EP0000009A1 - Method for the oxidation of quinine to quininone and quinidinone. - Google Patents

Abstract

1. A process for the oxidation of quinine to quininone and quinidinone by means of an Oppenauer type oxidation reaction, characterized in that said reaction is carried out with a basic reagent known as "Ketyl" resulting from the direct action, on a diphenylketone, of an alcaline metal in a solvent medium.

Description

The present invention relates to an oxidation process of the Oppenhauer type with a new reagent and its application to the manufacture of quininone and quinidinone, intermediates for the synthesis of quinidine.

Rabe et al. in 1909 [Ann. 364, 346] had already proposed a preparation of quininone and quinidinone from quinine or quinidine. Oxidation was carried out with very low yields.

Woodward [JACS 67, 1425 (1945)] and Rabe [Ber 51, 466 (1918)] subsequently produced syntheses making it possible to isolate a product with good yield.

Only the more recent studies by circular dichroism of the structure of the isolated products made it possible to define that the isolated product - most often of oily nature - and presenting in solution a mutarotation was in fact a mixture of two isomers: quininone and quinidinone (by analogy with the structure of the two natural cinchona alkaloids: quinine and quinidine).

It has been possible to highlight, in particular thanks to the synthesis work of USKOKOVIC (USP 3,753,992 - 1973), that the only crystalline form, m.p. -98 to 101 ° C had the structure of quinidinone. Quininone can only be isolated in the form of an oil.

The structures are shown in Figure 1.

Quininone and quinidinone, which are differentiated by the asymmetric C ₈ carbon isomerism of the quinuclidine nucleus, are generally two equilibrium forms, which explains the phenomenon of mutarotation in solution hitherto observed.

In the presence of a base of p _K sufficient to enolize the ketone, the balance between quininone and quinidinone operates between the forms indicated in FIG. 2.

This mechanism explains the differences in yields obtained and the lack of definition of the physicochemical characteristics of the product commonly called "quininone" which is in fact only the mixture of the two stereoisomers exhibiting the phenomenon of mutarotation in solution.

Most of the time, the oxidation efficiency is evaluated by UV spectrophotometric assay at 360 nm.

Oppenhauer's oxidation takes place in the case of cinchona alkaloids only in the presence of ketone of the benzophenone family. 1

• - le potentiel d'oxydation,
• - la réactivité à basse température,
• - les contraintes d'encombrement stériques,
• - l'absence de réactions secondaires.

This ketone, playing the role of proton acceptor, must fulfill a certain number of strict conditions with regard to:

• - the oxidation potential,
• - reactivity at low temperature,
• - steric bulk constraints,
• - the absence of side reactions.

Many benzophenone derivatives have been tested and have given substantially equivalent results. The other aromatic or aliphatic ketones (acetone, cyclohexanone, acetophenone, etc.) are inactive in the case of the products which interest us.

For economic reasons, only benzophenone and fluorenone are practically used.

Under these conditions, the oxidation of quinine and quinidine to quininone already described [WOODWARD, VENDLER, JACS 67, 1245 (1945)] [WARNHOFF, REYNOLDS, J. Org. Chem. 28, 1431 (1963)] is carried out only in the presence of 5 equivalent moles of acceptor ketone. When lower quantities are brought into contact, the OPPENHAUER-MEERWEIN-POONDORFF equilibrium conditions are met and 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.

The reaction being carried out in enolic form, it is necessary to introduce a base of p _K sufficient to enolize 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 p _K , are the alcoholates, and mainly the sodium, potassium and aluminum alcoholates, methyl, ethyl, isopropyl and tert-butyl alcohols.

These expensive products, dangerous to use, have the further disadvantage of releasing a primary alcohol in large quantities.

• - entrant en réaction, il provoque des réductions parasites de la quininone formée en sous-produits secondaires gênants (déplacement de l'équilibre vers les bases et épibases) ;
• - il nécessite des traitements de purification coûteux pour le recyclage des solvants (distillation fractionnée).

The presence of this alcohol has two main drawbacks:

• - entering into reaction, it causes parasitic reductions of the quininone formed into annoying secondary by-products (shift of balance towards bases and epibases);
• - it requires expensive purification treatments for the recycling of solvents (fractional distillation).

The object of the invention is mainly to use a base having the ideal characteristics of pK and compatibility which is a derivative "in situ" of the ketone used as proton acceptor.

Indeed, radical anions are known which are formed by the addition of an alkali metal atom (Me) to a ketone of the benzophenone series [BENT, HARRISSON, JACS 66, 969 (1944)].

dans le cas de la benzophénone.It is a radical anion presenting a tautomerism between two main forms:

in the case of benzophenone.

For fluorenone, the equilibrium can be represented analogously:

The "Ketyls" are prepared by simple addition of the alkali metal to a solution of ketone in a suitable aromatic solvent.

It is also possible to react an amalgam (for example a sodium amalgam).

We therefore use as quinine oxidant a "Ketyl" obtained by interaction of an alkali metal on a diphenyl ketone, more particularly on benzophenone or fluorenone.

