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Temozolomide intermediate compound VII

A technology for temozolomide and compounds, applied in the direction of organic chemistry and the like, can solve the problems of long route, unstable intermediate, high toxicity, etc., and achieve the effects of high reaction yield, simple operation and mild reaction

Pending Publication Date: 2021-10-12
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In order to solve the problems in the prior art that the preparation process of temozolomide is long, the intermediate is unstable, and a highly toxic chemical reagent needs to be used, the present invention provides a new temozolomide intermediate compound and a new method for preparing temozolomide using the compound; The method has short reaction route, simple operation, milder reaction, economical and environmental protection and high yield, and is suitable for industrial production

Method used

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  • Temozolomide intermediate compound VII
  • Temozolomide intermediate compound VII
  • Temozolomide intermediate compound VII

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Compound II (50.0g, 0.24mol) was dissolved in 120mL of glacial acetic acid and 360mL of dichloromethane mixture, stirred to dissolve, methylhydrazine (13.43g, 0.29mol) was slowly added dropwise to the reaction system, reacted at room temperature, and detected the reaction At the end, spin the dichloromethane to dryness, add 240mL methanol and 60mL trifluoroacetic acid, and stir the reaction. Cool down in an ice bath, filter under reduced pressure, wash the filter cake with ice methanol, and concentrate to remove the organic solvent to obtain Compound IV with a yield of 92.5% and a purity of 99.92% by HPLC.

Embodiment 2

[0063] Dissolve compound II (50.0g, 0.24mol) in 120mL of glacial acetic acid and 240mL of chloroform mixture, stir to dissolve, slowly add methylhydrazine (11.06g, 0.24mol) into the reaction system, react at room temperature, and detect the reaction At the end, spin the chloroform to dryness, add 200mL methanol and 60mL hydrochloric acid, and stir the reaction. Cool down in an ice bath, filter under reduced pressure, wash the filter cake with ice methanol, and concentrate to remove the organic solvent to obtain Compound IV with a yield of 88.1% and a purity of 99.87% by HPLC.

Embodiment 3

[0065] Compound II (50.0g, 0.24mol) was dissolved in 120mL glacial acetic acid and 300mL tetrahydrofuran mixture, stirred and dissolved, methylhydrazine (22.11g, 0.48mol) was slowly added dropwise into the reaction system, and reacted at room temperature to detect the end of the reaction. Spin the tetrahydrofuran to dryness, add 180mL methanol and 60mL glacial acetic acid, and stir the reaction. Cool down in an ice bath, filter under reduced pressure, wash the filter cake with ice methanol, and concentrate to remove the organic solvent to obtain Compound IV with a yield of 86.3% and a purity of 99.79% by HPLC.

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Abstract

The invention belongs to the field of pharmaceutical chemical industry, and particularly relates to a temozolomide intermediate compound VII, an imidazole azo intermediate compound is used as a raw material, is subjected to one-step hydrolysis and then is subjected to nucleophilic substitution with p-nitrophenyl chloroformate to obtain a new intermediate VII, and the invention also provides a new method for synthesizing temozolomide by using the intermediate. According to the method, the use of dangerous oxidative cyclization chemical reagents is avoided, the synthesized intermediate does not generate dimerization impurities, a green catalyst is used for replacing a traditional catalyst, the reaction is milder, economical and environment-friendly, the yield is high, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a temozolomide intermediate compound VII. Background technique [0002] Temozolomide, chemical name 8-carbamoyl-3-methylimidazol[5,1-d]-1,2,3,5-tetrazine-4(3H)-one, molecular formula: C 6 h 6 N 6 o 2 ; Molecular weight: 194.15; CAS registration number: 85622-93-1, the structural formula is as follows: [0003] [0004] Temozolomide was first developed by Aston University in the United Kingdom, and then Schering-Plough Pharmaceuticals of Germany obtained the development right, and it was launched in the United States in 1999. Pharmacological studies have proved that temozolomide is a new type of drug with good curative effect on glioma; it has high bioavailability, can be taken orally, easily penetrates the blood-brain barrier, has no superimposed toxicity compared with other drugs, and has a wider antitumor spectrum. At present, temozolomide is a...

Claims

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Application Information

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IPC IPC(8): C07D233/90C07D487/04
CPCC07D233/90C07D487/04Y02P20/55
Inventor 时江华闫路林刘忠
Owner LUNAN PHARMA GROUP CORPORATION