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Industrial production method of miriplatin

A production method, the technology of rice platinum, applied in the direction of chemical instruments and methods, organic chemistry, platinum group organic compounds, etc., can solve the problems of harsh process conditions and low solubility, and achieve the advantages of simple product separation, low cost and high yield Effect

Inactive Publication Date: 2015-06-24
TIANJIN TAIPU PHARMA SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method does not involve the use of solvents such as chloroform, according to relevant information (oxaliplatin USP) and our experiments found that: cis-dinitrate [(1R,2R)-1,2-cyclohexanediamine] platinum ( Ⅱ) The solubility in water is very small, and it takes a long time to completely generate cis-dinitrate [(1R,2R)-1,2-cyclohexanediamine-dihydrate] platinum (Ⅱ) aqueous solution in water
Moreover, the cis-dinitrate [(1R,2R)-1,2-cyclohexanediamine] platinum (II) solid needs to be concentrated by high-temperature distilled water, which requires harsh process conditions in industry

Method used

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  • Industrial production method of miriplatin
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  • Industrial production method of miriplatin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0045] Preparation of cis-[(1R,2R)-1,2-cyclohexanediamine-diiodo]platinum (Ⅱ):

[0046] Add 300mL of distilled water to 10g of potassium chloroplatinite, dissolve and filter, and add the filtrate to a 1000mL four-necked bottle. Dissolve 32g of potassium iodide in 150mL of distilled water, and then add it to the above reaction flask. After the mixture is stirred for 30 minutes, add 2.7g of (1R,2R)-1,2-cyclohexanediamine distilled aqueous solution (200mL of distilled water) dropwise. , reacted in the dark at 20-25°C for 20 hours, a dark yellow solid precipitated, filtered, washed with 50mL of ice water, 50mL of ethanol, and 50mL of diethyl ether in sequence, and dried to obtain 11.1g of a yellow solid, with a yield of 82%.

preparation Embodiment 1

[0048] Preparation of Miplatin:

[0049] 2.70g cis-[(1R,2R)-1,2-cyclohexanediamine-dichloro]platinum (Ⅱ), 2.41g silver nitrate and 50mL water, stirred and reacted at room temperature for 24 hours in the dark, filtered and filtered Silver chloride to obtain cis-[(1R,2R)-1,2-cyclohexanediamine-dihydrate] platinum aqueous solution for future use.

[0050] Add 4.87g of myristic acid, 2.98g of ammonia water (25% by weight) and 10mL of distilled water into a 250mL reaction bottle, heat to 40°C, after clarification, add the above-prepared cis-[(1R,2R)-1, 2-Cyclohexanediamine-dihydrate] platinum (II) filtrate. After dropping, the reaction system was reacted at 40° C. in the dark for 36 hours. Add 30mL of ethanol to the system at 40°C, stir and disperse for 3 hours, and filter to obtain 4.7g of platinum, with a yield of 84.7%, HPLC content of 99.3%, and chiral HPLC of 100%.

[0051] Example 2:

[0052] Preparation of Miplatin:

[0053] 4.0g cis-[(1R,2R)-1,2-cyclohexane...

Embodiment 3

[0056] Preparation of Miplatin:

[0057] 2.70g cis-[(1R,2R)-1,2-cyclohexanediamine-dichloro]platinum (Ⅱ), 2.41g silver nitrate and 50mL water, stirred and reacted at room temperature for 24 hours in the dark, filtered and filtered Silver chloride to obtain cis-[(1R,2R)-1,2-cyclohexanediamine-dihydrate] platinum (II) aqueous solution for future use.

[0058] Add 3.24g of myristic acid, 0.80g of potassium hydroxide and 10mL of distilled water into a 250mL reaction bottle, heat to 50°C, after clarification, add the above-prepared cis-[(1R,2R)-1,2-cyclohexanedi Amine-dihydrate] platinum (II) filtrate. After dropping, the reaction system was reacted at 50° C. in the dark for 24 hours. Add 110mL of ethanol to the system at 50°C, stir and disperse for 1 hour, and filter to obtain 4.3g of platinum, with a yield of 77.5%, HPLC content of 99.3%, and chiral HPLC of 100%.

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Abstract

The invention discloses an industrial production method of miriplatin. The method comprises the following steps: dropwise adding an aqueous solution of cis-dinitric acid[(1R,2R)-1,2-diaminocyclohexane-dihydrate]paltinum (II) into a substrate solution containing myristic acid, alkali metal hydroxide and water, stirring and reacting for 8-36 h at 40-80 DEG C after dropwise adding, adding alkyl alcohol as a disperse solvent during aftertreatment, stirring and dispersing at 20-80 DEG C for 0.5-3 h, and filtering to obtain miriplatin, wherein the alkali metal hydroxide is sodium hydroxide, potassium hydroxide or ammonium hydroxide, and the alkyl sulfhydrate is methanol, ethanol, isopropanol or n-butanol. According to the preparation method, haloalkanes such as chloroform, etc. are not used as a reaction solvent; the reaction is simple to operate by a reverse dripping method; the aftertreatment is simpler by using alkyl alcohol added after the reaction as a disperse solvent; and the miriplatin prepared by the above method has high quality, is low-cost and is easier for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a preparation method of miplatin which is easy for industrial production. Background technique [0002] Miriplatin is a fat-soluble platinum third-generation antineoplastic drug developed by Sumitomo Pharmaceutical Co., Ltd. and launched in Japan in 2009. It is considered to have a therapeutic effect on solid tumors such as liver cancer and malignant lymphoma. Its code name is SM-11355, and its chemical name is: (SP-4-2)-[((1R,2R)-1,2-cyclohexanedi Amine-кN 1 , кN 2 )] two (tetradecanoic acid)] platinum and hydrates thereof, the structural formula (I) is as follows: [0003] (I) [0004] The preparation method of Miplatin disclosed in the patent JP11315088 applied by Sumitomo of Japan is: using cis-[(1R,2R)-1,2-cyclohexanediamine-dihalogen] platinum (II) as the starting material in distilled water React with silver nitrate in the medium, filter after the react...

Claims

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Application Information

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IPC IPC(8): C07F15/00
CPCC07F15/0013
Inventor 陈滔于玲丽陈华范喜园
Owner TIANJIN TAIPU PHARMA SCI & TECH DEV
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