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Method for synthesizing lorlatinib

A synthesis method and technology of lorlatinib, applied in the field of synthesis of the drug lorlatinib, can solve the problems of high cost, long synthesis route, long time-consuming and the like, and achieve the effects of improved yield, simple operation and short synthesis steps.

Inactive Publication Date: 2019-01-18
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. A synthetic method has been proposed, 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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  • Method for synthesizing lorlatinib
  • Method for synthesizing lorlatinib
  • Method for synthesizing lorlatinib

Examples

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Embodiment 1

[0023] (1) N-((5-cyano-1-methyl-1H-pyrazol-3-yl)methyl)-4-fluoro-2-(1-hydroxyethyl)-N-methylbenzyl Amide synthesis

[0024]

[0025] or

[0026] (R)-N-((5-cyano-1-methyl-1H-pyrazol-3-yl)methyl)-4-fluoro-2-(1-hydroxyethyl)-N-methylbenzene Synthesis of formamide

[0027]

[0028] 50mL three-necked bottle, equipped with a thermometer, stirring bar, and dropping funnel, dissolve 0.11g (0.79mmol) of anhydrous aluminum trichloride in 8mL DCE, and slowly add 0.23g ( 1.51mmol) 4mL of IX DCE solution, dropwise completed, reacted at 20°C for 30min, then added 0.1g (0.61mmol) intermediate (9) or (9S), reacted for 3h, quenched the reaction solution with ice water, diatoms It was filtered with soil, washed with DCM, and the filtrate was extracted with DCM, dried over anhydrous sodium sulfate, and concentrated to obtain 0.15 g, with a yield of 78.9%. Column chromatography yielded 0.12g. ESI-MS (m / z): 317.1 [M+H]+, 339.1 [M+Na]+.

[0029] (2) 1-(2-(((5-cyano-1-methyl-1H-pyrazol-3...

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Abstract

The invention belongs to the technical field of medicines, and relates to a method for synthesizing lorlatinib (PF-06463922), which is finally synthesized from 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone and 1-methyl-3-((methylamino)methyl)-1H-pyrazol-5-nitrile through the reacting steps including aminolysis, substitution, coupling, chiral resolution and the like, or from (S)-5-fluoro-3-methyl isobenzofuran-1(3H)-ketone and 1-methyl-3-((methylamino)methyl)-1H-pyrazol-5-nitrile through the reacting steps including aminolysis, substitution, coupling and the like. According to the method, a novel method is provided to synthesis of an anti-tumor medicine lorlatinib (PF-06463922).

Description

technical field [0001] The invention relates to the technical field of medicines and relates to a synthesis method of medicine lorlatinib (PF-06463922). Specifically related to 5-fluoro-3-methylisobenzofuran-1(3H)-ketone and 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-carbonitrile through ammonolysis, Substitution, coupling, chiral resolution and other reaction steps are used to finally synthesize lorlatinib, or (S)-5-fluoro-3-methylisobenzofuran-1(3H)-one and 1-methyl-3 -((Methylamino)methyl)-1H-pyrazole-5-carbonitrile finally synthesizes lorlatinib through reaction steps such as ammonolysis, substitution, and coupling. 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 inhibit...

Claims

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Application Information

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IPC IPC(8): C07D498/18
CPCC07B2200/07C07D498/18
Inventor 沙宇陈家奇蒋清乾赵庆孟孙维全郭奥锋
Owner SHENYANG PHARMA UNIVERSITY
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