JP3022264B2 - Synthesis method of platinum complex - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing cis- [oxalato (trans-1-1,2-cyclohexanediamine) platinum (II)] which is a divalent platinum complex useful as a raw material for an anticancer drug. More specifically, cis- [oxalato (trans-1-1,2-cyclohexanediamine) platinum (I
I)].

[0002]

2. Description of the Related Art The cis- [oxalato (trans-1-1,2-cyclohexanediamine) platinum (II)] (hereinafter also referred to as "oxalato complex") represented by the formula (2) is obtained by combining potassium chloroplatinate (II) with Trans-1-1,2-cyclohexanediamine is reacted to convert to cis- [dichloro (trans-1-1,2-cyclohexanediamine) platinum (II)], which is further reacted with silver nitrate. Cis- [diaco (trans-1-1,2,1-2)
-Cyclohexanediamine) platinum (II)] (hereinafter also referred to as "diaco complex"), and then adding oxalic acid.

In this production method, when the reaction between the diako complex and oxalic acid is completed in a short time of about 2 hours, a high-purity product having a small amount of by-products can be obtained, but the yield is 50 to 6
There is a disadvantage that it is as low as 0%. On the other hand, if the reaction time of the above reaction is increased to about 24 hours in order to improve the yield, the yield is improved to about 70%. There is a problem that the amount increases and impurities are mixed into the target oxalato complex to lower its purity.

[0004] Pharmaceuticals such as anticancer drugs are required to have high purity, and if even a small amount of impurities are mixed, not only the activity as a drug is reduced by the amount of the impurities, but also the impurities cause a further reduction in activity. In the worst case, the impurity is toxic and its administration to the patient can be counterproductive.

When these impurities are mixed in the final product, not only the labor and cost required for the separation and removal thereof become enormous, but also a part of the target product is lost at the time of the separation and removal, so that the target generation of the impurities is prevented. It is most desirable to keep contamination of the product to a minimum. Therefore, at present, the production of impurities is suppressed by shortening the reaction time at the expense of improving the yield. However, it is natural that it is desirable to improve the yield without mixing impurities.

[0006]

SUMMARY OF THE INVENTION The present invention has been made in order to meet this demand, and it is intended to produce a desired high-purity platinum complex while suppressing contamination of impurities by a relatively simple operation. An object is to provide a method which can be synthesized in a yield.

[0007]

The method for synthesizing the platinum complex according to the present invention is represented by the following general formula 1 (wherein the configuration of 1,2-cyclohexanediamine is trans-1). Reaction of diaco complex with oxalic acid yields general formula 2
(Wherein the steric configuration of 1,2-cyclohexanediamine is a trans-1 form, and R is selected from the chemical formula 3, chemical formula 4, chemical formula 5, chemical formula 6, chemical formula 7, or chemical formula 8). A method of synthesizing an oxalato complex according to the present invention, wherein a pH is adjusted to 3.0 to 6.0 by adding an alkali solution at the time of adding oxalic acid.

Hereinafter, the present invention will be described in detail. In the present invention, when the dioxaplatinum complex of the formula 1 is reacted with oxalic acid to synthesize the desired oxalate complex of the formula 2,
It is characterized by adding an aqueous alkali solution.

Since the aqueous solution of the diako complex before the addition of oxalic acid or the like is strongly acidic (less than pH 1) and has a high hydrogen ion concentration, the dissociation degree of hydrogen ions of oxalic acid is reduced even when oxalic acid, which is a weak acid, is added. Low, and thus the concentration of oxalate ions in the aqueous solution is low, so that the rate of ligand exchange reaction between water molecules coordinated with the diako complex and oxalate ions in the aqueous solution is slow, and the target platinum complex. It is assumed that the oxalato complex cannot be synthesized in a short time with high yield.

In order to promote the ligand exchange reaction between the diako complex and oxalic acid, the present inventors increased the dissociation degree of oxalic acid to increase the oxalate ion concentration in the aqueous solution. Various experiments were performed under the hypothesis that it should be good.

Therefore, the present inventors thought that the pH of the aqueous solution should be increased in order to increase the oxalate ion concentration, and tried to increase the pH by adding an alkaline solution.
The oxalato complex, which is the target product, can be synthesized with high purity and high yield. As the alkaline solution, a potassium hydroxide solution, a sodium hydroxide solution, and a lithium hydroxide solution can be used.

