DE2207533A1 - Process for the isolation of indole alkaloids - Google Patents

Description

toilet: ¹ . - · -

. Pe.tentanw & ite '.-n- :. π. η .-. Γ.τ

il9 ~ 10.366P February 17, 1972

Judge Qedeon Vegy ^ -4eaeti Gy & r RT., Budapest (Hungary)

CONSTRUCTION FOR THE INSULATION OF UiDOI ₁ -ALKALOIDBI

The invention is a new process for the recovery and isolation of indole alkaloids aua aqueous. Media, E.g. auo retention liquids or also during processing obtained from alkaloid-containing raw materials dilute aqueous solutions.

209836/1166 f.7Λ20 / Si »,.

The indole alkaloids, such as the ergot alkaloids and the reserpine and vincamine-type alkaloids are im general valuable medicines. The methods that have hitherto been customary for their isolation are mostly based on their own properties of these alkaloids that the free bases and certain salts, e.g. the trichloroacetate and the rhodanate, are in Organic solvents dissolve well, but hardly or not at all in water, while most acid addition salts, like sulfates, phosphates, tartarates, citrates, etc., good in water, but bad or bad in organic solvents are not soluble at all. Due to this property, these alkaloids are isolated from them by accompanying substances The method of multiple phase changes is mostly used for contaminated solutions. However, this method has the disadvantage that when working up the usual starting solutions, which are created by Pennentation processes or by the Extraction of plant parts are taken, always work with very large amounts of largely dilute solutions got to. Working with such large amounts of liquid not only makes technological operations more cumbersome and equipment more expensive, it also causes them also material losses, since on the one hand the large ones Liquid quantities also from the poorly soluble substances always hold back considerable amounts and, on the other hand, the alkaloids during the multiple phases of the cycle and also easily hydrolyzed, oxidized or other harmful effects when the solutions obtained are concentrated can be decomposed. The selectivity of such operations is also often unsatisfactory, so that the obtained raw products still have to be further purified through additional costly operations.

These disadvantages of the known Iaolierungamethods are eliminated by the present invention, and it is a simple method for practically loss-free extraction and isolation of the indole alkaloids from dilute aqueous solutions Media required.

It has been found that the indole alkaloids are also made very dilute aqueous solutions practically quantitative

209836/1166

Can be precipitated when looking at these aqueous solutions with an iodine solution; the alkaloids are in the Form of an iodine complex which is insoluble in water, as a self Quickly settling and easily filterable precipitate is obtained, which then in small amounts of organic solvents can be dissolved and decomposed by reduction. In this way the alkaloids are then concentrated in Solutions, largely freed from the accompanying substances and obtained with very good yields.

This new process can mainly be used for the recovery and isolation of indole alkaloids, since with other alkaloids the complex formed with iodine is generally not deposited quantitatively and the precipitate obtained cannot be worked up so well either.

The invention is therefore a new process for the production of indole alkaloids from fermentation liquids and other dilute aqueous media, which is characterized in that it contains the indole alkaloids iodine is added to the aqueous medium, the iodine complex of the alkaloids obtained as a precipitate is separated off and converted into organic Solvents, releases the alkaloids through reductive decomposition of the iodine complex and if necessary recovers the iodine.

According to the invention, the procedure is such that fermentation liquids containing indole alkaloids are added or acidic aqueous solutions an aqueous one, salubilized with potassium iodide or with water-soluble organic one Adding iodine solution produced to solvents; this iodine solution is expediently added in smaller amounts Portions as long as no precipitation occurs when another portion is added. It becomes one that way eich achnell feee-settling dark brown precipitate received, which consists of the new iodine complexes of the alkaloids not previously known in the literature.

This precipitate is separated off, and then in an organic solvent that is immiscible with water, expediently moderately dissolved in benzene or di-chloroethane. This organic

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Solution of the complex is obtained while stirring vigorously with a such reducing agent treated, its normal redox potential lower than that of the iodide-iodine system; Sodium thiosulphate is expediently used as such a reducing agent., Sodium hydrogen sulfide, sodium hydroxide, ae orbic acid or hydrazine, applied in a weakly alkaline solution. After the suddenly occurring reduction has expired the stirring is stopped, the phases are separated and the organic phase, in which the indole alkaloids are dissolved, is worked up in a manner known per se, e.g. by evaporation, salt formation, etc.

