EP0000302B1 - Novel method for the preparation of quinidine. - Google Patents
Novel method for the preparation of quinidine. Download PDFInfo
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- 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
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- Prior art keywords
- quinidine
- process according
- quinidinone
- quinine
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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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- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
La présente invention se rapporte à un nouveau procédé de préparation de la quinidine, procédé impliquant notamment la réduction stéréospécifique de la quinidinone en quinidine.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.
La quinidine a été préparée depuis de nombreuses années par hémisynthèse à partir de la quinine.Quinidine has been prepared for many years by hemisynthesis from quinine.
En effet, cet alcaloïde naturel du quinquina très utile dans le traitement des maladies cardiaques. (comme anti-arrythmique n'est pas présent en quantité suffisante dans les écorces de quinquina pour assurer les besoins de l'industrie pharmaceutique.Indeed, this natural cinchona alkaloid very useful in the treatment of heart disease. (as anti-arrhythmic is not present in sufficient quantity in cinchona bark to meet the needs of the pharmaceutical industry.
Tous les procédés utilisés pour effecter l'hémisynthèse de la quinidine à partir de produits naturels sont des variations des réactions d'équilibres d'oxydo-réduction (oxydation d'OPPENHAUER - réduction de MEERWEIN-PONDORFF) (brevet allemand n° 883.154 (1953), n° 877.611 (1953).All the processes used to effect the hemisynthesis of quinidine from natural products are variations of the oxidation-reduction equilibrium reactions (oxidation of OPPENHAUER - reduction of MEERWEIN-PONDORFF) (German patent n ° 883.154 (1953 ), no.877.611 (1953).
En effet, en présence d'une cétone convenablement choisie (possédant un potentiel d'oxydation suffisant et une configuration moléculaire compatible avec les constantes d'encombrement stérique de la quinine et de quinidine), il s'établit un équilibre du type représenté sur la figure 1.Indeed, in the presence of a suitably chosen ketone (having a sufficient oxidation potential and a molecular configuration compatible with the constants of steric hindrance of quinine and quinidine), an equilibrium of the type shown on the figure 1.
La figure 1 montre clairement qu'un produit de départ unique se trouve dans les conditions de l'équilibre, en présence de 4 produits principaux de réaction:
- la quinine et son isomère en C9 épiquinine
- la quinidine et son isomère en Cµ épiquinidine
puis les intermédiaires de forme cétone en Cµ - . quininone et quinidinone
qui, en solution, sont en équilibre passant par un état transitoire commun.
- quinine and its C 9 epiquinine isomer
- quinidine and its C µ epiquinidine isomer
then the ketone intermediates in C µ - . quininone and quinidinone
which, in solution, are in equilibrium passing through a common transient state.
Le problème posé par cette hémisynthèse s'appréhende aisément: comment orienter l'équilibre vers la formation du produit désiré, à savoir la quinidine, tout en évitant surtout la formation de l'épiquinine et l'épiquinidine. Ces produits fatals sans utilisation thérapeutique ne peuvent pas, comme la quinine, être recyclés dans les conditions de la réaction. En effet, un mélange quinine + épiquinine ne donnera pas le même équilibre - toutes autres conditions étant maintenues égales - que la même quantité de quinine pure.The problem posed by this hemisynthesis is easily grasped: how to direct the balance towards the formation of the desired product, namely quinidine, while above all avoiding the formation of epiquinin and epiquinidine. These fatal products without therapeutic use cannot, like quinine, be recycled under the reaction conditions. Indeed, a quinine + epiquinine mixture will not give the same balance - all other conditions being kept equal - as the same amount of pure quinine.
D'autre part, le présence d'épibases est indésirable dans les sels de quinidine pharmaceutiques et, de plus, la présence de ces isomères, même en faibles quantités, provoque des retards de cristallisation et des chutes de rendement importantes lors de la préparation des différents sels de quinine et de quinidine à partir de leurs solutions saturées.On the other hand, the presence of epibases is undesirable in the pharmaceutical quinidine salts and, moreover, the presence of these isomers, even in small quantities, causes delays in crystallization and significant drops in yield during the preparation of the different quinine and quinidine salts from their saturated solutions.
