AT392273B - METHOD FOR PRODUCING PLATINUM COMPLEXES - Google Patents

Abstract

A process for the preparation of 1,1- cyclobutanedicarboxylato(2-aminomethylpyrrolidine)- platinum(II) of the following formula (I), which can be used as anticancer agent, and optically active derivatives thereof. The process proceeds via any one of the three following reaction routes (in which M is a sodium or potassium atom, X is a halogen atom, and the star indicates the asymmetry of the carbon atom at position 2 of the pyrrolidine ring). <IMAGE>

Description

AT 392 273 B

The present invention relates to a process for producing 1,1-cyclobutanedicarboxylato (2-aminomethylpyrrolidine) platinum (II) represented by the following formula (1), and optically active derivatives thereof:

X &gt; .0) (where the star indicates the asymmetry of the carbon atom at the 2-position of the pyrrolidine ring).

In particular, the present invention relates to a process for producing a platinum complex of the above formula (1) or optically active derivatives thereof by reacting a salt of tetravalent platinum acid with 2-aminomethylpyrrolidine or an optically active derivative thereof and then the tctrahalogeno- ( diammin) platinum (IV) with silver oxalate and the calcium salt of 1,1-cyclobutanedicarboxylic acid. Alternatively, the tetrahalo (diammine) platinum (IV) can be reacted with a silver salt of 1,1-cyclobutanedicarboxylic acid. The reaction product is then reduced

The present invention further relates to a process for producing a platinum complex of the above formula (1) or optically active derivatives thereof by suspending cis-dichloro (2-aminomethylpyrrolidine) platinum (II) or an optically active derivative thereof in water and then a silver salt of 1,1-cyclobutanedicarboxylic acid is added to start the reaction.

Since the anti-tumor activity of cisplatin (CDDP) was determined by Rosenberg et al. (Nature, 222.385 (.1969)], active research has been conducted on platinum complexes with antitumor activity. Although a number of organic platinum complexes with different ligands have been synthesized and their antitumor activities have been investigated, l, l-cyclobutanedicarboxylato (2-aminomethylpyrrolidine) platinum (II) and optically active derivatives thereof have a particularly salient antitumor activity, and these platinum complexes have been described by the following method described in J. Med. Chem., 21, 1315 (1978), Japanese Patent Publication No. 59-139360, Japanese Patent Publication No. 54-46752 , etc. (see Japanese Patent Publication No. 61-76497), synthesized:

O II -NH. MOOC '&gt; cC &gt; ---- &gt;

NH

Pt

O — C O —C II O &gt; o -2-

AT 392 273 B (in which M represents a hydrogen or sodium atom and the star has the meaning given above).

However, this conventional method has had the following problems: (1) Since three steps are required to obtain the final compound from the initial diamine, it takes several days to complete the synthesis process. (2) A lengthy post-treatment is necessary because the water used as a solvent in the synthesis step from the dichloro compound of the formula (3) to the dinitrato compound of the formula (4) has to be concentrated at a low temperature. (3) The silver chloride which is formed in the step of synthesizing the dichloro compound of the formula (3) to the dinitrato compound of the formula (4) has such a finely divided form that a very laborious effort is necessary to remove it. In addition, titration with NaCl is necessary to remove the excess silver ions, which leads to a very time-consuming aftertreatment.

In the course of intensive studies devoted to the development of a method for the efficient and time-saving production of the platinum complex of the formula (1), the inventors discovered the process according to the invention, which is described below, with which the above-mentioned problems of the process according to the prior art were successfully solved were.

The present invention comprises three basic processes for the preparation of 1,1-cyclobutanedicarboxylato- (2-aminomethylpyrrolidine) platinum (II) or an optically active derivative thereof, without the problems found so far occurring. In the first process, a salt of tetravalent platinum acid is reacted with 2-aminomethylpyrrolidine or an optically active derivative thereof to synthesize tetrahalo- (diammine) platinum (IV), which is then reacted with silver oxalate and the calcium salt of 1,1-cyclobutanedicarboxylic acid (below Reaction scheme I). In the second process, the synthesized tetrahalo (diammine) platinum (IV) is reacted with a silver salt of 1,1-cyclobutanedicarboxylic acid and the reaction product is then reduced (reaction scheme Π below). In the third method, cis-dichloro (2-aminomethylpyrrolidine) platinum (II) or an optically active derivative thereof is suspended in water and then a silver salt of 1,1-cyclobutanedicarboxylic acid is added to the suspension to start the reaction (reaction scheme III below).

