EP0000302B1 - Verfahren zur Herstellung von Chinidin - Google Patents

Verfahren zur Herstellung von Chinidin Download PDF

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Publication number
EP0000302B1
EP0000302B1 EP19780400020 EP78400020A EP0000302B1 EP 0000302 B1 EP0000302 B1 EP 0000302B1 EP 19780400020 EP19780400020 EP 19780400020 EP 78400020 A EP78400020 A EP 78400020A EP 0000302 B1 EP0000302 B1 EP 0000302B1
Authority
EP
European Patent Office
Prior art keywords
quinidine
process according
quinidinone
quinine
anyone
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
EP19780400020
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English (en)
French (fr)
Other versions
EP0000302A1 (de
Inventor
Jacques Bourrely
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
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
Priority claimed from FR7718397A external-priority patent/FR2394544A1/fr
Priority claimed from FR7718398A external-priority patent/FR2394545A1/fr
Application filed by Devinter Sa filed Critical Devinter Sa
Publication of EP0000302A1 publication Critical patent/EP0000302A1/de
Application granted granted Critical
Publication of EP0000302B1 publication Critical patent/EP0000302B1/de
Expired legal-status Critical Current

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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 a new process for the preparation of quinidine, a process involving in particular the stereospecific reduction of quinidinone to quinidine.
  • Quinidine has been prepared for many years by hemisynthesis from quinine.
  • the main quinidine manufacturing processes have thus achieved transformation coefficients which are only exceptionally less than 1.20 to 1.25 kg of quinine base anhydrous committed for 1 kg of quinidine based anhydrous isolated.
  • the volume of reactors required and the labor load are greater than in the case of a quantitative synthesis without recycling of raw material.
  • composition of the by-products is in equal parts: quinine, epiquinine and epiquinidine, i.e. 25% of epibases which cannot be recovered per operation, which is totally incompatible with a profitable production economy. Having resumed this work, an attempt was made to make these reductions at low temperature, but the improvement in efficiency observed does not balance the cost necessary for producing cold.
  • DIBAH diisobutylaluminum hydride
  • the reducing agent used in the present invention is an aluminum hydride, more particularly an alkylaluminum hydride or an aluminum-sodium hydride, more particularly an alkylaluminum-sadium hydride.
  • the heterocyclic organic base which can be used in the present invention is preferably pyridine or pyrrole, the carbon atoms of these heterocyclic molecules possibly comprising one or more alkyl substituents.
  • the amounts of cyclic organic base to be used are such that the concentration of said base in the solution where the reaction takes place is between 0.5 and 100 °%.
  • the reduction takes place in a solvent such as an organic solvent, benzene, toluene, xylene or an ether such as tetrahydrofuran, dioxane or dibutyl ether.
  • a solvent such as an organic solvent, benzene, toluene, xylene or an ether such as tetrahydrofuran, dioxane or dibutyl ether.
  • quinidinone does not generally constitute the basic product from which the semi-synthesis of quinidine is carried out; this basic product is generally quinine. It is therefore first of all necessary to transform the quinine base into quinidinone with the best possible yield. It is possible according to the invention to use any process for preparing quinidinone from quinine base; it is however desirable that the process which will be used makes it possible to obtain a pure quinidinone.
  • the preferred method for obtaining pure quinidinone which can be used as a reagent in the reduction reaction described above consists, starting from quinine base and carrying out on this quinine, an oxidation reaction of Oppenhauer type using a basic reagent resulting from the reaction of a diphenylketone on an alkali metal.
  • benzophenone or fluorenone will preferably be used; as the alkali metal, sodium or potassium will for example be used.
  • the basic reagent is itself prepared by the action of the alkali metal on the chosen ketone in a solvent medium which is preferably an aromatic medium.
  • quinine is oxidized almost quantitatively to quininone and quinidinone and the separation by crystallization of quinidinone from the mixture obtained makes it possible to shift the balance of the medium towards the preparation of quinidinone.
  • Examples 1 to 5 relate to the process for the reduction of quinidinone to quinidine and Example 6 to the preferred improved process for the preparation of quinidinone from quinine:
  • Distillation is carried out with fractionation (25 mm Hg) to remove the THF at the top with a minimum amount of toluene.
  • the crystals are filtered and re-extracted with toluene at 80 ° C.
  • the pyridine is removed under vacuum.
  • Example 5 was repeated, but using, in place of y picoline, 200 ml of 3-methylpyrrole.
  • the xylene solution is treated with water (20 ml) and then extracted with 100 ml of sulfuric acid diluted to 20%.
  • the cold sulfuric solution is neutralized by adding ammonia.
  • the quinidinone crystals are separated from the mixture.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (8)

