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Method for synthesizing temozolomide

A synthesis method and technology of temozolomide are applied in the synthesis field of antitumor drugs, which can solve the problems of complex route and low yield, and achieve the effect of high reaction efficiency and good industrialization prospect.

Active Publication Date: 2012-10-10
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are also other processes, but the routes are relatively complicated and the yield is very low, we think it is not advisable

Method used

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  • Method for synthesizing temozolomide
  • Method for synthesizing temozolomide
  • Method for synthesizing temozolomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (1) Preparation of 5-diazo-imidazole-4-carboxamide (DIC)

[0038] Add 6gNaNO to a 500ml three-necked bottle 2 and 108mlH 2 O, put it in a low-temperature constant temperature tank, stir to 0°C, then take 120ml of 2moL / L hydrochloric acid and 9gAIC, mix and stir evenly to form a green solution, add it to a 100ml constant pressure titration funnel, and slowly drop in the prepared sodium nitrite In the solution, stir at constant temperature for 2 hours, TLC detects the reaction, the developer is methanol and ethyl acetate (volume ratio is 4:5), the reaction is stopped according to the test results, the solution is transparent and light yellow with a small amount of precipitation, suction filtration, washing with ethanol for two and dried in vacuum at 50°C to obtain 5.8 g of a pale yellow solid.

[0039] (2) Synthesis of Temozolomide (TMZ)

[0040] Add 4.2lg DIC and 40ml DMSO to a 250ml single-necked flask, add 3.5ml MIC dropwise under electromagnetic stirring, and react...

Embodiment 2

[0044] (1) Preparation of 5-diazo-imidazole-4-carboxamide (DIC)

[0045] Add 5gNaNO to a 500ml three-necked bottle 2 and 90mlH 2 O, put it in a low-temperature constant temperature tank, stir to 0°C, then take 120ml 2moL / L hydrochloric acid and 7.5gAIC, mix and stir evenly to form a green solution, add it to a 100ml constant pressure titration funnel, and slowly drop in the prepared nitrous acid In sodium solution, stir at constant temperature for 2 hours, TLC detects the reaction, the developer is methanol and ethyl acetate (volume ratio is 4:5), stop the reaction according to the test results, the solution is transparent and light yellow with a small amount of precipitation, suction filtration, ethanol washing Twice, vacuum-dried at 50°C to obtain 4.7 g of light yellow solid.

[0046] (2) Synthesis of Temozolomide (TMZ)

[0047] Add 3gDIC and 30mlDMSO into a 250ml single-necked flask, add 2.5mlMIC dropwise under electromagnetic stirring, and react with light blocking at 2...

Embodiment 3

[0051] (1) Preparation of 5-diazo-imidazole-4-carboxamide (DIC)

[0052] Add 8gNaNO to a 500ml three-necked bottle 2 and 144mlH 2 O, put it in a low-temperature constant temperature tank, stir to 0°C, then take 120ml of 2moL / L hydrochloric acid and 12gAIC, mix and stir evenly to form a green solution, add it to a 100ml constant pressure titration funnel, and slowly drop in the prepared sodium nitrite In the solution, stir at constant temperature for 2 hours, TLC detects the reaction, the developer is methanol and ethyl acetate (volume ratio is 4:5), the reaction is stopped according to the test results, the solution is transparent and light yellow with a small amount of precipitation, suction filtration, washing with ethanol for two and vacuum-dried at 50°C to obtain 7.733 g of a pale yellow solid.

[0053] (2) Synthesis of Temozolomide (TMZ)

[0054] Add 3g DIC and 50ml DMSO to a 250ml single-necked flask, add 2.5ml MIC dropwise under electromagnetic stirring, react with l...

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Abstract

The invention discloses a method for synthesizing temozolomide. The method comprises the following steps of: slowly dropwise adding hydrochloric acid solution of 5-amino-imidazole-4-formamide into NaNO2 aqueous solution with stirring at the temperature of 0 DEG C, filtering, washing with ethanol, and drying to obtain light yellow solid 5-diazo-imidazole-4-formamide; dissolving the light yellow solid in dimethyl sulfoxide, performing electromagnetic stirring, dropwise adding methyl isocynate, reacting at room temperature in a dark place, adding acetic ether, continuously reacting, adding absolute ethanol, reacting with stirring at a low temperature, performing suction filtration, washing with ethanol and drying to obtain light pink solid; and dissolving the obtained solid in a mixed solvent of isopropyl alcohol and pyridine, uniformly stirring, heating with an oil bath, refluxing, filtering after the solid is dissolved while the solution is hot, removing impurities, collecting mother liquor, continuously stirring, cooling, separating, performing suction filtration, washing the solid with ethanol and drying to obtain white temozolomide powder. The method is safe, efficient, simple and convenient, and has high yield, high product purity and a good application prospect.

Description

Technical field: [0001] The invention relates to a method for synthesizing antineoplastic drugs, in particular to a method for synthesizing antineoplastic drug temozolomide. Background technique: [0002] Temozolomide, its chemical name is 3,4-dihydro-3-methyl-4-oxoimidazol[5,1,d]-1,2,3,5-tetrazine-8-amide. This product is a new drug for the treatment of glioma. It is an analogue of the alkylating agent mitozolomide, but the bone marrow suppression effect is significantly reduced and the tolerance is better. It is clinically used to treat refractory glioblastoma multiforme in adults [1, 2]. The only oral drug used to control the recurrence of brain tumors is carmustine, but carmustine has large and irreversible side effects, and temozolomide It is a relatively good new anticancer drug for the treatment of glioma and malignant melanoma. It is characterized by being stable in an acidic environment, fully absorbed after oral administration, bioavailability as high as 0.98, go...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
Inventor 周涛国鹏
Owner CENT SOUTH UNIV