CS251605B1 - Preparation method of the adrimycine - Google Patents

Abstract

Preparation of adriamycin by bromination of tuunomycin is carried out in an absolute mixture solvents of dioxane and dimethylsulfoxide at a volume ratio of 4 to 9: 1, at temperature + 2 to + 10 ®C, for 100 to 120 hours then the 14-bromodeunomycin precipitate is hydrolyzed in an alkaline medium and then the reaction mixture is neutralized with oxide carbon dioxide. The advantage is roughly double the reaction yield against the prior art.

Description

The invention relates to a process for the preparation of odriamycin by bromination from daunomycin. Adriamycin of Formula I

(1) is an enthrecycline antibiotic with an anticancer effect, which is used in the treatment of certain cancers (Carter et al., International Symposium on Adriamycin, Springer Verlag 1972). The preparation of adriamycin from daunomycin of formula II is described

wherein the reaction proceeds through the intermediate 14-helodaunomycin, whose alkaline hydrolysis produces adriamycin (U.S. Pat. No. 3,803,124). The halogenation, e.g. bromination, is carried out in a mixture of dioxane and methenol for 4 h at room temperature, whereupon the 14-bromo-daunomyein obtained is evaporated to dryness and recrystallized.

Alkaline hydrolysis, e.g. with sodium hydroxide solution at pH 10.3, yields the desired end product in a total yield of about 37%.

The disadvantage of this process is the low yields of adriamycin and the formation of decomposition products as well as the undesirable daunomycin derivative of formula III

/ 111 /

These disadvantages are overcome by the process for the preparation of adriemycin according to the invention, which is characterized in that the bromination of daunomycin of the above formula II is carried out in a mixture of ebsolute dioxane-type solvents and dimethylsulphoxide in obl. a ratio of 4 to 9, at a temperature of +2 to + 10 ° C, for 100 to 120 h, after which a 5 to 10-fold volume of absolute ether was added with the 14-bromodeunomycin precipitate of formula IV

The reaction mixture is neutralized with carbon dioxide.

The new process preserves the reaction stages of the synthesis of adriamycin from daunomycin, but alters the reaction conditions in the bromination of daunomycin, and completely the process for isolating the product 8 thus increases the synthesis yield by about twice as much as the above preparation.

In the first step, the bromination of daunomycin takes place in an environment of absolute polar solvents. Under preferred conditions, the bromination takes place in dioxane and dimethylsulfoxide, which are in a ratio of 4 to 9: 1, with the addition of 1.1 to 1.6 moles of bromine dissolved in a minor amount of chloroform. The reaction is carried out at a temperature of +2 to +10 ° C for 100 to 120 h. Addition of a multiple volume of absolute ether yields a precipitate of the 14-bromodomainycin of the above formula IV.

The bromo derivative thus prepared is hydrolyzed in a second step, e.g. 0.1 N sodium hydroxide for 5 to 20 minutes at 10 to 15 ° C. After completion of the reaction, neutralization with carbon dioxide is performed and the product is isolated. The obtained adriamycin base is converted into a salt form which is used in clinical practice. Prepared compounds were identified by UV, mass and NMR spectra. The final product is also chromatographically comparable to the adriamycin standard.

The following is an example of a production method according to the invention.

200 mg of daumomycin hydrochloride are suspended in 20 ml of absolute dioxane and dissolved by adding 4 ml of dry dimethyl sulfoxide. To the solution was added 72.5 mg of dry bromine in 1 mL of absolute chloroform. The reaction mixture is allowed to react at +2 ° C for 04 hours.

110 ml of absolute ether was then added to the reaction mixture and allowed to stand at 0 ° C for 0.5 h. again precipitated with ether. 212 mg of 14-bromo daunomycin, m.p. 176 C (crystallized chloroform, methanol) 150 mg of 14-bromdaunomycin was dissolved in 2 ml of methanol with the addition of 10 ml of 0.1 N sodium hydroxide.

The reaction mixture was left at 12 ° C for 10 minutes. The solution is neutralized with solid carbon dioxide and 50 ml of water are added. The reaction mixture is extracted repeatedly with chloroform until the orange phase of the aqueous phase is lost.

The chloroform extract was dried over sodium sulfate and evaporated to dryness from a water pump vacuum at 25 ° C. The residue was dissolved in 3.5 ml of absolute methanol and 3: 1 chloroform and 9.5 mg of dry hydrogen chloride in 5 ml of absolute ether was added.

90 ml of absolute ether are added and the mixture is left at 0 ° C for 20 minutes. The resulting precipitate was filtered off, washed with ether and recrystallized (methanol, ethanol, chloroform). 117.5 mg of adriamycin hydrochloride, m.p. Mp 206-208 ° C. The total yield of synthesis is 80%.

SUBJECT OF THE INVENTION

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of adrinemycin of formula I O 'OH COCH ₂ OH CH ₃ oo OH of NH _2/1 / bromination of daunomycin in a solvent mixture containing dioxan and hydrolyzing the resulting 14-bromdaunomycinu in an alkaline medium, characterized in that the bromination of daunomycin is carried out in a mixture of absolute type solvents, dioxane and dimethyl sulphoxide in 4 to 9: 1 v / v at +2 to +10 ° C for 100 to 120 hours, after adding 5-10 times the absolute ether volume, the 14-bromdaunomycin precipitate is subjected to the above hydrolysis and then the reaction mixture is neutralized with oxygen carbon dioxide. Severography, n. P., MOST