The amount of the alkaline solution to be added is determined by the pH of the aqueous solution.
Is adjusted to a range of 3.0 to 6.0. The reason why the pH is limited to this range is that if the pH is less than 3.0, a sufficient reaction promoting effect cannot be obtained, and if the pH exceeds 6.0, multimerization of the diako complex occurs. But this p
In the H range, even if the above-described reaction promotion and suppression of multimerization can be achieved to some extent, they may not be achieved to a sufficiently satisfactory degree. In order to achieve a sufficiently satisfactory reaction acceleration and suppression of multimerization, the pH is adjusted by adding an alkali.
It is desirable to set the range to 4.0 to 5.0.

The addition of the alkaline solution to the aqueous solution may be performed before, after, or simultaneously with the addition of oxalic acid, and the concentration of the alkaline solution is preferably about 10 to 15%. By the addition of the alkali, a yield substantially equal to the yield obtained by performing the reaction between the diako complex and the diako complex for 24 hours can be obtained in about 2 hours. The generation of impurities is suppressed by the reduced amount, and the coloring of the product is also eliminated, and it becomes possible to obtain the target oxalate complex of high purity in high yield.

[0014]

Next, examples relating to a method for synthesizing a platinum complex according to the present invention will be described.

[0015]

Example 1 562.5 g of potassium chloroplatinate and 154.8 g of trans-1--1,2-cyclohexanediamine
Was dissolved in 3.5 liters of water and mixed to obtain a cake-like cis- [dichloro (trans-1-1,2-cyclohexanediamine) platinum (II)] with a yield of 96% (re-formed). Without crystals). This was suspended in 5.7 liters of water, and the suspension was added with silver nitrate 442. After adding 2.8 liters of water in which Og was dissolved, the mixture was stirred at room temperature for 24 hours in a dark place, and the formed precipitate of silver chloride was removed by filtration.

Thereafter, 164.0 g of oxalic acid was added to the filtrate, and an aqueous potassium hydroxide solution was further added while measuring the pH of the filtrate until the pH reached about 4.5. After the addition, the mixture was allowed to react at room temperature for about 2 hours to obtain crude cis- [oxalato (trans-1-1,2-cyclohexanediamine) platinum (II)] (oxalato complex).
A yield of 1.5% could be obtained. Next, the crude crystals were dissolved in water while heating, filtered, cooled to room temperature, and the precipitated platinum crystals were collected by filtration and washed with a small amount of water. The obtained crystal was dried to obtain a target white platinum crystal having few impurities as described later.

[0017]

Comparative Example 1 An oxalato complex was synthesized under the same conditions as in Example 1 except that an aqueous potassium hydroxide solution was not added. As a result, crude crystals could be obtained at a yield of 58.5%. Next, the crude crystal was purified in the same manner as in Example 1 to obtain a white platinum crystal having few impurities as described later.

[0018]

Comparative Example 2 An oxalato complex was synthesized under the same conditions as in Comparative Example 1 except that the reaction time after the addition of oxalic acid was changed to 24 hours. As a result, crude crystals were obtained in a yield of 71.2%. Was. Next, the crude crystals were purified as in Example 1 to obtain light brown crystals.

The purity of the oxalato complexes of Example 1 and Comparative Examples 1 and 2 was determined by high performance liquid chromatography (HPLC).
The method was performed according to an absolute calibration method using the method. In other words, a known amount of the standard of the unreacted portion considered as an impurity is introduced stepwise, the peak area of the chromatogram is measured, and the calibration curve is created by plotting the component amount on the horizontal axis and the peak area on the vertical axis. did. Next, the oxalato complexes synthesized in the present example and comparative example were measured under the same conditions by HPLC, and the amount of the test component was determined from the peak area using a calibration curve to calculate the content in the sample.

The operating conditions of the chromatograph are as follows.

Chromatographic operating conditions 1 Detector: UV absorption spectrophotometer 220 nm Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was filled with 5 to 10 μm octadecylsilylated silica gel. Column temperature: 4.0 ° C Mobile phase: water-methanol mixture (97: 3) Flow rate: 0.7 mm

Chromatographic operating conditions 2 Mobile phase: water-methanol mixture (85:15) (Other operating conditions are in accordance with condition 1.)

Chromatographic operating conditions 3 Mobile phase: water / methanol mixed solution (40:60) (Other operating conditions are in accordance with condition 1.)

The contents of the target product and impurities according to the absolute calibration curve method are as summarized in Table 1.

[0025]

[Table 1]

Next, silver impurities contained in the oxalato complex synthesized as described above were measured by an atomic absorption method, and chlorine impurities were measured by a combustion potentiometric titration method in an oxygen flask.

