Isomerization pseudoephedrine ephedrine

Isomerization pseudoephedrine ephedrine

Over the last decade Ephedrine is widely used in medical practice, particularly in the treatment of asthma and as an agent for stimulating the blood circulation; diastereoisomer of this alkaloid — pseudoephedrine — for action similar to ephedrine, but much weaker, and therefore not applicable in medicine.

Ephedrine and pseudoephedrine are usually accompany each other in plants. These alkaloids are quite common; ephedra they occur in other plant species. Of these, only a few have commercial significance. Currently, a large number of harvested two types: equisetina Ephedra and Ephedra intermedia, which contain up to 3% of alkaloids (ephedrine and pseudoephedrine). Other species contain fewer alkaloids and also insufficiently studied in chemical botanical relationship.

The harvested ephedra on the share of pseudoephedrine on average 80% and 20% — for ephedrine.

It is now established that pseudoephedrine and its compounds have a number treokonfiguratsiyu and ephedrine — eritrokonfiguratsiyu.

The capacity for mutual conversion of these alkaloids was established long ago. In 1906, Schmidt when you try to prepare the racemate of ephedrine by boiling with 25 percent. hydrochloric acid was pseudoephedrine. Hence the idea of ​​the possibility of conversion of pseudoephedrine and ephedrine in the back. Mutual isomerization of these alkaloids has been studied for a long time and Schmidt Emde.

It should be noted the work Callis and Schmidt [14], which, they claim, able to completely transform pseudoephedrine ephedrine, pseudoephedrine hydrochloride by heating in a sealed tube with water, the addition of barite powder of Ba (OH) 2; for 8 hours under pressure at 170-180.

As should now be regarded as established that the conversion of the alkaloids are associated with the inversion of an OH group on the carbon atom located near a phenyl radical, as the reduction of both the alkaloid pass in one and the same dszoksiefedrin.

Isomerization associated with inversion OH group, may be carried out in various ways. Thus, when processing N-boiling atsetilefedrina 5 percent. a mixture of hydrochloric acid hydrochloride ephedrine and pseudoephedrine in the approximate ratio of 38:62. Mitchell got the same results, but only alkaloids were presented in reverse ratio (2 parts of ephedrine and pseudoephedrine, part 1).

This isomerization affecting the alpha-carbon atom from ephedrine is not found at the N-atsetilpsevdoefedrina that in acid and alkaline hydrolysis gives only pseudoephedrine. Characteristically, such isomerisation watched channel when heated with concentrated hydrochloric acid, N-benzoyl-dl-nor-ephedrine. The reaction produces only the O-benzoilnor-dl-pseudoephedrine; reaction is accompanied by the migration of the benzoyl group from N to O.

Hydrolysis individual chloro- and bromo derivatives of ephedrine and pseudoephedrine, obtained by substitution on a halogen hydroxyl, and a mixture of ephedrine and pseudoephedrine.

From the work Emde shows that chloride and bromide pseudoephedrine are more stable during hydrolysis than the same derivatives ephedrine.

However, these require additional data verification because the ratio of alkaloids determined only on the basis of the specific rotation of the mixture after hydrolysis of chloro and bromo.

In some cases, pseudoephedrine and ephedrine isomerization is accompanied by formation of byproducts that are not sufficiently studied.

Thus, cold sulfuric acid forms with both alkaloids same pseudoephedrine ester which by hydrolysis in boiling water or with hydrochloric acid gives a mixture of ephedrine and pseudoephedrine. A more prolonged action of concentrated sulfuric acid (5 days at 15 °) is obtained several side products, including, in particular, was found methylamine and others.

In normal, the factory method of isomerization of pseudoephedrine in a 50 percent. sulfuric acid obtained 10-15% resin and other products of irreversible changes in the study of which may give the material to elucidate the mechanism of isomerization pseudoephedrine ephedrine. It is possible that the isomerization with mineral acids takes place with the formation of intermediate products such as hlorefedringidrohlorid by the action of hydrochloric acid with hydrobromic acid bromefedringidrobromid and corresponding ester by the action of sulfuric acid. Hlorefedringidrohlorid quite easily obtained by the action of fuming hydrochloric acid efedringidrohlorid.

