HU203558B - New process for producing complexes of platinum - 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

The present invention relates to a novel process for the preparation of platinum complexes.

More particularly, the present invention relates to the preparation of 1,1-cyclobutanedicarboxylato [2- (aminomethyl) pyrrolidine] platinum (II) and its optically active derivatives of formula (I), wherein a * is the 2-position of the pyrrolidine ring. indicates the asymmetry of its carbon atom.

According to the invention, the platinum complex of formula (I) or an optically active derivative thereof is prepared by (a) reacting a tetravalent platinum acid salt with 2-aminomethylpyrrolidine or an optically active derivative thereof, and the resulting tetrahalo (diamine) - platinum (IV) complex is reacted with silver oxalate followed by calcium salt of 1,1-cyclobutane dicarboxylic acid, or the resulting platinum (IV) complex compound is reacted with silver salt of 1,1-cyclobutane dicarboxylic acid and the reaction product is reduced.

According to the invention, the above platinum complex of formula (I) or an optically active derivative thereof may also be prepared by suspending (b) cis-dichloro [2- (aminomethyl) pyrrolidine] platinum (II) or an optically active derivative thereof in water and adding the silver salt of 1,1-cyclobutanedicarboxylic acid to the suspension.

Since the discovery of the anti-tumor activity of cisplatin (CDDP) (Rosenberg et al., Natur. 222, 385 (1969)), intensive research has been underway to discover anti-tumor platinum complexes. Thus, a number of various platinum-containing organic platinum complexes have already been prepared and tested for antitumor activity. Of these, 1,1-cyclobutanedicarboxylate [2- (aminomethyl) pyrrolidine] platinum (n) and its optically active derivatives showed particularly good antitumor activity.

These platinum complexes are prepared in conventional manner, for example, according to J. Med. Chem., 21, 1315 (1978), or Japanese Patent Laid-Open Publication Nos. 59-139360 or 54-46572, etc. (see 61-76497). which is illustrated in Scheme 1. In the formulas of the reaction scheme

M represents a hydrogen atom or a sodium atom and * represents an asymmetric carbon atom.

The disadvantages of the above known process can be summarized as follows.

(1) From the starting diamine, the desired final product is prepared in three steps, while process (b) according to the invention provides the desired final product (2) In the known process, the desired compounds are prepared via dinitrate platinum compound, dichloroplatinum compound and silver. reaction with nitrate. After removing the AgCl precipitate from the reaction by centrifugation and filtration, excess silver ions in the reaction mixture must also be removed by the following procedure:

1) concentrate the filtrate,

2) precipitating excess silver ions from concentrated filtrate with aqueous NaCl,

3) filtering the resulting AgCl precipitate.

Repeat the above steps 1) to 2) to 3) until the excess silver ions are completely removed from the mixture, repeating the above treatment at least six times. The addition of NaCl in multiple portions by repeated treatments to remove excess silver ions is due to the fact that when large amounts of NaCl are added simultaneously to the concentrated filtrate, the dinitrate platinum compound is converted to the dichloroplatinum compound. The aqueous solution of NaCl should be added slowly by titration to avoid an overdose of NaCl. Therefore, the known procedure is extremely time-consuming, since the dinitrate compound itself takes much longer than all other reaction steps, and the titration process must also be performed with extreme caution (see Experimental Example).

As a result of our research, we have succeeded in developing methods for the preparation of the platinum complex of Formula (I) which can provide the desired compound in high yield in a short time, thereby avoiding the disadvantages of the known process.

According to the present invention, three basic processes for the preparation of 1,1-cyclobutanedicarboxylate [2- (aminomethyl) pyrrolidine] platinum (II) or their optically active derivatives have been developed, which have overcome the disadvantages of the known process.

In the first process, a tetravalent platinum acid salt is reacted with 2-aminomethylpyrrolidine, or an optically active derivative thereof, and the resulting tetrahalogen (diamine) platinum (IV) complex with silver oxalate followed by 1,1-cyclobutanedicarboxylic acid calcium salt (Scheme 2).

According to the second process, the resulting tetrahalo-diamine-platinum (IV) complex is reacted with a silver salt of 1,1-cyclobutanedioic acid and the reaction product is reduced (Scheme 3).

According to the third process, the cis-dichloro- [2- (aminomethyl) pyrrolidine] platinum (II) complex or its optically active derivative is suspended in water and the reaction is started by adding the silver salt of 1,1-cyclobutanedicarboxylic acid. (Scheme 4).

The invention has been developed according to the above three methods.

