IE46996B1 - Process for the preparation of quinidine - Google Patents

Abstract

1. A process for the preparation of quinidine from quinine by oxidation and reduction of the resulting quinidinone, characterized in that the reduction is effected owing to the action of a aluminium hydride in the presence of an organic heterocyclic base containing a basic nitrogen atom in said heterocycle.

Description

This invention relates to a new process for the preparation of quinidine, and in particular to a process involving the stereospecific reduction of quinidinone to quinidine.

Quinidine has been prepared for many years by partial synthesis from quinine.

In fact, this natural cinchona alkaloid which is very useful in the treatment of heart disease (such as antiarrhythmia) is not present in sufficient quantity in cinchona bark to meet the needs of the pharmaceutical industry.

All the processes used for carrying out the partial synthesis of quinidine from natural products are variations of oxido-reduction equilibrium reactions (Oppenhauer oxidation - Meerwein - Pondorff reduction) (German Patent Nos. 883,154 (1953) and 877,611 (1953)).

In fact, in the presence of a conventional selected ketone (possessing a sufficient oxidation potential and a molecular configuration compatible with the steric hindrance constants of quinine and quinidine), an equilibrium of the type represented in Figure 1 is set up.

Figure 1 clearly shows that during equilibrium conditions a single starting product is found in the presence of four principal reaction products: . quinine and its Cg isomer epiquinine . quinidine and its Cg isomer epiquinidine then the Cg ketone intermediates . quininone and quinidinone which are in equilibrium in solution and pass through a common transitory state.

The problem posed by this partial synthesis is easily understood : how to direc; the equilibrium towards the formation of the desired product, so as to achieve a build up of quinidine while at the same time avoiding the formation of epiquinine and epiquinidine.

These fatal products, which are without therapeutic use, may not be recycled under the conditions of the reaction unlike quinine. In fact, the mixture of quinine and epiquinine does not give rise to the same equilibrium - all other conditions being equal - as the same quantity of pure quinine.

On the other hand, the presence of epibases is undesireable in pharmaceutical salts of quinidine and, furthermore, the presence of these isomers, even in minute quantitites brings about a retardation of crystallisation and a significant droo in yield when the different salts of quinine and quinidine are being prepared from their saturated solutions.

Apart from maximally maintaining the conditions under which epibases are formed, the principal processes for the manufacture of quinidine are thus attaired at coefficients of transformation which are, withoutexception, less than 1.2 to 1.25 kg anhydrous quinine base used per kg anhydrous quinidine base isolated.

The major Inconvenience with these synthesis is the necessity of recycling circa 40 to 50% of the quinine used for subsequent operations.

Even if the setting up of the reaction and the obtainment of a satisfactory equilibrium may be simplified, the fact of having to recycle half of the charge of raw material per operation evidently entails costly charges in the subsequent treatment steps of the mother liquors, namely the separation of untransformed quinine and its purification prior to entering into reaction again.

Financial expenditure is increased on account of having to finance the weight of untransformed quinine. - 4 The volume of reactants necessary and the cost of man power are more important in the case of a quantitative synthesis where the raw material does not have to be recycled.

Recently, several groups of research workers have used certain aluminium hydrides in the total synthesis of a series of alkaloids of the quinine and quinidine family.

In particular, the reduction of quinidone to quinidine with the aid of diisobutylaluminium hydride in toluene has been described /Grethe, Uskokovic, JACS 93, 5904 (1971)/.

Nevertheless, the sole use of this type of reagent is not sufficient for setting up an industrial synthesis.

In fact, in the case of quinidine, the aforementioned byproducts (quinine and epibases) are still found in unacceptable quantities : 35% in the case of the cited reference, the true yield of quinidine isolated being only 65%.

Further, the composition of the hy products comprises in equal parts : quinine, epiquinine and epiquinidine, of which 25% of the epibases is non-recoverable per operation, which fact is totally incompatible with a profit-earning economic production.

Having reconsidered these works, one is temoted to carry out the reductions at low temperature, but the verified increase in yield does not balance the necessary cost involved in cold production.

The reduction of a ketone by diisobutyl-aluminium hydride takes place according to the following reaction scheme: C=0 + (i-C4Hg) 9'2 AlH· R ->CH - 0A1 (i-C4Hg)2 (I) quininone (II) /CH - OH + Al (OH) 3 + 2(i-C4H1Q) (III) In the case of quinidine, on account of the Cg asymmetric carbon atom, one might imagine that: - two stable complexes (II) might be capable of being formed (one corresponding to quinidine and the other to the epibase form), - On hydrolysis of the complex a rearrangement might take place directing the formation of the secondary alcohol (III) to the quinidine form or its corresponding epibase.

It has been found in a very surprising manner, that if the reduction of quinidinone to quinidine, by means of an aluminium hydride or an equivalent product, is carried out in the presence of an organic heterocyclic base containing a basic nitrogen atom in the said heterocycle, the reduction reaction is accomplished in an entirely stereospecific manner.

The reducing agent used in the present invention is an aluminium hydride, more particularly an alkylaluminium hydride or a sodium-aluminium hydride, especially an alkyl sodium-aluminium hydride.

The organic heterocyclic base used in the present invention is preferably pyridine or pyrrole, the carbon atoms of these heterocyclic molecules may be substituted by one or more alkyl groups.

The quantity of organic heterocyclic base to be used is such that the concentration of the said base in the - 6 solution, wherein the reaction is being carried out, should be between 0.5 and 100% The reduction takes place in a solvent such as an organic solvent, for example, toluene, xylene or an ether such as tetrahydrofuran, dioxan or dibutylether.

