CS209252B1 - Manufacturing proces of penicillamine - Google Patents

Description

(54) A method for producing penidlamine! The invention relates to a process for the preparation of penidlamine and its salts, in particular salts with hydrohalic acids, by cleavage of penidic acid or foamed acid.

Penidlamine, especially in its optically active, i.e., D (-) form, of the formula ^CH3 (!)

C — CH.COOH

Ζι l

CH SH NH ₂ .HX where X is chlorine or bromine has the ability to complex some metals, eg copper. In medicine, it is used to treat Wilson's disease, ie to release copper, accumulating in the body by poor metabolism.

The prior art process for the preparation of optically active penidlamine hydrochloride (British Pat. Nos. 854 339 and 959 817) is based on penicillin acid, obtained by alkaline hydrolysis of penicillin G and decarboxylation of the resulting penicillic acid. This is cleaved in the form of an aqueous solution of the sodium salt into mercuric chloride to form the insoluble mercuric complex, penidlamine and peniloaldehyde. Penidlamine hydrochloride is liberated from the complex by decomposition with hydrogen sulfide and purified via an isopropylidene derivative from which it is regenerated by boiling with dilute hydrochloric acid. The yields in this process are barely 40%.

The disadvantage of this method is, besides the low yield, the necessity to prepare penilic acid by decarboxylation of penicilic acid. Although this acid is also cleaved by mercuric salts into penidlamine and peniloaldehyde, yields are even lower (see T. Clarke et al., The Chemistry of Penidllin, p. 554, Princeton, N.J., 1949). Decomposition of Penile Acid Sodium in aqueous solution with mercury chloride; the team is dependent on accurate initial adherence to pH j and further processing of the mercury complex is associated with difficult and dangerous work with hydrogen sulfide, especially on a larger scale.

It has now been found that can be advantageously manufactured penidlamin ¹ and its salts, especially salts with metals halogenvodíj acids, acid cleavage or pěnilové foamer and method of the invention, i.e. whose principle consists in that the cleavage is carried out; hydrazine derivatives of the general formula: ___

209252 _!

wherein A is zero or -CO-, the substituents R ₁ and R ₂ , the same or different, denote hydrogen atoms, halogen atoms, nitro groups or alkyls having 1-3 carbon atoms, which together may form another fused aromatic nucleus, in aqueous medium in the presence of the acid whose salt is to be obtained at a temperature of 20-100 ° C, preferably at a temperature of 80-95 ° C.

Conveniently, the cleavage is carried out in an aqueous medium, in the presence of hydrogen halide, preferably chlorohydroic acid, in an amount of 1-5 mol. phenylhydrazine is used as the amount of the penicilic or penilic acid and the hydrazine derivative of the above formula;

2,4- dinitrophenylhydrazine.

Under the above conditions, cleavage of the thiazolidine ring of penilic or penicilic acid proceeds in a high yield, almost quantitatively. The hydrazine derivatives used react very readily with the carbonyl group of the penilaldehyde and give insoluble reaction products in a yield of up to 100%. After separation, the remaining solution of the penidlamine salt after evaporation with ether was evaporated to dryness in vacuo. The crude penicillamine salt is then purified, preferably by dissolving the residue to a saturated solution in butanol and precipitating the penicillamine salt from the solution with 3-4 times the volume of ethyl acetate. Thus, for example, the hydrochloride D (-) - foam is obtained ^. of amine in 85-95% yield, with an optical rotation of -52 to -54 (1.25% solution in N NaOH). The product thus obtained contains no starting materials and is suitable for clinical application.

The reaction can also be carried out with aryl-substituted semicarbazides, such as phenylcarbazide, but the yields are substantially lower, so that this method is less preferred than the process of the invention.

