IE46935B1 - Process 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

This invention relates to an Oppenhauer-tvpe process o£ oxidation by a new reagent and its application to the manufacture of quininone and quinidinone, synthetic intermediates of quinidine.

Rabe et al /Ann. 364, 346 (1900)/ have already proposed a preparation of guininone and quinidonone from quinine or quinidine. The oxidation was carried out with very low yields.

Woodward /JACS 67, 1425 (1945)/ aridRabe /Ber 51, 466 10 (1918)/ subsequently carried out syntheses which resulted in good yields of the product being isolated.

Only the most recent studies of the structure of the isolated products by circular dichroism have shown that the isolated product - usually of an oily character 15 which exhibits mutarotation in solution is, in fact, a mixture of two isomers : quininone and quinidinone (by analogy with the structure of the two natural alkaloids of cinchona : quinine and quinidine).

It has been discovered, in particular, due to the synthetic works of Oskokovic (U.S. Patent No. 3753992 - 1973), that only the crystalline form, m.p. 98 to lofc, has the structure of quinidinone. It is only possible to isolate quininone in the form of an oil.

The structures are indicated in Figure 1.

The two forms quininone and quinidinone, which are differentiated on the basis of isomerism at the asymmetric carbon atom at the C8 position of the quinuclidine nucleus, 6 9 3 5 are generally in equilibrium, which explains the phenomenon of mutarotation referred to above.

In the presence of a base of pK sufficient to enolise the ketone, the equilibrium between quininone and quinidinone takes place between the forms indicated in Figure 2.

This mechanism explains the different yields obtained and the failure to determine the physicochemical characteristics of the product commonly called quininone which is, in fact, a mixture of two stereoisomers which exhibit the phenomenon of mutarotation in solution.

Usually the yield from oxidation is evaluated by UV spectrophotometry at 360nm.

In the case of the cinchona alkaloids the Oppenhauer oxidation occurs only in the presence of a ketone of the benzophenone family.

The ketone, playing the role of an acceptor of protons, must fulfil a number of stringent conditions with regard to: - oxidation potential, - reactivity at low temperature, - constraints of steric hindrance, - absence of secondary reactions.

A number of benzophenone derivatives have been tested and have given practically equivalent results.

Other aromatic or aliphatic ketones (acetone, cyclohexanone, acetophenone, etc.,) are without activity in the case of the products of interest.

For economic reasons, only benzophenone and fluorenone are practically employed. 6935 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 achieved in the presence of only 5 mole equivalents of ketone acceptor. When smaller quantities are used, the OPPENHAUER-MEERWEINPOONDORFF equilibrium conditions occur and the quininone formed is found together with variable quantities of impurities, principally: quinine, quinidine, epiquinine, epiquinidine, quinicine (quinotoxine) which have the effect of reducing the yield of the reaction and the byproducts formed must be separated and purified before being recycled (in particular, it is noted that the presence of epibases - even in small amounts - considerably diminishes the yields obtained upon crystallisation of quinine and quinidine from their saturated solutions.

As the reaction takes place under enolic form, it is necessary to Introduce a base whose pK is sufficient to enolise the ketonic forms taking part in the reaction. A quantity of 2 to 7 mole equivalents has proven to be necessary in the various experiments described in the literature. The bases used, on account of their pK values, are alcoholates principally sodium, potassium and aluminium alcoholates of methyl, ethyl, isopropyl and tert - butyl alcohols.

These products are expensive and hazardous to use and,furthermore, they have the disadvantage of liberating a primary alcohol in significant amounts.

The presence of such an alcohol has two principal 30 disadvantages: - entering into the reaction, it initiates unwanted reductions of the quininone formed to troublesome secondary by-products (by displacing the equilibrium towards the bases and .epibases).

- It necessitates costly purification treatments for . recycling the solvents (fractional distillation)'.

The object of the present invention is principally to use a base having optimal characteristics of pK and compatibility and which is an in situ derivative of the ketone used as proton acceptor.

In fact, anion radicals formed by the addition of an atom of an alkaline metal (Me) to a ketone of the benzophenone series are known /Bent, Harrison, JACS 66, 969 (1944)7.

The anion radical in question exhibits tautomerism between two main forms in the case of benzophenone; OMe OMe For fluorenone, the equilibrium may be represented in 15 like manner; T* . © Γ-V 1 u ΙΟχΜ OMe OMe The ketyls are prepared by a simple addition of an alkaline metal to a solution of ketone in a suitable aromatic solvent. An amalgam may also be used (for example, a sodium amalgam.

A ketyl, obtained by the interaction of an alkaline metal with a diphenylketone, more particularly, benzophenone or fluorenone is then used as an oxidant for quinine. - 6 It has been established that an alkaloid base, in the presence of a ketyl solution, reacts very rapidly to give the desired ketonic form with a quantitative yield. The absence of by-products and impurities is noted In the reaction medium.

