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Preparation method of Gilteritinib key intermediate

A compound and solvent technology, applied in the field of drug synthesis, can solve the problems of heavy metal pollution, inability to provide large-scale production, and high production costs, and achieve the effects of avoiding metal lithium reagents, good methodological significance, and low cost.

Active Publication Date: 2020-07-17
苏州康纯医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The analysis found that the synthesis route has the following problems: TMPLi and LDA, which are sensitive to water and air, are used, and there are major safety risks in the scale-up, and the ultra-low temperature of -78°C is required, and the production cost is high
When cyclopropyl is introduced, cyclopropylboronic acid and palladium catalysts are required, the raw materials are expensive and the yield is low, and there is heavy metal pollution
Taken together, this synthetic route cannot provide the required 3,5-dichloro-6-ethylpyrazinecarboxamide on a large scale

Method used

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  • Preparation method of Gilteritinib key intermediate
  • Preparation method of Gilteritinib key intermediate
  • Preparation method of Gilteritinib key intermediate

Examples

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Embodiment 1

[0027] A method for preparing 3,5-dichloro-6-ethylpyrazinecarboxamide (compound I), such as Figure 4 shown, including the following steps:

[0028] (1) Preparation of compound III from compound II: add 600 ml of 1N sodium hydroxide solution to a 1000 ml reaction flask, add 100 g of ethyl propionoacetate dropwise into the reaction flask in an ice-water bath, after the addition is complete, warm to room temperature and stir for 12 h As above, dissolve 52 g of sodium nitrite in 200 ml of water, drop it into the reaction system, and add 200 ml of 1N hydrochloric acid dropwise at 5 °C, complete the dropwise addition within 1 hour, stir for 2-3 hours, and dilute the reaction solution with acetic acid Ethyl ester (300 mL*2) was extracted, the organic phase was washed with 500 ml of saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 65 g of off-white solid with a yield of 91% and a purity of 97%.

[0029] ESI-MS, m / z (%): 102 (M + H )+.

[0030] (2) Prep...

Embodiment 2

[0039] A method for preparing 3,5-dichloro-6-ethylpyrazinecarboxamide (compound I), such as Figure 4 shown, including the following steps:

[0040] (1) Preparation of compound III from compound II: add 600ml of 1N potassium hydroxide to a 1000ml reaction bottle, cool down to 0°C in an ice-water bath, add 100g of ethyl propionyl acetate dropwise, return to room temperature and stir for 12h, dissolve 52g of sodium nitrite in water Add 200ml of acetic acid dropwise to the reaction system, keep at 5°C, add 200ml of acetic acid dropwise, complete the dropwise addition within 1h, stir for 2-3h, add 300ml of ethyl acetate to the reaction solution for extraction twice, use saturated brine for the ethyl acetate phase 500ml was washed, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 65g of off-white solid with a yield of 91%.

[0041] ESI-MS, m / z(%):102 (M + H ) + .

[0042] (2) Preparation of compound V from compound III: add 100...

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Abstract

The invention relates to the field of drug synthesis, and particularly discloses a preparation method of a Gilteritinib key intermediate, namely a method for synthesizing a 3,5-dichloro-6-ethylpyrazinecarboxamide intermediate (compound I). The method is novel in route, simple and convenient to operate, high in yield, good in safety and suitable for industrial production, and comprises the following steps: by taking ethyl propionyl acetate as an initial raw material, carrying out hydrolytic acylation to obtain a compound III; carrying out ring closing on the compound III and aminomalononitrilep-toluenesulfonate to obtain a compound V; then carrying out amino diazotization chlorination to obtain a compound VI; carrying out phosphorus oxychloride transposition on the compound VI to obtain 3,5-dichloro-6-ethylpyrazine-2-carbonitrile (a compound VII); and hydrolyzing the compound VII to obtain the 3,5-dichloro-6-ethylpyrazinecarboxamide intermediate (compound I).

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of 3,5-dichloro-6-ethylpyrazine carboxamide, a key intermediate of Gilteritinib. Background technique [0002] 3,5-dichloro-6-ethylpyrazinecarboxamide is an important intermediate in synthetic medicine, which can be used to synthesize Gilteritinib. AML is a rapidly growing cancer that suppresses normal cells in the bone marrow and blood, resulting in a low number of normal blood cells and an ongoing need for blood transfusions. About 25% to 30% of AML patients have mutations in the FLT3 gene, which are associated with disease progression and a higher risk of relapse. Gilteritinib is a second-generation FLT3 inhibitor that inhibits the internal tandem duplication (ITD) of the FLT3 transmembrane region and the FLT3 tyrosine kinase domain (TKD), two common types of FLT3 mutations that account for about three-thirds of all AML cases. one-third. In add...

Claims

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Application Information

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IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 陈勇庄晓晓
Owner 苏州康纯医药科技有限公司
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