JPS6210930B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for purifying the anticancer substance cis-dichlorodiammine platinum ().
More specifically, the first invention converts cis-dichlorodiammine platinum () containing impurities into the general formula (). (In the formula, R ¹ and R ² represent a hydrogen atom or a lower alkyl group.) Formamides or general formula () (In the formula, R ³ and R ⁴ represent lower alkyl groups.) It is dissolved in a dialkyl sulfoxide represented by the formula or a mixed solvent thereof, and is then miscible with this solution, and cis-dichlorodiammine platinum () is hardly soluble. or a method for purifying cis-dichlorodiammine platinum (2), which is characterized by adding an insoluble solvent to precipitate crystals of cis-dichlorodiammine platinum (2), and the second invention is the first invention of the present invention. The present invention relates to a method for purifying cis-dichlorodiammine platinum () by combining the invention with a conventionally known purification method by recrystallization from water or an aqueous solvent. After carrying out, the obtained crystals are purified by recrystallization from water or an aqueous solvent, or conversely, the crude cis-dichlorodiammine platinum () is recrystallized from water or an aqueous solvent and then the first The present invention relates to a method for purifying cis-dichlorodiammine platinum () by carrying out the invention. Cis-dichlorodiammine platinum (hereinafter simply referred to as cis-DDP) is

It is a complex salt of divalent platinum having the structure of [Formula], and was created by M. Peyrone in 1844. However, in recent years, it has been used to treat sarcoma 180, leukemia, etc.
The inhibitory effect of L1210 on various experimental tumors such as Ehrlichi's ascites carcinoma and B-16 melanoma has been revealed, and its remarkable therapeutic effect on tumors in various parts of the human body, such as testicles, bladder, head and neck, and ovaries, has been confirmed. I have reached the point where Known methods for producing this substance include a method by L. Ramberg in which potassium chloroplatinate and ammonia are reacted in an aqueous solution, and a method by E. Biilmann in which ammonium chloride platinum and ammonia are reacted in an aqueous solution. However, in addition to the target product, the crude products obtained by these methods also contain [Pt(NH ₃ ) ₄ ]Cl ₂ (hereinafter referred to as by-product (1)), [Pt(NH ₃ ) ₃ Cl]Cl ( (hereinafter referred to as by-product (2)), [Pt(NH ₃ ) ₄ ] [PtCl ₄ ] (hereinafter referred to as by-product (3)), [Pt(NH ₃ ) ₃ Cl] ₂ [PtCl ₄ ] (hereinafter referred to as by-product (3)). Contains by-products such as living organisms (4). Recrystallization using water or dilute hydrochloric acid has been known as a purification method for cis-DDP, but with these purification methods, it is difficult to obtain a high-purity product even after repeating recrystallization twice. However, it is inevitable that the product still contains several percent of impurities, and in order to obtain a product with higher purity, further recrystallization is required, and a significant decrease in yield is unavoidable. The present inventors have conducted various studies to remove impurities that are difficult to remove using conventional methods, and have found that the main portion of these impurities are the above-mentioned byproducts (3) and (4), and
These impurities are
DDP is dissolved in the formamide of the general formula () or the dialkyl sulfoxide of the general formula (), and if any insoluble matter is removed, it is then miscible with this solution and cis-DDP is insoluble or poorly soluble. The present invention was completed based on the discovery that cis-DDP can be removed by adding a solvent to precipitate crystals of cis-DDP. Cis-DDP containing impurities to which the method of the present invention is applied include synthetic cis-DDP, cis-DDP obtained from synthetic products by both known crystallization methods from water or an aqueous medium, and cis-DDP recovered from recrystallization mother liquor. −
Contains various purity levels such as DDP. Formamides represented by the general formula () include formamide, dimethylformamide, diethylformamide, dipropylformamide, monomethylformamide, monoethylformamide, monopropylformamide, and the like. Considering the solubility and stability of cis-DDP in solution, formamide, dimethylformamide, monomethylformamide, monoethylformamide, monopropylformamide, etc. dissolve 2% or more of cis-DDP and are insoluble in cis-DDP. It is advantageous in use because of its activity. Examples of dialkyl sulfoxides represented by the general formula () include dimethyl sulfoxide and diethyl sulfoxide. Dialkyl sulfoxides dissolve 10% or more of cis-DDP at room temperature, but since cis-DDP is unstable in this solution, it is desirable to operate at low temperatures. When cis-DDP containing impurities is dissolved in these solvents, it is preferable to dissolve cis-DDP to a concentration near the saturation of these solvents.
For example, a suitable concentration is 1 to 5% for formamides and 5 to 20% for dialkyl sulfoxides. When insoluble matter is present in this solution, it is preferable to remove the insoluble matter by means such as filtration, centrifugation, and decantation. Cis-DDP is added to precipitate the resulting solution. Examples of solvents that are miscible with this solution of cis-DDP and in which cis-DDP is insoluble or poorly soluble include alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane, and tetrahydrofuran; Examples include hydrocarbon solvents such as benzene and toluene, substituted hydrocarbon solvents such as chlorobenzene, nitrobenzene, and chloroform, esters such as ethyl acetate, and water. Among these solvents are methanol, ethanol, acetone, which are cheap, harmless, and suitable for purification purposes.
Particularly advantageous is the use of benzene, ethyl acetate, etc., the amount of which is added is between 1 and 5 ml per cis-DDP solution.
Double volume, preferably 1.5 to 3 times volume. After adding and mixing these solvents, if necessary, the mixture is cooled to around 0 to 10°C for 30 minutes to several hours to complete precipitation of the target product, and separated by means such as filtration and dried. Note that the method of mixing the solution and the solvent may be reversed as the case may be, that is, the method of adding the solution of the target substance into the solvent may be used. The content of by-products (3) and (4) in the cis-DDP thus obtained is approximately 1% or less, and the yield varies depending on the purity of the raw materials, but is approximately 80% or more, and is contained in the mother liquor. It can be further improved by collecting the target object. Although the first invention of the present invention can also obtain a product of considerably high purity, as mentioned above, the first invention of the present invention is particularly advantageous in that the by-product (3) and ( Since this method is suitable for removing 4), extremely high purity cis-DDP can be obtained if purification is performed in combination with conventional methods. That is, crude cis-
After recrystallizing DDP from water or an aqueous solvent, the method of the first invention of the present invention is performed, or conversely, the method of the first invention of the present invention is first applied to crude cis-DDP, and then the method of the first invention is applied to crude cis-DDP. Purity 98% can be obtained by recrystallizing the purified cis-DDP from water or an aqueous solvent.
% or more of highly purified cis-DDP can be obtained in high yield. Dilute hydrochloric acid is usually used as the aqueous medium used for recrystallization in known methods. The present invention will be specifically explained below using examples. Example 1 (1) 20 g of potassium platinum chloride (K ₂ PtCl ₄ ) was added to water.
20 g of ammonium chloride and 36.4 ml of 3N ammonia water were added under stirring, and the solution was dissolved for 3 days for 4 days.
Keep at ~5°C. After the reaction, filter out the precipitated crystals of the target product and add 20 ml of water each.
Wash 3 times with ml. Crude crystals of cis-DDP obtained by drying under reduced pressure (purity 85%, UV ⁽ Note ⁾ ratio
1.58 Content of by-product (3) 5.5%, content of by-product (4) 6.5
%) [(Note) UV ratio; ultraviolet absorption maximum part (300~
302nm) absorption minimum part (245~
247 nm), which increases with increasing purity. ] Dissolve 1 g of each in formamides of general formula (1) or dialkyl sulfoxides of general formula (2) (hereinafter referred to as the first solvent), and then dissolve in a solvent that is miscible with this solution and in which cis-DDP is sparingly soluble or insoluble. (hereinafter referred to as the second solvent) to obtain purified cis-DDP, or this method is repeated twice, or a combination of the recrystallization of the present invention and known recrystallization from water or an aqueous solvent. Purified DDP was obtained. Purity and yield of cis-DDP obtained by cooling and recrystallizing after dissolving in water or hydrochloric acid water as a control,
Table 1 shows the contents of by-products (3) and (4).

