阅读说明：本技术 一种高效制备洛铂无水物的方法 (Method for efficiently preparing lobaplatin anhydride ) 是由 刘其星 普绍平 张林涛 丛艳伟 谢丽娇 王应飞 陈红娟 郭明里 于 2020-06-30 设计创作，主要内容包括：本发明公开了一种高效制备洛铂无水物的方法,以反式-1,2-二胺甲基-环丁烷盐酸盐和氯亚铂酸钾为原料,以水为溶剂,先将反式-1,2-二胺甲基-环丁烷盐酸盐在碱性条件下中和,使得反式-1,2-二胺甲基-环丁烷游离出,再与氯亚铂酸钾反应生成二氯化物；二氯化物和硝酸银置换反应,滤除产生的氯化银沉淀,将滤液与乳酸钠在一定的pH下反应,再将反应液移入截留分子量为200的透析袋中,透析后浓缩、干燥,即得无水物洛铂,本发明操作步骤少,合成时间短,操作简单,所得洛铂无水物纯度高、收率高。(The invention discloses a method for efficiently preparing lobaplatin anhydride, which takes trans-1, 2-diamine methyl-cyclobutane hydrochloride and potassium chloroplatinite as raw materials, takes water as a solvent, neutralizes the trans-1, 2-diamine methyl-cyclobutane hydrochloride under an alkaline condition to free the trans-1, 2-diamine methyl-cyclobutane, and then reacts with the potassium chloroplatinite to generate dichloride; performing a displacement reaction between dichloride and silver nitrate, filtering out silver chloride precipitate generated by filtration, reacting the filtrate with sodium lactate at a certain pH, transferring the reaction solution into a dialysis bag with the molecular weight cut-off of 200, and concentrating and drying after dialysis to obtain the anhydrous lobaplatin.)

1. A method for efficiently preparing lobaplatin anhydride is characterized in that trans-1, 2-diaminemethyl-cyclobutane hydrochloride and potassium chloroplatinite are used as starting materials, cis-dichloro- (trans-1, 2-diaminemethyl-cyclobutane) platinum (II) as an intermediate generated by the reaction is not required to be filtered out, silver nitrate is directly added for hydrolysis reaction, precipitate mainly containing silver chloride is filtered out, the collected filtrate and sodium lactate react under the condition of high pH to obtain lobaplatin mother liquor, the lobaplatin mother liquor is further filtered, the liquor is placed in a dialysis bag with the molecular weight cutoff of 200, and after full dialysis, the liquor is concentrated and dried to obtain the anhydrous lobaplatin.

2. The method for efficiently preparing lobaplatin anhydrate as claimed in claim 1, wherein: the method comprises the following steps:

(1) dissolving potassium platinochloride in water to obtain a potassium platinochloride aqueous solution;

(2) dissolving trans-1, 2-diaminemethyl-cyclobutane hydrochloride in water, adding an alkaline compound, fully mixing, adding into the potassium platinochloride aqueous solution prepared in the step (1), and stirring in a dark place;

(3) dissolving silver nitrate in water, adding the silver nitrate into the solution obtained in the step (2), stirring the solution in the dark, filtering out precipitates to obtain a filtrate, adding sodium lactate into the obtained filtrate, adding sodium hydroxide to adjust the pH value of the reaction solution after the sodium lactate is dissolved in the water, stirring the solution in the dark, and filtering out the precipitates again to obtain a filtrate;

(4) transferring the filtrate obtained in the step (3) into a dialysis bag with the molecular weight cutoff of 200, placing the dialysis bag into water, changing the dialyzed water every hour until no chloride in the water is detected by using 2% silver nitrate, evaporating the liquid in the dialysis bag by using a rotary evaporator until no water drops, transferring the solid obtained by dialysis into a forced air drying box, and drying to finally obtain the lobaplatin anhydride.

3. The method for efficiently preparing lobaplatin anhydrate as claimed in claim 1, wherein: the mass ratio of the potassium platinochloride to the water in the step (1) is (1-50): 1, the dissolving temperature is 40-80 ℃.

4. The method for efficiently preparing lobaplatin anhydride as claimed in claim 1, wherein in the step (2):

the mass ratio of the trans-1, 2-diaminemethyl-cyclobutane hydrochloride to the water is 1 (5-20);

the molar ratio of the potassium chloroplatinite to the trans-1, 2-diamine methyl-cyclobutane hydrochloride is 1 (1.2-1.8);

the molar ratio of the trans-1, 2-diaminemethyl-cyclobutane hydrochloride to the alkaline compound is 1 (1.0-1.4).

