WO2001066549A1 - Composes intermediaires - Google Patents

Composes intermediaires Download PDF

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Publication number
WO2001066549A1
WO2001066549A1 PCT/JP2001/001671 JP0101671W WO0166549A1 WO 2001066549 A1 WO2001066549 A1 WO 2001066549A1 JP 0101671 W JP0101671 W JP 0101671W WO 0166549 A1 WO0166549 A1 WO 0166549A1
Authority
WO
WIPO (PCT)
Prior art keywords
methoxy
formyl
general formula
chloride
production
Prior art date
Application number
PCT/JP2001/001671
Other languages
English (en)
Japanese (ja)
Inventor
Michiro Ohnoda
Junichiro Uda
Yasumasa Iwai
Takahiro Tanase
Original Assignee
Kyorin Pharmaceutical 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 Kyorin Pharmaceutical Co., Ltd. filed Critical Kyorin Pharmaceutical Co., Ltd.
Priority to AU2001236079A priority Critical patent/AU2001236079A1/en
Publication of WO2001066549A1 publication Critical patent/WO2001066549A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • 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
    • C07C67/313—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 doubly bound oxygen containing functional groups, e.g. carboxyl groups

Definitions

  • the present invention relates to a novel 4-methoxy-3-alkoxycarbonylphenylmethyl which is a production intermediate for producing a ⁇ ⁇ ⁇ ⁇ -benzyldioxothiazolidinylmethylbenzamide derivative useful for the treatment of diabetes and hyperlipidemia.
  • the present invention relates to a derivative hexamethylenetetraminium chloride, a method for producing the same, and uses thereof.
  • a ⁇ ⁇ ⁇ ⁇ -benzyldioxothiazolidinylmethylbenzamide derivative is known as a compound having an excellent hypoglycemic and hypolipidemic action (JP-A-9-48771).
  • ( ⁇ ) — 5— [(2,4 dioxothiazolidine-1-yl) methyl] — 2-methoxy ⁇ — [[4- (trifluoromethyl) phenyl] methyl] benzamide ( KR ⁇ -297) has been developed as a promising drug ( ⁇ . Nomura, et al., Bioorg. Med. Chem. Lett. 1999, 53.3). .
  • 5-formyl-12-methoxybenzoate is used as a starting material.
  • 5-Formyl-12-methoxybenzoic acid esters are known compounds, but no industrially advantageous production method capable of supplying them inexpensively and in large quantities has not been known. It is known that 5-formyl-2-methyl benzoate can be obtained, for example, by the following method.
  • the present invention provides a compound represented by the general formula (2):
  • R represents a lower alkyl group
  • the production process of the present invention adapts the so-called Somme 1 et reaction.
  • the compound of the general formula (1) is novel, has not been used for the production of 5-formyl-12-methoxybenzoate, and its industrial utility has not been known.
  • 5-formyl-l-2 is obtained by using hexamethylenetetramine chloride of a 4-methoxy-13-alkoxycarbonylphenylmethyl derivative represented by the general formula (1) as a production intermediate.
  • N-benzyldioxothiazo which is industrially advantageous for producing methoxybenzoic acid esters and is therefore promising for the treatment of diabetes and hyperlipidemia.
  • a lysinylmethylbenzamide derivative can be produced industrially advantageously.
  • the lower alkyl group in the present invention is a methyl group, an ethyl group or a propyl group, and is preferably a methyl group.
  • the compound of the general formula (1) is obtained as follows. That is, the public knowledge (R. Jot et al., Bull. Soc. Chem. Fr. _
  • the compound of the general formula (2) which is easily synthesized by a known method is dissolved in an organic solvent, and commercially available hexamethylenetetramamine is added thereto with stirring. After cooling with heating and stirring, it can be taken out as crystals.
  • the organic solvent 1 to 2 times the amount of ethyl acetate or toluene is used, and in this case, about 1/2 times the amount of alkanols such as isopropanol is added to form a mixed solvent. It is preferable to use them.
  • the amount of hexanemethylentramine used in the reaction is preferably from 1 to 1.2 equivalents of the compound of the general formula (2).
  • the heating and stirring are performed at a temperature of from the boiling point of the solvent to 100 ° C. for 2 to 5 hours.
  • the precipitated crystals are collected by filtration, washed with an organic solvent, and dried, whereby the compound of the general formula (1) can be obtained with high yield and high purity.
  • the thus-obtained compound of the general formula (1) can be easily converted to 5-formyl-2-methoxybenzoate of the general formula (3) by acid hydrolysis. That is, the compound of the general formula (1) is suspended in a 50% aqueous solution of 50% acetic acid, and the mixture is heated and stirred at 90 ° C to 110 ° C. The hydrolysis reaction is completed in 2-3 hours. Then, the mixture is cooled to room temperature or lower, and the crystals are collected by filtration, washed with water, and dried to obtain 5-formyl-2-methoxybenzoate.
  • the 5-formyl-12-methoxybenzoate obtained by this method contains almost no impurities, so there is no need to recrystallize, etc. Can be used accordingly.
  • reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 16 O mL of toluene.
  • N-benzyldioxothiazo useful for the treatment of diabetes and hyperlipidemia
  • a new 4-methoxy intermediate was used as a new production intermediate in order to produce the starting material 5-formyl-12-methoxybenzoate on an industrial scale.
  • Hexamethylenetetramethyl chloride of a 3-alkoxycarbonylphenylmethyl derivative was found. By further hydrolyzing this, 5-formyl-12-methoxybenzoate could be industrially advantageously produced.
  • N-benzyldioxothiazolidinylmethylbenzamide derivative which is promising for the treatment of diabetes and hyperlipidemia, is manufactured on an industrial scale using 5-formyl-2-methoxybenzoate as a raw material. It became possible to do.

