Preparation method of nedaplatin with extremely low silver content

A nedaplatin and extremely low technology, applied in the field of nedaplatin preparation, can solve the problems of difficulty in accurately grasping the amount of potassium iodide used, silver ions cannot be completely removed, and it is not conducive to the removal of silver ions, etc. Stable, easy-to-use effects

Inactive Publication Date: 2012-04-18
NANJING UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Because of the intermediate link of the preparation reaction (preparation of intermediate-cis diammine platinum nitrate) and the final link of the preparation reaction (obtaining the crude product of nedaplatin), it is difficult to quickly determine the residual silver ion in the intermediate or crude product of nedaplatin. Quantity (accurate determination of residual silver, requires special instruments, takes a long time), there is a problem that it is difficult to accurately grasp the amount of potassium iodide used
Insufficient use of potassium iodide will lead to incomplete removal of silver ions
Potassium iodide is used excessively, can introduce new impurity (iodide ion) in the final nedaplatin product; Excessive potassium iodide may react with nedaplatinum to produce new impurity; Excessive potassium iodide also can form stable complex with silver iodide precipitation ( AgI 2 ), to promote the partial dissolution of the silver iodide precipitate, which is not conducive to the removal of silver ions

Method used

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  • Preparation method of nedaplatin with extremely low silver content
  • Preparation method of nedaplatin with extremely low silver content
  • Preparation method of nedaplatin with extremely low silver content

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add 19.32 g (0.04 mol) of cis-diiododiammine platinum and 90 ml of deionized water into the reaction flask, and add a solution made of 13.59 g (0.08 mol) of silver nitrate (0.08 mol) and 50 ml of deionized water under stirring, and keep away from light at 25°C The reaction was stirred for 5h. The yellow silver iodide solid was filtered off to obtain a bright yellow filtrate (cis diammine platinum nitrate solution).

[0029] Put the filtrate in a 200mL beaker, insert the anode (graphite column, Φ0.8×4.0cm) and the cathode (stainless steel plate, 3.0×4.0cm), the pole distance is 1cm, adjust the electrolysis voltage to 1.75 volts, and the current to 20mA, power on and electrolyze 2h (until there is no significant increase in the black deposits deposited on the stainless steel plate). HPLC tracking showed that there was no significant change in the main components and impurities of the reaction solution before and after electrolysis.

[0030] After filtering, add 3.92 g o...

Embodiment 2

[0033] Add 19.32 g (0.04 mol) of cis-diiododiammine platinum and 90 ml of deionized water into the reaction bottle, add a solution made of 13.59 g (0.08 mol) of silver nitrate (0.08 mol) and 50 ml of deionized water under stirring, and keep away from light at 20°C The reaction was stirred for 6h. The yellow silver iodide solid was filtered off to obtain a bright yellow filtrate (cis diammine platinum nitrate solution).

[0034] The filtrate was placed in a 200mL beaker, the electrolysis device was the same as in Example 1, the electrolysis voltage was adjusted to 1.50 volts, the current was 10 milliamps, and the electrolysis was performed for 3 hours (the sediment deposited on the stainless steel plate did not increase significantly). HPLC tracking showed that there was no significant change in the main components and impurities of the reaction solution before and after electrolysis.

[0035] After filtering, add 3.92 g of sodium glycolate (0.04 mol) to the filtrate, adjust t...

Embodiment 3

[0038]Add 19.32 g (0.04 mol) of cis-diiododiammine platinum and 90 ml of deionized water into the reaction bottle, add a solution made of 13.59 g (0.08 mol) of silver nitrate (0.08 mol) and 50 ml of deionized water under stirring, and keep away from light at 25°C The reaction was stirred for 5h. The yellow silver iodide solid was filtered off to obtain a bright yellow filtrate (cis diammine platinum nitrate solution).

[0039] Add 3.92 g of sodium glycolate (0.04 mol) to the filtrate, adjust the pH to 7.0 with 2M sodium hydroxide solution, heat at 60° C., and stir for 6 hours. Concentrate under reduced pressure, crystallize, filter, wash the filter cake with a small amount of ice water, and dry to obtain 6.51 g of nedaplatin, with a yield of 53.7%.

[0040] Detected by atomic absorption spectrometry, the silver content in nedaplatin is 83ppm; analyzed by high performance liquid chromatography, the content of nedaplatin is 99.11%, and related substances <1.00%.

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Abstract

The invention relates to a preparation method of nedaplatin with an extremely low silver content. The preparation method comprises the following steps: allowing cis-diiododiammine platinum to react with silver nitrate at 10-90 DEG C for 0.5-8 hours, filtering, adding the filtrate in an electrolytic cell composed of an anode (a graphite rod) and a cathode (stainless steel), adjusting the electrolytic voltage and current to allow residual silver ions in the solution to be reduced and precipitated, filtering, adding sodium glycollate into the filtrate, adjusting the pH to become neutral, reacting at 40-70 DEG C for 3-10 hours, performing reduced-pressure concentration and crystallization, filtering, washing the filter cake, drying to obtain the nedaplatin with an extremely low silver content. The reaction molar ratio of cis-diiododiammine platinum and silver nitrate is 1:2, and the reaction molar ratio of cis-diiododiammine platinum and sodium glycollate is 1:1. The electrolytic voltage is 0.6-3.0 V, and the current is 5-200 mA. The nedaplatin prepared by the method of the invention has a silver content of less than 1.0 ppm; the content of nedaplatin in the product is more than 99.00%, and the content of related substances is less than 1.00%; the product quality is stable.

Description

technical field [0001] The invention relates to a preparation method of nedaplatin with extremely low silver content. Background technique [0002] Nedaplatin (Nedaplatin), the chemical name is (SP-4-3)-diamine[(hydroxy-κO)acetic acid (2-)-κO]platinum, and the English chemical name is (SP-4-3)-Diammine[ (hydroxy-κO)acetato(2-)-κO]platinum, CAS[95734-82-0], molecular formula: C 2 h 8 N 2 o 3 Pt, the structural formula is: [0003] [0004] Nedaplatin is a new generation of platinum-based antineoplastic drugs after cisplatin and carboplatin. Nedaplatin was researched and developed by Shionogi Pharmaceutical Co., Ltd. of Japan, and was approved for marketing in Japan for the first time in 1995. It is used for the treatment of head and neck tumors, small cell and non-small cell lung cancer, esophageal cancer, bladder cancer, testicular cancer, ovarian cancer, Cervical cancer, etc. Clinical studies have shown that nedaplatin has a broad anti-cancer spectrum and is effec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00C25C1/20
Inventor 王浦海高鹏朱磊陈宁毛柯
Owner NANJING UNIV OF TECH
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