5. The method for efficiently preparing lobaplatin anhydride as claimed in claim 1, wherein in the step (2): the temperature of the light-proof stirring reaction is 30-60 ℃, and the time of the light-proof stirring reaction is 0.5-4.0 h.

6. The method for efficiently preparing lobaplatin anhydride as claimed in claim 1, wherein in the step (2): the alkaline compound is one of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.

7. The method for efficiently preparing lobaplatin anhydride as claimed in claim 1, wherein in the step (3):

the mass ratio of the potassium platinochloride to the silver nitrate is 1 (2.5-3.0);

the mass ratio of the sodium lactate to the water is 1 (5-20);

the molar ratio of the potassium platinochloride to the sodium lactate is 1 (1-3);

the molar ratio of the potassium platinochloride to the sodium hydroxide is 1 (0.8-1.2).

8. The method for efficiently preparing lobaplatin anhydride as claimed in claim 1, wherein in the step (3): adding silver nitrate, and stirring in a dark place for reaction at the temperature of 30-60 ℃ for 0.5-2.0 h; adding sodium lactate, stirring in the dark at the temperature of 30-60 ℃ for reaction, and stirring in the dark for 0.5-2.0 h.

9. The method for efficiently preparing lobaplatin anhydride as claimed in claim 1, wherein in the step (3): and adding sodium hydroxide to adjust the pH value of the reaction solution to 7-10, and reacting for 3-8 h.

10. The method for efficiently preparing lobaplatin anhydride as claimed in claim 1, wherein in the step (4): the water bath temperature of the rotary evaporator is 40-60 ℃, and the vacuum degree is 150-50 hPa/mbar; in the step (4): the temperature of the air-blast drying box is 40-60 ℃, and the drying time is 4-12 h.

Technical Field

The invention relates to the field of chemical synthesis, in particular to a method for efficiently preparing lobaplatin anhydride.

Background

Lobaplatin (lobaplatin), also known as platinum and leplatin, has the chemical name of 1, 2-diaminemethyl-cyclobutane-lactic acid platinum (II), and has the following chemical structural formula:

it is a third-generation platinum antineoplastic drug developed by ASTAMedica, Germany. Research shows that the medicine has definite cytotoxic effect on various animal and human tumor cell strains, has the same or better tumor inhibiting effect as cisplatin and carboplatin, has no cross drug resistance with cisplatin, has strong anticancer activity and small toxic and side effects, has good solubility and is stable in water, and is mainly used for treating chronic granulocytic leukemia, metastatic breast cancer which can not be treated by operation and small cell lung cancer.

After the original patent EP0324154 described the preparation method of lobaplatin for the first time, the method for preparing lobaplatin by ion exchange method (see "lobaplatin as an antitumor drug", "synthesis of lobaplatin" and patent CN102020679A), the method for preparing lobaplatin by one-step reaction (see patent CN101787052A), and the method for preparing lobaplatin by adjusting the pH of the reaction solution (see patent CN103467528A and the synthesis process of lobaplatin optimized by orthogonal test method) were reported in succession. In the method, the ion exchange method has the longest steps and takes the longest time, and more introduced impurities are introduced, particularly, when the reactant is subjected to ion exchange with anion exchange resin, monohydroxy nitrate impurities are likely to be generated due to incomplete ion exchange, so that the difficulty in purifying the product is improved, and the production cost is increased; the one-step reaction method has the advantages of minimum steps and short total preparation time, but Cl is introduced in the reaction process^-、I^-、K⁺Trans-1, 2-diaminemethyl-cyclobutane and L-lactic acid can not be effectively removed in the product, and the product quality is poor; the method for adjusting the pH of the reaction solution has the advantages of few reaction steps, short production period, low production cost and simple operation, but a large amount of acetone is needed in the purification process to obtain a product with higher purity, so that the production scale of the lobaplatin is limited. Based on the good water-soluble characteristic of lobaplatin, the lobaplatin is fast and fast under the condition of ensuring the purity of the lobaplatinThe method can produce lobaplatin with little or no toxic chemicals, and is the content of key research and breakthrough.