The present invention is carried out on the basis of these three methods.

The reaction schemes for the three methods of the invention are shown below:

Reaction scheme I

O (5) (6)

O

-3-

AT 392 273 B

Reaction scheme II ΛΊΗ.

NH K2PtX6 'NH,' nh

X, l2 \ I / X Pt / I \ y X x

AgOOC AgOOC X &gt; (5)

O 'NH., Ί

Reduction pt X &gt; NH ^ O (1)

Reaction scheme III

AgOOC AgOOC &gt; o nh2 * l K? PtCl4 NH --- NH2 \ / CI * 'Pt NH ^ XC1 (2) (3)

O NH. * L pt; _ "X &gt; 2 \ / 0 —C ·

Pt.

NH / '\ 0-CO (1) (where M is a sodium or potassium atom, X is a halogen atom and the asterisk has the meaning given above).

The methods according to the invention are explained in more detail below.

Procedure according to reaction scheme I:

A tetrahalogeno (2-aminomethylpyrrolidine) platinum (IV) corresponding to formula (5) or an optically active derivative thereof is suspended in water and mixed with a 2 equivalent amount of silver oxalate. The suspension is reacted with stirring at a temperature in the range of 60-100 ° C usually for a period of 1-2 hours. The reaction solution is filtered to remove the insoluble constituents and the filtrate is concentrated in vacuo. The precipitate is washed with water and dried to obtain oxalato (2-aminomethylpyrrolidine) platinum (II) or an optically active derivative thereof. The aqueous solution of the oxalato (2-aminomethylpyrrolidine) platinum (II) thus obtained is mixed with an equivalent or greater amount of the calcium salt of 1,1-cyclobutanedicarboxylic acid and the mixture is stirred at a temperature of 80-100 ° C., usually for a period of time implemented from 2 - 5 h. The reaction solution is filtered to remove precipitated calcium oxalate. Thereafter, the filtrate is concentrated in vacuo and the precipitate is washed with water and dried to obtain 1,1-cyclobutanedicarboxylato- (2-aminomethylpyrrolidine) platinum (II) represented in formula (1) or an optically active derivative thereof. -4-

AT 392 273 B

Procedure according to reaction scheme Π

A tetrahalogeno (2-aminomethylpyrrolidine) platinum (IV) shown in Formula (5) is reacted with an equivalent amount of the silver salt of 1,1-cyclobutanedicarboxylic acid. In the presence of 2 equivalents of silver nitrate, the reaction product is reduced with a suitable reducing agent to obtain 1,1-cyclobutanedicarboxylato (2-aminomethylpyrrolidine) platinum (II) or an optically active derivative thereof.

Process according to the reaction scheme ΙΠ cis-dichloro (2-aminomethylpyrrolidine) platinum (II), represented in formula (3), or an optically active derivative thereof is suspended in water and mixed with an equimolar amount of the silver salt of 1,1-cyclobutanedicarboxylic acid. The mixture is reacted with stirring at a temperature of 0-100 ° C, preferably 20-60 ° C, usually for a period of 0.5-4 hours.

The reaction solution is filtered to remove the precipitated silver chloride and the filtrate is concentrated in vacuo. The precipitate is washed with water and dried with aeration, usually at a temperature in the range of 0-80 ° C, to 1,1-cyclobutanedicarboxylato- (2-aminomethylpyrrolidine) platinum (II), represented in formula (1), or optically to obtain the active derivative thereof.