En se maintenant au maximum à l'écart des conditions de formation des épibases, les principaux procédés de fabrication de quinidine sont ainsi parvenus à des coefficients de transformation qui ne sont qu'exceptionnellement inférieurs à 1,20 à 1,25 kg de quinine base anhydre engagée pour 1 kg de quinidine base anhydre isolée.By keeping as far as possible from the epibase formation conditions, 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.
L'inconvénient majeur de ces synthèses est de nécessiter le recyclage d'environ 40 à 50% de la quinine engagée en des opérations ultérieures.The major drawback of these syntheses is that it requires the recycling of approximately 40 to 50% of the quinine used in subsequent operations.
Même si la mise en réaction et l'obtention d'un équilibre satisfaisant peuvent être simplifiées, le fait de devoir recycler par opération la moitié de la charge de matière première entraîne bien évidemment des charges coûteuses dans les phases ultérieures de traitement des eaux mères, séparation de la quinine non transformée, purification avant remise en réaction.Even if the reaction and obtaining a satisfactory equilibrium can be simplified, the fact of having to recycle by operation half of the charge of raw material obviously leads to costly charges in the subsequent phases of mother liquor treatment, separation of the unprocessed quinine, purification before reacting.
Les frais financiers sont augmentés du fait du financement du ballast de quinine non transformé.Financial costs are increased due to the financing of the unprocessed quinine ballast.
Le volume des réacteurs nécessaires et la charge de main-d'oeuvre sont plus importants que dans le cas d'une synthèse quantitative sans recyclages de matière première.The volume of reactors required and the labor load are greater than in the case of a quantitative synthesis without recycling of raw material.
Récemment, plusieurs groupes de recherches ont utilisé certains hydrures d'aluminium dans la synthèse totale de séries d'alcaloïdes de la famille de la quinine et la quinidine.Recently, several research groups have used certain aluminum hydrides in the total synthesis of series of alkaloids from the quinine and quinidine families.
En particulier, la réduction de la quinidone en quinidine a été décrite à l'aide de l'hydrure de diisobutylaluminium dans le toluène [Grethe, Uskokovic, JACS 93, 5904 (1971)].In particular, the reduction of quinidone to quinidine has been described using diisobutyl aluminum hydride in toluene [Grethe, Uskokovic, JACS 93, 5904 (1971)].
Cependent, l'utilisation seule de ce type de réactif n'est pas suffisante pour rentabiliser une synthèse industrielle; en effet, à côté de la quinidine, on retrouve les sous-produits déjà cités (quinine et épibases) en quantité inacceptable: 35% dans le cas de la référence citée, le rendement réel de quinidine isolée n'étant que de 65%.However, the use of this type of reagent alone is not sufficient to make industrial synthesis profitable; in fact, alongside quinidine, there are the by-products already mentioned (quinine and epibases) in an unacceptable amount: 35% in the case of the cited reference, the actual yield of isolated quinidine being only 65%.
De plus, la composition des sous-produits est en parts égales: la quinine, l'épiquinine et l'épiquinidine, soit 25% d'épibases non récupérables par opération, ce qui est totalement incompatible avec une économie rentable de production. Ayant repris ces travaux, on a tenté d'effectuer ces réductions à basse température, mais l'amélioration de rendement constatée n'équilibre pas le coût nécessaire à la production du froid.In addition, the 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.
La réduction d'une cétone par l'hydrure de diisobutylaluminium (DIBAH) s'effectue selon le schéma réactionnel suivant:
Dans le cas de la quinidine, du fait du carbone asymétrique en Cs, on peut imaginer que:
- - soit deux complexes (11) stables sont susceptibles de se former (l'un correspondant à la forme quinidine, l'autre à la forme épibase),
- - soit lors de l'hydrolyse du complexe un réarrangement peut avoir lieu orientant la formation de l'alcool secondaire (III) vers la forme quinidine ou épibase correspondante.
