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WO2000073273A1 - Procede d'obtention de derives 2-halo-3-(3-quinolyl) acide proprionique - Google Patents

Procede d'obtention de derives 2-halo-3-(3-quinolyl) acide proprionique Download PDF

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Publication number
WO2000073273A1
WO2000073273A1 PCT/JP2000/002001 JP0002001W WO0073273A1 WO 2000073273 A1 WO2000073273 A1 WO 2000073273A1 JP 0002001 W JP0002001 W JP 0002001W WO 0073273 A1 WO0073273 A1 WO 0073273A1
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WO
WIPO (PCT)
Prior art keywords
general formula
derivative represented
quinolyl
formula
quinoline
Prior art date
Application number
PCT/JP2000/002001
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English (en)
Japanese (ja)
Inventor
Shogo Sakuma
Tuyoshi Endo
Original Assignee
Nippon Chemiphar Co., Ltd.
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 Nippon Chemiphar Co., Ltd. filed Critical Nippon Chemiphar Co., Ltd.
Priority to AU34551/00A priority Critical patent/AU3455100A/en
Publication of WO2000073273A1 publication Critical patent/WO2000073273A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms

Definitions

  • the present invention relates to a method for producing a 2-halo-3 (3-quinolyl) propionic acid derivative.
  • R represents a hydrogen atom or a lower alkyl group
  • X represents a halogen atom
  • the 2-halo-3- (3-quinolyl) propionic acid derivative represented by the following formula can be used as a synthetic intermediate for pharmaceuticals, agricultural chemicals, etc., and has an action to improve insulin resistance, especially blood glucose.
  • 5 [(7-benzyloxy-13-quinolyl) methyl] —2,4-thiazolidinedione (hereinafter referred to as thiazolidinedione derivative), which is useful as an antihypertensive, blood lipid lowering agent, and visceral fat reducing agent It can be used as a synthetic intermediate.
  • thiazolidinedione derivative [(7-benzyloxy-13-quinolyl) methyl] —2,4-thiazolidinedione (hereinafter referred to as thiazolidinedione derivative), which is useful as an antihypertensive, blood lipid lowering agent, and visceral fat reducing agent It can be used as a synthetic intermediate.
  • the present inventors have used 7-benzyloxy 12-halo-3-quinoline carbaldehyde or 7-hydroxy-13-quinoline ditrile as a starting material, and have a simple method and have a good yield.
  • the present inventors have found a method for obtaining a 2-halo 3 _ (3-quinolyl) propionic acid derivative at a rate, and have completed the present invention.
  • R represents a hydrogen atom or a lower alkyl group.
  • the present invention relates to a method for producing a 2-halo-3- (3-quinolyl) propionic acid derivative represented by the formula: ⁇ Law B>
  • a base and a halogen or hypohalogenate are allowed to act on a 3-quinolinecarboxamide derivative represented by the following general formula (V):
  • the present invention relates to a method for producing a 2-halo-3- (3-quinolyl) propionic acid derivative represented by the formula: Further, the present invention provides a compound represented by the general formula (II):
  • the present invention relates to a 3- (3-quinolyl) propionic acid derivative represented by the following formula:
  • R 1 represents a hydrogen atom or a benzyl group
  • R 2 represents a cyano group or a carbamoyl group.
  • 2-Halo 3- (3-quinolyl) propionic acid derivative represented by the above general formula (I) In a conductor, a 3- (3-quinolyl) propionic acid derivative represented by the above general formula (e1) and a 3- (3-quinolyl) acrylic acid derivative represented by the above general formula (ill) And R is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms such as a methyl group or an ethyl group.
  • X is a halogen atom such as a chlorine atom, a bromine atom or an iodine atom.
  • the halogen represented by Z examples include a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom is preferable.
  • the 3- (3-quinolinyl) acrylic acid derivative represented by the general formula (ill) and the 3-quinoline carbaldehyde derivative represented by the general formula (IV) the quinoline ring It is preferable that a certain benzyloxy group is substituted at the 7-position.
  • the benzyloxy group on the quinoline ring is in the 7-position.
  • the substitution position of RiO— is preferably 7-position of the quinoline ring.
  • the 2-halo 3- (3-quinolyl) propionic acid derivative represented by the general formula (I) and the 3- (3-quinolyl) propionic acid derivative represented by the general formula (II) A 3- (3-quinolyl) acrylic acid derivative represented by the general formula (ill), a 3-quinoline carbaldehyde derivative represented by the general formula (IV), and a A 3-quinoquinoline derivative represented by the above general formula (VII) wherein R 1 is a benzyl group (a 3-quinolinecarboxamido derivative represented by the above general formula (VI))
  • Toxic, ethoxy, propoxy, trifluor Carbon number 1-6 alkoxy group such as a main butoxy group, a methyl group, Echiru group, It may have a substituent such as an alkyl group having 1 to 6 carbon atoms such as propyl group and trifluoromethyl.
  • This reaction is carried out under an atmosphere of argon or nitrogen in a solvent such as THF, DMSO, DMF or HMPA (hexamethylphosphoric triamide), LDA (lithium diisopropyl amide), lithium isoprobicyclo.
  • a solvent such as THF, DMSO, DMF or HMPA (hexamethylphosphoric triamide), LDA (lithium diisopropyl amide), lithium isoprobicyclo.
  • a solvent such as THF, DMSO, DMF or HMPA (hexamethylphosphoric triamide), LDA (lithium diisopropyl amide), lithium isoprobicyclo.
  • a solvent such as THF, DMSO, DMF or HMPA (hexamethylphosphoric triamide), LDA (lithium diisopropyl amide), lithium isoprobicyclo.
  • an organic lithium such as hexylamide, n-butyllithium or sec-butyllithium, or
  • the 3- (3-quinolyl) propionic acid derivative represented by the above general formula (II) is a 3- (3-quinolyl) acrylic acid derivative represented by the above general formula (ill).