Quinidinone does not generally constitute the starting basic product from which quinidine is partially synthesized this basic product is generally quinine. It is advisable first of all to transform the quinine base to quinidinone with the best yield possible. According to the present invention it is possible to use any process for preparing quinidinone from the quinine base; nevertheless it is desirable that the process used allows for the obtainment of pure quinidinone.

The preferred process for obtaining pure quinidinone for use as reactant in the reduction reaction hereinbefore described consists in subjecting quinine base to an Oppenhauer type oxidation reaction by means of a basic reagent resulting from the reaction of.a diphenylketone with an alkaline metal.

Preferably the diphenylketone used is benzophenone or. fluorenone; for the alkaline metal sodium or potassium is used fir example. The basic reagent is itself prepared by the action of an alkaline metal on a selected ketone in a solvent medium which is preferably an aromatic medium.

Under such conditions, quinine is oxidized in a quasiquantitative manner to quininone and quinidinone and the separation of quinidinone from the mixture obtained,by crystallisation,displaces the equilibrium in the medium towards the preparation of quinidinone.

The following non-limiting Examples illustrate the invention; Examples 1 to 5 relate to the process of reducing quinidinone to quinidine and Example 6 relates to the preferred perfected process for preparing quinidinone from quinine. 6 9 9 6 Example 1 Into a dry reactor flushed with nitrogen are introduced - 500 ml tetrahydrofuran - 100 g crystalline quinidinone - 25 ml anhydrous pyridine.

While maintaining a temperature less than 15°C, a 25% solution of DIBAH in toluene is run in.

At the end of the addition, control TLC indicates that the reduction is completed.

Fractional distillation (25 mm Hg) is carried out so as to remove the THF with a minimal quantity of toluene.

After cooling, a quantity of water is added which is necessary to decompose the aluminium complex, the water is added in slight excess in proportion to the stochiometry.

The reaction medium is filtered and the crystals are reextracted with toluene at 80°C. g of quinidine base are obtained from the toluene solution, m.p. = 173°C., aD (1.3% in ethanol) = 256°. Example 2 Example 1 is repeated using the following reactants: - 600 ml anhydrous pyridine - 100 g crystalline quinidinone - 300 ml 25% solution of DIBAH in toluene The pyridine is removed under vacuum.

The reaction mass is taken up again in 750 ml of a 50/50 water/ethanol mixture, after refluxing for 2 hours and cooling, 92.7 g of qulnidina base are obtained, m.p. = 174.5°C.

Example 3 The procedure of Example 1 is adopted using the following reactants: - 300 ml tetrahydrofuran - 250 ml anhydrous nyridine 4699 6 - 8 - 100 g crystalline quinidinone - 250 ml of a 255 solution of DIBAH in toluene. 94.5 g of quinidine having a melting point of 174°C are obtained.

Example 4 The procedure of Example 1 is adopted using the following reactants: - 500 ml tetrahydrofuran - 100 g of crystalline quinidinone - 320 ml anhydrous Τ' picoline - 250 ml of a 25% solution of DIBAH in toluene 89 g of quinidine are obtained.

Example 5 Example 4 is repeated, but 200 ml of 3-methylpyrrole 15 is used in place of 7* picoline. g of quinidine are obtained.

Example 6 2.4 g of sodium are 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 are introduced slowly.

The solution then turns a blue-green colour, characteristic of ketyl (presence of electrons).

In a second reactor 13 g of anhydrous quinine base 25 are dissolved in 50 ml of boiling xylene.

This solution is poured into the preceding solution. After 60 minutes under reflux, the reaction is complete.

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

The cold sulphuric solution is neutralized by the addition of ammonia.

An oil separates from the solution which crystallises slowly after seeding. - 9 The quinidinone crystals are separated from the mixture.

Weight obtained: 12.2 g (94% of theory) Thin layer chromatography.

Eluant acetone: DMF 80:20, 1 spot, Rf = 0.8

Claims (10)

CLAIMS:

1. A process for the preparation of quinidine from quinine by oxidation of quinine to quinidinone followed by reduction of the quinidinone formed, wherein the reduction is carried out by the action of an aluminium hydride in the presence of an organic heterocyclic base containing a basic nitrogen atom in the said heterocycle.

2. A process according to claim 1, wherein the aluminium hydride is selected from alkylaluminium hydrides, more particularly dialkylaluminium hydrides and alkyl sodium-aluminium hydrides.

3. A process according to claim 1 or 2, wherein the said heterocyclic base is selected from pyridine and pyrrole and the Various alkyl substituents on the carbon atoms of these molecules.

4. A process according to claims 2 and 3, wherein the aluminium hydride is diisobutylaluminium hydride.

5. A process according to claims 1 to 4, wherein the said base is pyridine which is used at a concentration greater than 0.5%.

6. A process according to claims 1 to 4, wherein the hydride is used in the form of a solution in an aromatic solvent or in an ether such as tetrahydrofuran, dioxan or dibutylether.

7. A process according to claims 1 to 6, wherein quinidinone is used in the form of a solution of this molecule in a solvent selected from pyridine and mixtures of pyridine with an ether, such as tetrahydrofuran, dioxan and dialkyl ethers.

8. A process according to claim 1, wherein the starting quinidinone is obtained from quinine by an Oppenhauertype oxidation reaction by means of a reagent resulting - 11 from the reaction of a diphenylketone, such, for example, as benzophenone or fluorenone, on an alkaline metal.

9. A process for the preparation of quinidine substantially as hereinbefore described with reference to the accompanying Examples.

10. Quinidine whenever prepared by a process claimed in a preceding claim.