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Preparation method of acetylation intermediate of (S)-5-fluoro-3-methylisobenzofuran-3-one

A technology of methyl isobenzene and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, can solve problems such as low economic benefits, difficult industrial production, and long reaction steps, and achieve the goals of reducing environmental pollution, improving product quality, and enhancing acidity Effect

Inactive Publication Date: 2019-06-07
杭州科耀医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The inventors have found that when the above method is adopted, the acetaldehyde used in the reaction process is easily gasified, a large amount of by-products will be generated, the pollution is serious, it is not easy to be industrialized, and the reaction steps are long and the economic benefit is low.

Method used

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  • Preparation method of acetylation intermediate of (S)-5-fluoro-3-methylisobenzofuran-3-one
  • Preparation method of acetylation intermediate of (S)-5-fluoro-3-methylisobenzofuran-3-one
  • Preparation method of acetylation intermediate of (S)-5-fluoro-3-methylisobenzofuran-3-one

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Experimental program
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Effect test

Embodiment 1

[0034] (1) In a four-neck flask equipped with a thermometer and a stirrer, add 1.2 mol of potassium carbonate to dissolve in 3 times the volume of water, then add 5 times the weight of toluene and 1.2 mol of N,N-diisopropylamine reaction solution , start stirring, control the reaction temperature at 10-20°C, and start to add 1.0mol p-fluorobenzoyl chloride dropwise. After 2 hours of reaction, the reaction liquid is separated, and the organic phase is spin-dried to obtain intermediate a with a yield of 95% and a purity of 99%. %.

[0035] The structure of intermediate a is as follows:

[0036]

[0037] NMR data: 1 H NMR (400MHz, CDCl 3 ):δ7.29-7.34(m,2H),7.04-7.10(m,2H),3.67(s,2H),1.33(s,12H)ppm;

[0038] (2) Add 1.2 mol of n-butyllithium THF solution dropwise to 4 times the weight of intermediate a, and control the temperature at -70 to -60°C. After about 1 hour of reaction, add dropwise to 1.0 mol of N,N - In dimethylacetamide and 1 times weight THF solution, add dropw...

Embodiment 2

[0043] (1) In a four-neck flask equipped with a thermometer and a stirrer, add 1.2 mol of potassium carbonate to dissolve in 3 times the volume of water, then add 5 times the weight of toluene and 1.2 mol of N,N-diisopropylamine reaction solution , start stirring, control the reaction temperature at 10-20°C, start to drop 1.0mol of p-fluorobenzoyl chloride, react for 2 hours, separate the reaction solution, and spin dry to obtain intermediate a with a yield of 95% and a purity of 99%.

[0044] (2) Add 1.2 mol of n-butyllithium THF solution dropwise to 4 times the weight of intermediate a, and control the temperature at -70 to -60°C. After about 1 hour of reaction, add the reaction solution dropwise to 1.4 mol In N,N-dimethylacetamide and 1 times weight THF solution, add dropwise for 0.5h, keep it warm for 2h, add dilute hydrochloric acid dropwise to quench, spin the reaction solution to dryness, filter, and recrystallize with 3 times weight methanol, then Acetylated intermedia...

Embodiment 3

[0046] (1) In a four-neck flask equipped with a thermometer and a stirrer, add 1.2 mol of potassium carbonate to dissolve in 3 times the volume of water, then add 5 times the weight of toluene and 1.2 mol of N,N-diisopropylamine reaction solution , start stirring, control the reaction temperature at 10-20°C, start to drop 1.0mol of p-fluorobenzoyl chloride, react for 2 hours, separate the reaction solution, and spin dry to obtain intermediate a with a yield of 95% and a purity of 99%.

[0047] (2) Add 1.2 mol of n-butyllithium THF solution dropwise to the THF solution of 4 times the weight of intermediate a, and control the temperature at -70 to -60°C. After about 1 hour of reaction, add dropwise to 1.8 mol of N,N - In dimethylacetamide and 1 times weight THF solution, add dropwise for 0.5h, keep warm for 2h, add dropwise dilute hydrochloric acid to quench, spin the reaction solution to dryness, filter, and recrystallize with 3 times weight methanol to obtain acetyl Compound i...

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Abstract

The invention provides a preparation method of an acetylation intermediate of (S)-5-fluoro-3-methylisobenzofuran-3-one. The method comprises the following steps: (1) performing a reaction on a fluoroaromatic compound and a metal organic reagent to obtain an ortho-metal intermediate; and (2) performing a reaction on the ortho-metal intermediate obtained in the step (1) and an acetylation reagent, and after the reaction is completed, performing post-treatment to obtain the acetylation intermediate. The method provided by the invention has the advantages of a short reaction route, simple operation, environmental friendliness, safety and economy, thereby having wide application prospects.

Description

technical field [0001] The present invention belongs to the preparation method of pharmaceutical intermediates, in particular to the acetylation intermediate of (S)-5-fluoro-3-methylisobenzofuran-3-one, an important raw material used in Lorlatinib method of preparation. Background technique [0002] Lorlatinib is a novel, reversible, potent small molecule ALK and ROS1 inhibitor developed by Pfizer. 3rd generation ALK inhibitors. (S)-5-fluoro-3-methylisobenzofuran-3-one is the main raw material for the production of Lorlatinib (Lorlatinib), an important chemical and pharmaceutical intermediate, which can be used for dyes, Hair dye, medicine, pesticide materials and other fields. [0003] There are few reports on the preparation method of (S)-5-fluoro-3-methylisobenzofuran-3-one, and the existing preparation of (S)-5-fluoro-3-methylisobenzofuran-3 - Ketones generally use the following acetylated intermediates: [0004] [0005] DMG: -CON - R, -CONR 2 , Wait. [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C235/84C07D263/14
CPCC07C231/12C07D263/14C07C233/65C07C235/84
Inventor 周军明任川
Owner 杭州科耀医药科技有限公司
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