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Osimertinib intermediate and preparation method thereof

A technology of intermediates and compounds, which is applied in the field of osimertinib intermediates and its preparation, can solve the problems of increasing the production cost of the final product, high purification cost, and high quality risk, and achieves reduced electron cloud density, high reaction yield, The effect of speeding up the reaction rate

Inactive Publication Date: 2018-06-08
瑞博(杭州)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

[0011] The patented route applied by Beijing Kanglisheng puts the condensation reaction of compounds 8 and 9 in the last step, resulting in the quality of the final product depending on the reaction and purification of the last step, which has a high quality risk and will increase the production cost of the final product , even the purification cost of the final product is much higher than that of the intermediate

Method used

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  • Osimertinib intermediate and preparation method thereof
  • Osimertinib intermediate and preparation method thereof
  • Osimertinib intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040]

[0041] Take a 500ml four-necked flask, put in compound A (20.17g, 108.36mmol), triethylamine (18.57g, 183.52mmol), dissolve in dichloromethane (320ml), stir under nitrogen protection, and cool down to 0°C. A mixed solution of acetyl chloride (12.56g, 161.15mmol) and dichloromethane (30ml) was added dropwise at 0-5°C. After the dropwise addition was completed, the reaction was continued. After the reaction, add water (150ml), stir for 30min, and filter with suction. The filter cake was washed twice with water (20ml×2), and the filter cake was dried to obtain 23.63 g of solids, with a molar yield of 95.58%. 1H NMR (400MHz, DMSO) δ2.13(s, 3H), 3.99(s, 3H), 7.33(d, J=13.2Hz, 2H), 8.87(d, J=8.4Hz, 2H), 9.58(s , 1H). MS(ES+): m / z 229[M+H] +

Embodiment 2

[0046]

[0047] Take a 50ml one-mouth bottle, put in compound B (5.30g, 23.23mmol), N,N,N-trimethylethylenediamine (3.33g, 32.59mmol), sodium carbonate (3.30g, 23.88mmol), add absolute ethanol (30ml), stirred evenly, protected by nitrogen, and heated to 80°C for 1.5 hours. After the reaction was completed, the reaction solution was concentrated to dryness at 40° C. under reduced pressure, and the residue was added with dichloromethane (30 ml) and stirred for 10 minutes, and suction filtered. The filter cake was washed twice with dichloromethane (10ml×2). The filtrate was concentrated to dryness at 40°C under reduced pressure to obtain a blood-red oily liquid (7.20 g, 23.20 mmol), with a molar yield of 99.87%. 1 H NMR (400MHz, DMSO) δ2.07(s, 3H), 2.12(s, 6H), 2.43(t, J=7.6Hz, 2H), 2.80(s, 3H), 3.22(t, J=6.4Hz ,2H), 3.93(s,3H), 6.77(s,1H), 8.47(s,3H), 9.25(s,1H). MS(ES+): m / z 311[M+H]+

Embodiment 3

[0049]

[0050] Take a 100ml autoclave, add absolute ethanol (25.29g), potassium hydroxide (1.37g, 24.42mmol) and water (8.49g), and stir to dissolve. Compound C (4.68g, 15.06mmol) was added and flushed with nitrogen protection. Seal the autoclave and heat up to 120°C for reaction. After the reaction was complete, dichloromethane (30ml) and water (20ml) were added, stirred for 30min, and separated. The organic phase was concentrated to dryness at 55°C under reduced pressure to obtain a blood-red oily liquid (3.84 g, 14.31 mmol), with a molar yield of 95.03%. 1 H NMR (400MHz, DMSO) δ2.10(s, 6H), 2.32(t, J=6.8Hz, 2H), 2.70(s, 3H), 3.03(t, J=6.8Hz, 2H), 3.87(s ,3H), 4.91(s,1H), 6.75(s,1H), 7.11(s,1H). MS(ES+): m / z 269[M+H] +

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Abstract

The invention belongs to the field of medicine synthesis and particularly relates to an osimertinib intermediate and a preparation method thereof. The provided osimertinib intermediate is a compound in a formula C and has a structural formula in the description, wherein R is alkyl or aryl; R1 is alkyl, more preferably, methyl. After the compound in the formula C is hydrolyzed, the compound and a compound in a formula E are subjected to a condensation reaction, a compound in a formula F is prepared, wherein R is alkyl or aryl; R1 is alkyl, more preferably, methyl.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to osimertinib intermediates and preparation methods thereof. Background technique [0002] AstraZeneca's Tagrisso (osimertinib, AZD9291), used to treat patients with metastatic non-small cell lung cancer (NSCLC) who carry EGFRT790M mutations and are refractory to EGFR tyrosine kinase inhibitor treatment, in November 2015 It was approved in the United States under accelerated approval on the 13th. The structural formula of AZD9291 is as follows: [0003] [0004] The substance patent for osimertinib is WO2013014448 (applicant: AstraZeneca). This patent not only protects osimertinib but also discloses the synthesis route of osimertinib. The inventor reviewed the synthesis process and found that the yield of the condensation reaction of compounds 1 and 2 was 90%-95%, and the yield of the nucleophilic substitution reaction of compound 3 and trimethylethylenediamine was 75-8...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/43C07C231/12C07C217/84C07C213/02C07D403/04
CPCC07C213/02C07C231/02C07C231/12C07C233/43C07D403/04C07C217/84C07C233/25
Inventor 张现毅姜有鱼王崇高红军车大庆
Owner 瑞博(杭州)医药科技有限公司
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