CS217191B1 - Method of making the 1-lobeline from refuse lobeline basis - Google Patents

Description

The present invention relates to a process for the production of 1-lobelin from waste lobelia bases, non-crystalline and unprocessable, remaining after hydrogenation of lobelanine hydrochloride, isolation of d, l-lobelin base and unreduced lobelanine in the hydrochloride form.

A key substance in the synthesis of l-lobelin (I)

is lobelanin (II)

which in the form of toluenesulfomethylate or hydrochloride is partially reduced (hydrogenated) to racemic lobelin. Hydrogenation produces a mixture of all three lobelia alkaloids, ie lobelin (I), lobelanin (II) and lobelanidine (III)

From this mixture, a further ethereal solution is obtained from which the racemic lobelin base crystallizes in a yield of 20 to 25 217191.

After the isolation of lobelin, a considerable amount of dense oily fractions remains, from which the starting lobelin may be recovered as the hydrochloride in a yield of not more than 25% (BIOS Final Report 766, 106; 187 (DRP 532,535). However, this product is contaminated with lobelanidine hydrochloride, which is formed by complete reduction of lobelanine. The amount of lobelanine hydrochloride obtainable from the waste fractions depends on the pH. By suitable treatment thereof, lobelanine hydrochloride free of lobelanidine hydrochloride can be isolated in a maximum yield of 10%. The pH has been lowered, i.e. if greater amounts of hydrochloric acid are used, both lobelanine hydrochloride and lobelanidine hydrochloride are eliminated.

Another very lossy operation in the production of 1-lobelin is the resolution of the racemate into the optically active component, especially the desired 1-form. This operation, carried out with dibenzoyl-d-tartaric acid, yields lobelin in about 70% yield, calculated on the total 1-form content, while still about 30% 1-lohelin and all d-lobelin remain in the mother liquors, of which are regenerated and converted to lobelanidine by complete reduction.

In addition to lobelanine, this alkaloid is another source of lobelin that can be obtained by partial oxidation of manganese dioxide, potassium permanganate or chromium trioxide in a strongly diluted aqueous solution or acetic acid.

Due to the low yields of lobelanin reduction resulting in a mixture of all three lobelium alkaloids, the reprocessing of all of the waste components to 1-lobelin is very important from the point of view of production efficiency.

Wieland, Scheuing and Winterhalden (DRP 532,535, British Patent No. 314,532, US Patent No. 1,946,345) have disclosed a method by which d-lobelin can be converted again into a racemate. By catalytic reduction of d-lobelin, lobelanidine was prepared which was partially oxidized by the above reagents in a strongly dilute aqueous solution or in acetic acid. Absolutely £

the equivalence of the two hydroxyl groups of lobelanidine caused, as in the reduction of lobelanin, a mixture of all three alkaloids, which were then separated by successive concentration of the ether extract.

The crude racemic lobelin contained in the second of the three fractions obtained was isolated in a yield of about 36%. The separation in this way is very imperfect, since racy lobelin is present both in the first fraction containing predominantly lobelanidine and in the third fraction containing predominantly lobelanin.

It has now been found that 1-lobelin can be obtained from lobelanin in a much higher overall yield by treating the oil fractions remaining after the reduction of lobelanin, which is still a non-recoverable waste. These waste oil fractions contain, in addition to lobelanidine and unreacted lobelanine, lobelin, which can be reduced to lobelanidine, and converted back to d, l-lobelin as mentioned above by paper chromatography.

Accordingly, the present invention provides a process for the production of 1-lobelin from lobelia waste bases, non-crystalline and unprocessable, remaining after hydrogenation of lobelanine hydrochloride, after isolation of d, l-lobelin base and unreduced lobelanin in the hydrochloride form. The principle of the process according to the invention consists in the catalytic hydrogenation of the waste lobelia base, followed by the isolation of lobelanidine from the hydrogenated product in a manner known per se in the form of a salt with a mineral acid, in particular nitric acid. upon conversion to sulfate, it partially oxidizes manganese dioxide to d, l-lobelin in a known manner.

The hydrogenation of the waste lobelia base mixture is carried out in a methanolic solution using PtO ₂ as a catalyst, at room temperature and at atmospheric pressure. After completion of the hydrogenation and removal of the catalyst, the solution was evaporated and the residue was diluted

21719 * with ethanol and acidification with nitric acid eliminates lobelanidine as a well-crystallizing nitrate in a yield of about 25% based on the total amount of the starting lobelia waste base mixture.

The isolated lobelanidine nitrate serves as a starting material for the conversion in the base to obtain further d, l-lobelin by partial oxidation by any of the known methods.

By using waste lobelium bases which have not been economically viable so far, the process according to the invention has been able to substantially increase the production of 1-lobelin and reduce production costs by using simple technical means.

Exemplary embodiment

Acidic mother liquors after the hydrogenation of lobelanine hydrochloride, from which racemic lobelin was isolated and recovered unreduced lobelanine in the form of the hydrochloride, which is a non-crystalline and still unprocessable waste, were made alkaline with ammonia to pH 10. 80 l of methanol, 150 g PtOg are added and reduced with hydrogen gas until its consumption (about 700 to 800 l) is virtually stopped. After the catalyst has been filtered off, the methanol is distilled off and the syrup-like distillation residue is diluted with a quadruple volume of ethanol. Acidification of the solution to pH 3-4 with nitric acid precipitates lobelanidine nitrate in a yield of 3.5 kg (25% calculated on a basis). The obtained lobelanidine can then be converted to d, l-lobelin by some of the known methods, e.g. by partial oxidation with manganese dioxide.

Claims (1)

SUBJECT OF THE INVENTION A process for producing 1-lobelin from lobelia waste bases, non-crystalline and not yet processable, remaining after hydrogenation of lobelanine hydrochloride, after isolation of d, l-lobelin base and unreduced lobelanin hydrochloride, characterized in that the waste lobelia bases are catalytically hydrogenated, whereupon lobelanidine is isolated from the hydrogenation product in a manner known per se in the form of a salt with a mineral acid, in particular nitric acid, whereupon lobelanidine base is liberated from this salt, which after conversion into sulphate o. in a manner known per se, it partially oxidizes manganese dioxide to d, l-lobelin.