EP0000009B1 - Verfahren zur Oxydation von Chinin zu Chininone und Chinidinone. - Google Patents

Verfahren zur Oxydation von Chinin zu Chininone und Chinidinone. Download PDF

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Publication number
EP0000009B1
EP0000009B1 EP78400019A EP78400019A EP0000009B1 EP 0000009 B1 EP0000009 B1 EP 0000009B1 EP 78400019 A EP78400019 A EP 78400019A EP 78400019 A EP78400019 A EP 78400019A EP 0000009 B1 EP0000009 B1 EP 0000009B1
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EP
European Patent Office
Prior art keywords
quininone
quinidinone
quinine
solution
oxidation
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.)
Expired
Application number
EP78400019A
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English (en)
French (fr)
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EP0000009A1 (de
Inventor
Jacques Bourrelly
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.)
Devinter Sa
Original Assignee
Devinter Sa
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Filing date
Publication date
Application filed by Devinter Sa filed Critical Devinter Sa
Publication of EP0000009A1 publication Critical patent/EP0000009A1/de
Application granted granted Critical
Publication of EP0000009B1 publication Critical patent/EP0000009B1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine

Definitions

  • the present invention relates to an oxidation process of the Oppenauer type with a new reagent and its application to the manufacture of quininone and quinidinone, intermediates for the synthesis of quinidine.
  • the quininone and quinidinone differentiated by the asymmetric carbon isomerism at C s of the quinuclidine nucleus are generally two forms in equilibrium, which explains the phenomena of mutarotation in solution hitherto observed.
  • the quininone formed is found in the presence of variable amounts of impurities, mainly: quinine, quinidine, epiquinine, epiquinidine, quinicine (quinotoxin ), which has the effect of reducing the reaction yield, the by-products formed having to be separated and purified before being recycled (it is noted in particular that the presence - even in small proportions - of epibases considerably reduces the crystallization yields of quinine and quinidine from their saturated solutions.
  • impurities mainly: quinine, quinidine, epiquinine, epiquinidine, quinicine (quinotoxin )
  • the reaction being carried out in enolic form it is necessary to introduce a base of PK sufficient to enolate all of the ketone forms contributing to the reaction.
  • a base of PK sufficient to enolate all of the ketone forms contributing to the reaction.
  • An amount of 2 to 7 equivalent moles has proved necessary in the various experiments described in the literature.
  • the bases used, because of their PKI are the alcoholates, and mainly the sodium, potassium and aluminum alcoholates, methyl, ethyl, isopropyl and tert-butyl alcohols.
  • the object of the invention is mainly to use a base having the ideal characteristics PK and compatibility which is an "in situ" derivative of the ketone used as proton acceptor.
  • Ketyls are prepared by simple addition of the alkali metal to a solution of ketone in an appropriate aromatic solvent.
  • a “Ketyl” obtained by interaction of an alkali metal with a diphenylketone, more particularly with benzophenone or fluorenone, will therefore be used as the quinine oxidant.
  • the reaction of quinine and "Ketyl” is carried out in a solvent medium; said solvent is selected from aromatic hydrocarbons, C 6 -C 9 saturated cyclic hydrocarbons, C 6 -C 9 or aliphatic hydrocarbons corresponding to naphtha or gas oil cuts.
  • the xylene solution is treated with water (20 ml), then extracted with 100 ml of sulfuric acid diluted to 20%.
  • the cold sulfuric solution is neutralized by adding ammonia.
  • the crystals that form are composed of quinidinone; as quininone and quinidinone are in equilibrium in the oil obtained, the precipitation of quinidinone has the consequence of shifting said equilibrium towards the production of quinidinone.
  • the cold sulfuric solution is neutralized by adding ammonia. Decanting oil. It is separated and crystallized by seeding and appropriate treatment.
  • the mixed solutions are kept at reflux for 5 hours.
  • a “Ketyl” fluorenone solution is produced from 9 g of fluorenone in anhydrous toluene.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Quinoline Compounds (AREA)

Claims (3)

1. Verfahren zur Oxydierung von Chinin zu Chininon und Chinidinon mittels einer Oxydierungsreaktion nach Oppenauer, dadurch gekennzeichnet, dass die genannte Reaktion mit Hilfe eines basischen Reagens, des sogenannten "Ketyl" durchgeführt wird, das aus der unmittelbaren Wirkung eines Alkalimetalls in einem Lösungsmittel auf ein Diphenylketon entsteht.
2. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass das Diphenylketon unter Benzophenonen und Fluorenonen gewählt wird.
3. Verfahren gemäss einem der Ansprüche 1 und 2, dadurch gekennzeichnet, dass das für die Herstellung von "Ketyl" verwendete Lösungsmittel unter aromatischen Kohlenwasserstoffen mit 6 bis 9 Kohlenstoffatomen, gesättigten ringförmigen Kohlenwasserstoffen mit 6 bis 9 Kohlenstoffatomen und aliphatischen Kohlenwasserstoffen gewählt wird, die Naphthaschnitten und Gasöl ensprechen.
EP78400019A 1977-06-15 1978-06-14 Verfahren zur Oxydation von Chinin zu Chininone und Chinidinone. Expired EP0000009B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7718398A FR2394545A1 (fr) 1977-06-15 1977-06-15 Procede de fabrication de quininone et de quinidinone, intermediaires de synthese de la quinidine
FR7718398 1977-06-15

Publications (2)

Publication Number Publication Date
EP0000009A1 EP0000009A1 (de) 1978-12-20
EP0000009B1 true EP0000009B1 (de) 1980-07-23

Family

ID=9192140

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78400019A Expired EP0000009B1 (de) 1977-06-15 1978-06-14 Verfahren zur Oxydation von Chinin zu Chininone und Chinidinone.

Country Status (4)

Country Link
EP (1) EP0000009B1 (de)
DE (1) DE2860032D1 (de)
FR (1) FR2394545A1 (de)
IE (1) IE46935B1 (de)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1165604B (de) * 1957-12-18 1964-03-19 Chininfabrik Braunschweig Buch Verfahren zur sterischen Umlagerung von Chinaalkaloiden
FR2332279A1 (fr) * 1975-11-19 1977-06-17 Nativelle Sa Ets Procede d'oxydation des alcaloides du quinquina
FR2332278A1 (fr) * 1975-11-19 1977-06-17 Nativelle Sa Ets Procede de transformation stereochimique des alcaloides du quinquina

Also Published As

Publication number Publication date
IE46935B1 (en) 1983-11-02
FR2394545A1 (fr) 1979-01-12
IE781204L (en) 1978-12-15
EP0000009A1 (de) 1978-12-20
DE2860032D1 (en) 1980-11-13

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