[Table] Example 2 6.64g of the crude crystals of cis-DDP used in Example 1 were
Add to 466ml of 0.1N hydrochloric acid and heat to 80℃ to dissolve.
Filter when hot and add 10 each of hot 0.1N hydrochloric acid from above the filter.
Wash 3 times with ml and combine the filtrate and washing solution. This solution was cooled on ice for 2 hours, and the precipitated cis-DDP crystals were filtered, washed three times with 10 ml each of distilled water, and dried. Obtained cis-DDP (purity 92%, UV ratio 2.53 content of by-product (3) 2.5%, content of by-product (4) 2.0%) 5.19 g
(yield 84.3%). The entire amount of cis-DDP obtained is dissolved in 200 ml of dimethylformamide, filtered, and washed three times with 10 ml of dimethylformamide each time. Combine the filter washing liquid and pour into 400ml of methanol while stirring.
Cool on ice for 30 minutes, filter out the precipitated crystals, wash with 10 ml of methanol four times, and dry. Cis DDP (purity
98.5%, UV ratio 4.53 content of by-product (3) 0.2%, content of by-product (4) below 0.2%) 4.5g was obtained. yield
97.6%. Example 3 (1) 3.29 g of the crude cis-DDP crystals used in Example 1 were dissolved in 98 ml of dimethylformamide, insoluble materials were filtered off, and the solution was washed three times with 5 ml of dimethylformamide each. Combine the filtrate and washing liquid and add 220ml of methanol.
Pour into the mixture while stirring. After keeping the temperature at 3-5 DEG C. for 1 hour, the precipitated crystals are collected by filtration, washed four times with 7 ml of methanol each, and dried under reduced pressure. cis-
2.51 g of DDP (purity 94.5%, UV ratio 3.25 content of by-product (3) 0.6%, content of by-product (4) 0.4%) is obtained. Yield 84.9%. (2) Dissolve 1.13 g of cis-DDP obtained in (1) in 81 ml of 0.1N hydrochloric acid at 80°C, filter while hot, wash the filter with a small amount of 0.1N hydrochloric acid, and separate the filtrate and washing liquid. Combine and keep at 3-5°C for 2 hours. The precipitated cis-DDP is collected by filtration, washed with a small amount of cold water, and then dried under reduced pressure. Cis DDP (purity
98%, UV ratio 4.55, content of by-product (3) 0.2%,
Obtain 1.06 g of by-product (4) (content 0.2%). Yield 96.3
%. (3) Regarding 530 mg of cis-DDP obtained in (2),
Recrystallize with 0.1N hydrochloric acid again to obtain cis-
Obtain 500 mg of DDP (100% purity, UV ratio 5.00). Yield 96.1%. (4) Dissolve 1.0 g of cis-DDP obtained in (1) in 60 ml of water, filter while hot, wash with a small amount of hot water, combine the filtrate and washing liquid, and heat to 3-5℃. Keep for 2 hours. After filtering out the precipitated target substance and washing it with a small amount of cold water,
Dry under reduced pressure. Cis-DDP (99% purity,
UV ratio 4.70) get 730mg. Yield 76.5%. Example 4 (1) 6.77 g of crude crystals of cis-DDP used in Example 1
was dissolved in 270 ml of dimethylformamide, the insoluble materials were filtered out, and 3
Wash twice. Combine the filtrate and washing solution and pour into 600 ml of methanol with stirring. After cooling on ice for 3 hours, the precipitated crystals are filtered, washed four times with 10 ml of methanol each, and dried under reduced pressure. Cis-DDP (purity
94.5%, UV ratio 3.25, content of by-products (3) 0.6
%, content of by-product (4) 0.4%) 5.09 g was obtained. Yield 83.6%. (2) The total amount of cis-DDP obtained in (1) was recrystallized from dimethylformamide-methanol in the same manner as in (1), and cis-DDP (purity 97.5%, UV ratio
4.31, content of by-product (3) and by-product (4) respectively
(0.2% or less) yields 4.41 g. Yield 89.4%. Example 5 3 g of crude crystals of cis-DDP used in Example 1 were dissolved in the first solvent and filtered, the second solvent was added to the filtrate, and after cooling on ice for 30 minutes, the precipitated target product was filtered out. After dyeing with the second solvent, it was dried under reduced pressure to obtain the following results.

