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Preparation method of lobaplatin

A technology of lobaplatin and chloroplatinite, which is applied in the field of preparation of lobaplatin, can solve the problems of poor product purity and content repeatability, difficulty in making preparations, and increased production costs, so as to shorten the reaction time and reduce production costs. The effect of low cost and short production cycle

Active Publication Date: 2013-12-25
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] CN1120046A uses the same preparation method, then recrystallizes lobaplatin crude product with acetone / water system to obtain lobaplatin trihydrate, and proposes the disadvantages of lobaplatin anhydrate by comparison: it is easy to deliquesce and become sticky, it is difficult to make preparations, and Poor repeatability of product purity and content
The entire reaction steps are long, many operations, and time-consuming, resulting in increased production costs, and the introduction of many impurities increases the requirements for product purification

Method used

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  • Preparation method of lobaplatin
  • Preparation method of lobaplatin
  • Preparation method of lobaplatin

Examples

Experimental program
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Effect test

Embodiment 1

[0042] Embodiment 1: the preparation method of lobaplatin and trihydrate

[0043] Add 20.7g (0.05mol) of potassium chloroplatinite into 200mL of purified water, stir and dissolve until clear, add 5.7g (0.05mol) of trans-diaminomethylcyclobutane under nitrogen protection, and stir at 20°C in the dark for reaction 8 hours, filtered, washed the filter cake with an appropriate amount of purified water, absolute ethanol, and ether in sequence, and dried the filter cake in vacuum at 50°C for 4 hours to obtain 18.1 g of dichloro-1,2-diaminomethylcyclobutane platinum, Yield 95.3%.

[0044] Disperse 17.1g (0.045mol) of dichloro-1,2-diaminomethylcyclobutane platinum in 170mL of purified water, stir until evenly mixed, add 15.2g (0.09mol) of silver nitrate, and then add 21mL of acetone , 35 ° C dark stirring reaction for 1.5 hours.

[0045] Cool the reaction solution at -5°C for 3 hours, filter the resulting silver chloride precipitate, and wash the filter cake with an appropriate amou...

Embodiment 2

[0047] Embodiment 2: the preparation method of lobaplatin and trihydrate

[0048] Add 41.5g (0.10mol) of potassium chloroplatinite into 600mL of purified water, stir and dissolve until clear, add 11.4g (0.10mol) of trans-diaminomethylcyclobutane under nitrogen protection, and stir at 25°C in the dark for 10 hours, filtered, washed the filter cake successively with appropriate amount of purified water, absolute ethanol, and ether, and dried the filter cake in vacuum at 40°C for 5 hours to obtain 36.5 g of dichloro-1,2-diaminomethylcyclobutane platinum, The yield is 96.1%.

[0049] Disperse 34.2g (0.09mol) of dichloro-1,2-diaminomethylcyclobutane platinum in 500mL of purified water, stir until evenly mixed, add 30.5g (0.18mol) of silver nitrate, and then add 50mL of acetone , 40 ° C dark stirring reaction for 2 hours.

[0050] Cool the reaction solution at 0°C for 4 hours, filter the resulting silver chloride precipitate, and wash the filter cake with an appropriate amount of ...

Embodiment 3

[0052] Embodiment 3: the preparation method of lobaplatin and trihydrate

[0053] Add 103.8g (0.25mol) of potassium chloroplatinite into 2000mL of purified water, stir and dissolve until clear, add 28.5g (0.25mol) of trans-diaminomethylcyclobutane under nitrogen protection, and stir at 30°C in the dark for 16 hours, filtered, washed the filter cake with an appropriate amount of purified water, absolute ethanol, and ether in sequence, and dried the filter cake in vacuum at 30°C for 6 hours to obtain 91.5 g of dichloro-1,2-diaminomethylcyclobutane platinum, Yield 96.3%.

[0054] Disperse 91.2g (0.24mol) of dichloro-1,2-diaminomethylcyclobutane platinum in 1800mL of purified water, stir until evenly mixed, add 81.5g (0.48mol) of silver nitrate, and then add 150mL of acetone , 45°C and stirred in the dark for 3 hours.

[0055] Cool the reaction solution at 5°C for 6 hours, filter the resulting silver chloride precipitate, and wash the filter cake with an appropriate amount of pu...

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Abstract

The invention provides a preparation method of lobaplatin and lobaplatin trihydrate. Trans-diamine methyl cyclobutane reacts and synthesizes with chloroplatinite in water at the atmosphere of inert gas to generate dichloride, wherein the trans-diamine methyl cyclobutane and the chloroplatinite are taken as raw materials, and the water serves as a solvent; replacement reaction is performed on the dichloride and silver nitrate, so that silver chloride sediments are generated after filtration; filter liquor reacts with L-lactic acid and / or L-lactate under a certain pH value condition so as to generate the lobaplatin; then water / acetone recrystallization is performed on the lobaplatin, so that high-purity lobaplatin trihydrate is obtained. The preparation method provided by the invention includes few reaction steps, and is short in reaction time, high in reaction efficiency, easy and convenient to operate and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation method of lobaplatin. Background technique [0002] Lobaplatin (D19466) is the third-generation platinum antineoplastic drug after cisplatin and carboplatin. The chemical name of lobaplatin is cis-[trans-1,2-cyclobutylbis(methylamine)- N,N′]-[(2S)-lactic acid-O 1 ,O 2 ] - Platinum(II). Formula-I shows the structure of lobaplatin trihydrate. : [0003] [0004] Lobaplatin was developed by Asta Medica AG of Germany. In 2003, the State Food and Drug Administration approved Lobaplatin as a national first-class new drug. Lobaplatin is an alkylating agent, which has definite cytotoxic effect on various animal and human tumor cell lines, similar and strong antitumor effect to cisplatin, and still has a certain cytotoxic effect on cisplatin-resistant cell lines , which is less toxic, has good solubility and is stable in water. Mainly for patients with inoperable ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00
Inventor 赵小伟蔡继兰杜有国李振
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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