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A kind of preparation method of pralatrexate

A technology of temperature control and crystallization, which is applied in the field of medicine, can solve the problems of failing to meet the refining requirements, the increase of impurities, and no refining effect, etc., and achieve the effects of reducing the impact of product quality, high purity and yield, and simple operation

Active Publication Date: 2020-06-02
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Pralatrexate is an amphoteric compound, insoluble in organic solvents such as formic acid, acetic acid, and low-molecular alcohols, DCM, EA at room temperature, and easily soluble in alkaline solutions, DMF, DMSO and other solutions, but in alkaline solvents , the amino group on pteridine in the pralatrexate structure is easily hydrolyzed into a hydroxyl group, and the use of alkaline solvents for purification will not only have no refining effect, but will also increase the size of impurities; when using DMF, DMSO and other solvents for refining, due to the higher boiling points of DMSO and DMF , and pralatrexate is thermally unstable, and will cause DMF and DMSO residues to exceed the standard; the existing technology is useful for beating and purifying methanol, methanol and dichloromethane mixture, which cannot meet the refining requirements

Method used

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  • A kind of preparation method of pralatrexate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 20g of PLQS-6 and 100ml of acetone into a 2L three-necked flask and stir. When the temperature is controlled at about 10°C, the bottle becomes a suspension. Start adding 15ml of 1.0mol / L sodium hydroxide aqueous solution dropwise, and control the rate of addition so that the temperature of the reaction flask is 10~13°C, after the dropwise addition is completed, keep stirring for 2 hours, continue to add 15ml of 1.0mol / L sodium hydroxide aqueous solution dropwise, repeat the above operation until all the 91ml of sodium hydroxide aqueous solution is added dropwise, continue to keep stirring for 2 hours, and the reaction solution is clear. Sampling for HPLC detection; the reaction is complete, put the three-neck bottle in a cold bath to cool down to 0-5°C, add 720ml of absolute ethanol dropwise, at this time, a yellow solid precipitates, after the dropwise addition, continue to keep stirring for 1 hour, filter, and add to the filter cake Dissolve in 200ml of purified wa...

Embodiment 2

[0031] Add 20g of PLQS-6 and 200ml of dioxane into a 2L three-neck flask and stir. When the temperature is controlled at about 10°C, the bottle becomes a suspension. Start to add 15ml of 1.0mol / L sodium carbonate aqueous solution dropwise, and control the dropping speed to make the reaction bottle The temperature is 10-13°C. After the dropwise addition is completed, keep stirring for 2 hours, continue to add 15ml of 1.0mol / L sodium carbonate aqueous solution dropwise, repeat the above operation until all the 91ml of sodium carbonate aqueous solution is added dropwise, continue to keep warm and stir for 4 hours, and the reaction solution is clear. Sampling for HPLC detection; the reaction is complete, put the three-neck bottle in a cold bath to cool down to 0-5°C, add 720ml of absolute ethanol dropwise, at this time, a yellow solid precipitates, after the dropwise addition, continue to keep stirring for 1 hour, filter, and add to the filter cake Dissolve in 200ml of purified wat...

Embodiment 3

[0033] Add 20g of PLQS-6 and 60ml of acetone into a 2L three-neck flask and stir. When the temperature is controlled at about 10°C, the bottle becomes a suspension. Start to add 15ml of 1.0mol / L sodium hydroxide aqueous solution dropwise, and control the rate of addition so that the temperature of the reaction flask is 10~13°C, after the dropwise addition is completed, keep stirring for 2 hours, continue to add 15ml of 1.0mol / L sodium hydroxide aqueous solution dropwise, repeat the above operation until all the 91ml of sodium hydroxide aqueous solution is added dropwise, continue to keep stirring for 2 hours, and the reaction solution is clear. Sampling for HPLC detection; the reaction is complete, put the three-neck bottle in a cold bath to cool down to 0-5°C, add 720ml of acetone dropwise, at this time, a yellow solid precipitates, after the dropwise addition, continue to keep stirring for 1 hour, filter, add 200ml of filter cake to purify Dissolve in water, stir with 200ml o...

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Abstract

The invention belongs to the technical field of medicine and particularly relates to a preparation method of pralatrexate finished products. The method comprises the following steps: by taking PLQS-6as a raw material and respectively taking acetone, methyl ethyl ketone, butanone, dioxane and the like as solvents, performing temperature control, and dropwise adding inorganic base in batches to control the generation of impurities; after the reaction is completed, dropwise adding a crystallization solvent to enable pralatrexate to be crystallized; collecting pralatrexate crystallized solids; adding the solids to purified water to be dissolved; performing washing with dichloromethane; and then, adjusting the pH value with acetic acid to obtain pralatrexate solids. The synthetic method provided by the invention is simple and easy to operate, the impurities are easy to remove, the yield and the purity of the prepared pralatrexate are higher, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of pralatrexate. Background technique [0002] Pralatrexate, trade name Folotyn, is the first new targeted folic acid preparation approved by the FDA for the treatment of peripheral T-cell lymphoma. The chemical name of pralatrexate is 10-propargyl-10-desazaaminopterin. First disclosed in "Synthesis and Antitumor Activity of 10-Propargyl-10-deazaaminopterin" J.Medical Chem.36:2228-2231 (1993) by Joseph I. DeGraw; J William T. Colwell et al. It was then studied by Sirotanak et al and O'Connor et al. Its molecular structure is as follows: [0003] [0004] Pralatrexate is synthesized from p-carboxyphenylacetic acid as a starting material through a series of chemical transformations. Firstly, the intermediate 4-methyl formate, methyl phenylacetate (PLQS-1), the intermediate ɑ-propargyl-(4-methyl formate)-methyl phenylacetate (PLQS-2), the int...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D475/08
CPCC07D475/08
Inventor 张贵民陈成富魏传兵
Owner LUNAN PHARMA GROUP CORPORATION
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