【table】

Claims (1)

[Claims] 1. Cis-dichlorodiammine platinum () containing impurities is expressed by the general formula () (In the formula, R ¹ and R ² represent a hydrogen atom or a lower alkyl group.) Formamides represented by the general formula () (In the formula, R ³ and R ⁴ represent lower alkyl groups.) Dissolved in the dialkyl sulfoxide represented by the formula or a mixed solvent thereof, and then miscible with this solution, and cis-dichlorodiammine platinum () is difficult to dissolve. by adding a soluble or insoluble solvent,
1. A method for purifying cis-dichlorodiammine platinum (), which comprises precipitating crystals of cis-dichlorodiammine platinum (). 2 (a) Cis-dichlorodiammine platinum () containing impurities is expressed by the general formula (In the formula, R ¹ and R ² represent a hydrogen atom or a lower alkyl group.) Formamides represented by or the general formula (In the formula, R ³ and R ⁴ represent lower alkyl groups.) Dissolved in the dialkyl sulfoxide represented by the formula or a mixed solvent thereof, and then miscible with this solution, and cis-dichlorodiammine platinum () is difficult to dissolve. A soluble or insoluble solvent is added to precipitate crystals of cis-dichlorodiammine platinum (2), and (b) the obtained cis-dichlorodiammine platinum (2) is dissolved in water or an aqueous solution to form cis-dichlorodiammine platinum (2). ) to obtain purified crystals of cis-dichlorodiamine platinum (), or (a) and (b) above.
By replacing the steps of , first recrystallize with water or an aqueous solution, then dissolve in a solvent of general formula () or general formula (), and then dissolve cis-dichlorodiammine platinum which is miscible in this solution and is 1. A method for purifying cis-dichlorodiammine platinum, which comprises adding a solvent in which () is poorly soluble or insoluble to precipitate crystals of cis-dichlorodiammine platinum () to obtain purified cis-dichlorodiammine platinum ().