- - either two stable complexes (11) are capable of forming (one corresponding to the quinidine form, the other to the epibase form),
- - Either during the hydrolysis of the complex a rearrangement can take place directing the formation of secondary alcohol (III) towards the corresponding quinidine or epibase form.
Il a été trouvé de façon très surprenante que, si la réduction de la quinidinone en quinidine, au moyen d'un hydrure d'aluminium ou d'un produit équivalent, était réalisée en présence d'une base organique hétérocyclique comportant un atome d'azote basique dans ledit hétérocycle, la réaction de réduction s'effectuait de façon entièrement stéréospécifique.It has been found very surprisingly that, if the reduction of quinidinone to quinidine, by means of an aluminum hydride or an equivalent product, was carried out in the presence of a heterocyclic organic base comprising an atom of basic nitrogen in said heterocycle, the reduction reaction was carried out entirely stereospecifically.
Le réducteur utilisé dans la présente invention est un hydrure d'aluminium, plus particulièrement un hydrure d'alkylaluminium ou un hydrure d'aluminium-sodium, plus particulièrement un hydrure d'alkylaluminium-sadium.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.
La base organique hétérocyclique utilisable dans la présente invention est de préférence la pyridine ou le pyrrole, les atomes de carbone de ces molécules hétérocycliques pouvant comporter un ou plusieurs substituants alkyles.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.
Les quantités de base organique cyclique à utiliser sont telles que la concentration de ladite base dans la solution où s'effectue la réaction soit comprise entre 0,5 et 100°%.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 °%.
La réduction a lieu dans un solvant tel qu'un solvant organique, le benzène, le toluène, le xylène ou un éther tel que le tétrahydrofuranne, le dioxanne ou le dibutyléther.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.
Mais la quinidinone ne constitue pas généralement le produit de base au départ duquel on effectue la semi-synthèse de la quinidine; ce produit de base est généralement la quinine. Il convient donc tout d'abord de transformer la quinine base en quinidinone avec le meilleur rendement possible. Il est possible selon l'invention d'utiliser n'importe quel procédé pour préparer la quinidinone à partir de la quinine base; il est cependant souhaitable que le procédé qui sera utilisé permette l'obtention d'une quinidinone pure.However, 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.
Le procédé préféré pour obtenir la quinidinone pure utilisable comme réactif dans la réaction de réduction décrite précédemment consiste, à partir de la quinine base et à réaliser sur cette quinine, une réaction d'oxydation de type Oppenhauer au moyen d'un réactif basique résultant de la réaction d'une diphénylcétone sur un métal alcalin.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.
Comme diphénylcétone, on emploiera de préférence la benzophénone ou la fluorénone; comme métal alcalin, on utilisera par exemple du sodium ou du potassium. Le réactif basique est lui-même préparé par action du métal alcalin sur la cétone choisie en un milieu solvant qui est de préférence un milieu aromatique.As diphenylketone, 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.
Dans de telles conditions, la quinine est oxydée de façon quasi-quantitative en quininone et quinidinone et la séparation par cristallisation de quinidinone du mélange obtenu permet de déplacer l'équilibre du milieu vers la préparation de la quinidinone.Under such conditions, 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.
Les exemples non limitatifs ci-après illustrent l'invention; les exemples 1 à 5 concernent le procédé de réduction de la quinidinone en quinidine et l'exemple 6 le procédé perfectionné préféré de préparation de la quinidinone à partir de la quinine:The nonlimiting examples below illustrate the invention; 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:
Dans un réacteur sec balayé à l'azote, on introduit:
- - 500 ml de tétrahydrofuranne,
- - 100 g de quinidinone cristallisée,
- - 25 ml de pyridine anhydre.
- - 500 ml of tetrahydrofuran,
- - 100 g of crystallized quinidinone,
- - 25 ml of anhydrous pyridine.