Atomic absorption operation conditions Gas used: flammable gas acetylene combustible gas air Lamp: silver hollow cathode lamp Pumping length: 328.1 nm

The purity test method by the atomic absorption method followed the standard addition method. That is, three sample solutions of the same volume were taken, a standard solution was added so that the test element was contained in each step, and further added to the solvent to make a constant volume. The absorbance of each solution was measured, and the amount of the standard element (concentration) added was plotted on the horizontal axis, and the absorbance was plotted on the vertical axis, and the respective values were plotted on a graph. The regression line obtained from the plot was extended, and the amount of the test element (concentration as silver atoms) was determined from the distance between the intersection with the horizontal axis and the origin.

Oxygen Flask Combustion Potentiometric Titration Conditions Oxygen flow rate: 200 ml / min Argon flow rate: 250 ml / min Electric furnace temperature: 850 to 950 ° C. Endpoint potential: 293 mV Titration current: 1. OmA

The chlorine content (chlorine concentration) was calculated based on the following equation. Chlorine concentration (ppm) = [measurement plant (μg) × 1000] /
[Sample amount (mg) x recovery rate]

The amounts of silver impurities and chlorine impurities thus obtained were summarized in Wheat 2. In both Tables 1 and 2, from the viewpoint of measurement accuracy, the detection of an impurity amount of less than 0.04% is inaccurate. It was described.

[0032]

[Table 2]

[0033]

Example 2 An oxalato complex was synthesized under the same conditions as in Example 1 except that potassium hydroxide was added until the pH reached 3.0. The yield of the obtained oxalato complex was 59.5%.

[0034]

Example 3 An oxalato complex was synthesized under the same conditions as in Example 1 except that the addition of potassium hydroxide was performed until the pH reached 6.0. The yield of the obtained oxalato complex was 66.5%, and a slight multimer of the diako complex was observed.

[0035]

According to the present invention, there is provided a method for synthesizing an oxalate complex represented by the general formula 2 by reacting a diako complex represented by the general formula 1 with oxalic acid. The method for synthesizing a platinum complex is characterized in that the pH is adjusted to 3.0 to 6.0 by the addition of a platinum complex.

According to the method of the present invention, the suppression of the dissociation of oxalate ions due to the low pH, which has been a factor inhibiting the reaction between the conventional diako complex and oxalate ions, can be achieved by adding an alkaline solution to the oxalate ions. In the pH range where dissociation occurs
H is shifted so that it can be eliminated. Therefore,
The degree of dissociation of oxalic acid increases and a large amount of oxalate ion is generated, and the reaction between the diako complex and the oxalate ion is promoted, so that the desired oxalate complex can be synthesized in a relatively short time. If the pH in this case is too low, sufficient dissociation of oxalic acid will not occur, and if it is too high, the diako complex will proceed to multimerization. Therefore, in the present invention, the pH of the aqueous solution is shifted to the range of 3.0 to 6.0 by adding an alkaline solution, thereby achieving the promotion of the reaction and the suppression of multimerization.

However, in this pH range, even though the reaction progress and the suppression of multimerization can be achieved to some extent, they may not be achieved to a sufficiently satisfactory degree. In order to achieve a sufficiently satisfactory reaction promotion and suppression of multimerization, it is desirable to adjust the pH range to 4.0 to 5.0 by adding an alkali (claim 2).

As the alkaline solution, a potassium hydroxide solution, a sodium hydroxide solution, and a lithium hydroxide solution (Claim 3) can be used, and the addition of the alkaline solution promotes the reaction and suppresses multimerization. Is achieved, and a high-purity oxalato complex can be synthesized in a high yield.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07F 15/00 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A cis- [diaco (trans-1-cyclohexanediamine) represented by the general formula 1 (wherein the configuration of 1,2-cyclohexanediamine is a trans-1 form). Platinum (II)] is reacted with oxalic acid to give a compound of the general formula 2 (wherein the configuration of 1,2-cyclohexanediamine is a trans-1 form, and R is In the method for synthesizing cis- [oxalato (trans-1-1,2-cyclohexanediamine) platinum (II)] represented by the following formula (5, selected from formula 6, formula 7 or formula 8): A method for synthesizing a platinum complex, wherein the pH is adjusted to 3.0 to 6.0 by adding an alkaline solution during the addition. Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image Embedded image 2. The method for synthesizing a platinum complex according to claim 1, wherein the pH is adjusted to 4.0 to 5.0. 3. The method for synthesizing a platinum complex according to claim 1, wherein the alkaline solution is one of a potassium hydroxide solution, a sodium hydroxide solution, and a lithium hydroxide solution.