CS267251B1 - Method of cis-diaminodichloroplatinum complex preparation - Google Patents

Abstract

The solution relates to the method of preparation ois-diamine dichloroplatin complex I, which is used to prepare antitumor drugs. According to the solution, the complex I prepares controlled tetrachloroplatinate ammonolysis potassium, sodium or potassium ammonium at a concentration in the presence chloride of said elements by a certain concentration and hydrogen chloride by addition ammonia, its solution or solution ammonium carbonate or a solid form thereof at a certain temperature and pH. Compared with the methods used so far is preparation of the complex I according to the invention more rapidly and the product is cleaner, especially in terms of content Magnus salt.

Description

The invention relates to a process for the preparation of a cis-diamine dichloroplatinum complex of formula I

useful in the preparation of anticancer drugs.

Various methods for preparing small amounts of complex I have been described in the literature, the most commonly of which is given in Inorganic Syntheses (Vol 7, p. 241) and consists of ammonolysis of pure potassium tetrachloroplatinate solution in the presence of ammonium chloride with ammonia at below The pH of the reaction mixture reaches 9.0 to 9.2, the reaction takes 1 to 2 days and the product is heavily contaminated with Magnus salts, the removal of which requires repeated recrystallization or another purification method. IONCH ANSSSR, 20, 95/194? /) Is faster, but part of the product decomposes to platinum black, the removal of which is possible only by recrystallization with ultrafiltration of the solution · Preparation of the complex I through the corresponding platinum coordination compounds in which the acid ligand is bromine or iodine (Spanish patent C.472 342, US patent £ 4,273,755) j® lengthy and the product is additionally contaminated with silver ions ·

By studying the ammonolysis of solutions containing alkali metal tetrachloroplatinate, alkali metal chlorides, ammonium chloride and hydrogen chloride, we found that the determining factor of the rate of formation and purity of complex I is the temperature and acidity of the reaction mixture. ammonium carbonate ·

The result of the study is the original procedure for the preparation of complex I by controlled ammonolysis of a solution of potassium and / or sodium and / or ammonium tetrachloroplatinate with a concentration of 0.1 to 2 mol -1 in the presence of potassium and / or sodium chloride and / or ammonium chloride. 1 to 5 mol ·! “ ¹ and hydrogen chloride with a concentration of 0.01 to 5 mol ·! ¹ , by continuously or successively adding ammonia and / or ammonia solution and / or ammonium carbonate solutions with a concentration of 0.1 to 5 mol% and / or solid ammonium carbonate to a stirred reaction mixture at a temperature of 10 to 80 ° C and pH 4, 0 to 8.5,

After cooling the reaction mixture, complex I is isolated and further processed in a known manner into a highly pure substance suitable for medical purposes.

One of the advantages of this process is the possibility of combining a solid and a liquid source of ammonia, which can be used especially in ammonolysis of alkali metal tetrachloroplatinate solutions which contain large amounts of free hydrochloric acid and whose pH is close to zero. reaction volume, and thus to increase the yield of complex I · Another advantage compared to known processes is a significantly higher purity of the product, especially in terms of salt content Magnuse ·

Example 1.

To 48.0 ml of a solution of potassium tetrachloroplatinate prepared by reduction of potassium hexachloroplatinate with hydrazine hydrochloride containing 362.6 g of potassium tetrachloroplatinate and 177.6 g of hydrogen chloride, 283 g of ammonium chloride are added. The reaction mixture is heated to 60 DEG C. and for 45 minutes. se za in—

267 251 is added, with vigorous stirring, an ammonia solution having a concentration of 1.6 mol, l * at such a rate that the pH of the reaction mixture rises steadily to 4.5 to 5. The ammonia solution is added continuously for about 120 minutes so that the pH solution was maintained at 4.4 to 4.5. The resulting yellow solution was cooled to 4 ° C and the precipitate formed was collected on a frit, washed with 0.1 M hydrochloric acid solution and dried. 165 S 'of yellow crystalline substance are obtained, containing 90 parts by weight of complex I.

Example 2

To 7,000 ml of a solution containing 670 g of potassium tetrachloroplatinate and 255 S of hydrogen chloride, 600 g of ammonium chloride and 200 g of potassium chloride are added and solid ammonium carbonate is added portionwise to the mixture with vigorous stirring so that the pH of the solution reaches 6.5 · Pot® · the solution is heated to 45 ° C and the pH of the reaction mixture is maintained between 6.0 and 6.5 by continuous addition of saturated ammonium carbonate solution until the solution turns yellow to ocher or the first crystalline fractions precipitate . The resulting suspension is filtered on a frit at 45 DEG C. and worked up as in Example 1. The yield is 240 g of product containing 92% of complex I.

Example 3

The potassium tetrachloroplatinate solution adjusted to pH 6.5 in the same manner as in Example 2 is heated to 50 DEG C. · The pH of the solution is further maintained at 5.8 to 6.2 with vigorous stirring by continuous addition of a 2.6 ammonia solution. moth,!" ¹ until the solution turns yellow to ocher. The reaction mixture is cooled to 4 [deg.] C. and worked up as described in Example 1. 290 g of complex I with an impurity content of less than 10 parts by weight are obtained.

Example 4

In 13 000 ml of a solution of potassium tetrachloroplatinate prepared by reduction of potassium hexachloroplatinate with hydrochloride

267 251 hydrazine (containing 1 244 g of potassium tetrachloroplatinate and 473 8 hydrogen chloride) are dissolved at 20 ° C

600 g of ammonium chloride · The pH of the reaction mixture is then adjusted with gradual addition of NH solution with stirring

3.0 mol> l ¹ with a concentration of 2.6 up to a value of 8.0 to 8.2 and maintained at this value until the color of the liquid phase changes from the original red to yellow and from the ocher · The reaction mixture is cooled to 0 ° C to 4 ° C and the voluminous precipitate was isolated by filtration, washed with sodium chloride -1, 0,1 M ₀ l, dried and recrystallized.

The yield is a yellow product weighing 400 g containing 98% of complex I.

Claims (1)

Process for the preparation of a cis-diamine dichloroplatinum complex of formula I characterized in that the controlled ammonolysis of potassium and / or sodium and / or ammonium tetrachloroplatinate at a concentration of 0.1 to 2 mol%! ¹ is carried out in the presence of potassium and / or sodium and / or ammonium chloride at a concentration of 0.1 to 5 mol.1, and hydrogen chloride at a concentration of 0.01 to 5 mol.1, by continuous or gradual addition of ammonia and / or ammonia solution and / or ammonium carbonate solution with a concentration of 0.1 to 5 mol ·! ¹ and / or solid ammonium carbonate into a stirred reaction mixture at a temperature of 10 ° C to 80 ° C and a pH of 4.0 to 8.5, after which the precipitated complex I is isolated after cooling.