Abstract

Au cours de la production de dérivés de N-benzyldioxothiazolidinylméthyl-benzamide présentant une grande utilité dans le traitement des diabètes et de l'hyperlipidémie, il est nécessaire de développer de nouveaux intermédiaires pour la production à l'échelle industrielle d'esters de 5-formyl-2-méthoxybenzoate. Ces derniers sont utilisés comme produits de départ dans la production de dérivés. L'invention traite aussi de procédés permettant de produire ces esters et leurs intermédiaires. Les recherches ont montré que les chlorures de 4-méthoxy-3-alcoxycarbonylphényl-méthylhéxaméthylènetétraminium représentés par la formule générale (1) (où R est un alkyle inférieur) présentent une grande utilité comme intermédiaires dans la production d'esters de 5-formyl-2-méthoxybenzoate à l'échelle industrielle.
PCT/JP2001/001671 2000-03-07 2001-03-05 Composes intermediaires WO2001066549A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001236079A AU2001236079A1 (en) 2000-03-07 2001-03-05 Intermediate compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000062215 2000-03-07
JP2000-62215 2000-03-07

Publications (1)

Publication Number Publication Date
WO2001066549A1 true WO2001066549A1 (fr) 2001-09-13

Family

ID=18582254

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/001671 WO2001066549A1 (fr) 2000-03-07 2001-03-05 Composes intermediaires

Country Status (2)

Country Link
AU (1) AU2001236079A1 (fr)
WO (1) WO2001066549A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010042704A1 (fr) 2008-10-10 2010-04-15 Meadwestvaco Corporation Système de gestion de vapeur de carburant à fragmentation proportionnée de l'écoulement

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5259198A (en) * 1975-11-11 1977-05-16 Ici Ltd Production of quartanary ammonium salt
JPS5690031A (en) * 1979-12-21 1981-07-21 Sumitomo Chem Co Ltd Preparation of aromatic aldehyde
JPS62155236A (ja) * 1985-12-27 1987-07-10 Seitetsu Kagaku Co Ltd ヒドロキシベンズフルデヒドの製造法
JPH01316363A (ja) * 1988-03-03 1989-12-21 Toyama Chem Co Ltd ピペラジン誘導体およびその塩
JPH0948771A (ja) * 1995-06-02 1997-02-18 Kyorin Pharmaceut Co Ltd Ｎ−ベンジルジオキソチアゾリジルベンズアミド誘導体及びその製造法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5259198A (en) * 1975-11-11 1977-05-16 Ici Ltd Production of quartanary ammonium salt
JPS5690031A (en) * 1979-12-21 1981-07-21 Sumitomo Chem Co Ltd Preparation of aromatic aldehyde
JPS62155236A (ja) * 1985-12-27 1987-07-10 Seitetsu Kagaku Co Ltd ヒドロキシベンズフルデヒドの製造法
JPH01316363A (ja) * 1988-03-03 1989-12-21 Toyama Chem Co Ltd ピペラジン誘導体およびその塩
JPH0948771A (ja) * 1995-06-02 1997-02-18 Kyorin Pharmaceut Co Ltd Ｎ−ベンジルジオキソチアゾリジルベンズアミド誘導体及びその製造法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010042704A1 (fr) 2008-10-10 2010-04-15 Meadwestvaco Corporation Système de gestion de vapeur de carburant à fragmentation proportionnée de l'écoulement

Also Published As

Publication number Publication date
AU2001236079A1 (en) 2001-09-17

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