CS208139B2 - Method of making the ergotamintartrate - Google Patents

Description

(54) Method of producing ergotamintartrate

The present invention relates to a new process for the production of ergotamintarthritis.

Ergotamintartrate is a well-known and important product in human therapy and, therefore, is of great practical importance for industrial large-scale production of ergotamintartrate, in accordance with pharmacopoeial prescriptions.

There are already many ways to make this product. Thus, for example, the method of A. Stoll / Helv. Chim. Aeta 28, 1 305 (1945)] and crushed ergotamine crystals containing acetone and water with a stoichiometric amount of d-tartaric acid to a slurry and rapidly heated with methanol containing 20% water, during which the ergotamine tartrate in crystalline form is separated.

According to Soviet Patent Specification No. 268,594, 85-90% ergotamine, 5-10% ergot amine and an alkaloid base containing about 5% ergometrine are dissolved in methanol and mixed with a 5.2% aqueous tartaric acid solution, and then the separated ergotamintartrate is separated. .

The yield is 91% ergotamine content of total alkaloids, the quality of the product obtained is not mentioned in the cited patent.

Methods of salt formation in an aqueous methanolic medium have the disadvantage that chemically pure ergotamine, as well as crystalline ergotamines containing less than a stoichiometric amount of solvent in A. Stall crystals, form anergotamine crystals with 2 moles of acetone and 2 moles of water, see Helv. Chim. Acta 28, 1 304 (1945)] are only transiently soluble in methanol, and thus the ergotamine base may be excreted from the solution prior to the formation of ergotamine tartrate, as a result of which the obtained ergotamine tartrate is contaminated with a considerable amount of ergotamine base.

According to German patent documents. No. 2,021,706 and 2,037,560, ergotamine is dissolved in chloroform and the solution is mixed with a stoichiometric amount of d-tartaric acid dissolved in methanol. After evaporation of the solution, ergotamintartret is obtained in crystalline form.

According to Polish Patent Specification No. 61,719, a stoichiometric amount of a 2-4% solution of d-tartaric acid in methanol is added to the ergotamine solution prepared with trichlorethylene and the crystalline product obtained is separated.

In these methods, the disadvantage of salt formation in methanol is avoided since the ergotamine base in chlorinated hydrocarbons is kept stable in solution. At the same time, there is another disadvantage that the product can be contaminated with other alkaloids present in the starting solution, in particular the therapeutically effective ergotaminin produced during industrial processing.

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a new process for the production of ergotamine tartrate free of all the disadvantages of the known processes, in which the salt is formed in a stable and chemically pure ergotamine solution so as to obtain a pure product in high yield. from the pharmacopoeia.

It has been discovered that by dissolving ergotamine at room temperature in a given amount of a mixture of methanol and dichloromethane of a certain composition, ergotamine is stable in solution, whereas the ergotamine formed during processing is not dissolved at all and can be easily removed. When a stoichiometric amount of d-tartaric acid dissolved in methanol is then added to the solution obtained, ergotamintartrate of purity corresponding to the prescriptions of the pharmacopoeia is separated.

The present invention provides a process for the preparation of ergotamine tartrate by reacting ergotamine with d-tartaric acid in the presence of a solvent, characterized in that ergotamine is dissolved in a 4: 1 to 3: 1 mixture of methanol and dichloromethane at room temperature; The solution is mixed with the methanolic solution of tartaric acid used in a 2-5% molar excess and the precipitated crystalline ergotamine tartrate is separated from the reaction mixture.

A 4: 1 to 3: 1 mixture of methanol and dichloromethane is used in the process according to the invention in a quantity of 12 to 15 times by volume, based on the weight of the alkaloid base to be dissolved.

In a practical embodiment of the process of the invention, the ergotamine crystals containing acetone and water are dissolved at room temperature in a twelve-fifteen-fold volume of 4: 1 to 3: 1 methanol / dichloromethane based on the alkaloid base weight, or the undissolved residual ergotamine is filtered. the solution is clarified with activated carbon as required, and then the clear solution is mixed with a 2-5% excess of an 8 to 12% methanolic d-tartaric acid solution.

