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Method for preparing lobaplatin trihydrate by usingoxalate

A technology of lobaplatin trihydrate and oxalate, applied in the field of preparation of lobaplatin trihydrate, can solve the problems of incomplete reaction, low lobaplatin yield, unstable properties, etc. Conducive to the effect of synthesis and complete reaction

Active Publication Date: 2011-04-20
GUIZHOU YIBAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] However, in further research, we found that using acrylonitrile or 1,2-dicyanocyclobutane as raw materials to synthesize lobaplatin, there are many types of raw materials, the process is complicated and cumbersome, and the intermediate product trans-diaminomethyl cyclobutane Butane is unstable in nature and is in a liquid state, which is inconvenient for storage and transportation, which brings inconvenience to the further generation of lobaplatin; use K in the reaction 2 PtCl 4 Low activity, resulting in incomplete reaction and low yield of lobaplatin

Method used

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  • Method for preparing lobaplatin trihydrate by usingoxalate
  • Method for preparing lobaplatin trihydrate by usingoxalate
  • Method for preparing lobaplatin trihydrate by usingoxalate

Examples

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Embodiment 1

[0055] The preparation of used raw material diaminomethylcyclobutane oxalate

[0056] (1) Take 200ml of acrylonitrile, add 0.05g of Fecl3 and 0.044g of p-methoxyphenol at a temperature of 215°C and pressurize nitrogen to 17bar, and mix and react for 8 hours. After the reaction is complete, 20ml of dark red liquid is obtained. After distillation at 170-180°C, 10g of crude dicyanocyclobutane can be obtained, the cis-trans ratio is about 4:6, and then the crude product is distilled at 140-160°C, rectified and cis-trans converted to obtain trans-dicyanocyclobutane Cyclobutane 6.5g, melting point 37.5°C;

[0057] (2), after feeding ammonia gas into the trans-dicyanocyclobutane, the temperature rose to 70-85°C, the hydrogen gas was pressurized to 20bar, activated nickel was catalyzed, the reaction time was 20h, and 16ml of light yellow liquid was obtained. That is, trans-diaminomethylcyclobutane;

[0058] (3) 16ml of trans-diaminomethylcyclobutane and 3.5g of anhydrous oxalic acid...

Embodiment 2

[0059] Embodiment 2: the preparation of lobaplatin trihydrate

[0060] 1. Synthesis and preparation of diiodide

[0061] 1.1 Add 41.5g of potassium chloroplatinite into 120ml of purified water, stir to dissolve completely, and completely dissolve 99.6g of potassium iodide in 120ml of purified water under dark conditions, then add it into the solution of potassium chloroplatinite and stir for 30 minutes;

[0062] 1.2 Dissolve 31.2g of oxalate and 22.4g of potassium hydroxide in 200ml of purified water respectively, mix and react the two for 20 minutes, remove impurities by suction filtration, measure the pH value to 10, then add to the solution of 1.1, avoid light and stir for reaction 120 minutes;

[0063] 1.3 After the reaction is finished, filter the feed liquid with suction, rinse the filter cake with purified water, 150ml of water each time, until the washed water is free of chloride when detected with 2% silver nitrate solution, and filter the filter cake at 45-55°C Aft...

Embodiment 3

[0078] Preparation of lobaplatin trihydrate

[0079] 1. Synthesis and preparation of diiodide

[0080] 1.1 Add 23.1g of potassium chloroplatinite into 100ml of purified water, stir to dissolve completely, and completely dissolve 46.2g of potassium iodide in 60ml of purified water under dark conditions, then add it into the potassium chloroplatinite solution and stir for 20 minutes;

[0081] 1.2 Dissolve 20g of oxalate and 16.7g of potassium hydroxide in 150ml of purified water respectively, mix and react the two for 10 minutes, filter to remove impurities, measure the pH value to 11, then add to the solution of 1.1, and stir in the dark for 100 minute;

[0082] 1.3 After the reaction is finished, filter the feed liquid with suction, rinse the filter cake with purified water, 100ml of water each time, until the washed water is free of chloride when detected with 2% silver nitrate solution, and filter the cake at 45-55°C Vacuum drying for 15 hours gave 31 g of the crude produc...

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Abstract

The invention relates to a method for preparing a lobaplatin trihydrate by using oxalate, diaminomethyl cyclobutane oxalate, potassium chloroplatinite and potassium iodide are taken as raw materials, and the method comprises the following steps: firstly replacing the potassium chloroplatinite to potassium iodoplatinite, neutralizing the oxalic acid in diaminomethyl cyclobutane under alkaline condition, enabling the diaminomethyl cyclobutane to be freed, and then reacting the diaminomethyl cyclobutane with K2PtI4 (potassium iodoplatinate) for synthesizing a diiodide; enabling the diiodide to carry out replacement reaction with silver nitrate to generate silver iodide precipitate, enabling reactants after filtering out the precipitate to carry out ion exchange with anion exchange resin, then synthesizing a lobaplatin anhydride with lactic acid, re-crystallizing the anhydride in water / acetone mixed solution, and finally obtaining a lobaplatin trihydrate product. The raw materials used in the method have stable performances, the reaction is fuller and more complete, and the yield of the lobaplatin trihydrate is high.

Description

technical field [0001] The invention relates to a preparation method of lobaplatin trihydrate, in particular to a method for preparing lobaplatin trihydrate with oxalate. Background technique [0002] Lobaplatin (D19466), also known as Lobaplatin, is the third-generation platinum-based antineoplastic drug developed by ASTA Medica AG after cisplatin and carboplatin. Its chemical name is: 1,2-diaminomethyl-cyclobutane-lactate platinum. Molecular formula is C 9 h 18 N 2 o 3 Pt, the molecular weight is 397.34, the chemical structure formula is as follows: [0003] [0004] Lobaplatin has an alkylating effect and is an alkylating agent (broad sense). Studies have shown that it has definite cytotoxic effects on a variety of animal and human tumor cell lines, which is equivalent to or better than cisplatin and carboplatin in tumor inhibition, and has the same toxic effect as carboplatin, and has no cross-resistance to cisplatin . It has strong anticancer activity, low to...

Claims

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Application Information

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IPC IPC(8): C07F15/00
Inventor 窦啟玲钟洪生周黎亚彭雯
Owner GUIZHOU YIBAI PHARMA CO LTD
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