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Temozolomide intermediate compound

A technology for temozolomide and a compound, which is applied in the field of drug synthesis, can solve the problems of low yield and long route, and achieves the effects of high selectivity, easy operation, and avoiding silica gel column chromatography operation.

Pending Publication Date: 2022-06-07
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] 3) The problem of long route and low yield;

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0077] At room temperature, 5-amino-4-imidazolium cyanide (SM-1, 18.10g, 0.10mol) and carbonyldiimidazole (SM-2, 17.84g, 0.11mol) were added to 80ml of acetonitrile, and the temperature was controlled to reflux for reaction. After completion, the reaction solution was cooled to -10°C and stirred to precipitate a solid, filtered and dried to obtain compound I-1 with a yield of 85.5% and a purity of 99.86%.

Embodiment 2

[0079] At room temperature, 5-amino-4-imidazolium cyanide (SM-1, 18.10 g, 0.10 mol) and carbonyldiimidazole (SM-2, 16.22 g, 0.10 mol) were added to 80 ml of tetrahydrofuran, and the temperature was controlled to reflux for reaction. After completion, the reaction solution was cooled to -10°C and stirred to precipitate a solid, filtered and dried to obtain compound I-1 with a yield of 83.6% and a purity of 99.68%.

Embodiment 3

[0081] At room temperature, add 5-amino-4-imidazolium cyanide (SM-1, 18.10 g, 0.10 mol) and carbonyldiimidazole (SM-2, 29.19 g, 0.18 mol) into 80 ml of 1,2-dichloroethane, and control the temperature. The reaction was refluxed. After the reaction was detected, the reaction solution was cooled to -10°C and stirred to precipitate a solid, filtered and dried to obtain compound I-1 with a yield of 81.3% and a purity of 99.22%.

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a temozolomide intermediate compound. According to the preparation method, 5-amino-1H-imidazole-4-nitrile is taken as an initial raw material and reacts with N, N '-carbonyldiimidazole, and the new temozolomide intermediate 5-amino-1-(1H-imidazole-1-carbonyl)-1H-imidazole-4-nitrile is obtained. Meanwhile, the invention provides a method for preparing temozolomide by using the novel intermediate compound. The method comprises the following steps: reacting 5-amino-1-(1H-imidazole-1-carbonyl)-1H-imidazole-4-nitrile with methylamine hydrochloride, diazotizing the obtained product, cyclizing, and hydrolyzing cyano to obtain temozolomide. The synthesis method of the novel intermediate provided by the invention is simple, the reaction of the novel intermediate and methylamine hydrochloride can effectively avoid the use of a highly toxic reagent methyl isocyanate and methylamino formyl chloride with higher toxicity and irritation, diazotization and ring-closure reaction are realized in one step, and the separation of unstable diazonium salt is avoided. The synthetic route is short, the yield is high, the reaction condition is mild, the process is stable, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a temozolomide intermediate compound. Background technique [0002] Temozolomide, chemical name is 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-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. It is an alkylated anticancer drug with broad-spectrum antitumor activity, especially against glioma (brain cancer) and melanoma (skin cancer). In terms of efficacy, alkylating agents such as cyclophosphamide, nitrogen mustard, and carbazide are less effective than temozolomide in the treatment of brain tumors. Temozolomide itself has no activity and is a prodrug. It is currently believed that DNA methylation and mismatch repair failure are the main mechanisms of temozolomide cy...

Claims

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Application Information

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IPC IPC(8): C07D233/90C07D487/04
CPCC07D233/90C07D487/04Y02P20/55
Inventor 周发玲时江华
Owner LUNAN PHARMA GROUP CORPORATION
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