SU1256698A3 - Method of producing platinum iv cis-dichloro-trans-dioxy-bis (isopropyl amine) - Google Patents

Abstract

The platinum cpd. of formula (I) in practically pure form is made by reacting cis-dichloro-di(isopropylamine) platinum (II) with H2O2. The product is isolated and is dissolved in N,N'-dimethylacetamide (DMA). The 1:1 addition compound of (I) with DMA is isolated, then DMA is removed by treatment in vacuo at below 80≰C, pref. below 50≰C. (I) is useful for treating cancer and malignant neoplasms.

Description

The invention relates to an improved process for the preparation of cis-dichloro-trans-dioxy-5c (isopropylamine) platinum, which finds use as a component of an antitumor composition.

The purpose of the invention is to create an improved process for the production of cis-dichloro-TpQHc-dioxy-5c- (isopropylamine platinum, allowing the pure product to be obtained.

Example. Preparation of raw product G - - -

Prcrystallized cis -Pt (i-CjH NH / CIj); (26.8 g) are suspended in 50 ml of hot water and to the resulting suspension 1 00 i-ш (100 vol.) Of hydrogen peroxide is added with stirring. The reaction sludge is boiled for half an hour until it does not turn yellow, after which the mixture is cooled and filtered. The filter residue is washed first with water, then diethyl ether and then dried in air. The yield of air-dry product 10.5 g (35% of theoretical).

Elemental analysis. Calculated. %: C 16.55; H 4.87; N 6.43; About 11.03; C 16.28 /

Found,%: C 16.59; H 4.90; N 6.48; About 10.80; CH 16.20. .

The absorption spectrum of the hydroxyl group (stretching vibrations of 0-H bond) in the region of 3515 cm is present in the IR spectrum of the product.

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Preparation of the adduct with dimethyl acetamide and isolation of practically pure Q product.

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The crude product (11 g), obtained similarly decomposed, is dissolved in N, N-dimethylacetamide (approximately 1 l) and the resulting solution is filtered through a glass porous filter having porosity no. 4 to remove any undissolved impurities. The solution is then cooled to 5 ° C for 2 hours, seeded to prevent supersaturation, i.e. to prevent the formation of a perennial solution, and leave for several days at -10 ° C. Formed during this time. the crystalline precipitate is filtered off, washed with diethyl ether and dried to constant weight.

Removal of H, N-dimethyl acetamide in order to obtain an essentially pure desired product is carried out by heating the obtained D9 crystals with a temperature of 50 ° C or lower at a residual pressure of 0.1 mm Hg. for several days or until thermogravimetric analysis of the product and / or analysis by gas-liquid chromatography shows no trace of N, N-dimethylacetamide.

The results of the analysis of cis, trans, 4Mc- (Pt Cl, j- (OH) i (i-PrNH,) 2. —The proposed compounds are obtained in several experiments. Compounds are obtained as separate batches A, B and C, which are then mix thoroughly with each other and homogenize to obtain a mixed (composite) batch X (appearance yellow powders).

Elemental analysis of the compounds is given in table. one.

Table 1

Data analysis by high pressure liquid chromatography is given in Table. 2

Party

% purity 97.31

: E:;:

Spreadsheets

B C 100.17 97.63

The content of contaminants in the analyzed products is given in Table. 3

Table 3

The moisture content in products is less than 0.25 wt.% In all batches (determined by the method of thermogravimetric analysis).

FIG. 1 shows the IR spectrum of an adduct with hydrogen peroxide; in Fig-.2 IR spectrum of a new dimethylacetamide adduct; in fig. 3 — IR spectrum of the proposed compound; in fig. 4 - powder X-ray diffraction pattern (pattern). known adduct with hydrogen peroxide, where H is the main peaks; in fig. 5 - the same, new dimethylacetamide adduct; in fig. 6 is the same as the proposed compound; in fig. 7 - chromatograms of various compounds; in fig. 8 - results of thermogravimetric analysis of various compounds; in fig. 9 is a stereoscopic image (spatial image) of the molecular structure of a dimethylacetamide adduct.

