Process for production of cis-dichloro- (trans-1-1, 2-cyclohexanediamine) plati- num (II) Field of the Invention The invention deals with a new process for production of an antitumor effective compound cis-dichloro-(rans-1-1, 2-cyclohexanediamine) platinum (II) complex of the formula which is an intermediate in the synthesis of metal-containing antitumor agent oxaliplatin, i. e. (trans-l-1, 2-cyclohexanediamine)-(oxalato) platinum (II).

Background of the Invention The cis-dichloro-(trans-1-1, 2-cyclohexanediamine) platinum (II) was prepared until now according to US patent No. 4, 169, 846, by a long-termed reaction of potassium tetrachloroplatinate (II) with trans-l 2-cyclohexanediamine followed by recrystallization of the obtained raw product from boiling 0. 1 M hydrochloric acid. This known procedure has however several basic disadvantages. One of these disadvantages is in that the starting optically active trans-l-isomer of 1, 2-cyclohexanediamine is relatively expensive starting material. Other disadvantage is in that the recrystallization of the obtained raw product requires large amounts of diluted hydrochloric acid due to a low solubility of the cis-dichloro-(trans-1-1, 2-cyclohexanediamine) platinum (II) complex and the obtained yields of this final product are relatively low. Finally, the second starting material, i. e. crystalline potassium tetrachloroplatinate (II), is rather expensive as well.

The goal of the present invention is to find a new process for preparation of the cis- dichloro- (trans-1-1, 2-cyclohexanediamine) platinum (II) which would not suffer from the above disadvantages.

Summary of the Invention The above discussed disadvantages are not exhibited in a novel method for production of the cis-dichloro-(trans-1-1, 2-cyclohexanediamine) platinum (II) characterised in reacting 1 molar equivalent of alkali metal salt of tetrachloroplatinate (II) in an aqueous solution with 0. 9 to 1. 7 molar equivalents of trans-1-1, 2-cyclo- hexanediammonium tartrate at a pH value of the reaction medium between 7 and 12 that has been obtained by alkalinization thereof by an alkali metal hydroxide, followed by separation of the solid product from the aqueous reaction medium. In a particularly advantageous embodiment of the process of the invention, 1 molar equivalent of an alkali metal salt of tetrachloroplatinate (II) is treated with 1. 1 to 1. 3 molar equivalents of trans-1-1, 2-cyclohexanediammonium tartrate. Advantageously, the alkalinity of the reaction mixture is maintained during the reaction by additions of an alkali metal hydroxide within the pH range from 8 to 11. In a preferred embodiment, the aqueous suspension of trans-1-1, 2-cyclohexanediammonium tartrate is first alkalinized by an alkali metal hydroxide to a pH value higher than 8 and, prior to mixing with the aqueous solution of alkali metal tetrachloroplatinate (II), the obtained solution is separated from insoluble impurities present.

As the aqueous solution of an alkali metal tetrachloroplatinate (II), a raw aqueous solution of potassium tetrachloroplatinate (II) obtained by reduction of potassium hexachloroplatinate (IV) by hydrazinium dichloride, separation of insoluble parts and neutralisation of the free hydrochloric acid present in the obtained aqueous solution by an alkali metal hydroxide, may advantageously be used.

The process of the invention proceeds according the following reaction scheme : M2PtCL + C6Hlo (NH3) 2C4H406 + 2 MOH--> [PtC12 [C6HIo (NH2) 2]] + C4H406M2 + 2MCI + 2 H20 wherein M means an alkali metal.

Reaction temperature is not a critical parameter within the process of the invention.

The obtained cis-dichloro- (trans-1-1, 2-cyclohexanediamine) platinum (II) may be separated from the reaction mixture by standard separation techniques, washed with a diluted hydrochloric acid and/or by water and/or by a water miscible organic solvent,

advantageously by a low boiling alcool, and optionally also by ether, and subsequently dried.

The optically active trans-1-1, 2-cyclohexanediammonium tartrate may be prepared in advance by reaction of trans-1, 2-cyclohexanediamine with L (+)-tartaric acid, wherein it is not necessary to convert the said product to trans-1-1, 2-cyclohexanediamine by an otherwise difficult process which is very sensitive to the presence of even trace amounts of the air (decomposition of the tartrate, extraction of the liberated free diamine by an organic solvent, removal thereof by distillation and distillation of trans-1-1, 2-cyclo- hexanediamine in vacuo).

By using a slight excess of trans-1-1, 2-cyclohexanediammonium tartrate, one may obtain almost theoretical consumption of alkali metal tetrachloroplatinate (II) which is the most expensive part of the whole system, whereby eventual losses are mainly the losses during manipulation.