Disclosure of Invention

The invention aims to provide a method for efficiently preparing lobaplatin anhydride, which comprises the following steps of taking trans-1, 2-diaminemethyl-cyclobutane hydrochloride and potassium chloroplatinite as starting materials, directly adding silver nitrate for hydrolysis reaction without filtering out an intermediate cis-dichloro- (trans-1, 2-diaminemethyl-cyclobutane) platinic (II) generated by the reaction, filtering out a precipitate mainly containing silver chloride, reacting the collected filtrate with sodium lactate under a high pH condition to obtain lobaplatin mother liquor, further filtering, placing the liquor in a dialysis bag with the molecular weight cutoff of 200, fully dialyzing, concentrating and drying to obtain the anhydrous lobaplatin, wherein the specific design scheme is as follows:

a method for efficiently preparing lobaplatin anhydrate comprises the following steps:

(1) dissolving potassium platinochloride in water to obtain a potassium platinochloride aqueous solution;

(2) dissolving trans-1, 2-diaminemethyl-cyclobutane hydrochloride in water, adding an alkaline compound, fully mixing, adding into the potassium platinochloride aqueous solution prepared in the step (1), and stirring in a dark place;

(3) dissolving silver nitrate in water, adding the silver nitrate into the solution obtained in the step (2), stirring the solution in the dark, filtering out precipitates to obtain a filtrate, adding sodium lactate into the obtained filtrate, adding sodium hydroxide to adjust the pH value of the reaction solution after the sodium lactate is dissolved in the water, stirring the solution in the dark, and filtering out the precipitates again to obtain a filtrate;

(4) transferring the filtrate obtained in the step (3) into a dialysis bag with the molecular weight cutoff of 200, placing the dialysis bag into water, changing the dialyzed water every hour until no chloride in the water is detected by using 2% silver nitrate, evaporating the liquid in the dialysis bag by using a rotary evaporator until no water drops, transferring the solid obtained by dialysis into a forced air drying box, and drying to finally obtain the lobaplatin anhydride.

Preferably, the mass ratio of the potassium platinochloride to the water in the step (1) is (1-50): 1, the dissolving temperature is 40-80 ℃.

Preferably, in the step (2): the preferable mass ratio of the trans-1, 2-diaminemethyl-cyclobutane hydrochloride to the water is 1 (5-20); the preferable molar ratio of the potassium chloroplatinite to the trans-1, 2-diamine methyl-cyclobutane hydrochloride is 1 (1.2-1.8); the preferable molar ratio of the trans-1, 2-diaminemethyl-cyclobutane hydrochloride to the alkaline compound is 1 (1.0-1.4);

preferably, in the step (2): the temperature of the light-proof stirring reaction is 30-60 ℃, and the time of the light-proof stirring reaction is 0.5-4.0 h.

Preferably, in the step (2): preferably, the basic compound is one of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.

Preferably, in the step (3): the preferable mass ratio of the potassium platinochloride to the silver nitrate is 1 (2.5-3.0); preferably, the mass ratio of the sodium lactate to the water is 1 (5-20); the preferable molar ratio of the potassium platinochloride to the sodium lactate is 1 (1-3); the preferable molar ratio of the potassium platinochloride to the sodium hydroxide is 1 (0.8-1.2);

preferably, in the step (3): adding silver nitrate, and stirring in a dark place for reaction at the temperature of 30-60 ℃ for 0.5-2.0 h; adding sodium lactate, and stirring in the dark at the temperature of 30-60 ℃ for 0.5-2.0 h;

preferably, in the step (3): and adding sodium hydroxide to adjust the pH value of the reaction solution to 7-10, and reacting for 3-8 h.

Preferably, in the step (4): the water bath temperature of the rotary evaporator is 40-60 ℃, and the vacuum degree is 150-50 hPa/mbar.

Preferably, in the step (4): the temperature of the air-blast drying box is 40-60 ℃, and the drying time is 4-12 h.

The invention has the advantages that: the invention takes trans-1, 2-diaminemethyl-cyclobutane hydrochloride and potassium chloroplatinite as starting materials, an intermediate cis-dichloro- (trans-1, 2-diaminemethyl-cyclobutane) platinic (II) generated by the reaction is not required to be filtered out, silver nitrate is directly added for hydrolysis reaction, a precipitate mainly containing silver chloride is filtered out, and the collected filtrate is reacted with sodium lactate under the condition of higher pHAnd (3) obtaining lobaplatin mother liquor, further filtering, putting the liquor into a dialysis bag with the molecular weight cutoff of 200, fully dialyzing, concentrating and drying to obtain anhydrous lobaplatin. The whole operation process is not required to be carried out under the protection of inert gas, the generated intermediate is not required to be filtered or refined as reported in other documents, the operation steps are greatly reduced, the reaction time is shortened, and Cl existing in the system can be removed by a dialysis bag^-、NO₃ ^-、K⁺、Na⁺And the trans-1, 2-diaminemethyl-cyclobutane and sodium lactate which may exist are filtered out, so that the purity of the lobaplatin is ensured. In a word, the method for preparing the lobaplatin has the advantages of few operation steps, short synthesis time, simple operation, high product yield and high purity.

Drawings

FIG. 1 shows the NMR spectrum of the prepared lobaplatin anhydride.

Detailed Description

The following describes the embodiments of the present invention in more detail with reference to specific examples.