CS277517B6 - A method of purifying codeine prepared by morphine methylation - Google Patents

Abstract

The invention provides for the preparation of codeine in pharmacopoeial quality without side substances resulting from the methylation of morphine by extracting the prepared codeine in an organic solvent into an aqueous solution of inorganic or organic acid in the pH range of 7 to 5.4, preferably in the range of 6.8 to 6.0, after separating the aqueous layer by its extraction with a chlorinated organic solvent, precipitating the codeine base, dissolving it in ethanol and crystallization from an aqueous-alcoholic solution of phosphoric acid in the form of codeine phosphate in pharmacopoeial quality according to the requirements of the German Pharmacopoeia DAB 9. The field of application is the pharmaceutical industry.

Description

Method for purifying codeine prepared by methylation of morphine

Field of technology

The invention relates to a process for the production of chemical substances, in particular to the purification of codeine prepared by the methylation of morphine.

Current state

Requirements for pharmacopoeial quality parameters of pharmaceutical substances! prepared synthetically reduce or completely eliminate the presence of by-products.

Codeine, as an active ingredient in the manufacture of pharmaceutical preparations, is predominantly produced synthetically by the methylation of morphine isolated from poppy capsules. By-products from the methylation of morphine have been identified. The presence of 6-methylcodeine has been described by S. Pfeifer: Pharmazie 18, 409,

1963, which isolated it by multiple crystallization of codeine prepared by methylation. Demina, L.G. et al .: Ž.prikl.chim. 38, 399, 1965 described the isolation of alpha-methylmorpholinemetin isolated by a combination of separation on ion exchangers and fractional crystallization of sulfate salts. Cs. Author's Certificate No. 223 100 describes the presence of chlorinated 2-O-alkyl and 3-O-alkenyl derivatives and solves the process for purifying codeine synthesized from morphine by extracting an aqueous solution of codeine salts with a chlorinated organic solvent in the range of pH 4.0 to 5.5. Of the procedures described above for the industrial purification of codeine, only the procedure according to MS. author's certificate No. 223 100. in industrially produced codeine and its salts purified by the process according to MS. The presence of chlorinated 3-O- (1,2-dichlorovinyl) -morphine was proved by the author's certificate No. 223 100.

The essence of the invention

Purification of codeine and its salts from the above-described by-products has been solved by extracting codeine from an organic solvent, preferably a toluene solution, by gradually adding an aqueous solution of an inorganic or organic acid having 1 or 2 carbons in the range of values. pH 7.0 to 5.4, preferably in the range of 6.8 to 6.0, the aqueous solution after separation of the toluene layer is extracted with a chlorinated organic solvent, preferably trichlorethylene, the codeine base is precipitated from the aqueous layer by adjusting the pH in the range of 8 to 9, after separation, the codeine base is dissolved in 3 to 5 times the amount of aqueous or aqueous-alcoholic phosphoric acid solution, the pH of the solution is adjusted to 4.0 to 4.5 and the codeine phosphate is allowed to crystallize, from which the codeine base is released after separation. without by-products.

The details of the process according to the invention are apparent from the exemplary embodiment.

Exemplary embodiment

Example 1

To 500 L of a toluene solution of codeine prepared by methylation of morphine containing 35 kg of codeine base was gradually added 160 L of a 3.5% aqueous formic acid solution with stirring, then the pH of the aqueous layer was measured and adjusted by further addition to 10 to 20 L of aqueous solution. formic acid to 6.8. The aqueous layer is separated, the residual toluene is distilled off with steam and extracted three times with 50 l of trichlorethylene with stirring for 10 to 15 minutes each time. The aqueous solution is stripped of trichlorethylene residues by steam blowing and purified with 0.5 kg of activated carbon. From an aqueous solution of codeine formate, codeine base is precipitated with ammonia water to pH 8.5. The codeine base is filtered off and dried. Approximately 32 kg of codeine base, free of methylation by-products, are obtained, which is dissolved in 90 l of ethanol, 20 l of a 40% strength aqueous solution of phosphoric acid are added and the codeine phosphate is allowed to crystallize at pH 4.2. The crystallized codeine phosphate is filtered off, washed with 15 l of 50% aqueous ethanol and dried. Codeine phosphate meeting the quality parameters of the German Pharmacopoeia DAB 9 is obtained with the purity and color of a solution containing 99.95%.

Applicability of the invention

The invention is useful in the pharmaceutical industry.

Claims (1)

A process for purifying codeine prepared by methylation of morphine comprising extracting crude codeine in an aqueous solution of an inorganic or organic acid having 1 or 2 chlorinated organic solvents, characterized in that the crude codeine solution in an organic solvent, preferably toluene, is extracted by successive addition of aqueous inorganic solution. or an organic acid having a carbon number of 1 or 2 in the range of pH 7 to 5.4, preferably in the range of 6.8 to 6.0, the aqueous solution after separation of the toluene layer is extracted with a chlorinated organic solvent, preferably trichlorethylene, from the aqueous layer. the codeine base precipitates by adjusting the pH to between 8 and 9, after separation the codeine base is dissolved in ethanol and an aqueous or aqueous-alcoholic phosphoric acid solution is added, the pH of the solution is adjusted to between 4 and 4.5 and the codeine phosphate is allowed to crystallize from after separation, the codeine base is released without side substances.