En maintenant une température inférieure à 15°C, on coule 250 ml de solution de DIBAH à 25% dans le toluène.Maintaining a temperature below 15 ° C., 250 ml of 25% DIBAH solution in toluene are poured in.
En fin d'addition, un contrôle CCM indique que la réduction est terminée.At the end of the addition, a CCM check indicates that the reduction is complete.
On effectue une distillation avec fractionnement (25 mm Hg) pour éliminer en tête le THF avec une quantité minimale de toluène.Distillation is carried out with fractionation (25 mm Hg) to remove the THF at the top with a minimum amount of toluene.
Après refroidissement, on ajoute la quantité d'eau nécessaire pour décomposer le complexe aluminium avec un léger excès par rapport à la steochiométrie.After cooling, the quantity of water necessary to decompose the aluminum complex is added with a slight excess relative to the steochiometry.
On filtre et on réextrait les cristaux avec du toluène à 80°C.The crystals are filtered and re-extracted with toluene at 80 ° C.
On obtient à partir de la solution toluénique 96 g de quinidine base, F. = 173°C, αD (1,596 dans éthanol) = 256°C.96 g of quinidine base are obtained from the toluene solution, mp = 173 ° C, α D (1.596 in ethanol) = 256 ° C.
On reproduit l'exemple 1 en utilisant les réactifs suivants:
- - 600 ml de pyridine anhydre,
- - 100 g de quinidinone cristallisée,
- -300 ml de solution de DIBAH à 25% dans le toluène.
- - 600 ml of anhydrous pyridine,
- - 100 g of crystallized quinidinone,
- -300 ml of 25% DIBAH solution in toluene.
La pyridine est chassée sous vide.The pyridine is removed under vacuum.
La masse réactionnelle est reprise dans 750 ml de mélange eau/éthanol 50/50, après reflux de 2 h et refroidissement, on obtient 92,7 g de quinidine base, F. = 174,5°C.The reaction mass is taken up in 750 ml of water / ethanol mixture 50/50, after reflux for 2 h and cooling, 92.7 g of quinidine base are obtained, mp = 174.5 ° C.
On opère comme dans l'exemple 1 en utilisant les réactifs suivants:
- - 300 ml de tétrahydrofuranne,
- - 250 ml de pyridine anhydre,
- - 100 g de quinidinone cristallisée,
- -250 ml d'une solution de DIBAH à 25% dans le toluène.
- - 300 ml of tetrahydrofuran,
- - 250 ml of anhydrous pyridine,
- - 100 g of crystallized quinidinone,
- -250 ml of a 25% DIBAH solution in toluene.
On a obtenu 94,5 g de quinidine ayant une température de fusion de 174°C.94.5 g of quinidine was obtained having a melting temperature of 174 ° C.
On opère comme dans l'exemple 1 en utilisant les réactifs suivants:
- - 500 ml de tétrahydrofuranne,
- - 100 g de quinidinone cristallisée,
- - 320 ml de y picoline anhydre,
- -250 ml d'une solution de DIBAH à 25% dans le toluène.
- - 500 ml of tetrahydrofuran,
- - 100 g of crystallized quinidinone,
- - 320 ml of anhydrous picoline,
- -250 ml of a 25% DIBAH solution in toluene.
On a obtenu 89 g de quinidine.89 g of quinidine were obtained.
On a reproduit l'exemple 5, mais en utilisant, à la place de la y picoline, 200 ml de 3-méthyl- pyrrole.Example 5 was repeated, but using, in place of y picoline, 200 ml of 3-methylpyrrole.
On a obtenu 87 g de quinidine.87 g of quinidine were obtained.
On met en suspension 2,4 g de sodium dans 40 ml de xylène anhydre au reflux afin d'obtenir une bonne dispersion.2.4 g of sodium are suspended in 40 ml of anhydrous xylene at reflux in order to obtain a good dispersion.
