EP0000679A1 - Verfahren zur Herstellung von Glafenin - Google Patents

Verfahren zur Herstellung von Glafenin Download PDF

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Publication number
EP0000679A1
EP0000679A1 EP78400060A EP78400060A EP0000679A1 EP 0000679 A1 EP0000679 A1 EP 0000679A1 EP 78400060 A EP78400060 A EP 78400060A EP 78400060 A EP78400060 A EP 78400060A EP 0000679 A1 EP0000679 A1 EP 0000679A1
Authority
EP
European Patent Office
Prior art keywords
quinoline
glycerol
glyceryl
anthranilate
glafenine
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
EP78400060A
Other languages
English (en)
French (fr)
Other versions
EP0000679B1 (de
Inventor
Sylvano Casadio
Henri Dr. Cousse
Pierre Hascoet
Gilbert Dr. Mouzin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pierre Fabre SA
Original Assignee
Pierre Fabre SA
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 Pierre Fabre SA filed Critical Pierre Fabre SA
Publication of EP0000679A1 publication Critical patent/EP0000679A1/de
Application granted granted Critical
Publication of EP0000679B1 publication Critical patent/EP0000679B1/de
Expired legal-status Critical Current

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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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms

Definitions

  • the present invention carried out at the Pierre FABRE Research Center relates to a new process for the preparation of the ⁇ -monoglyceride of 4 (2'-carboxyphenylamino) -7-chloro-quinoline of formula:
  • This chemical compound is known for its analgesic properties; it is used as an active ingredient in many pharmaceutical specialties. This molecule will be mentioned below by its international common name glafenine.
  • Glafenine (I) is prepared by condensation in hydrochloric medium of 4,7-dichloro-quinoline (II) with methyl anthranilate (III), this intermediate methyl ester is then transesterified by glycerol acetonide (V) and finally acid hydrolysis of compound (VI) leads to glafenine (I) according to the reaction scheme:
  • the present invention relates to a very simple process which makes it possible to prepare glafenine under very economical conditions.
  • glafenine is prepared by condensation of the glyceryl anthranilate of formula: on 4,7-dichloro-quinoline:
  • This condensation is preferably carried out in a hydrochloric medium.
  • the glafenine obtained is separated from the reaction medium by known methods, it can in particular be precipitated by neutralization of the reaction medium.
  • the crude glafenine obtained can be purified for example by recrystallization from a solvent or mixture of organic solvent such as the chloroform-ethanol mixture.
  • the glyceryl anthranilate is preferably prepared by condensation of glycerol on isatoic anhydride in basic medium as a condensing agent.
  • This process is preferably carried out using an excess of glycerol as solvent, so the glyceryl anthranilate is obtained in solution in glycerol and this solution can be used in the process according to the present invention without having to isolate the anthranilate, which further improves the overall yield of the process.
  • This process for the preparation of glafenine has the advantage of using only products widely available commercially and inexpensively.
  • isatoic anhydride which is experiencing industrial development as a synthesis intermediary in the dye industry can, thanks to new synthesis processes, be obtained at prices much lower than the prices of anthranilic acid which constitutes the basic product in known syntheses of glafenine.
  • this synthetic method makes it possible to significantly increase the yields of glafenine compared to known methods, in particular by limiting the number of reaction steps.
  • reaction medium is then cooled to 20 ° C. and transferred to a 200 l tank in which it is treated slowly with 60 l of an aqueous sodium hydroxide solution N, then the neutralization is completed by adding sodium bicarbonate.
  • the precipitate is separated as previously by wringing; the crude glafenine thus obtained has, after drying, a melting point of 163 ° C.
  • glafenine is obtained with a yield varying according to the case from 65 to 75% compared to 4,7-dichloro-quinoline with an instant melting point at the Kofler block of 169-170 ° C.
  • the residual chloroform content is less than 1,000 ppm.
  • the present invention also relates, as a medicament, to glafenin obtained by implementing the method according to the present invention.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)
EP78400060A 1977-07-26 1978-07-18 Verfahren zur Herstellung von Glafenin Expired EP0000679B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7722900 1977-07-26
FR7722900A FR2398733A1 (fr) 1977-07-26 1977-07-26 Nouveau procede de preparation de la glafenine

Publications (2)

Publication Number Publication Date
EP0000679A1 true EP0000679A1 (de) 1979-02-07
EP0000679B1 EP0000679B1 (de) 1981-06-24

Family

ID=9193813

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78400060A Expired EP0000679B1 (de) 1977-07-26 1978-07-18 Verfahren zur Herstellung von Glafenin

Country Status (7)

Country Link
EP (1) EP0000679B1 (de)
JP (1) JPS5424881A (de)
CA (1) CA1107737A (de)
DE (1) DE2860803D1 (de)
ES (1) ES472072A1 (de)
FR (1) FR2398733A1 (de)
IT (1) IT1156878B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2549830A1 (fr) * 1983-07-25 1985-02-01 Corbiere Jerome Nouveau procede d'obtention de quinoleines substituees

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHIMIE THERAPEUTIQUE, 1, 65-70 (1966) *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2549830A1 (fr) * 1983-07-25 1985-02-01 Corbiere Jerome Nouveau procede d'obtention de quinoleines substituees

Also Published As

Publication number Publication date
CA1107737A (fr) 1981-08-25
FR2398733A1 (fr) 1979-02-23
EP0000679B1 (de) 1981-06-24
IT1156878B (it) 1987-02-04
FR2398733B1 (de) 1980-02-29
DE2860803D1 (en) 1981-10-01
ES472072A1 (es) 1979-03-16
IT7850438A0 (it) 1978-07-24
JPS5424881A (en) 1979-02-24

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