It is found that the basic alkalot, put in the presence of the "Ketyl" solution, reacts very quickly to give the desired ketone form with a quantitative yield. The absence of by-products and impurities in the reaction medium is noted.

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.

• - obtention avec un excellent rendement de la cétone désirée,
• - simplification de la réaction qui s'opère dans des conditions optimales de durée et de température,
• - remplacement d'un alcoolate coûteux et dangereux par l'emploi d'un métal alcalin (principalement de sodium) d'usage répandu dans l'industrie chimique et bon marché,
• - élimination des problèmes de recyclage de solvants, car il ne se forme plus une mole d'alcool aliphatique par mole d'alcoolate engagé.

The advantages of this invention are manifold:

• - obtaining with an excellent yield of the desired ketone,
• - simplification of the reaction which takes place under optimal conditions of time and temperature,
• - replacement of an expensive and dangerous alcoholate by the use of an alkali metal (mainly sodium) widely used in the chemical industry and inexpensive,
• - Elimination of solvent recycling problems, because one mole of aliphatic alcohol is no longer formed per mole of alcoholate involved.

All of these properties made it possible, as will be seen in the examples describing below, without implied limitation, the applications of the invention, to obtain under good economic conditions quininone and quinidinone from mixtures epibases hitherto considered as fatal byproducts of the hemisynthesis of cinchona alkaloids (in particular quinidine).

EXAMPLE 1

2.4 g of sodium are suspended in 40 ml of anhydrous xylene at reflux, in order to obtain a good dispersion.

After cooling to 90 ° C., 36 g of anhydrous benzophenone are slowly introduced.

The solution then takes the blue-green color, characteristic of "Kétyl" (presence of electrons),

In a second reactor, 13 g of anhydrous quinine base are dissolved in boiling in 50 ml of xylene.

This solution is poured into the previous solution. After 60 minutes at reflux, the reaction is complete.

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.

An oil separates which crystallizes slowly after sowing.

• Poids obtenu : 12,2 g (94 % de la théorie) de quinidinone
• Chromatographie en couches minces
• Eluant acétone 80/DMF 20, 1 tache, Rf : 0,8

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.

• Weight obtained: 12.2 g (94% of theory) of quinidinone
• Thin layer chromatography
• Eluent acetone 80 / DMF 20, 1 spot, Rf: 0.8

EXAMPLE 2

24 g of sodium are suspended in 40 ml of anhydrous toluene, with heating, to obtain a fine division of the metal by fusion.

In parallel, 360 g of anhydrous benzophenone are dissolved in 450 ml of dry toluene. These two solutions are mixed and maintained at reflux for 15 minutes.

130 g of anhydrous quinine base are dissolved at the boil in 500 ml of anhydrous toluene. This solution is poured hot into the benzophenone "Ketyl" solution. After 30 minutes at reflux, the reaction is complete.

The toluene solution cooled to 50 ° C is washed with water, then extracted with 700 ml of dilute sulfuric acid.

• Poids d'huile obtenu : 124 g de quininone, p.f. 102°C CCM 1 tache, Rf 0,8

The cold sulfuric solution is neutralized by adding ammonia. Decanting oil. It is separated and crystallized by seeding and appropriate treatment.

• Weight of oil obtained: 124 g of quininone, mp 102 ° C TLC 1 spot, Rf 0.8

EXAMPLE 3

dans le toluène anhydre.To a solution of fluorenone "Ketyl prepared from 180 g of fluorenone and 130 g of sodium in anhydrous xylene, a solution of 65 g of mixture is added, of the following composition:

in anhydrous toluene.

The mixed solutions are kept at reflux for 5 hours.

The reaction is then complete.

• quininone + quinidinone : 39 g
• cinchoninone + cinchonidinone : 16 g

55 g of a product containing:

• quininone + quinidinone: 39 g
• cinchoninone + cinchonidinone: 16 g

EXAMPLE 4

A “Ketyl” fluorenone solution is produced from 9 g of fluorenone in anhydrous toluene.

To this solution, a solution of 37 g of anhydrous quinidine base in 150 ml of anhydrous toluene is added hot.

After 15 minutes of reflux, the reaction is complete.

After appropriate treatment, 36 g of pure quinidinone (TLC) are obtained (97% of theory).

Claims (3)

1. Process for the oxidation of quinine to quininone and quinidinone, by means of an oxidation reaction of the Oppenhauer type, characterized in that said reaction is carried out using a basic reagent known as "Ketyl" resulting from l 'direct action, on a diphenyl ketone, of an alkali metal in a solvent medium. 2. Method according to claim 1, characterized in that the diphenylketone is chosen parmiles benzophénonesetles fluorenones. 3. Method according to one of claims 1 and 2, characterized in that the solvent used for the preparation of "Ketyl" is chosen from C ₆ -C ₉ aromatic hydrocarbons, saturated C ₆ -C ₉ cyclic hydrocarbons and aliphatic hydrocarbons corresponding to naphtha and diesel fuel cuts.

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