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Preparation method of low-iron methotrexate

A technology of aminopterin and iron armor, which is applied in the field of compound preparation, can solve the problems of product quality failing to meet customer requirements, unable to meet special requirements, and increasing production costs, so as to achieve low production costs, high product quality, and high yield big effect

Active Publication Date: 2012-04-04
HUZHOU ZHANWANG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Low-iron methotrexate (iron content requirement not greater than 1ppm) has been a product expected by domestic and foreign preparation industries that have incompatibility with metal ions in recent years, but because domestic and foreign pharmacopoeias have not controlled this index on this product, The level of iron content in the product depends entirely on the input raw materials. The iron content of the product before treatment is generally about 10ppm, so the existing methotrexate products cannot meet the special requirements of some domestic and foreign preparation industries
[0004] Some people have tried to use high-quality raw materials, non-metallic equipment and repeated purification methods for trial production, but the result is that the product quality not only fails to meet the customer's requirements, but also increases the production cost. Therefore, the development of low-iron methotrexate or Production is a problem to be overcome

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0028] Use glutamic acid and p-chlorobenzoyl chloride as main raw materials to synthesize p-chlorobenzoyl glutamic acid; then use p-chlorobenzoyl glutamic acid, monomethylamine and zinc chloride as main raw materials to synthesize p-thaminobenzidine Zinc acylglutamate; then take p-thaminobenzoylglutamate zinc, tetraaminopyrimidine sulfate, and tribromoacetone as raw materials to add hydrochloric acid to generate aminobenzoyl glutamic acid, and then add sodium hydroxide to hydrolyze to generate intermediate The product is methotrexate sodium salt, and then removes iron from methotrexate sodium salt.

[0029] The specific method for removing iron ions is: mix and dissolve methotrexate sodium salt and water at a solid-to-liquid ratio of 1:20, and then flow the resulting mixed solution into an inorganic filler with silica gel as a carrier at a flow rate of 0.3 L / min. Packed plexiglass filter column, the ratio of the length to diameter of the filter column is 10:1, and the silica g...

Embodiment 2

[0034] The preparation method is the same as in Example 1. The difference is that the specific method for removing iron ions is: mix and dissolve methotrexate sodium salt and water at a solid-to-liquid ratio of 1:10, and then flow the resulting mixed solution into a silica gel-based carrier at a flow rate of 0.5 L / min. The plexiglass filter column filled with inorganic fillers, the ratio of the length to diameter of the filter column is 8:1, and the silica gel is bonded with carboxylic acid groups.

[0035] Then the obtained filtrate is pumped into a glass neutralization tank, neutralized with sulfuric acid, filtered, washed with water and washed with alcohol to obtain low-iron methotrexate.

[0036] The iron content in methotrexate was measured with an atomic absorption spectrophotometer, and the results showed 0.5 ppm.

[0037]

Embodiment 3

[0039] The preparation method is the same as in Example 1. The difference is that the specific method of removing iron ions is: mix and dissolve methotrexate sodium salt and water at a solid-to-liquid ratio of 1:30, and then flow the resulting mixed solution into a silica gel-based carrier at a flow rate of 0.1L / min. The plexiglass filter column filled with inorganic filler, the ratio of the length to diameter of the filter column is 13:1, and the silica gel is bonded with a phosphoric acid group.

[0040] Then the obtained filtrate is pumped into a ceramic neutralization kettle, neutralized with sulfuric acid, filtered, washed with water and washed with alcohol to obtain low-iron methotrexate.

[0041] The iron content in methotrexate was measured with an atomic absorption spectrophotometer, and the results showed 0.7ppm.

[0042]

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Abstract

The invention relates to a preparation method of a compound, in particular to a preparation method of low-iron methotrexate. The preparation method is characterized in that iron ions are removed out of methotrexate sodium salt which serves as an intermediate product, and the preparation method comprises the following specific steps of: mixing and dissolving methotrexate sodium salt in water in a solid-liquid ration of 1: (10-30), and then enabling the obtained mixed solution to flow into an organic glass filter column filled with inorganic filler at a flowing speed between 0.1L / min and 0.5L / min, wherein the carrier of the organic glass filter column is silica gel, the length-to-diameter ratio of the filter column is (13-8):1, and the silica gel is bonded with a group with a cation resin exchange function; and pumping the obtained filtrate into a nonmetal neutralization kettle, neutralizing with sulfuric acid, filtering, washing with water, and washing with ethanol to finally obtain the low-iron methotrexate. The preparation method disclosed by the invention has the advantages of low production cost and high yield, and the prepared product has high quality.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of low-iron methotrexate. Background technique [0002] The appearance of methotrexate is orange-yellow crystalline powder. It is a broad-spectrum anti-tumor drug commonly used. It can treat various malignant tumors, especially when a large dose is applied to tumors that are ineffective with small doses, it can achieve good curative effect. It has a significant curative effect on membranous epithelial carcinoma, malignant mole and various types of acute leukemia. [0003] Low-iron methotrexate (iron content requirement not greater than 1ppm) has been a product expected by domestic and foreign preparation industries that have incompatibility with metal ions in recent years, but because domestic and foreign pharmacopoeias have not controlled this index on this product, The level of iron content in the product depends entirely on the input raw materials. Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/08
Inventor 潘继成刘光海
Owner HUZHOU ZHANWANG PHARMA
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