  • Lower alcohols such as methanol, ethanol and isopropanol, and solvents such as THF, dioxane, DMSO or DMF (dimethylformamide), iron chloride, nickel chloride, cobalt chloride, zinc chloride, nickel acetate , Sodium hypophosphite, sodium hydride, sodium borohydride, diisopropylaluminum hydride, sodium cyanoborohydride in the presence of a metal catalyst such as palladium carbon
  • a metal catalyst such as palladium carbon
  • the 3- (3-quinolyl) propionic acid derivative represented by the above general formula (II) The compound is prepared by converting a 3- (3-quinolyl) acrylic acid derivative represented by the above general formula (ill) into a solvent such as hydrochloric acid or acetic acid, a metal such as Sn, Fe, ⁇ , or a neutral compound. conditions, Ri by the exerting a metal M g, or base under conditions that Njiru groups are not eliminated, can be obtained even if particular cowpea performing catalytic hydrogenation reduction.
  • the 3- (3-quinolyl) propionic acid derivative represented by the general formula (II) is a derivative of the 3- (3-quinolyl) acrylic acid derivative represented by the general formula (ill). It can also be obtained by converting the chlorine atom at the 2-position to another substituent such as a bromine atom or an iodine atom, and then applying the above-described reduction reaction.
  • the 3- (3-quinolyl) acrylic acid derivative represented by the general formula (ill) is obtained by adding THF, DMS ⁇ , DMF, dioxane to the 3-quinolinecarbaldehyde derivative represented by the general formula (IV). Or, in a solvent such as 1,2-dimethoxane or the like, in the presence of a base such as sodium hydride, alkyl lithium or sodium methoxide, and a dihydroquinone such as methyl dimethyl acetate. (Wittig) can be obtained by acting a reagent.
  • the 3-quinolinecarbaldehyde derivative represented by the general formula (IV) is represented by the following general formula (XI): Can be obtained by allowing phosphorus oxychloride and DMF to act on the acetoanilide derivative represented by
  • a method for obtaining the 3-aminoquinoline derivative represented by the general formula (V) from the 3-quinolincarpoxamide derivative represented by the general formula (VI) is a method for dissolving dioxane, water, or the like.
  • sodium hydroxide, hydroxide hydroxide, barium hydroxide, sodium methoxide, sodium hydroxide are added to the 3—quinolinecarboxamide derivative represented by the general formula (vi).
  • halogens such as bromine and chlorine
  • sodium hypobromite, hypohalites such as sodium hypochlorite, or hypobromite
  • hypohalous acid such as chlorous acid.
  • the method for obtaining a 2-halo-3- (3-quinolyl) propionic acid derivative represented by the general formula (I) from a 3-aminoquinoline derivative represented by the general formula (V) is represented by the general formula (V)
  • a hydrohalic acid such as aqueous hydrogen bromide or concentrated hydrochloric acid
  • the reaction is carried out by diazotizing by reacting with um, and then reacting the alkyl acrylate in the presence of a copper catalyst (cuprous oxide, cuprous chloride).
  • the 3-quinolinecarboxamide derivative represented by the general formula (VI) can be obtained by the following synthesis route.
  • the 3-quinolinitritol derivative of the general formula (VIII) is heated with a base such as sodium hydroxide or sodium hydroxide under heating (preferably, the reaction is carried out by heating to reflux) or subjecting to a hydrolysis reaction.
  • a base such as sodium hydroxide or sodium hydroxide under heating
  • a 3-quinolinitrile derivative of the formula (X) and a benzyl halide such as benzyl chloride are heated (preferably). Or under reflux with heating).
  • Methyl 3- (7-benzyloxy-3-3-quinolyl) propionate Methyl 3- (7-benzyloxy-2-chloro-3-quinolinyl) acrylate obtained in Example 2 (180 mg, 0.1 mg).
  • 51 mmol) and nickel chloride hexahydrate (24 mg, 0.1 mmol) are suspended in a mixed solvent of dimethylformamide / methanol (1.5 mL / 1.5 mL). Then, the mixture was cooled on ice to keep the internal temperature at 10 ° C or less.
  • sodium borohydride (10 O mg, 2.64 mmol) was slowly added over 10 minutes. After stirring for 3 hours under the same conditions, the mixture was returned to room temperature and stirred for 10 hours.
  • 3,3-Dimethoxypropionitrile (91% content, 12.7, 0.10 mo1) was dissolved in toluene (60 mL), and sodium methoxide (6.48) was dissolved. g, 0.12 m 01), and then methyl formate (12.3 mL, 0.20 m 01) was added dropwise while maintaining the internal temperature at 30 to 35 ° C. After the addition was completed, the mixture was further stirred at room temperature for 22 hours. Next, a mixture of concentrated hydrochloric acid (26.7 mL, 0, 32 mol) and methanol (30 mL) was added dropwise over 5 minutes under ice cooling, and the temperature was returned to room temperature for 30 minutes. Stirred.
  • 3-Amino 7-benzyloxyquinoline (2.3 g, 9.2 mimol) was dissolved in a mixed solvent of acetate and water (25 mL / 6 mL). After that, concentrated hydrochloric acid (2. 5 mL) was added. After the reaction temperature was lowered to 5 ° C. or lower, an aqueous solution of sodium nitrite (833 mg (12 mmol) /1.6 mL) was added over 5 minutes. After maintaining the reaction temperature at 5 ° C and stirring for 20 minutes, methyl acrylate (6 mL, 67.5 millimol) was added over 5 minutes. Then, cuprous oxide (120 mg) was slowly added, and the reaction temperature was increased to 37 ° C, followed by vigorous stirring under the same conditions for 1 hour.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention concerne un procédé d'obtention d'alkyl 3-(7-benzyloxy-3-quinolyl)-2-halopropionates convenant comme intermédiaires pour la synthèse de 5-[(7-benzyloxy-3-quinolyl)méthyl]-2.4-thiazolidinedione ayant un effet hyperglycémique, qui consiste à utiliser 7-benzyloxy-2-halo-3-quinolinecarbaldéhyde ou 7-hydroxy-3-quinolinenitrile comme matériau de départ.
PCT/JP2000/002001 1999-05-28 2000-03-30 Procede d'obtention de derives 2-halo-3-(3-quinolyl) acide proprionique WO2000073273A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34551/00A AU3455100A (en) 1999-05-28 2000-03-30 Process for the preparation of 2-halo-3-(3-quinolyl)propionic acid derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP14895699 1999-05-28
JP11/148957 1999-05-28
JP14895799 1999-05-28
JP11/148956 1999-05-28

