic acid is condensed with power rangeol (compound [5]) to give two corresponding diastereomers, which are separated by silica gel chromatography and then hydrolyzed. Then, an optically active substance can be obtained. Skip these steps 2
  • the compound of the present invention has the following general formula [1]
  • Ar a is phenyl / reoxy, phenol, halogen and phenyl, oxocyclopentylmethyl, alkenylamino, or 2_phenyl-1,3-dioxan-2-yl. Or a group substituted with
  • R represents a hydrogen atom or a carboxyl protecting group
  • R 1 represents an optionally substituted alkyl group, respectively, or
  • Ar a represents a phenyl group
  • R represents a hydrogen atom or a carboxyl protecting group
  • R 1 represents a branched alkyl group or an aralkyl group, respectively.
  • 2-aryl-2-fluoroalkanoic acid and esters thereof, and optically active substances thereof can be obtained by the production method of the present invention described above.
  • a compound in which R 1 is an aralkyl group can also be produced by using N-fluorobenzenesulfonimide instead of perchloryl fluoride. Specific examples of the compounds are shown in Tables 3 and 4.
  • Methyl 2- (3-benzoylphenol) propanoate [2c] 1.0 g, ethylene glycol 0.85 mL, p-toluenesulfonic acid monohydrate 70 mg and toluene 20 mL heated for 18 hours I returned it. To the reaction mixture was added 10 mL of saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solution was concentrated.
  • ⁇ ⁇ ⁇ 66 '(HS' s) 66 '(HS ⁇ 6 ⁇ ' ⁇ ) ⁇ -99: 9 (OQD) ⁇ ⁇ - ⁇ ⁇
  • ⁇ ⁇ 8 ⁇ ') 00 ⁇ ⁇ ' (HS 's) 00 ⁇ ⁇ ' (HS 's) ⁇ 6' ( ⁇ ' ⁇ ) ⁇ -99: 9 ODOD) ⁇ ⁇ - ⁇ ⁇
  • fluorination of the asymmetric central site of 2-arylalkanoic acids can be performed in a short process.
  • compounds in which a fluorine atom is introduced at the chiral center have uses such as antipyretic, analgesic and anti-inflammatory drugs, enhanced side effects, reduced side effects, new optical resolution agents, and liquid crystal raw materials.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Abstract

L'invention concerne une méthode servant à préparer un ester d'acide 2 aryl-2-fluoroalcanoïque en quantités importantes au moyen d'un nombre limité d'étapes, ainsi qu'un nouveau composé d'acide 2 aryl-2-fluoroalcanoïque préparé au moyen de cette méthode. Ce composé, qui possède un atome de fluor introduit dans son centre chiral, augmente l'activité pharmacologique d'un agent antipyrétique/analgésique/anti-inflammatoire, diminue les effets secondaires de cet agent et est utile en tant que nouvel agent de résolution optique, matière première de cristal liquide, par exemple. Dans la formule (I), Ar représente aryle éventuellement substitué, Ra représente un groupe protecteur carboxy et R1 représente alkyle éventuellement substitué.
PCT/JP2005/020217 2004-11-02 2005-11-02 Acide 2 aryl-2-fluoroalcanoique, son ester et methodes servant a preparer ces derniers Ceased WO2006049211A1 (fr)

Priority Applications (1)

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JP2006542425A JPWO2006049211A1 (ja) 2004-11-02 2005-11-02 ２−アリール−２−フルオロアルカン酸及びそのエステル並びにそれらの製造方法

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JP2004-319031 2004-11-02
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JP2005122104 2005-04-20
JP2005-122104 2005-04-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017105827A (ja) * 2011-08-19 2017-06-15 ザ・トラスティーズ・オブ・プリンストン・ユニバーシティＴｈｅ Ｔｒｕｓｔｅｅｓ Ｏｆ Ｐｒｉｎｃｅｔｏｎ Ｕｎｉｖｅｒｓｉｔｙ Ｃ−ハロゲン結合形成

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5589247A (en) * 1978-06-21 1980-07-05 Ici Australia Ltd Insecticidal fluorinated ester
WO1996023759A1 (fr) * 1995-01-31 1996-08-08 Nagase & Company, Ltd. Procede de racemisation d'acides carboxyliques a activite optique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5589247A (en) * 1978-06-21 1980-07-05 Ici Australia Ltd Insecticidal fluorinated ester
WO1996023759A1 (fr) * 1995-01-31 1996-08-08 Nagase & Company, Ltd. Procede de racemisation d'acides carboxyliques a activite optique

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BUDAVARI S. ET AL.: "The Merck Index", vol. 12TH ED., 1996, MERCK RESEARCH LABORATORIES DIVISION OF MERCK & CO., INC., pages: 675 - 676, XP008063202 *
DURANT G.J. ET AL.: "Nonsteroidal Antiinflammatory Agents. Some Arylacetic Acids", JOURNAL OF MEDICINAL CHEMISTRY, vol. 8, 1965, pages 598 - 603, XP002997909 *
HIDEHITO H. AND TAKEUCHI Y.: "Simple procedure for preparation of alpha-fluoro esters by fluorination of ester enol silyl ethers with perchloryl fluoride", JOURNAL OF FLUORINE CHEMISTRY, vol. 117, no. 2, 28 October 2002 (2002-10-28), pages 173 - 176, XP004389693 *
SCHLOSSER M. ET AL.: "Alpha-Fluoro Analogues of Inflammation Inhibiting alpha-Arylpropionic Acids", TETRAHEDRON, vol. 52, no. 24, 10 June 1996 (1996-06-10), pages 8257 - 8262, XP004103874 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017105827A (ja) * 2011-08-19 2017-06-15 ザ・トラスティーズ・オブ・プリンストン・ユニバーシティＴｈｅ Ｔｒｕｓｔｅｅｓ Ｏｆ Ｐｒｉｎｃｅｔｏｎ Ｕｎｉｖｅｒｓｉｔｙ Ｃ−ハロゲン結合形成

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