Examples

1. A mixture of 74.4 g of 95% penicillic acid, 40 g of {

2,4- dinitrophenylhydrazine, 18ml conc. hydrochloric acid and 2000 ml of distilled water are heated to 80-90 ° C with vigorous stirring. Initially, the reaction mixture foams strongly with released carbon dioxide and the red 2,4-dinitrophenylhydrazine slowly changes to yellow 2,4-dinitrophenylhydrazone>

Claims (3)

SUBJECT Process for the preparation of penicillamine and its salts, in particular salts with hydrohalic acids, by cleavage of penicilic acid or penilic acid, characterized in that the cleavage is carried out with a hydrazine derivative of the general formula Π: (AT) A.NH.NH, Wherein A denotes a single bond or a group R 1! -CO-, R and R _2, which may be identical or; denotes hydrogen, halogen, nitro. Peniloaldehyde. After 6 hours, the reaction mixture was stirred for 1 hour. It is cooled to 10-15 ° C, the precipitated crystalline substance is filtered off with suction and washed thoroughly with distilled water. After drying, 71 g of 2,4-dinitrophenylhydrazone are obtained. peniloaldehyde sb. 193 ^e C. The yellow filtrate containing dissolved penicillamine hydrochloride is concentrated in vacuo at 60 ° C to a volume of 150-200 ml, filtered with charcoal and then evaporated to dryness. The crude product obtained was dissolved in 60 ml of n-butanol with gentle heating and 220 ml of anhydrous ethyl acetate was added to the solution. The solution was allowed to crystallize at 0-5 ° C for 24 hours. The precipitated product is filtered off with suction, washed with a small amount of ethyl acetate and dried at 80 ° C. 31 g of D - (-) - penicillamine hydrochloride are obtained, i.e. 83.5%. M.p. 205 ° C (dec.), [Α] D = -53 ° (C = 1.25%, 1 N NaOH). By treatment of the mother liquors and crystallization of the second product, 4 g of a satisfactory quality can be obtained. Total yield: 35 g. ie 94.5%. 2. A mixture of 31 g of penilic acid, 19.8 g of 2,4-dinitrophenylhydrazine, 8.9 ml of conc. hydrochloric acid and 500 ml of distilled water was heated with stirring {6 hours at 80-90 ^e C. After cooling and the precipitated 2,4-dinitrophenyl peniloaldehy {bromide (34.8 g) filtered off with suction, washed with 200 ml of distilled water, and I The filtrate was treated with ether as in Example 1 after extraction with ether. The D (-) - penicillamine hydrochloride was obtained in a yield of 16.1 g, i.e. 86.6%, bt. 204-206 ° C (dec.), [Α] D = -53 °. 3. A mixture of 13.8 g 95% penicillic acid, 4 g phenylhydrazine, 3.4 ml conc. hydrochloric acid and 220 ml of distilled water are heated to 80 ° C with stirring. Decarboxylation occurs during the reaction and incomplete crystalline phenylhydrazone of penilaldehyde begins to precipitate out of solution. After 5 hours of heating, the reaction mixture is cooled, filtered from the precipitates, extracted with ether (100 ml) and concentrated to dryness in vacuo. The crystalline residue is dissolved in 5 ml of butanol and filtered from the impurities. By adding 20 ml of ethyl acetate to the filtrate, D (-) - penicillamine hydrochloride is isolated in a yield of 3.8 g, ie 55.3%. Mp 202-204 ° C (dec.)? / Α / θ ⁰ = -52 °. / { BACKGROUND OF THE INVENTION a group or alkyl having 1-3 carbon atoms which may be linked together by one or more carbon atoms. form an additional condensed and aromatic nucleus, in an aqueous medium in the presence of the acid whose salt is to be obtained, at a temperature of 20-100 ° C, preferably at 80-95 ° C. 2. Process according to claim 1, characterized in that phenylhydrazine or 2,4-dinitrophenylhydrazine is used as the derivative of the general formula II. j 3. A method according to claim 1, wherein the cleavage is carried out in an aqueous medium, e.g. the presence of hydrochloric acid, preferably hydrochloric acid, in an amount of 1-5 mol 1 mol of penicillic or penile acid starting material.