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Synthetic method for temozolomide intermediate

A technology for the synthesis of temozolomide and its synthesis method, which is applied in the field of synthesis of temozolomide intermediates, can solve the problems of long steps and low yield, and achieve the effects of short preparation route, reduced production cost and increased safety

Inactive Publication Date: 2019-03-15
湖北一半天制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method uses the intermediate 5-aminoimidazole-4-carboxamide-1-nitromethylformamide, which is synthesized in two steps, with long steps and low yield

Method used

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  • Synthetic method for temozolomide intermediate
  • Synthetic method for temozolomide intermediate
  • Synthetic method for temozolomide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Add 5-aminoimidazole-4-carboxamide (160.0g, 1.27mol) and carbamoyl chloride (237.52g, 2.54mol) into acetonitrile (640mL), cool the solution to -5~5°C, add three Ethylamine (282.44mL, 2.03moL) was added at a rate of 10g / h, and the internal temperature was controlled at 0-10°C. After the addition, the temperature was raised to 10-20°C, and stirring was continued for 2h. HPLC monitoring showed that the raw material conversion rate was 95.95%, filtered, the filter cake was mixed with water (640mL) and stirred for 30min, filtered, the filter cake was washed with acetonitrile (48mL), and air-dried at 50°C for 12h to obtain Intermediate 1 (204.96g) , the yield was 89.60%, and the purity was 99.40%.

Embodiment 2

[0020] Add 5-aminoimidazole-4-carboxamide (160.0g, 1.27mol) and carbamoyl chloride (237.52g, 2.54mol) into acetonitrile (480mL), cool the solution to -5~5°C, add three Ethylamine (317.75mL, 2.29moL) was added at a rate of 10g / h, and the internal temperature was controlled at 10-20°C. After the addition, the temperature was raised to 10-20°C, and stirring was continued for 2h. HPLC monitoring showed that the conversion rate of the raw material was 87.10%, filtered, the filter cake was mixed with water (480mL) and stirred for 30min, filtered, the filter cake was washed with acetonitrile (48mL), and air-dried at 50°C for 12h to obtain Intermediate 1 (172.71g) , the yield was 75.50%, and the purity was 99.40%.

Embodiment 3

[0022] Add 5-aminoimidazole-4-carboxamide (160.0g, 1.27mol) and carbamoyl chloride (237.52g, 2.54mol) into acetonitrile (640mL), cool the solution to -5~5°C, add three Ethylamine (388.36mL, 2.79moL) was added at a rate of 10g / h, and the internal temperature was controlled at 20-30°C. After the addition, the temperature was raised to 10-20°C, and stirring was continued for 2h. HPLC monitoring showed that the conversion rate of the raw material was 90.43%, filtered, the filter cake was mixed with water (480mL) and stirred for 30min, filtered, the filter cake was washed with acetonitrile (54mL), and air-dried at 50°C for 12h to obtain Intermediate 1 (191.69g) , the yield was 83.80%, and the purity was 99.00%.

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Abstract

The invention discloses a synthetic method for a temozolomide intermediate. The temozolomide intermediate is synthesized from 5-aminooimidazole-4-formamide and methylaminoformyl chloride by a one-stepmethod. The synthetic method comprises the following steps: dissolving the 5-aminooimidazole-4-formamide and the methylaminoformyl chloride in an organic solvent, cooling to the temperature of minus5-5 DEG C, dropwise adding triethylamine, heating and keeping stirring for 2-3 h, filtering, washing, and drying for 12 h at the temperature of 50+ / - 5 DEG C under vacuum to obtain the temozolomide intermediate. The method is high in safety, use of methyl isocyanate as a highly toxic reagent is avoided, the raw material conversion ratio is high and is 95% or above, the purity of the product is 98.3% or above, the reaction conditions are mild, aftertreatment is simple, and the materials can be fed directly without further purification for next reaction.

Description

technical field [0001] The invention belongs to the field of medicine preparation, in particular to a method for synthesizing a temozolomide intermediate. Background technique [0002] Temozolomide, as a new type of alkylating agent antineoplastic drug, can be administered orally, has high bioavailability, good tissue distribution, can pass through the blood-brain barrier, has a good effect on brain tumors, and can also be used to treat melanoma Wait. It was launched in Europe in 1998 and approved in the United States in 1999. At present, there are many syntheses of temozolomide reported at home and abroad, but there are many defects. The first is to use 4-amino-5-carbamoyl imidazole monohydrate as raw material, carry out diazotization reaction with sodium nitrite under acidic conditions, carry out cyclization reaction with methyl isocyanate, obtain crude product, refine ( CN200410020233.4). The second is to generate methyl isocyanate in situ, and perform ring closure re...

Claims

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Application Information

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IPC IPC(8): C07D233/90
CPCC07D233/90
Inventor 刘振东甘丰瑞邓志军
Owner 湖北一半天制药有限公司
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