Similarly, should, apparently, and the action of alkalis on ephedrine and pseudoephedrine, but a message Callis and Schmidt [14] complete conversion of pseudoephedrine ephedrine under the influence of barium hydroxide was not confirmed by our experience and that of other authors.

From the patent literature it is known that ephedrine and pseudoephedrine racemize readily when heated with alkali alcoholates. From the racemate can regain the starting optically active components.

Complex metal compounds and salts thereof with ephedra alkaloids, probably also influence the course of the isomerization reaction.

Complexes of these alkaloids with CuS04 (or rather, with Cu (OH) 2 in the presence of alkali) were obtained and described Tungfengom Chin; Unfortunately, the author does not result in their composition.

The formation of the complex compound, probably due to the mandatory presence of two functional groups of these alkaloids and OH -NHCH3; Thus, according to Haley, dezoksiefedrin this complex does not.

The question of the isomerization pseudoephedrine ephedrine bought from us important works after PS Massagetova, opened in the 30s in Kazakhstan and Central Asia, large industrial thickets ephedra.

Isomerization method used in the chemical-pharmaceutical plant Chimkent developed VNIKhFI leads to the loss of up to 50% pseudoephedrine. In order to improve the yield of ephedrine and pseudoephedrine in the isomerization was undertaken this work.


Work on the isomerization pseudoephedrine ephedrine was carried out in three directions.

1. Isomerization psezdoefedrina in ephedrine in strict accordance with the factory method to identify possible gaps in the plant technology and the product of irreversible changes that should provide material for the construction of hypotheses about the mechanism of isomerization.

2. Isomerization of 50-percent. sulfuric acid, as in the previous case, but the introduction of various additives as additional catalysts. The additives were tested different substances, which could give complex compounds of methylamine and hydroxyl groups creating steric hindrance for attaching the hydroxyl side-NH-CH3 group.

3. Study of the effects of other agents that promote isomerization pseudoephedrine ephedrine.

Isomerization pseudoephedrine ephedrine

For the isomerization was taken 200 g of pseudoephedrine with t. Pl. 117 ° C and 550 ml of sulfuric acid (sp. Gravity 1.4). Sulfuric acid is heated to 80-90 ° C; to the hot sulfuric acid is gradually added pseudoephedrine; mixture was brought to a boil (t. bales. 117 ° C) and refluxed for 2 hours 15 minutes. The mixture was then cooled to 50 ° C and neutralized (temperature not higher than 70 ° C) is 25 percent. ammonia until alkaline to phenolphthalein; Further it is cooled to room temperature and filtered with suction, and the filter cake is pseudoephedrine. Thereafter pseudoephedrine removed from the filter and shaken with 70-80 ml of water (twice) and again filtered. All of the filtrates are collected together and agitated in a separatory funnel with dichloromethane (10 times 50 ml). The filtrate was evaporated and strongly once again shaken with dichloroethane. Dichloroethane extracts were neutralized by 28 percent. ethanolic solution of hydrochloric acid or dry hydrogen chloride gas until slightly acidic. The released ephedrine hydrochloride is filtered, washed on the filter with 50 ml of dichloromethane, dried and weighed. Mp. crude ephedrine hydrochloride 212-214 ° C. Pseudoephedrine-return was in our experience a high degree of purity and had m. Sq. 115-116 ° C (Vol. Mp. Pseudoephedrine base 117-118 ° C).

Pseudoephedrine-return re-used for the isomerization with the corresponding amount of acid in the same way; such isomerization have been six (until exhaustion taken pseudoephedrine).

Dichloroethane-alcohol liquor from each isomerization evaporated; thus obtained was a rather large number of alkaloids hydrochlorides, which we have studied. Failed to allocate an additional amount of ephedrine and pseudoephedrine; the last was again the isomerization. Evaporation of the mother liquor dropped 46 g of the crystalline hydrochloride, which is neutralized with 25 percent. ammonia in aqueous solution; THe 19 g of water-insoluble base which turned psevdoefedriiom.