Dae used iodine for complex formation, which after reduction in the form of iodide in the aqueous phase is present, can be recovered in the form of elemental iodine by oxidation, expediently with fuming nitric acid and be used again.

The advantages of the method according to the invention can can be summarized in the following way:

a / The indole alkaloids can also be obtained from very dilute fermentation liquids or aqueous-acidic solutions, can be quantitatively recovered in one step in the form of a precipitate; the accompanying impurities are not precipitated, so that not only an enrichment, but also a purification of the alkaloids is achieved will;

b / In contrast to the known methods, the filling-based method according to the invention does not result in any This causes decomposition of the alkaloids, so that there are no losses and the yield is greatly increased will;

c / the process does not require large liquid containers; the much smaller devices are much cheaper.

The inventive method is further illustrated by the following examples t

example 1

10 liters of a filtered fermentation liquid ■ a Claviceps paspali culture, which 1500 mcg / ral lyser

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A acid amide is added at ", iimj.erteniperatur with stirring with a solution containing 20 # potassium iodide and 10% iodine. The dark brown precipitate formed is filtered off and 1 liter of chloroform turns yellow. The solution is then mixed with 500 ml of a 5% sodium hydroxide and 10% The organic phase is separated off, dried over anhydrous sodium sulfate and evaporated under reduced pressure until the product crystallizes. 9.75 g of lysergic acid amide / 65 % of theory / are obtained.

Example 2

12 liters of filtered fermentation liquid of a Claviceps fusiforrais culture, which total 2900 mcg / ml Contains elimoclavin and agroclavin, worked up according to Example 1. lis become 38.8 g from Elimoclavin and Agroclavin / 3: 1 / existing mixed crystals / 68.3 5 »d.th./ obtain.

Example 3

10 kg of dry, crushed plant parts of Vinca minor are made alkaline with ammonia and extracted with toluene in the known manner. From the toluene extract, the alkaloids dissolve in 15 liters of aqueous 5% tartaric acid. The -acid to this V / EIEE obtained (l5 liters) aqueous-solution of the alkaloids is is at room temperature, with stirring, with 250 ml of a 10% iodine and 20% potassium iodide solution or waesrige added dissolved in acetone 25 g of iodine, üb a rapidly settling dark brown precipitate is obtained. If further precipitate erachoints with further addition of iodine solution, then the filling is completed by adding further iodine solution. The iodine coraplex obtained as a precipitate is then filtered off and ooforb, dissolved in 2 liters of dichlorohthane in a moist state. 1 liter of an aqueous solution containing 5% sodium hydroxide and 10 % sodium thiosulphate is added to this solution while stirring vigorously. After the phases have been filled, the organic phase is dried over anhydrous potassium carbonate and evaporated to dryness under reduced pressure. In this V.'olac

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the total alkaloids of Vinca minor are obtained with a yield of 20% higher than was possible with the methods known up to now.

209816/1166

Claims (7)

Claims 1. Process for the production of indole alkaloids auo Fermentation fluids and other dilute aqueous Media, characterized in that the indole alkaloids are used containing aqueous medium mixed with iodine, the iodine complex obtained as a precipitate of the alkaloids is separated and dissolves in organic solvents, which releases the alkaloids through reductive decomposition of the iodine complex and If so desired, the iodine can be recovered. 2. The method according to claim 1, characterized in that that the iodine is in the form of an aqueous iodine solution containing potassium iodide or an acetone Iodine solution used. 3. The method according to claim 1, characterized in that that the iodine complex obtained as a precipitate of the alkaloids in aromatic hydrocarbons or in chlorinated aliphatic hydrocarbons dissolves. 4. The method according to claim 1, characterized in that the dissolved iodine complex by reduction with decomposed in an aqueous solution of alkali thiosulphates or alkali sulphates. 5. The method according to claim 1, characterized in that one containing ergot alkaloids aqueous Solutions or filtered fermentation liquids as Starting materials used. 6. The method according to claim 1, characterized in that alkaloids of the reserpine type containing aqueous Solution used as starting materials. 7. The method according to claim 1, characterized in that that aqueous extracts containing alkaloids of the vincamine type are used as starting materials. 20ΊΘ836 / 1166