According to the invention, l, l-cyclobutanedicarboxylato (2-aminomethylpyrrolidm) platinum (II), which is potentially used as an anti-cancer agent, or optically active derivatives thereof can be effectively synthesized within a short period of time. The particular advantages of the present invention are as follows: (i) In the known process, the water which is used as a solvent in the step of synthesizing the dichloro compound according to formula (3) to form the dinitrato compound according to formula (4) has to be concentrated at low temperature , which requires a considerable amount of time for the after-treatment. This stage is eliminated from all of the methods of the present invention, which significantly reduces the time required to complete the synthesis reaction. (ii) In the known method, very fine particles of silver chloride are formed, which have to be separated off by filtration, which requires a lot of work and time and the use of special media, such as that of a Millipore filter. In the processes according to the invention, which go through reaction stages I and II, a particulate insoluble substance (a silver halide) forms, but the particles agglomerate in the reaction system to grow into grains. Therefore, they can be separated very easily, so that the time required for the synthesis is shortened. (iii) In the known process, two steps are required to convert the starting dichloro compound of formula (3) into the final compound [d. i. to obtain the platinum complex according to formula (1)]. In the process according to the invention, which runs through reaction scheme III, only one step is necessary to obtain the compound of the formula (3). As a result, the total time of synthesis is reduced to several hours, as opposed to the several days that used to be. (iv) In the known method, a considerable time is required to separate the silver ions which are obtained in the step of synthesizing the dinitrato compound according to formula (4) from the dichloro compound according to formula (3). This step is not necessary in the process according to the invention which goes through reaction scheme III, and it can therefore be completed in a very short period of time.

The invention is illustrated by the following examples, without being limited thereto.

example 1

Sodium chloroplatinate (IV) (56.2 g, 0.1 mol) was dissolved in water and a 1N solution of NaOH (220 ml), which was (R) -2-aminomethylpyrrolidine dihydrochloride (19.03 g, 0.11 mol) contained, added to the solution. After stirring at room temperature for 5 hours, concentrated HCl (19 ml) was added and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and the precipitate collected by filtration was dried at 50 ° C for 5 hours to obtain 34.4 g of tetrachloro [(R) -2-arninomethylpyrrolidine] platinum (IV) (yield 79%). F. 240 ° C (with decomposition).

N 6.41 N 6.47

Calculated (%) C 13.74 H 2.77

Found (%) C 13.80 H 2.61! R vKBrmax cm'1: 3220.3170.1580 5-

AT 392 273 B

Example 2

Potassium bromatinate (IV) (30 g, 39.9 mmol) was suspended in water (300 ml) and an aqueous solution (80 ml) containing 3.51 g (87.7 mmol) NaOH and 7.58 g (43.8 mmol) (R) -2-aminomethylpyrrolidine dihydrochloride added to the suspension. After stirring for 3 hours at room temperature, 15 ml of 47% hydrobromic acid were added and the mixture was stirred at 80 ° C. for 20 minutes. The mixture was cooled to 5 ° C and stirred for 1 hour. The crystalline precipitate was collected by filtration and dried at 60 ° C for 2 hours to obtain 23.2 g of tetrabromo [(R) -2-aminomethylpyrrolidineplatinum (IV) (yield 94%). F. 263 ° C (with decomposition). CHN Br Pt Calculated (%) 10.00 2.04 4.59 51.85 31.40 Found (%) 9.77 1.97 4.56 51.98 31.73! R vKBrmax cm'1: 3500, 3150.1560

Example 3

Tetrachloro [(R) -2-aminomethylpyrrolidine] platinum (IV) (1.0 g, 2.3 mmol) and silver oxalate (1.53 g, 5 mmol) were added with 50 ml of water and the mixture under reflux for 1 h heated with stirring. The mixture was cooled to room temperature and the insoluble material was filtered off. The filtrate was concentrated in vacuo to a volume of about 5 ml. The crystalline precipitate was collected by filtration and dried to obtain 0.67 g of oxalato [(R) -2-aminomethylpyrrolidine] platinum (II) (yield 76%).

Elemental analysis according to C ^ H ^ N ^ O ^ Pt

Calculated (%) C 21.94 H 3.16 0 7.31

Found (%) C 21.64 H 3.09 0 7.18

The oxalato [(R) -2-aminomethylpyrrolidine] platinum (II) (0.67 g, 1.8 mmol) thus obtained was dissolved in 45 ml of water and the calcium salt of 1,1-cyclobutanedicarboxylic acid (0.42 g, 2 , 3 mmol) was added to the solution. The mixture was heated under reflux and with stirring for 2 hours. After cooling to room temperature, the insoluble material was filtered off and the filtrate was concentrated in vacuo to a volume of 3 ml. The crystalline precipitate was taken up by filtration and dried to give 0.65 g of 1,1-cyclobutanedicarboxylato [(R) -2-aminomethylpyrrolidine ] platinum (II) (yield 82%).