2-4. in the formulas M is sodium or potassium,

X represents a halogen atom and * represents an optically active carbon atom.

The methods of the invention are described in more detail below.

In Scheme 2, the tetrahalo- [2- (aminomethyl) -pinOlidinium] platinum (IV) complex of formula (5), or an optically active derivative thereof, is suspended in water and 2 equivalents of a silver oxalate A suspension are added. At 60 to 100 ° C for 1-2 hours

HU 203 558 Β veijuk. Insoluble materials in the reaction mixture were removed by filtration and the filtrate was concentrated in vacuo. The precipitated product is washed with water and dried.

The capon oxalate [2- (aminomethyl) pyrrolidine] platinum (II) complex or its optically active derivative is dissolved in water and an equal amount or excess of 1,1-cyclobutanedicarboxylic acid calcium salt is added. The reaction mixture is stirred at 80-100 ° C, usually for 2-5 hours. The precipitated calcium oxalate was removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure and the precipitated product was washed with water and dried. The reaction product provides 1,1-cyclobutanedicarboxylate [2-aminomethyl-pyrrolidine] -platin platinum (II) or an optically active derivative thereof.

In Scheme 3, the tetrahalo [2- (aminomethyl) pyrrolidine] platinum (IV) complex (5) is reacted with an equal amount of 1,1-cyclobutanedicarboxylic acid silver salt. The reaction product is reduced in the presence of two equivalents of silver nitrate to give a 1,1-cyclobutanedicarboxylato-2- [2- (aminomethyl) pyrrolidine] platinum (II) complex or an optically active derivative thereof.

In Scheme 4, the cis-dichloro- [2- (aminomethyl) -pinolidine] -platin (II) complex of formula (3) or an optically active derivative thereof is suspended in water and equimolar

1,1-Cyclobutanedicarboxylic acid silver salt was added. The mixture is stirred at a temperature between 0 ° C and 100 ° C, preferably between 20 ° C and 60 ° C, usually through 0.5 to 4 lead. The precipitated silver chloride was removed from the reaction mixture by filtration and the filtrate was concentrated in vacuo. The precipitated product is washed with water and dried under aeration, usually between 0 and 80 ° C. 1,1-Cyclobutanedicarboxylate [2- (aminomethyl) pyrrolidine] platinum (II) or an optically active derivative thereof is obtained.

1,1-cyclobutanedicarboxylate / 2-aminomethylpyrrolidine / platinum (II) or an optically active derivative thereof, which is useful as an anticancer agent, can be efficiently prepared in a short time. The advantages of the process according to the invention are as follows:

(i) In the known process, the preparation of the dinitro compound (4) from the dichloro compound (3) involves the removal of excess silver ions by NaCl titration in several steps, which is extremely time consuming. This reaction step was eliminated from the processes of the invention, thus significantly reducing the time required for the process.

(ii) in the known process, silver chloride is formed in the form of a very fine precipitate and must be removed by centrifugation and filtration, which requires a great deal of work and time, as well as special equipment such as a Millipore filter. The second,

Also in Scheme 3 and 4, insoluble material (silver halide) is formed, but the particles agglomerate in the reaction medium and have a larger size. Thus, they can be easily removed by filtration with Celite and fiberglass filter paper, which also reduces the time required for the process.

(iii) In the known process, the final product (i.e., the platinum complex of formula (1)) is prepared from the starting dichloro compound of formula (3) in two steps. In the process of Scheme 4 of the present invention, compound (3) can be obtained in a single step from compound (1). As a result, the overall reaction time is reduced to a few hours, as opposed to the few days required in the known process.

The invention is illustrated by the following non-limiting examples.

Example 1

Preparation of tetrachloro [(R) -2- (aminomethyl) pyrrolidine] platinum (IV)

56.2 g (0.1 mol) of sodium chloroplatinate (IV) are dissolved in water and 220 ml of 19.3 g (0.11 mol) of (R) -2-aminomethyl-0-pyrrolidinedi hydrochloride)

1N sodium hydroxide solution was added. The reaction mixture was stirred at room temperature for 5 hours, then concentrated hydrochloric acid (19 ml) was added and the mixture was refluxed for 1 hour. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration and dried at 50 ° C for 5 hours.

34.4 g (79%) of the title compound are obtained.

240 DEG C. (with decomposition).

Elemental analysis results for Ci ₅ Hj ₂ N ₂ Cl ₄ 0t:

C, 13.74; H, 2.77; N, 6.41. Found: C, 13.80; H, 2.61; N, 6.47. IR n _max KBr (cm ^_1):

3220, 3170, 1580.