Water and ammonia liquor was extracted with dichloromethane, and out of the hydrochloric acid was deposited 13.5 g of ephedrine and 34 g of liquid salts of unknown composition (discards); after the complete evaporation of the dichloroethane were allocated tarry residues in an amount of 10.1 g

As a result, multiple exhaustive isomerization of 200 g was obtained alkaloids 138.52 grams of ephedrine base, which is 69.25% as against 50% taken at the factory regulations. Products profound changes do not represent ephedrine or pseudoephedrine was obtained 57.8 g (28.90%). Unaccounted losses amounted to 3.68 g (1.84%).

Some increase in yield of ephedrine to be due to the complete use of ephedrine and pseudoephedrine, the solution in the form of hydrochloride in dichloroethane queen cells, more thorough cleaning pseudoephedrine, ephedrine, Vågå oil separation time alkaloids from each other, the use of hydrogen chloride gas instead of its alcoholic solution to precipitate the hydrochloride ephedrine dichloroethane extracts.

Options isomerization experiments with pseudoephedrine

In order to shift the equilibrium in the isomerization toward ephedrine several experiments were conducted with additions of various substances as catalysts, as well as acids and alkalis.

The results obtained should be considered preliminary, as the work was carried out with small amounts of pseudoephedrine and isomerization products have not been thoroughly identified. For each experiment, the isomerization is taken 10 g of pseudoephedrine, 25 ml of 50 percent. sulfuric acid and a catalyst is added. The reaction takes place at the boiling temperature of the reaction mixture during

2 hours and 15 minutes. Then isomerizate neutralized 25 percent. ammonia solution until alkaline to phenolphthalein. Pseudoephedrine return precipitate filtered, the residue on the filter was washed three times with distilled water with vigorous suction, the filtrate is extracted three times with dichloromethane (50 ml) and dichloroethane extract are combined and ephedrine precipitated by passing dry hydrogen chloride gas. The precipitated hydrochloride ephedrine is filtered, dried and weighed. In cases of interest are determined the specific rotation, and so on. Mp. ephedrine hydrochloride obtained.

As catalyze isomerization additives tested various elements which as ions could give complex salts mainly methyl amino group and create steric hindrance for attaching hydroxyl from this group, and the anions of weak with large molecule acid that could shift the reaction in the desired direction. Additives have also been tried adsorbents, and organic solvents, which could contribute to convergence methylamino and phenyl groups, facilitating connection hydroxyl trans towards methylamino group.

Thus, relatively better results were obtained with the addition of metal catalysts as iodine and copper sulfate; ephedrine is obtained by addition of iodine was racemic. When making copper sulfate ephedrine yield, compared with the plant, increases twice (50.1% vs. 25%), and the losses are reduced by 2.5-fold (9% vs. 25%). In comparison with our control experiment yield ephedrine introduction of copper sulfate (at single isomerization) increases by 11.3%.

Increased yields in control experiments apparently explained by a more thorough separation of alkaloids and using hydrogen chloride gas instead of 28 percent. alcoholic solution; when using the latter salt alkaloids partially soluble in alcohol, is added to the neutralization point, and pass into the liquor.

We were tested and the results of experiments Callis Schmidt, who argued that in the presence of Ba (OH) 2 may completely transform pseudoephedrine ephedrine; also studied isomerises action alkalis and acids at high temperatures and pressures.

Even at higher temperatures and pressures than experimental conditions Callis Schmidt and barium hydroxide isomerized pseudoephedrine. The action of various acids (boron, silica and oxalic) of pseudoephedrine, a mixture of different products which require further study.


1. In the isomerization method of pseudoephedrine at factory has been found that by careful extraction of ephedrine dichloroethane alcoholic mother liquor, after repeated washing pseudoephedrine isomerization and by passing hydrogen chloride gas instead of use it is possible to bring the alcoholic solution ephedrine to yield 70% (instead of 50% by According to the plant).

2. Experiments with various additives including complexing agents, have shown that the presence of copper increases the yield of isomerization products (up to 50% at one isomerization).

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