The method of purification of cis-dichlorobenzophenone (ii)

 

(57) Abstract:

Describes an improved purification method known connections - CIS-dichlorobenzophenone (II), which is used in medicine as a substance anticancer drugs. How is that rough salt containing impurities CIS-[PT(NH₃)₂CL₂] and CIS-[PT(i-C₃H₇NH₂)CL₂, is dissolved in an aqueous solution of ammonium chloride with a concentration of 0.12 to 0.15 mol/l at 75-85^oWith mass ratio W:t=20-25:1, then injected solid ammonium oxalate in an amount to provide a molar ratio of it to PT, is equal to 4-5:1, filter out impurities, and the filtrate is treated with concentrated hydrochloric acid at room temperature. The yield of the target product is 60%. The impurity content of less than 1%. 1 N. p. F.-ly, 1 table.

The invention relates to methods of obtaining pure CIS-dichlorobenzophenone (II), which is used in medicine as a substance anticancer drugs II and III generation.

Describes several ways of obtaining and purification of compounds of this class [1 - Patent UK 2060615, CL. 01 G 55/00, 1981, 2 - Kabanov Century. And. , To monitorability (II) [2 - Kabanov Century I., Kozhukhovskaya, And.. Starkov A. K. RF Patent 2086559 C1, C 07 F 15/00 1997. ] including the interaction of tetrachloroplatinate (II) with potassium ammonium oxalate, isopropylamino and hydrochloric acid. 3 g K₂PtCl₄(7,2310^-3mol) and 5.1 g₂WITH₂O₄H₂O (27,6910^-3mol) and 0,771 g (NH₃)₂C₂O₄(5,4310^-3mol) dissolved in 24 ml of water and heated at 60^oWith over 30 min, maintaining the pH= 6.5 by adding sodium hydroxide (5,7910^-3mol). Then maintain the reaction mixture for 2 h (preventing darkening of the solution). Add 24 ml of concentrated hydrochloric acid and incubated for 40 minutes Precipitated light yellow precipitate of CIS-dichlorobenzophenone (II) is filtered off, washed with alcohol and dried. The total number of the selected set is 1,163 g, which corresponds to 47% of theoretical yield. The reaction scheme for CIS-dichlorobenzophenone (II) includes the following stages:

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In the process in pilot-scale draft salt" may contain impurities 2-4% wt. symmetric diamines PT(II). Therefore there was a need to amend the method of obtaining a development of the method of purification "rough salt of CIS-[Pt(NH₃)(i-3)(i-C₃H₇NH₂)CL₂] based on the dual process of recrystallization "black salt" from dimethylformamide with filtering solution. Then add 50% Hcl and the mixture was kept at 5^oC for 30 minutes, the precipitate was separated, washed with ethanol. The yield of purified product is 20% wt. in relation to the draft of salt. The disadvantage of this method is the need for at least two precrystallization that significantly reduces the yield of the final product, using as a solvent of dimethylformamide, environmentally hazardous substances, the complexity of the refining of platinum from working solutions containing formamide.

The invention consists in the following: salt CIS-dichlorobenzophenone(II) is dissolved in 75-85^oWith in an aqueous solution of ammonium chloride, 0,12-0,15 mol/g and the mass ratio of W:t=20-25:1, introducing crystalline ammonium oxalate in the amount of 4-5:1 with respect to Pt(mol), heated for 2 hours, the precipitate is filtered off and treat the filtrate with concentrated hydrochloric acid. Thus obtained CIS-dichlorodiammineplatinum(II) contains an admixture of 0.5% CIS-[Pt(NH₃)₂Cl₂is my salt.