1. Verfahren zur Herstellung von Chinidin aus Chinin durch Oxydierung und Reduktion des gebildeten Chinidinons, dadurch gekennzeichnet, dass die Reduktion dank der Wirkung eines Aluminium-Hydrids in Gegenwart einer organischen heterozyklischen Base durchgeführt wird, welche in dem genannten Heterozyklus ein basisches Stickstoffatom enthält.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass das Aluminium-Hydrid unter den Alkylaluminium-Hydriden, insbesondere den Dialkylaluminium-Hydriden und den Natrium-Alkylaluminium-Hydriden gewählt wird.
3. Verfahren nach einem der Ansprüche 1 und 2, dadurch gekennzeichnet, dass die genannte heterozyklische Base unter Pyridin, Pyrrol und ihren verschiedenen Derivaten gewählt wird, die auf Kohlenstoffatomen alkylsubstituiert sind.
4. Verfahren nach einem der Ansprüche 2 und 3, dadurch gekennzeichnet, dass das Aluminium-Hydrid das Diisobutylaluminium-Hydrid ist.
5. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass die genannte Base das Pyridin ist und dass sie als Konzentration von mehr als 0,5% benutzt wird.
6. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass das Hydrid in Form einer Lösung in einem aromatischen Lösungsmittel oder in einem Äther, zum Beispiel Tetrahydrofuran, Dioxan und Dibutyläther, benutzt wird.
7. Verfahren nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass das Chinidinon in Form einer Lösung dieses Moleküls in einem Lösungsmittel benutzt wird, das unter Pyridin und den Mischungen von Pyridin mit einem Äther, wie Tetrahydrofuran, Dioxan und den Dialkyläthern gewählt wird.
8. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass das Ausgangs-Chinidinon durch eine Oxydierungsreaktion des Chinins vom Typ Oppenhauer erhalten wird, mittels eines aus der Reaktion eines Diphenylketons, wie zum Beispiel Benzophenon und Fluorenon, mit einem Alkylmetallentstehenden Reagens.
EP19780400020 1977-06-15 1978-06-14 Verfahren zur Herstellung von Chinidin Expired EP0000302B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FR7718397A FR2394544A1 (fr) 1977-06-15 1977-06-15 Procede de reduction stereospecifique de la quinidinone en quinidine
FR7718397 1977-06-15
FR7718398 1977-06-15
FR7718398A FR2394545A1 (fr) 1977-06-15 1977-06-15 Procede de fabrication de quininone et de quinidinone, intermediaires de synthese de la quinidine

Publications (2)

Publication Number Publication Date
EP0000302A1 EP0000302A1 (de) 1979-01-10
EP0000302B1 true EP0000302B1 (de) 1980-10-01

Family

ID=26220080

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19780400020 Expired EP0000302B1 (de) 1977-06-15 1978-06-14 Verfahren zur Herstellung von Chinidin

Country Status (3)

Country Link
EP (1) EP0000302B1 (de)
DE (1) DE2860188D1 (de)
IE (1) IE46996B1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1240167A1 (de) * 1999-12-23 2002-09-18 Academic Pharmaceuticals, Inc. Optisch aktive isomere von quinin und quinidin und deren biologische wirkung

Family Cites Families (4)

* 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
CH590274A5 (de) * 1970-03-16 1977-07-29 Hoffmann La Roche
FR2332278A1 (fr) * 1975-11-19 1977-06-17 Nativelle Sa Ets Procede de transformation stereochimique des alcaloides du quinquina
FR2332279A1 (fr) * 1975-11-19 1977-06-17 Nativelle Sa Ets Procede d'oxydation des alcaloides du quinquina

Also Published As

Publication number Publication date
IE46996B1 (en) 1983-11-30
DE2860188D1 (en) 1981-01-08
EP0000302A1 (de) 1979-01-10
IE781203L (en) 1978-12-15

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