Example 4

50 ml of water were added to tetrachloro [(R) -2-aminomethylpyrrolidine] platinum (IV) (1.0 g, 2.3 mmol) and silver oxalate (1.53 g, 5 mmol) and the mixture was refluxed and stirred 1 heated for h. The calcium salt of 1,1-cyclobutanedicarboxylic acid (0.75 g, 4.1 mmol) was added to the reaction solution and the mixture was heated under reflux and stirring for 2 hours. After the reaction mixture had cooled to room temperature, the insoluble material was filtered off and the filtrate was concentrated to a volume of about 5 ml. The crystalline filling was collected by filtration and dried to obtain 0.67 g of 1,1-cyclobutanedicarboxylato [(R) -2-aminomethylpyirolidine] platinum (II) (yield 64%).

Example 5

The tetrabromo [(R) -2-aminomethylpyirolidine] platinum (IV) (15.0 g, 24.4 mmol) synthesized according to Example 2 was treated according to Example 4 to give 8.53 gl, l-cyclobutanedicarboxylato [(R) - 2-aminomethylpyrrolidineplatinum (Π) (yield 77%).

Example 6

Tetrachloro [(R) -2-aminomethylpyrrolidine] platinum (IV) (4.37 g, 10 mmol) and a silver salt of 1,1-cyclobutanedicarboxylic acid (3.08 g, 10 mmol) were mixed with 400 ml of water and the mixture was stirred at room temperature for 15 h. The insoluble material was filtered off and silver nitrate (3.40 g, 20 mmol) and hydrazine hydrate (0.250 g, 5 mmol) were added to the filtrate. After the mixture was stirred at room temperature for 3 hours, a 1N solution of NaOH (20 ml, 20 mmol) was added and the mixture was stirred for a further hour. After the insoluble matter had been filtered off, the filtrate was concentrated to a volume of 30 ml.

The crystalline precipitate was collected by filtration and dried to give 2.28 g of 1,1-6-

Claims (3)

AT 392 273 B cyclobutanedicarboxylato [(R) -2-aminomethylpyrrolidine] platinum (II) (yield 50 ° C.). Example 7 (R) -cis-dichloro (2-aminomethylpyrrolidine) platinum (II) (4.95 g, 13.5 mmol) was suspended in 420 ml of water and the silver salt of 1,1-cyclobutanedicarboxylic acid synthesized by a conventional method ( 4.85 g, 13.5 mmol) was added to the suspension, followed by stirring at room temperature for 2 hours. The precipitated silver chloride was separated off and the resulting solution was concentrated in vacuo to a volume of 50 ml, whereupon white crystals had precipitated. The solution was stirred for a further hour at room temperature and the crystals formed were taken up by filtration. The crystals were washed with water and dried with aeration at 60 ° C for 8 hours to obtain 4.92 g of (R) -l, l-cyclobutanedicarboxylato- (2-aminomethylpyrrolidine) platinum (II) (yield 80%). F. 256 ° C (with decomposition). PATENT CLAIMS 1. Process for the preparation of a platinum complex of the formula (1) (in which the asterisk indicates the asymmetry of the carbon atom at the 2-position of the pyrrolidine ring) or an optically active derivative thereof, characterized in that a salt of the tetravalent platinum acid is reacted with 2-aminomethylpyrrolidine or an optically active derivative thereof and then the resultant is obtained Tetrahalogeno (diammine) platinum (IV) with silver oxalate and the calcium salt of 1,1-cyclobutanedicarboxylic acid. 2. Process for the preparation of a platinum complex of the formula (1): -7- AT 392 273 B (in which the asterisk indicates the asymmetry of the carbon atom at the 2-position of the pyrrolidine ring) or an optically active derivative thereof, characterized in that a salt of tetravalent platinic acid with 2-aminomethylpyrrolidine or an optically active derivative thereof, and then reacting the tetrahalo (diammine) platinum (IV) thus obtained with the silver salt of 1,1-cyclobutanedicarboxylic acid 3. Process for the preparation of a platinum complex of the formula (1): (in which the asterisk indicates the asymmetry of the carbon atom at the 2-position of the pyrrolidine ring) or an optically active derivative thereof, characterized in that cis-dichloro (2-aminomethylpyrrolidine) platinum (II) or an optically active derivative thereof is suspended and then the silver salt of 1,1-cyclobutanedicarboxylic acid is added to this suspension. -8th-