RU2457838C1 - Method of obtaining trans-1,2-diaminocyclohexane tetrachloroplatinum (iv) - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry and pharmaceutics and deals with method of obtaining anti-tumour preparation of II generation, namely, trans-1,2-diaminocyclohexane tetrachloroplatinum (IV), which lies in the fact that chloroplatinic acid is subjected to interaction with trans-1,2-diaminocyclohexane dihydrochloride in water solution of hydrochloric acid with further filtration, separation of sediment, its dissolution in water and addition of lithium hydroxide.

EFFECT: output constitutes 80% of theoretical output.

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Description

The invention relates to methods for producing platinum (IV) compounds, namely, trans-1,2-diaminocyclohexantetrachloroplatinum (IV) (ormaplatin, tetraplatin), which is a second-generation antitumor drug.

There are several ways to obtain the compound trans-1,2-diaminocyclohexantetrachloroplatinum (IV), which are based on the amination reactions of the platinum (II) complex and its further oxidation in N, N-dimethylformamide-HCl-Cl ₂ medium at a temperature of 100 ° C (Eastland GJ // Drugs Fut. 1987. V.12. I.2. P. 139-141; Anderson WK, Quagliato DA, Haugwitz RD, et al. // Cancer Treat. Rep. 1986. V.70. P.997- 1002). The synthesis is carried out according to reaction (1) (where C ₆ H ₁₀ (NH ₂ ) ₂ -trans-d, l-1,2-diaminocyclohexane):

Closest to the claimed is a method for producing trans-1,2-diaminocyclohexantetrachloroplatinum (IV), based on the interaction of potassium hexachloroplatinate (IV) with trans-1,2-diaminocyclohexane dihydrochloride (Wyrig SD, Chaney SG // J. Label. Compounds Radiopharm. 1990. V.28. I.7. P.753-756; Upjohn. Natl Canser Inst. // Drugs Fut. 1991. V.16. I.2. P.187). The synthesis is carried out according to reaction (2):

A solution of potassium hexachloroplatinate (IV) (6.2 mg, 0.0128 mmol) in 2.9 ml of 1.0 N hydrochloric acid was evaporated almost to dryness under vacuum until an orange precipitate formed, and then a solution of 2.4 mg (0.013 mmol) of trans-1,2-diaminocyclohexane dihydrochloride in 2 ml of water. This solution, protected from light, was stirred for 10 hours. After that, the solution was evaporated in vacuo, and the solid product was separated from the starting material by suction in 2 ml of acetone. The acetone solution was filtered, concentrated to 0.2 ml and diluted with 2.0 ml of diethyl ether. The resulting suspension was centrifuged and the top of the solution was aspirated with a pipette. Ether was added, centrifuged, and the substance that floated to the surface was removed. The procedure was repeated twice. The resulting yellow precipitate was dried to constant weight. The yield of the target product was 3.1 mg (54%).

The disadvantage of this method, as well as the previous one, is the low yield of the main product, the use of additional reagents (acetone, diethyl ether, dimethylformamide), as well as the complexity and duration of the process of isolation of this substance using evaporation, salting out, centrifugation.

The goal is achieved:

- the creation of an optimal ratio of the concentration of the complex in solution, the concentration of trans-1,2-diaminocyclohexane dihydrochloride and the pH of the medium;

- the use of lithium hydroxide to increase the yield of the main product;

- reduction of synthesis time.

The essence of the proposed method is as follows.

Trans-1,2-diamine-cyclohexane dihydrochloride is added to platinum chloride in hydrochloric acid at room temperature. The precipitate formed is filtered off, washed with glacial acetic acid and dried. Then the precipitate is dissolved in water, adding lithium hydroxide. The reaction is carried out at room temperature. The process is completed when the solution above the precipitate becomes pale yellow. The trans-1,2-diamine-cyclohexantetrachloroplatin (IV) compound is filtered off, washed with alcohol and dried.

The basis of the proposed method for producing trans-1,2-diaminocyclohexantetrachloroplatinum (IV) is based on the following new data:

- found the maximum accumulation of the target product from the pH of the medium;

- minimized the processes of hydrolysis of the complex compounds of platinum (IV), which reduce the yield and purity of the product.

Comparison with the prototype shows that the proposed method has the following advantages:

- simplifies the synthesis of the target product;

- no additional reagents are used;

- processes of evaporation, salting out and centrifugation are excluded;

- reduced time to obtain the target complex of platinum (IV);

As a result, we obtain an increase in the yield and purity of the target product, trans-1,2-diaminocyclohexantetrachloroplatinum (IV), up to 80%.