Furthermore, one of the advantages of the process for preparation of cis-dichloro- (trans- 1-1, 2-cyclohexanediamine) platinum (II) according to the invention is a possibility of continual maintaining of the proper alkalinity of the reaction medium by addition of an alkali metal hydroxide at approximately constant value of pH, advantageously in a pH range between 8 and 11. Thereby, formation of both reaction by-products and impurities is minimise. The termination of the reaction is indicated by the fact that the pH of the reaction system does not drop and maintains steady in the absence of addition of the alkali metal hydroxide.

The trans-1-1, 2-cyclohexanediammonium tartrate may, prior to the reaction with alkali metal tetrachloroplatinate (II), be made free from present insoluble impurities by such a way that its aqueous suspension is made alkaline by an alkali metal hydroxide to pH value of at least 8 and the obtained solution is brought into the reaction after separation of impurities.

Another advantage of the process for production of cis-dichloro-(rans-1-1, 2-cyclo- hexanediamine) platinum (II) according to the invention is based on the possibility to use a raw solution of potassium tetrachloroplatinate (II) obtained by reduction of potassium hexachloroplatinate (IV) with hydrazinium dichloride, removing insoluble matter and neutralisation of free hydrochloric acid by an alkali metal hydroxide, in the place of the solution of an alkali metal tetrachloroplatinate (II). This way, one may avoid a necessity

of preparation of a crystalline potassium tetrachloroplatinate (II) requiring concentration of large volumes of a solution of potassium tetrachloroplatinate (II) containing considerably high amounts of free hydrochloric acid and precipitation of the product by concentrated hydrochloric acid, which is difficult and risky as far as exhalations are concerned.

In the next part of the disclosure, the invention will be further illustrated by means of more concrete examples of its embodiment, whereby these examples are of illustrative character only and they by no way limit the scope of the invention which is unambiguously defined by patent claims.

Within the examples, the unit operations were performed, whenever necessary or possible, under limited access of air and the used water was purged with nitrogen prior its use.

Examples of the Invention Example 1 1084.6 g of an intermediate from production of cis-diammin-dichloroplatinum (II) represented by an aqueous solution containing 100. Og of potassium tetrachloroplatinate (II), was allowed to stand for three days at 5°C. The precipitated part of unreacted potassium hexachloroplatinate (IV) was filtered off. Strongly acidic filtrate was charged into a 2 liter vessel equipped by a stirrer, combined pH-electrode, nitrogen inlet and inlet for reactants, and was neutralised by an aqueous solution (approx.

2 M) of potassium hydroxide to pH = 5. 7. The adjusted solution was mixed with a second solution prepared by suspending of 73. 5 g of pre-made trans-1-1, 2-cyclo- hexanediammonium tartrate in 600 ml water, alkalinisation to pH = 8. 3 by potassium hydroxide solution of the above concentration, and filtration. In further, pH value of the reaction mixture was maintained at 9. 5-10. 0 by addition of approx. 2M solution of potassium hydroxide via a peristaltic pump. After 10 hours of stirring, when the pH value was constant, the formed cis-dichloro-(trans-l-1, 2-cyclohexane- diamine) platinum (II) was filtered off, washed with demineralised water, ethanol and ether and dried in vacuum oven to constant weight.

The yield was 89. ou of cis-dichloro-(trans-1-1, 2-cyclohexanediamine) platinum (II) i. e.

97.3% of theory, based on the content of potassium tetrachloroplatinate (II) in the starting material.

Example 2 47.6 g of pre-made trans-1-1, 2-cyclohexanediammonium tartrate was suspended in 400 ml of water and the pH value was adjusted to 8. 15 by the aid of an aqueous solution of potassium hydroxide (approx. 2M). The obtained solution was filtered and charged together with 65. 0 g of crystalline potassium tetrachloroplatinate (II) into 1 liter vessel equipped by a stirrer, combined pH-electrode, nitrogen inlet and inlet of potassium hydroxide. The pH value of the reaction mixture was kept at a value of approx. 10 by additions of potassium hydroxide solution of the above concentration. The formed cis- dichloro- (trans-I-1, 2-cyclohexanediamine) platinum (II) was filtered off, washed with water, diluted hydrochloric acid (0. 3 M HCI), ethanol and ether and dried in vacuum oven to constant weight.

The yield was 58. 1 g of cis-dichloro-(trans-1-1, 2-cyclohexanediamine) platinum (II), i. e.

97.6% of theoretical yield, based on the starting potassium tetrachloroplatinate (II).