Après refroidissement à 90°C, on introduit lentement 36 g de benzophénone anhydre.After cooling to 90 ° C., 36 g of anhydrous benzophenone are slowly introduced.
La solution prend alors la couleur bleu-vert, caractéristique du Ketyl (présence d'électrons).The solution then takes on the blue-green color, characteristic of Ketyl (presence of electrons).
Dans un second réacteur, on dissout à ébullition 13 g de quinine base anhydre dans 50 ml de xylène.In a second reactor, 13 g of anhydrous quinine base are dissolved in boiling in 50 ml of xylene.
On coule cette solution dans la solution précédente. Après 60 min au reflux, la réaction est complète.This solution is poured into the previous solution. After 60 min at reflux, the reaction is complete.
La solution xylénique est traitée à l'eau (20 ml) puis extraite par 100 ml d'acide sulfurique dilué à 20%.The xylene solution is treated with water (20 ml) and then extracted with 100 ml of sulfuric acid diluted to 20%.
On neutralise par addition d'ammoniaque la solution sulfurique froide.The cold sulfuric solution is neutralized by adding ammonia.
Il se sépare une huile qui cristallise lentement après ensemencement.An oil separates which crystallizes slowly after sowing.
Les cristaux de quinidinone sont séparés du mélange.The quinidinone crystals are separated from the mixture.
Poids obtenu: 12,2 g (94% de la théorie)Weight obtained: 12.2 g (94% of theory)
Chromatographie en couches mincesThin layer chromatography
Eluant acétone 80/DMF 20 1 Tache Rf = 0,8Eluent acetone 80 / DMF 20 1 Spot Rf = 0.8
Claims (8)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7718398A FR2394545A1 (en) | 1977-06-15 | 1977-06-15 | PROCESS FOR MANUFACTURING QUININONE AND QUINIDINONE, QUINIDINE SYNTHESIS INTERMEDIARIES |
| FR7718397 | 1977-06-15 | ||
| FR7718398 | 1977-06-15 | ||
| FR7718397A FR2394544A1 (en) | 1977-06-15 | 1977-06-15 | Quinidine prepn. by oxidn. of quinine then stereospecific redn. - of quinidinone with aluminium hydride cpd. in presence of heterocyclic base |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0000302A1 EP0000302A1 (en) | 1979-01-10 |
| EP0000302B1 true EP0000302B1 (en) | 1980-10-01 |
Family
ID=26220080
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19780400020 Expired EP0000302B1 (en) | 1977-06-15 | 1978-06-14 | Novel method for the preparation of quinidine. |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0000302B1 (en) |
| DE (1) | DE2860188D1 (en) |
| IE (1) | IE46996B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2291301A (en) | 1999-12-23 | 2001-07-03 | Academic Pharmaceuticals, Inc. | Optically active isomers of quinine and quinidine and their respective biological action |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1165604B (en) * | 1957-12-18 | 1964-03-19 | Chininfabrik Braunschweig Buch | Method for the steric rearrangement of china alkaloids |
| CH590274A5 (en) * | 1970-03-16 | 1977-07-29 | Hoffmann La Roche | |
| FR2332279A1 (en) * | 1975-11-19 | 1977-06-17 | Nativelle Sa Ets | QUINQUINA ALKALOID OXIDATION PROCESS |
| FR2332278A1 (en) * | 1975-11-19 | 1977-06-17 | Nativelle Sa Ets | Isomerisation of cinchona alkaloids - by ketone oxidn. and isopropanol redn. continuously distilling the solvent used |
-
1978
- 1978-06-14 DE DE7878400020T patent/DE2860188D1/en not_active Expired
- 1978-06-14 EP EP19780400020 patent/EP0000302B1/en not_active Expired
- 1978-06-15 IE IE120378A patent/IE46996B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE781203L (en) | 1978-12-15 |
| IE46996B1 (en) | 1983-11-30 |
| DE2860188D1 (en) | 1981-01-08 |
| EP0000302A1 (en) | 1979-01-10 |
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