Example 2

Preparation of Tetrabromo - [(R) -2- (aminomethyl) pyrrolidine] platinum (IV) Potassium bromoplatinate (IV) (g, 39.9 mmol) was suspended in water (300 ml) and aqueous solution (80 ml) was added. containing 3.51 g (87.7 mmol) of sodium hydroxide and 7.58 g (43.8 mmol) of (R) -2-aminomethyl-pyrrolidine di (hydrochloride). The suspension was stirred at room temperature for 3 hours, then 15 ml of 47% hydrobromic acid was added and the mixture was stirred at 80 ° C for 20 minutes. The reaction mixture was stirred at 5 'C for 20 minutes. The reaction mixture was cooled to 5 ° C and stirred for 1 hour. The precipitated crystals were collected by filtration and dried at 60 ° C for 2 hours.

Yield: 23.2 g (94%).

Melting point: 263 'C (dec.).

Elemental analysis results for C ₅ H ₁₂ N ₂ Br ₄ Pt:

Calculated: C, 10.00; H, 2.04; N, 4.59; Br, 51.85; Pt, 31.40;

Found: C, 9.77; H, 1.97; N, 4.56; Br, 51.98; Pt, 31.73.

IR vKBr _(cm ^-1): 3500,31,50,1560. 5

Example 3 (1) Preparation of Oxalate [(R) -2- (aminomethyl) pyrrolidine] platinum (II)

A mixture of 1.0 g (2.3 mmol) of tetrachloro [(R) -2-aminomethyl-10-pyrrolidine] platinum (IV) and 1.53 g (5 mmol) of silver oxalate in 50 mL of water was added. while stirring, reflux for 1 hour. The reaction mixture was cooled to room temperature and the insoluble material was removed by filtration. The filtrate was evaporated in vacuo for about 15 minutes. Concentrate to 5 ml. The precipitated crystals were collected by filtration and dried.

0.67 g (76%) of the title compound is obtained.

Elemental analysis for C ₇ H ₁₂ N ₂ O ₄ Pt: C, 21.94; H, 3.16; N, 7.31; Found: C, 21.64; H, 3.09; N, 7.18.

(2) Preparation of 1,1-Cyclobutanedicarboxylato-1 (R) -2- (aminomethyl) pyrrolidine] platinum (H)

0.67 g (1.8 mmol) of ocalato - [(R) - 25 - (2-aminomethyl) pyrrolidine] platinum (II) obtained in Step (1) are dissolved in 45 ml of water and 0.42 g is added to the solution. g (2.3 mmol) of calcium 1,1cyclobutanedicarboxylate was added. The mixture was stirred at reflux for 2 hours. After cooling to room temperature, the insoluble material was filtered off and the filtrate was concentrated in vacuo to 3 ml. The precipitated crystalline material is filtered off and dried.

Title compound 0.65 g (82%) of product, [<x] D ²⁰ = 40.1 (0, lg / 20mlH Loom ₂ 0). 35

Example 4 Preparation of 1,1-Cyclobutanedicarboxylate - [(R) -2- (aminomethyl) pyrrolidine] platinum (II)

1.0 g (2.3 mmol) of tetrachloro [(R) -2-aminomethyl-40-pyrrolidine] platinum (IV) and 1.53 g (5 mmol) of silver oxalate are added to 50 ml of water, and the mixture is refluxed for 1 hour with stirring.

To the reaction mixture was added 0.75 g (4.1 mmol) of calcium 1,1-cyclobutanedicarboxylate, and the mixture was heated under reflux for 2 hours with stirring. The reaction mixture was cooled to room temperature, the insoluble material was filtered off and the filtrate was concentrated to ca.

ml. The precipitated crystals were collected by filtration and dried. 50

0.67 g (64%) of the title compound is obtained, [α] ²⁰ D = -40.4 (0.1 g / 20 ml H ₂ 0.100 mm).

Example 5 Preparation of 1-Cyclobutanedicarboxylate - [(R) -2- (amino-55-methyl) -pyrrolidine] -Platinum (II)

15.0 g (24.4 mmol) of tetrabromo - [(R) -2-aminomethyl-pyrrolidine] -platin (IV) prepared in Example 2 are treated as described in Example 4.

8.53 g (77%) of the title compound are obtained, [α] ²⁰ D 60 = -40 (2 '(0.1 g / 20 ml H ₂ 0.100 mm).