FIG. 1-3, infrared spectra (IR spectra) of various compounds are shown. The most distinctive and prominent feature of all these spectra is the presence of absorption bands in the region of 3500 cm, characteristic for OH stretching vibrations, which indicates that both the known adduct with hydrogen peroxide and the previously unknown adduct with

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0 dimethylacetamide and the proposed compound in practically pure form are individual compounds, each of which can be separated as a separate, capable of being characterized by standard methods, substances, which is confirmed by the figures shown in FIG. 4-6 X-ray powder diffraction patterns. 10 each of the figures given 20 angle. and also the distance between the crystallographic planes (A).

FIG. 7 shows the amount of H, K, -dimethylacetamide (DMMA), present in batches A, 3. C and X (as measured by gas-liquid chromatography). For this range, a similar characteristic in batches A, B, C and X is compared with the 20 standard, in which dimethylacetamide is present in a concentration of the order of 1% by weight.

FIG. 8 shows the results of thermogravimetric analysis of various compounds, where the line corresponds to the known adduct of the mentioned coordination compound with hydrogen peroxide; Line 2 is a previously unknown adduct of this compound with N, N -dimethylacetamide; Line 3 corresponds to the proposed compound in its pure form.

In order to facilitate the presentation of the results, the recorder recording curves are arbitrarily changed on the Weight Loss axis, graduated to weight%. As can be seen from FIG. 8, line 1 indicates a greater weight loss at a temperature of about 160 ° C, which occurs due to the loss of the tRance-hydroxyl groups, as well as hydrogen peroxide, while lines 2 and 3 show almost the same weight loss at this temperature, due to the loss of only TRON with - hydroxyl (it) groups. The sloping shoulder present on line 2, rising to a temperature on the order of, represents a loss of N, N-dimethyl acetamide, so that after this the compounds represented by lines 2 and 3 look almost identical.

Presented in FIG. 3, a stereoscopic image is obtained by X-ray crystallographic study of the N, N-dimethylacetamide adduct single crystal. All po5

S12566986

the torture to select a single crystal of the practical compound leads to the agglomerate-pure coordination compound of microcrystallites; powdered platinum (iv) dinane from a single crystal x-ray (de agram) of which la K, s-dimethylacetamide adduct is shown in FIG. 6

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Claims (1)

METHOD FOR PRODUCING 4IS-DICHLOR- - TRANS-DIOXY-Sue (ISOPROPYLAMINE) PLA TINY (1U) by the interaction of cis-dichlorodi (isopropylamine) platinum with hydrogen peroxide at a volume ratio of 2: 1 in a medium of water during boiling with the release of the product, its subsequent purification and air drying, characterized in that, in order to increase the purity of the product, air -dry product is treated with Ν, ^-1 -dimethylacetamide, kept at (+5) - (- 10) ° C and the target product adduct with с, Ν -dimethylacetamide is obtained at a molar ratio of 1: ', after which it is decomposed in vacuum at a temperature below 50 ° C and secrete the target product. g SU „„ 1256698 cm 1256698. The crude product (11 g), obtained as described above, was dissolved in N, N-dimethylacetamide (approximately 1 L) and the resulting solution 5 was filtered through a glass porous filter having porosity No. 4 to remove any insoluble impurities. The solution is then cooled to 5 ° C for 2 hours, seeded to prevent oversaturation, i.e. to prevent the formation of a supersaturated solution, and left for several days at -10 ° C. The crystalline precipitate formed during this time is filtered off, washed with diethyl ether and dried to constant weight. Removal of Ν, Ν-dimethylacetamide in order to obtain practically the desired target product is carried out by heating the obtained crystals of other 50 ° C or lower at a residual pressure of 0.1 mm Hg. for several days or until 25 thermogravimetric analysis of the product and / or analysis by gas-liquid chromatography shows the absence of traces of Ν, Ν-dimethylacetamide in it. 30 Results of analysis of cis, trans 4nc- (Pt Cl ₂ - (OH) ₁ (i-PrNH ₂ ) _a . - the proposed compounds are obtained in several experiments. The compounds are obtained as separate batches of 35 A, B and C, which are then carefully mixed with each other and homogenized to obtain a mixed (composite) batch X (appearance yellow powders). Elemental analysis of the compounds is given in table. 1.