Oxaliplatin medicament composition, preparation method thereof and method for synthesizing oxaliplatin as raw medicinal material

A technology of oxaliplatin and composition, which is applied in the field of synthesis of raw material oxaliplatin, can solve the problems of reducing product yield, operator injury, poor molding and the like

Active Publication Date: 2009-12-30
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But, the problem that this method exists is: silver ion exists in the product
[0011] U.S. Patent US5290961A discusses in the background technology that the synthetic technique that contains silver nitrate, oxalic acid in the prior art exists problem is: silver ion exists in the product
[0018] However, mannitol as a carrier also has some disadvantages: mannitol for injection is expensive as a lyophilized carrier, and oxaliplatin has a large filling volume and is easy to separate out due to its poor solubility. To a certain extent, it has a stabilizing effect on the solution, but it also brings problems. Due to the high solid content and large filling volume, there is a high risk of frying bottles in the production process of oxalipl

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  • Oxaliplatin medicament composition, preparation method thereof and method for synthesizing oxaliplatin as raw medicinal material
  • Oxaliplatin medicament composition, preparation method thereof and method for synthesizing oxaliplatin as raw medicinal material
  • Oxaliplatin medicament composition, preparation method thereof and method for synthesizing oxaliplatin as raw medicinal material

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0147] [Embodiment 1] intermediate (I)---cis-dichloro (trans-(-)-1,2-cyclohexanediamine) synthesis of platinum

[0148] At room temperature, put 10g (4.07mmol) of potassium chloroplatinite into a 150ml three-necked flask, add 100ml of distilled water, and add 2.887g (25.28mmol) of trans-cyclohexane distilled in 15ml of distilled water under stirring. The amine was added dropwise in about 10 minutes, then stirred and reacted at room temperature for 8 hours, and the reaction liquid was detected by thin-layer chromatography to the end point, the reaction solution was filtered, washed three times with 30ml of purified water, once with 20ml of ethanol, once with 20ml of ether, 65 After drying at °C for 4 hours, 8.42 g of a yellow solid product was obtained, with a yield of 91.9%.

Example Embodiment

[0149] [Embodiment 2] Intermediate (II) - the synthesis of cis-dinitro (trans-(-)-1,2-cyclohexanediamine) platinum

[0150] At room temperature, put 8g (21.16mmol) of intermediate I and 6.828g (40.19mmol) of silver nitrate into a 2000ml three-necked flask, add 1200ml of water, blow nitrogen, stir the reaction under dark conditions, and heat up to 50°C. Under reaction for 12 hours, spot plate monitoring, then add 304mg (1.83mmol) of potassium iodide (dissolved in 8ml distilled water) to the there-necked flask, add nitrogen, continue to stir for 1 hour, filter with water membrane, then wash the filter cake with a little purified water, A colorless transparent solution of Intermediate II was obtained.

Example Embodiment

[0151] [Example 3] Synthesis of Oxaliplatin

[0152] Add the intermediate II solution into a 2000ml three-neck flask, protect it with nitrogen, stir it under dark conditions, raise the temperature in a water bath to 50°C, then slowly add 7.80g (42.31mmol) potassium oxalate (dissolved in 60ml distilled water) for about 5min, drop After the addition is complete, add nitrogen, continue the reaction for 3-4 hours, and monitor by pointing the plate. After the reaction is completed, cool the reaction solution to room temperature with water, and filter it with a water membrane to obtain the reaction solution of oxaliplatin. Concentrate under reduced pressure at 65°C to a large amount of solid Precipitate, stop concentrating, cool down with water, filter, and wash the filter cake three times with 40ml×3 purified water, three times with 30ml×3 absolute ethanol, and finally wash with 20ml ether, and dry at 55°C for 4 hours. 6.4 g of white oxaliplatin crystals were obtained.

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Abstract

The invention relates to an oxaliplatin medicament composition as an anticancer medicament, a preparation method thereof and a method for synthesizing oxaliplatin as raw medicinal material. The composition comprises oxaliplatin and lactose, wherein the mass ratio of the oxaliplatin to the lactose is 1:12-1:20. The composition can be added with injection water and pH regulator and made into freeze-dried powder injection through freeze drying. The freeze-dried powder injection not only has the advantages of good formability, plump shape and the like, but also overcomes the prejudice that oxaliplatin freeze-dried powder injection taking the lactose as a freeze-drying carrier is not good in formability and the like. The synthesis method comprises: 1) taking K2PtCl4 and trans-diaminocyclohexane as raw materials to prepare an intermediate (I); 2) forming an intermediate (II) through intermediate reaction; and 3) forming the oxaliplatin through the reaction of the intermediate (II) and potassium oxalate solution, wherein the step 2) also comprises a process of adding KI for reaction. The method has the advantages of simple reaction, mild conditions, short time and no silver ions in products.

Description

technical field [0001] The invention relates to an anticancer drug oxaliplatin pharmaceutical composition, a preparation method thereof, and a synthesis method of a crude drug oxaliplatin. Background technique [0002] Oxaliplatin (Oxaliplatin) was first disclosed in 1978, and the compound was claimed in US Patent No. 4,169,846A, and the preparation method of the compound was given. The basic steps of the method are: (1) reacting dichlorocyclohexane diammine platinum with silver nitrate solution; (2) removing silver chloride precipitate; (3) adding dibasic acid such as oxalic acid to react. [0003] [0004] Although the above-mentioned synthetic route is relatively simple, the requirements are harsh, and each step needs to be stored away from light, which undoubtedly increases equipment, and the reaction yield of the last step is very low, and the ratio of raw materials required is also relatively high, thus increasing the production cost. Conducive to industrialized pr...

Claims

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Application Information

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IPC IPC(8): A61K31/282A61K31/194A61K9/19C07F15/00A61J3/02A61P35/00
Inventor 李明华宋显荣李华
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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