The resulting crystalline ergotamintartrate suspension is then conveniently cooled to 0 to + 5 ° C and stirred at this temperature for several hours. The crystalline product is then collected by filtration, washed at 0 ° C to + 5 ° C with methanol and dried.

The process according to the invention is illustrated by the following examples. However, these examples are not intended to limit the invention in any way.

Example 1 g of ergotamine crystallized from acetone and water (ergotamine content 82 95, ergotamine not included, loss on drying 17.5%) is dissolved at room temperature with stirring in a mixture

100 ml of methanol and 30 ml of dichloromethane. (The resulting sulfur solution was stirred for a further 2 hours, no precipitation was observed, so the solution was sufficiently stable.) 1 g of activated carbon was then added to the solution, stirred at room temperature for 20 minutes and then filtered. The charcoal remaining on the filter is then washed with 40 ml of methanol and the wash liquid is combined with the original filtrate.

A solution of 1.1 g of d-tartaric acid in 10 ml of methanol is then added to the clear ergotamine solution obtained in this way while stirring at room temperature. The excretion of ergotamine tartrate begins 1 to 2 minutes after the addition of the tartaric acid solution. The precipitated crystalline product suspension is then cooled to 0 to + 5 ° C with stirring and stirred at this temperature for 2 to 3 hours.

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The crystalline product obtained is filtered off, washed with 10 ml of methanol cooled to 0 DEG C. and dried. 8.8 g of ergotamintartrate (92% of theory), m.p. 184 DEG-186 DEG C., [.alpha.] D @ 20 = -156 DEG (C = 0.6, chloroform); this value is specific to the base rotation. Content of active substance in the product: 99% (calculated on the dry substance). Loss on drying: 3.5%.

Example 2 kg of crystalline ergotamine containing acetone and water (ergotamine content 79%, ergotamine content 5%, loss on drying 15.45) were dissolved at room temperature with stirring in a mixture of 200 L of methanol and 50 L of dichloromethane. The undissolved residual ergotamine is filtered off and dried (918 g). This ergotaminin is longer aside for epimerization.

To the filtered solution was added 4 kg of activated carbon and stirred at room temperature for 20 minutes. The mixture is then filtered, the adsorbent remaining on the filter is further washed with 80 ml of methanol and the wash liquid is combined with the original filtrate.

A solution of 2.1 kg of tartaric acid in 20 liters of methanol was added to the clear solution obtained at room temperature and with stirring. Ergotamintartrate begins to secrete one to two minutes after the addition of tartaric acid.

The crystalline suspensions are cooled to 0 to + 5 ° C with stirring and stirred at this temperature for 2 to 3 hours. The crystalline product is then filtered off, washed with 20 liters of methanol cooled to 0 DEG C. and dried.

This gives 16.4 kg of ergotamintartrate (88% of theory), m.p. 185-187 [deg.] C, [delta] -154 [deg.] (C = 0.6, chloroform). This value is specific to the base rotation. The active compound content, calculated on the dried substance, is 98.6%. Loss on drying: 4.2%.

Claims (2)

SUBJECT OF THE INVENTION Process for the preparation of ergotamine tartrate by reacting ergotamine with d-tartaric acid in the presence of a solvent, characterized in that ergotamine is dissolved in a 4: 1 to 3: 1 mixture of methanol and dichloromethane at room temperature, or any undissolved ergotamine is removed, the solution is combined with a methanolic solution of d-tartaric acid, which is used in a 2-5% molar excess, and the precipitated ergotamine tartrate crystals are separated from the reaction mixture. 2. The process of claim 1 wherein the ergotamine is dissolved in a twelve to fifteen times the volume of methanol / dichloromethane based on the alkaloid base weight.