Publications (1)

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WO2000073273A1 true WO2000073273A1 (fr) 2000-12-07

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06145146A (ja) * 1992-11-06 1994-05-24 Chisso Corp オキシネイト誘導体
EP0787725A1 (fr) * 1994-10-20 1997-08-06 Nippon Chemiphar Co., Ltd. Derive de quinoline
WO1998020871A1 (fr) * 1996-11-08 1998-05-22 Nippon Chemiphar Co., Ltd. Agent diminuant la graisse viscerale
WO1998028254A1 (fr) * 1996-12-24 1998-07-02 Nippon Chemiphar Co., Ltd. Derives d'acide propionique
WO1998028305A1 (fr) * 1996-12-20 1998-07-02 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Nouveaux analogues de la camptothecine, leur application comme medicaments et les compositions pharmaceutiques les contenant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06145146A (ja) * 1992-11-06 1994-05-24 Chisso Corp オキシネイト誘導体
EP0787725A1 (fr) * 1994-10-20 1997-08-06 Nippon Chemiphar Co., Ltd. Derive de quinoline
WO1998020871A1 (fr) * 1996-11-08 1998-05-22 Nippon Chemiphar Co., Ltd. Agent diminuant la graisse viscerale
WO1998028305A1 (fr) * 1996-12-20 1998-07-02 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Nouveaux analogues de la camptothecine, leur application comme medicaments et les compositions pharmaceutiques les contenant
WO1998028254A1 (fr) * 1996-12-24 1998-07-02 Nippon Chemiphar Co., Ltd. Derives d'acide propionique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 66, 1967, Columbus, Ohio, US; abstract no. 55355N, ZYMALKOWSKI,F.: "Quinolines,IsoQuinolines,and other 6-Membered rings" page 5223; XP002929656 *
LIEBIGS ANN. CHEM, vol. 699, 1966, pages 98 - 106 *

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