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Preparation method of lorlatinib

A technology of lorlatinib and compounds, applied in the field of preparation of lorlatinib, which can solve problems such as unfavorable industrial production, reduced synthesis efficiency of lorlatinib, and limitation of application of lorlatinib

Pending Publication Date: 2021-05-21
SHANGHAI TIANCI INT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are many disadvantages in the synthetic method of lorlatinib in the prior art, such as long synthetic route, high cost, long time-consuming, low yield, etc., resulting in reduced synthetic efficiency of lorlatinib, which is not conducive to industrial production, thereby limiting Application of lorlatinib

Method used

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  • Preparation method of lorlatinib
  • Preparation method of lorlatinib

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preparation example Construction

[0082] The preparation method of lorlatinib

[0083] The present invention provides a kind of preparation method of lorlatinib, described method comprises the steps:

[0084] (1) In the first solvent, under the first basic reagent, the compound of formula VI and the compound of formula VII undergo a coupling reaction under the catalysis of a palladium catalyst to obtain the compound of formula V;

[0085]

[0086] (2) In the second solvent, under the second basic reagent, the compound of formula V and the compound of formula IV undergo Williamson reaction to obtain the compound of formula III;

[0087]

[0088] (3) the compound of formula III undergoes hydrolysis reaction and acidolysis reaction successively to obtain the compound of formula II;

[0089]

[0090] (4) the compound of formula II is subjected to condensation reaction to obtain the compound of formula I;

[0091]

[0092] The preparation of formula V compound

[0093] The present invention provides ...

Embodiment 1

[0170] Preparation of compound (Ⅴ)

[0171]

[0172] Add 28.8g (0.1mol) of compound (Ⅵ) and 32.9g (0.1mol) of compound (Ⅶ), 400ml of 1,4-dioxane and 100ml of water into a 1L reaction flask, pass through nitrogen protection, add 0.3g of 1,1 '-bis(diphenylphosphino)ferrocenepalladium dichloride and 34.6g (0.25mol) of potassium carbonate were heated up to 70°C and reacted for 3h. Cool down to room temperature, remove insoluble matter by filtration, concentrate the filtrate under reduced pressure, add ethyl acetate for extraction, wash the ethyl acetate layer with water, and concentrate the ethyl acetate layer to dryness to obtain 40.3 g of a yellow solid with a molar yield of 88%, MS (ESI ): [M]=458.51.

Embodiment 2

[0174] Preparation of Compound (Ⅲ)

[0175]

[0176] Add 27.5g (0.06mol) of compound (Ⅴ), 400ml of acetone, 16.6g (0.12mol) of powdered potassium carbonate, 17.4g (0.063mol) of compound (Ⅳ) to a 1L reaction flask, raise the temperature to 55°C, react for 18h, and cool down to room temperature, filter. The filtrate was concentrated to dryness, 80ml of n-hexane and 20ml of ethyl acetate were added, stirred, filtered, and dried to obtain 36.4g of compound (Ⅲ), with a molar yield of 95%. MS (ESI): [M] = 638.69.

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Abstract

The invention relates to a preparation method of lorlatinib. Specifically, the invention provides a preparation method of lorlatinib. According to the method, a compound 1-methyl-3-((methyl-t-butyloxycarboryl-amino) methyl)-1H-pyrazole-4-bromine-5-nitrile as shown in a formula VII and a compound 2-(t-butyloxycarboryl-amino)-3-hydroxy-5-bromopyridine as shown in a formula VI are used as raw materials and subjected to a coupling reaction, a Williamson reaction, a hydrolysis reaction, an acidolysis reaction and a condensation reaction, so as to prepare lorlatinib. The preparation method of the lorlatinib has the advantages of being short in synthesis route, simple and convenient to operate, mild in reaction condition, high in yield and the like, and is suitable for industrial production of the lorlatinib.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of 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. However, there are many disadvantages in the synthetic method of lorlatinib in the prior art, such as long synthetic route, high cost, long time-consuming, low yield, etc., resulting in reduced synthetic efficiency of lorlatinib, which is not conducive to industrial production, thereby limiting Application of lorlatinib. [0003] Therefore, there is a need in the art to develop a simple and efficient synthetic method for lorlatinib. Contents of the in...

Claims

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Application Information

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IPC IPC(8): C07D498/18
CPCC07D498/18
Inventor 李函璞李勇刚王卓殷保胜
Owner SHANGHAI TIANCI INT PHARMA
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