The basis of the proposed method is based on the following transformation of complexes of platinum(II) in aqueous solutions of ammonium oxalate. Impurities CIS-[Pt(A)₂Cl₂], where A= NH₃i-C₃H₄NH₂translate to less soluble chelates [Pt(A)₂C₂O₄] who Excel in the sediment according to the equation:

CIS-[PT(A)₂CL₂] + (NH₄)₂C₂O₄--> [Pt(A)₂C₂O₄]+2NH₄Cl, A=NH₃i-C₃H₇NH₂< / BR>
The filtrate remains complex [Pt(NH₃)(i-C₃H₇NH₂)C₂O₄] formed by the reaction: CIS-[PT(NH₃)(i-C₃H₇NH₂)Cl₂] + (NH₄)₂C₂O₄--> [PT(NH₃)(i-C₃H₇NH₂)C₂O₄] + 2NH₄Cl

Subsequent treatment with hydrochloric acid filtrate containing the complex [Pt(NH₃)(i-C₃H₇NH₂)C₂O₄] , leads to the formation of the final product by the reaction:

[PT(NH₃)(i-C₃H₇NH₂)C₂O₄] + 2HCl --> CIS-[PT(NH₃)(i-C₃H₇NH₂)Cl₂] + H₂C₂O₄< / BR>
From comparison with the prototype of the proposed method has the following differences:

- the original salt is dissolved in the attachment g:t=20-25:1 with the introduction of solid ammonium oxalate in number, providing the molar ratio of it to platinum, equal 4-5:1;

- increases the yield of the purified product.

Example. 18.0 g (5,2610^-2mole) rough salt of CIS-dichlorobenzophenone(II) under continuous stirring portions add 400 ml heated to 75^oWith a solution of ammonium chloride of 2.56 g (4,7810^-2mole), is dissolved within 60 minutes 3 Quiroga at 80^oTo add crystalline ammonium oxalate 33 g (2,3210^-1mole), dissolved in 120 minutes of continued stirring, after which the solution is cooled to room temperature and the precipitate is filtered off. To the filtrate is poured 800 ml of concentrated hydrochloric acid at room temperature. After 40 minutes the precipitate CIS-dichlorobenzophenone(II) is separated from the solution, washed with alcohol and dried. The yield of purified product is 10,80 g, which corresponds to 60% of theoretical. The original draft salt contains 4% of CIS-[PT(NH₃)₂CL₂] and 2% [Pt(i-C₃H₇NH₂)₂Cl₂] impurities in the purified product these impurities is 0.5% and less than 0.4%, respectively. The content of impurities in the products is determined according to the chemical, spectrophotometric and x-ray analysis [3 - W the owls of platinum(II). Coord. chemistry, 1986, T. 12, 8, S. 1127-1131. 4 - Jelihovsky N. N., Djakov, B., Fatkin L. Yu , Bokarev, S. C. Synthesis and physico-chemical study of the CIS diaminedichloroplatinum with various amines. Coord. chemistry. 1991, T. 17, 10, S. 1412 - 1415].

Further examples are given in the table.

As the environment dissolution rough salt of CIS-dichlorobenzophenone(II) use of 0.12 to 0.15 mol/ l aqueous solution of NH₄Cl. At a lower concentration becomes appreciable hydrolysis of the original product, leading to the formation of dimers and trimers of these complexes of platinum(II), which reduces the yield of the pure product. The increase in the concentration of the chloride ion is more than 0.15 mol/ l complicates the process of reaction formation oxalateonline complex. The mode of dissolution ratio (W:t 20-25:1) and temperature (75-85^o(C) is selected based on the need of a higher yield of the target product and prevent its hydrolysis. The ratio of ammonium oxalate and the original product is 4-5 mol/mol, which provides the reaction of the exchange. The upper limit is limited by the solubility of salts in the system, as well as the influence on the yield of the target product, the lower weight of the reaction of chlorite replacement is isoamsa concentrated hydrochloric acid to increase the yield of the target product by reducing its solubility with increasing acid concentration.

The method of purification of CIS-dichlorobenzophenone (II) containing impurities of CIS-[Pt(NH₃)₂Cl₂] and CIS-[Pt(i-C₃H₇NH₂)₂Cl₂] by recrystallization rough salt, characterized in that the rough salt of CIS-dichlorobenzophenone (II) containing the impurities dissolved in an aqueous solution of ammonium chloride with a concentration of 0.12 to 0.15 mol/l at 75-85^oWith mass ratio W: t= 20-25: 1, then injected solid ammonium oxalate in an amount to provide a molar ratio of it to PT, is equal to 4-5: 1, filter out impurities, and the filtrate is treated with concentrated hydrochloric acid at room temperature.