Synthesis process of methotrexate

A methotrexate and synthetic process technology, which is applied in the field of pharmaceutical compounds, can solve problems such as complex operation process, difficult to obtain raw materials, and high requirements for reaction conditions, and achieve the effects of simple process operation, short production cycle, and high purity

Pending Publication Date: 2021-05-28
贵州中森医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After querying and analyzing a large number of literatures and summarizing them, we found that if the intermediates are first synthesized and then methotrexate is synthesized, the raw materials required for the experiment are difficult to obtain, and the reaction conditions are relatively high and the operation process is complicated.

Method used

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  • Synthesis process of methotrexate
  • Synthesis process of methotrexate
  • Synthesis process of methotrexate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The synthetic technique of embodiment 1 methotrexate

[0046] 1) Synthesis of crude methotrexate

[0047] Synthesis method: Take 250ml of distilled water, 39g of L-p-aminobenzoyl glutamic acid zinc salt, 9.6g of 2,4,5,6-tetraaminopyrimidine sulfate, put them into a flask, adjust with 12mol / L concentrated hydrochloric acid The pH of the solution is 2-3, add 36ml of ethanol, 12g of 1,1,3-tribromoacetone, reflux reaction at 25°C, after the reaction lasts for 2 hours, add 2g of sodium acetate trihydrate to it, and continue the reaction for 24 hours to obtain Crude methotrexate.

[0048] synthetic route:

[0049]

[0050] 2) refining the synthetic methotrexate crude product into pure methotrexate

[0051] Synthesis method: put the synthesized methotrexate yellow solid in a round bottom flask, add 100ml of distilled water into it, the solid part dissolves, then adjust the pH to 10-11 with 40% NaOH solution, the yellow solid gradually dissolves until the solution turns r...

Embodiment 2

[0054] The synthetic technique of embodiment 2 methotrexate

[0055] 1) Synthesis of crude methotrexate

[0056] Synthesis method: Take 200ml of distilled water, 30g of L-p-aminobenzoyl glutamic acid zinc salt, 8g of 2,4,5,6-tetraaminopyrimidine sulfate, put them into a flask, adjust the solution with 12mol / L concentrated hydrochloric acid PH to 2-3, add 30ml of ethanol, 8g of 1,1,3-tribromoacetone, reflux reaction at 20°C, after the reaction lasts for 1 hour, add 1g of sodium acetate trihydrate to it, and continue the reaction for 20 hours to obtain formazan Crude aminopterin;

[0057] synthetic route:

[0058]

[0059] 2) refining the synthetic methotrexate crude product into pure methotrexate

[0060] Put the synthesized yellow solid methotrexate in a round-bottomed flask, add 100ml of distilled water into it, the solid part dissolves, then adjust the pH to 10-11 with 35% NaOH solution, the yellow solid gradually dissolves until the solution is reddish brown and clear...

Embodiment 3

[0063] The synthetic technique of embodiment 3 methotrexate

[0064] 1) Synthesis of crude methotrexate

[0065] Synthesis method: Take 300ml of distilled water, 50g of L-p-aminobenzoyl glutamic acid zinc salt, 11g of 2,4,5,6-tetraaminopyrimidine sulfate, put them into a flask, adjust the solution with 12mol / L concentrated hydrochloric acid PH to 2-3, add 42ml of ethanol, 16g of 1,1,3-tribromoacetone, condense and reflux reaction at 30°C, after the reaction lasts for 4 hours, add 4g of sodium acetate trihydrate to it, and continue the reaction for 28 hours to obtain formazan Crude aminopterin;

[0066] synthetic route:

[0067]

[0068] Refining synthetic crude methotrexate into pure methotrexate

[0069]Put the synthesized yellow solid of methotrexate in a round bottom flask, add 100ml of distilled water into it, the solid is partially dissolved, then adjust the pH to 10-11 with 45% NaOH solution, the yellow solid gradually dissolves until the solution is reddish brown ...

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Abstract

The invention relates to a synthesis process of methotrexate, which comprises the following steps: synthesizing a methotrexate crude product, preparing the synthesized methotrexate crude product into methotrexate disodium salt, adjusting the pH value to 5-6, and refining into a methotrexate pure product, the reaction synthesis steps are less, the raw materials are easy to purchase, the cost is low, and the experimental operation is simple; the methotrexate disodium salt is recrystallized and separated out by acetone, the yield is improved, and the purity of the compound after detection reaches 99% or above.

Description

technical field [0001] The invention relates to the field of pharmaceutical compounds, in particular to a synthesis process of methotrexate. Background technique [0002] Tumor is also known as a neoplasm, which is a very common and frequently occurring disease. The incidence of tumor is extremely high. Children, young people and the elderly are all at risk of disease, and it can occur in any part of the human body. Tumor is the abnormal proliferation of tissue cells caused by various factors, and the formation of tumor is its main clinical manifestation. There are two types of tumor cells, one is benign and will not endanger life, and the other is malignant and can be called cancer. The three basic characteristics of cancer are immortality, migration and loss of contact inhibition, which is also difficult for this type of tumor primary cause of cure [1] . In addition, the physiological, biochemical state and morphological characteristics of cancer cells are very differen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/08
CPCC07D475/08
Inventor 汤磊张毅王建塔朱高峰崔杏
Owner 贵州中森医药有限公司
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