CS219420B1 - A method for preparing a crystalline ergotamine base from its salts - Google Patents

Abstract

A method for preparing crystalline ergotamine base from its salts, consisting in suspending the ergotamine salt in acetone or a mixture of acetone with a maximum of 20% methanol, ethanol, dioxane, tetrahydrofuran or ethylene glycol, and adding to the suspension an aqueous solution containing an equivalent amount of base, e.g. sodium or potassium bicarbonate, sodium or potassium carbonate, sodium, potassium, calcium or barium hydroxide, or ammonia, thereby dissolving the salt and releasing the ergotamine base, which crystallizes from the given medium.

Description

The invention relates to the production of ergotamine, an ergot alkaloid, which has a wide application in gynecology, internal medicine and neurology in the form of addition salts, usually tartrates. Extraction of the relevant ergot type yields a crude summary of ergot alkaloids containing ergotamine and ergotaminin as the main constituents. Ergotaminin is epimerized to ergotamine by preparation of ergotamine sulfate [Taj. čs. Pat, No. 343; Helv. Chim. Acta 28, 1283 (1945); Acta Pol. Pharm. XXII, 237 (1965);].

For further processing into ergotamine tartrate, ergotamine base should be released from ergotamine sulphate. According to MS. taj. U.S. Pat. No. 755, the base was liberated with an aqueous solution of an inorganic base and extracted into ether. After addition of water to the concentrated ether solution, the ergotamine aqueous ether base crystallizes. The process essentially utilizes the low solubility of ergotamine base in ether; a considerable amount of ether is required for the extraction, and therefore only a small amount of ergotamine sulphate is processed in one batch. The procedure is lengthy and laborious. A major disadvantage is the low refining effect of crystallization of ergotamine from aqueous ether. Therefore, further crystallization from eg aqueous acetone [Helv. Chim. Acta 28, 1283 (1945);].

The process according to the invention removes the above drawbacks and makes it possible to prepare ergotamine sulphate directly with an aqueous acetone base (ergotamine without intermediate extraction of immiscible solvents. This is achieved by adding an aqueous base solution such as sodium or potassium carbonate, sodium or potassium bicarbonate, sodium, potassium, calcium or barium, or ammonia, to a suspension of ergotaminium sulphate in acetone or in a mixture of acetone with another solvent such as methanol, ethanol, dioxane, tetrahydrofuran or ethylene glycol.

The ergotamine sulphate dissolves and releases the ergotamine base. The precipitated inorganic salt is either filtered off and the ergotamine aqueous acetone base crystallizes from the clear solution, or the ergotamine acetone base is crystallized together with the inorganic salt, which is separated in a subsequent operation by dissolving the ergotamine base in methanol / methylene chloride and filtering off the insoluble matter. The base can also be liberated by adding a suitable adsorbent to decolorize a solution of, for example, activated carbon, alumina or silica gel. According to the invention, the ergotamine base is obtained in the desired purity and in high yield.

It has further been found that the ergotamine base can also be released from ergotamine salts other than sulfate, for example chloride, tartrate, acetate, methanesulfonate, hydrophosphate or oxalate. This can be used in laboratory preparations or to prepare very pure ergotamine by repeatedly preparing the appropriate salt and releasing the ergotamine base.

The following examples illustrate the embodiment of the invention:

Example 1 kg of ergotamine sulphate is suspended in a mixture of 49 l of acetone and 7 l of ethanol, 0.5 kg of activated carbon is added to the suspension and the mixture is heated to 50 ° C. A solution of 1.4 kg of sodium bicarbonate in 14 L of water is then added to the suspension, the solution is filtered and the activated carbon is washed on the filter with 7 L of acetone. The ergotamine water-acetone base crystallizes from the filtrate upon cooling, which is filtered off with suction and washed with acetone.

Example 2 kg of ergotamine sulphate is suspended in 170 l of acetone and a solution is added to the suspension

3.5 kg of sodium bicarbonate in 50 l of water. The suspension dissolves and, upon cooling, the aqueous acetone base of ergotamine begins to crystallize together with sodium sulfate, which is isolated by filtration.

Example 3

150 g of ergotaminium chloride are suspended in a mixture of 150 ml of dioxane and 900 ml of acetone, the mixture is heated to boiling and then a solution of 20 g of sodium carbonate in 300 ml of water is added. After filtration, the water-acetone base of ergotamine crystallizes from the filtrate.

Example 4 g of ergotamine acetate are suspended in 50 ml of acetone and 5 ml of ethylene glycol and a solution of 1 g of sodium hydroxide in 15 ml of water is added to the heated suspension. After the suspension is dissolved, the solution is filtered and the water-acetone base of ergotamine crystallizes from the filtrate after cooling.

Claims (1)

SUBJECT A process for preparing a crystalline ergotamine base from its salts, characterized in that the ergotamine salt is suspended in acetone or a mixture of acetone with a maximum of 20% methanol, ethanol, dioxane, tetrahydrofuran or ethylene glycol and an aqueous solution containing an equivalent amount of base or potassium, sodium or potassium carbonate, sodium, potassium, calcium or barium hydroxide, or ammonium to dissolve the salt and release the ergatamine base, which crystallizes from the environment.