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Synthesis of 5-fluoro-3-methylisobenzofuran-1(3h)-one

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

Active Publication Date: 2022-03-25
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • Synthesis of 5-fluoro-3-methylisobenzofuran-1(3h)-one
  • Synthesis of 5-fluoro-3-methylisobenzofuran-1(3h)-one
  • Synthesis of 5-fluoro-3-methylisobenzofuran-1(3h)-one

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Embodiment 1

[0040] (1) Synthesis of 4-nitrophthalimide

[0041]

[0042] 1L three-neck bottle, equipped with a thermometer and a mechanical stirring device, dissolve phthalimide with 160ml concentrated sulfuric acid, cool down to below 10°C, add the prepared mixed acid dropwise (under ice bath, add 142.4ml concentrated sulfuric acid to 155.3ml concentrated nitric acid solution), the reaction is exothermic, the temperature is controlled at 15-20 ° C, the dropwise addition is completed, stirred at room temperature for 3 hours, the reaction solution is poured into 2 times the amount of crushed ice, stirred, suction filtered, and washed with water to obtain a light The yellow solid was naturally dried at room temperature, and 150 g was fed to obtain 146.4 g of a white powdery solid, with a yield of 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 bottle equipped with a thermometer and a mechanical stirring ...

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Abstract

The invention belongs to the technical field of medicine, and relates to a method for synthesizing 5-fluoro-3-methylisobenzofuran-1(3H)-ketone. 8-step reactions including cyclization, diazotization, bromination, and esterification give 5-fluoro-3-methylisobenzofuran-1(3H)-ketone. The invention realizes the preparation of the key intermediate 5-fluoro-3-methylisobenzofuran-1(3H)-ketone of the antitumor drug lorlatinib (PF-06463922), and the total yield can reach more than 7.0%, The operation is simple, the post-processing is convenient, the time consumption is short, and the cost is low, which is conducive to realizing industrialization. The reaction steps such as substitution, coupling, and chiral resolution finally synthesize lorlatinib, which provides a new method for the synthesis of the antitumor drug lorlatinib.

Description

technical field [0001] The present invention relates to the field of pharmaceutical technology, and relates to the key intermediates of lorlatinib (PF-06463922) 5-fluoro-3-methylisobenzofuran-1(3H)-one and (S)-5-fluoro-3 - Synthetic method of methylisobenzofuran-1(3H)-one. The intermediate and 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-carbonitrile are finally synthesized into lorlatinib through reaction steps such as ammonolysis, substitution, coupling and chiral resolution. , providing a new method for the synthesis of antitumor drug lorlatinib. Background technique [0002] Lorlatinib (PF-06463922) is an ALK inhibitor modified by Pfizer of the United States through Crizotinib. The drug entered clinical trials in 2014 for the treatment of lung cancer, mainly for the first generation Non-small cell lung cancer patients with resistance to ALK inhibitor crizotinib and second-generation ALK inhibitors Ceritinib and Alectinib. In its published patents WO 2013132376, US 8...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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