The reaction of quinine and the ketyl is carried out in a solvent medium; the solvent is chosen from Οθ Cg aromatic hydrocarbons, Cg - Cg saturated cyclic hydrocarbons or aliphatic hydrocarbons corresponding to the naphtha or oil - gas fractions.

The advantages of the present invention are numerous: obtainment of an excellent yield of the desired ketone, - simplification of the reaction which is performed under optimal conditions of duration and temperature, - replacement of an expensive and hazardous alcoholate by the use of an alkaline metal (principally sodium) which is cheap and is of wide spread use in the chemical industry, - elimination of the problems of recycling solvents, because no more than one mole of aliphatic alcohol is formed per mole of alcoholate used.

All of these properties together have permitted quinone and quinidinone to be obtained under economical conditions from a mixture of epibases, which heretofore have been considered to be fatal by-products of the partial synthesis of cinchona alkaloids, (in particular quinidine), as will be seen from the following non-limiting Examples.

Example 1 2.4 g of sodium is suspended in 40 ml of anhydrous xylene under reflux so as to obtain a good dispersion.

After cooling to 90°C, 36 g of anhydrous benzophenone is added slowly. 4633S - The solution then becomes a blue-green colour characteristic of ketyl (presence of electrons). g of anhydrous quinine base is dissolved in 50 ml of boiling xylene in a second reactor.

This solution is run into the preceding solution after refluxing for 60 minutes, the reaction is complete.

The xylene solution is treated with water (20 ml) and then extracted with 100 ml of 20% sulphuric acid. The cold sulphuric solution is neutralized by addition of ammonia.

An oil separates from the solution which slowly crystallises after seeding.

The crystals which form are composed of quinidinone; as quinone and quinidinone are in equilibrium in the oil obtained, the precipitation of quinidinone consequently displaces the equilibrium towards the production of quinidinone.

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

Example 2 g of sodium is suspended in 40 ml anhydrous toluene, with heating, so as to obtain a fine partition of metal by fusion.

Simultaneously, 360 g of anhydrous benzophenone is dissolved in 450 ml of dry toluene. These two solutions are mixed and are maintained under reflux for 15 minutes. 130 g of anhydrous quinine base is dissolved in 500 ml of boiling anhydrous toluene. This hot solution is poured into the solution of benzophenone ''ketyl. After 30 minutes under reflux, the reaction is complete.

The toluene solution is cooled to 50°C and washed with water, it is then extracted with 700 ml of dilute sulphuric acid. 6935 The cold sulphuric solution is neutralized by the addition of ammonia. An oil is decanted. The oil is separated and crystallises on seeding by suitable treatment.

Weight of oil obtained: 124 g quininone, m.p. 102°C.

T.L.C. 1 spot, Rf- 0.8 Example 3 A solution of fluorenone ketyl” is prepared from 10 180 g of fluorenone and 130 g of sodium in anhydrous 1 xylene, a solution of 65 g of the mixture in anhydrous toluene having the following composition is added: Epiquinine 35% Epiquinidine 24% Quinine 7% Quinidine 3% Quininone 2% Quinotoxine 2% Epicinchonine + Epicinchonidine 12% Various alkaloids and other cinchonines 15% The mixed solutions are maintained under reflux for 5 hours.

The reaction is then complete.

After suitable treatment one obtains 55 g of a product containing: quininone + quinidinone : 39 g cinchoninone + cinchonidinone : 16 g Example 4 A solution of fluorenone ketyl is prepared from g of fluorenone in anhydrous toluene.

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

After 15 minutes under reflux, the reaction Is complete.

After suitable treatment, one obtains 36 g of pure quinidinone (T.L.C.) (97% of theory).

Claims (5)

1. CLAIMSi1. A process for the oxidation of quinine to quininone and quinidinone by means of an Oppenhauer type oxidation reaction, wherein the reaction is carried 5 out with the aid of a basic reagent called a ketyl which is formed by the direct action of an alkaline metal on a diphenylketone in a solvent medium.

2. A process according to claim 1 wherein the diphenylketone is chosen from benzophenones and 10 fluorenone.

3. A process according to one of claims 1 and 2, wherein the solvent employed for the preparation of the ketyl is chosen from an aromatic Cg-Cg hydrocarbon, a Cg-Cg saturated cyclic hydrocarbon or an aliphatic 15 hydrocarbon corresponding to the naphtha and oil gas fractions.

4. A process for the oxidation of quinine to quininone and quinidinone substantially as hereinbefore described with reference to the accompanying Examples. 20

5. Quininone or quinidinone whenever prepared by a process claimed in a preceding claim.