Example 6 Preparation of 1,1-Cyclobutanedicarboxylate - [(R) -2- (aminomethyl) pyrrolidine] platinum (II)

Tetrachloro [(R) -2- (aminomethyl) pyrrolidine] platinum (IV) (4.37 g, 10 mmol) and silver 1,1-cyclobutanedicarboxylate (3.08 g, 10 mmol) were added in 400 mL. water, and the mixture was stirred at room temperature for 15 hours. The insoluble material was filtered off and 3.40 g (20 mmol) of silver nitrate and 0.250 g (5 mmol) of hydrazine hydrate were added to the filtrate. After stirring at room temperature for 3 hours, 1N sodium hydroxide solution (20 mL, 20 mmol) was added and the reaction stirred for 1 hour. The insoluble material was filtered off and the filtrate was concentrated to 30 ml. The precipitated crystalline material is collected by filtration and dried.

2.28 g (50%) of the title compound are obtained, [α] ²⁰ D = -40.3 ° (0.1 g / 20 ml H ₂ 0.100 mm).

Example 7 Preparation of (R) -1,1-Cyclobutanedicarboxylato [2- (aminomethyl) pyrrolidine] platinum (II)

4.95 g (13.5 mmol) of (R) -cis-dichloro- [2- (aminomethyl) pyrrolidine] platinum (II) are suspended in 420 ml of water and 4.85 g (13 g) are added to the suspension. (5 mmol) of silver 1,1-cyclobutanedicarboxylate, prepared in a known manner. The reaction mixture was stirred at room temperature for 2 hours. The silver chloride precipitated was removed and the resulting solution was concentrated under reduced pressure to 50 ml, whereupon a white crystalline precipitate formed. The solution was stirred at room temperature for an additional 1 hour and the resulting crystalline material was removed by filtration. The crystals were washed with water and dried under aeration at 60 ° C for 8 hours.

4.92 g (80%) of the title compound are precipitated.

M.p. 256 ° C (with decomposition), [α] ²⁰ D = 40.4 (0.1 g / 20 ml H ₂ 0.100 mm).

Elemental analysis results for CjjH ₁₈ N ₂ O ₄ Pt:

H, 4.15; N, 6.40. Found: C, 30.08; H, 4.09; N, 6.37.

Experimental example

200 g of cis-dichloro- (2-aminomethyl) pyrrolidine / platinum (II) / 186 g of AgNO _{3 are} reacted with 111 g of water. Then about 8 L of the supernatant fluid was cooled in a cooling centrifuge (Model RS-18GL,

TOMY SEIKO CO., LTD., Japan) was centrifuged to remove the silver chloride precipitate. In addition, the remaining 3 L of the reaction mixture, from which the precipitate could not be removed by centrifugation, was filtered through Celite and glass fiber filter paper to remove the AgCl precipitate. The resulting filtrate was concentrated. An aqueous solution of NaCl was added to the concentrated filtrate to precipitate excess silver ions in the form of AgCl. The mixture was filtered through a membrane filter. The filtrate was concentrated. Above

By repeating the procedure six times (concentration, precipitation of AgCl, filtration, concentration), excess Ag ions can be almost completely removed. Concentration of the last filtrate gives the dinithioplatin compound (4)

The dinitroplatinum compound, which is still intermediate, can be prepared by the above procedure in almost 2 days.

In contrast, starting from the same amount of material in the methods of the invention, AgClot is removed from the reaction mixture by filtration over Celite and fiberglass filter paper for about 1 hour.

Thus, the single step of the known process, the preparation of the dinitroplatinum intermediate, is much more time consuming than any of the processes of the invention, even if the number of reaction steps is the same.

Patent Claim Point

Claims (1)

Patent Claim Point Live the Platinum Complex of Formula (I) - In the Formula * the C-2 position of the pyrrolidine ring 5 asymmetry or optically active derivatives thereof from 2-aminomethylpyrrolidine, characterized in that a) A tetravalent platinum acid salt is reacted with 2-aminomethylpyrrolidine or an optically active derivative thereof, followed by the resulting tetrahalo- (diamine) platinum (IV) with silver oxalate followed by the calcium salt of 1,1-cyclobutanedicarboxylic acid or By reacting with a silver salt of 1,1-cyclobutanedicarboxylic acid and reducing the reaction product, or b) suspending cis-dichloro- (2-aminomethyl) pyrrolidine-platinum (II) or an optically active derivative thereof in water and adding the silver salt of 1,1-cyclobutane dicarboxylate.