Examples of the method

Example 1

To 4 g of H ₂ [PtCl ₆ ] * 6H ₂ O (7.7 · 10 ^-3 mol) add 1.48 g of trans-1,2-C ₆ H ₁₀ (NH ₃ ) ₂ * 2Cl (7.9 · 10 ^-3 mol) in 10 ml of 3 M HCl at room temperature. After 20 minutes, the precipitate formed is filtered off, washed with glacial acetic acid and dried in vacuo. To the obtained intermediate product - 3.84 g {trans-1,2-C ₆ H ₁₀ (NH ₃ ) ₂ } [PtCl ₆ ] (7.3 · 10 ^-3 mol), 0.63 g LiOH * H ₂ O (1.5 · 10 ^-2 mol) in 30 ml of H ₂ O. The reaction is conducted at room temperature with stirring for 2 hours until the color of the solution above the precipitate changes from red to pale yellow. The process is stopped, and the precipitate is filtered off, washed with alcohol and dried. The resulting compound crystallizes in the form of crystalline hydrate - [Pt {trans-1,2-C ₆ H ₁₀ (NH ₂ ) ₂ } Cl ₄ ] * 1 / 3H ₂ O, according to x-ray diffraction analysis (Khokhar AR, Xu Q., Al- Baker S. // J. Inorg. Biochem. 1993. V. 52. i.1. P. 51-58). The amount of the target product 2.82 g, which is 80% of theoretical. The target product is characterized by the following methods: elemental analysis, XRD, IR spectroscopy and UV spectrophotometry. Impurities of other complex compounds of platinum (IV-II) were not found.

Example 2

To 2 g of H ₂ [PtCl ₆ ] * 6H ₂ O (3.85 · 10 ^-3 mol) add 0.74 g of trans-1,2-C ₆ H ₁₀ (NH ₃ ) ₂ * 2Cl (3.95 · 10 ^-3 mol) in 5 ml of 3 M HCl at room temperature. After 20 minutes, the precipitate formed is filtered off, washed with glacial acetic acid and dried in vacuo. To the resulting product, 1.92 g of {trans-1,2-C ₆ H ₁₀ (NH ₃ ) ₂ } [PtCl ₆ ] (3.7 · 10 ^-3 mol) was added 15 ml of H ₂ O. The reaction was carried out at room temperature with stirring. After 2 hours, the process is stopped, and the precipitate is filtered off, washed with alcohol and dried. The yield of the target product is 48% of theoretical (0.85 g). The target product is isolated as the crystalline phase [Pt {trans-1,2-C ₆ H ₁₀ (NH ₂ ) ₂ } Cl ₄ ] * 1 / 3H ₂ O, which is characterized by elemental analysis, XRD, IR spectroscopy and UV spectrophotometry . Impurities of other complex compounds of platinum (IV-II) were not found.

Example 3

To 6 g of H ₂ [PtCl ₆ ] * 6H ₂ O (1.15 · 10 ^-2 mol) add 2.22 g of trans-1,2-C ₆ H ₁₀ (NH ₃ ) ₂ * 2Cl (1.2 · 10 ^-2 mol) in 15 ml of 3 M HCl at room temperature. After 20 minutes, the precipitate formed is filtered off, washed with glacial acetic acid and dried in vacuo. To the resulting product, 5.76 g of {trans-1,2-C ₆ H ₁₀ (NH ₃ ) ₂ } [PtCl ₆ ] (1.1 · 10 ^-2 mol) was added 1.26 g of LiOH * H ₂ O (3.0 · 10 ^-2 mol ) in 45 ml of H ₂ O. The reaction is carried out at room temperature with stirring. After 2 hours, when the solution above the precipitate becomes pale yellow, the process is stopped and the precipitate is filtered off, washed with alcohol and dried. The yield of the target product is 58% of theoretical (3.05 g). The product - [Pt {trans-1,2-C ₆ H ₁₀ (NH ₂ ) ₂ } Cl ₄ ] * 1 / 3H ₂ O was characterized by the following methods: elemental analysis, XRD, IR spectroscopy and UV spectrophotometry. Impurities of other complex compounds of platinum (IV-II) were not found.

Example 1 shows the optimal conditions for obtaining the complex compound trans-1,2-diaminecyclohexantetrachloroplatinum (IV), both in the concentration of platinum in the solution and in the purity of the main product. The addition of hydrochloric acid prevents the hydrolysis of {trans-1,2-C ₆ H ₁₀ (NH ₃ ) ₂ } [PtCl ₆ ] and does not give rise to an amination reaction in the preparation of the intermediate in the first step. Lithium hydroxide is necessary to neutralize the hydrochloric acid released during the hydrolysis of {trans-1,2-C ₆ H ₁₀ (NH ₃ ) ₂ } [PtCl ₆ ], so that the amination process is complete and the yield of the target product is increased. If neutralization with lithium hydroxide is not carried out, as a result of the amination reaction, the pH of the solution will decrease, which will lead to protonation of trans-1,2-diaminecyclohexane and the rate of obtaining the target product will decrease, and the yield will decrease (example 2). With an increase in the concentration of lithium hydroxide, the process of alkaline hydrolysis is realized, and hydrolyzed forms of platinum (IV) complexes are formed, and the amount of the main product decreases (Example 3).

Thus, this method allows to obtain a compound of trans-1,2-diaminocyclohexantetrachloroplatinum (IV) in high yield and without impurities (example 1).

Claims (1)

A method of producing trans-1,2-diaminecyclohexantetrachloroplatinum (IV) from an aqueous solution using trans-1,2-diaminecyclohexane dihydrochloride, characterized in that the platinum chloride is reacted with trans-1,2-diaminecyclohexane dihydrochloride in an aqueous solution of hydrochloric acid at room temperature, the precipitate formed is filtered off, washed with glacial acetic acid, dried and dissolved in water, 2 equivalents of lithium hydrochloride are added with respect to the initial platinum complex and the process of lead ut at room temperature, followed by isolation of the target product by filtration.