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Synthesizing method of 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone

A technology of methyl isobenzene and formylbenzoic acid, which is applied in the field of medicine, can solve the problems of long synthetic route, high cost, and long time-consuming, and achieve the effects of low cost, short time-consuming, and convenient post-processing

Active Publication Date: 2019-01-04
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In its published patents WO 2013132376, US 8680111, JP 2015510879, EP2822953, CN 104169286, US 2016115178, WO 2014207606, four synthetic routes of the drug and its intermediates are introduced. The intermediate 5-fluoro-3-methyl The synthetic method of isobenzofuran-1(3H)-one, the patent WO2013132376 provides a synthetic method, but the synthetic route is long, the cost is high, the time is long, and the yield is low

Method used

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  • Synthesizing method of 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone
  • Synthesizing method of 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone

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Embodiment 1

[0040] (1) Synthesis of 4-nitrophthalimide

[0041]

[0042] 1L three-neck flask, equipped with thermometer and mechanical stirring device, dissolve phthalimide with 160ml concentrated sulfuric acid, cool to below 10℃, add dropwise the prepared mixed acid (142.4ml concentrated sulfuric acid is added to 155.3ml under ice bath Concentrated nitric acid solution), the reaction is exothermic, the temperature is controlled at 15-20 ℃, the dripping is completed, stirring at room temperature for 3 hours, the reaction solution is poured into 2 times the amount of crushed ice, stirring, suction filtration, suction filtration, water washing Yellow solid, natural drying at room temperature, feed 150g, obtain white powdery solid 146.4g, yield 74.7%. ESI-MS (m / z): 193.0 [M+H]+, 385.0 [2M+H]+.

[0043] (2) Synthesis of 4-aminophthalimide

[0044]

[0045] 2L three-necked flask, equipped with thermometer and mechanical stirring device, add hydrochloric acid, add stannous chloride under stirring, t...

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Abstract

The invention relates to the technical field of medicine and relates to a synthesizing method of 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone. The 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone is synthesized by subjecting the initial raw material phthalimide to 8 steps such as nitration, reduction, cyclizing, diazotization, bromination and esterification. The method has the advantages that the preparation of the 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone which is the key intermediate of the antitumor drug Lorlatinib (PF-06463922), total yield can reach 7.0% or above, and the method is simpleto operate, convenient in post-processing, low in time consumption, low in cost and beneficial to industrialization; the Lorlatinib is synthesized by subjecting the intermediate and 1-methyl-3-(( methylamino)methyl)-1H-pyrazol-5-nitrile to ammonolysis, substitution, coupling, chiral resolution and the like, and a new method is provided for the synthesizing of the antitumor drug Lorlatinib.

Description

Technical field [0001] The present invention relates to the technical field of medicines, and relates to 5-fluoro-3-methylisobenzofuran-1(3H)-one and (S)-5-fluoro-3, the key intermediate of the medicine loratinib (PF-06463922) -Methyl isobenzofuran-1(3H)-one synthesis method. This intermediate and 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-carbonitrile undergoes ammonolysis, substitution, coupling, chiral resolution and other reaction steps to finally synthesize loratinib , Provides a new method for the synthesis of anti-tumor drug loratinib. Background technique [0002] Loratinib (PF-06463922) is an ALK inhibitor modified by Pfizer (Crizotinib). The drug entered clinical trials in 2014 for the treatment of lung cancer, mainly for the first generation Patients with non-small cell lung cancer who are resistant to ALK inhibitor crizotinib and second-generation ALK inhibitors Ceritinib (Ceritinib) and Alectinib (Alectinib). In its published patents WO 2013132376, US 8680111,...

Claims

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Application Information

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IPC IPC(8): C07D307/88C07D209/48C07C51/09C07C65/30C07B57/00
CPCC07B57/00C07C51/09C07D209/48C07D307/88C07B2200/07C07C65/30
Inventor 沙宇蒋清乾李晓利付更艳孙维全陈家奇石博文郭奥锋
Owner SHENYANG PHARMA UNIVERSITY
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