Preparation method of lapatinib intermediate and analogues thereof

A compound and reaction time technology, applied in chemical recycling, organic chemistry, etc., can solve problems such as environmental pollution, waste of raw materials, and difficulty in recycling

Active Publication Date: 2012-01-18
UNIV OF SCI & TECH OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the synthetic methods of lapatinib bases and their analogues reported in the prior art all adopt homogeneous catalysts. Becau...

Method used

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  • Preparation method of lapatinib intermediate and analogues thereof
  • Preparation method of lapatinib intermediate and analogues thereof
  • Preparation method of lapatinib intermediate and analogues thereof

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preparation example Construction

[0040] The invention discloses a preparation method of a compound, comprising the following steps:

[0041] Step a) the compound shown in formula I is refluxed with 4-chloro-6-iodo-quinazoline in isopropanol,

[0042]

[0043] Formula I,

[0044] Wherein, R is a methyl group, a halogen substituent, an ester group or a cyano group;

[0045] Step b) diatomaceous earth, tin dichloride, trifluoroacetic acid, H 2 PdCl 4 Mix it with polyvinylpyrrolidone in water, heat it to 100-150°C, and get Pd catalyst after reaction;

[0046] Step c) the product obtained in step a), the Pd catalyst, 5-formylfuran boronic acid and K 2 CO 3 Mixing and reacting in the first organic solvent, the reaction temperature is 70-90°C;

[0047] Step d) mixing the reaction product obtained in step c), the organic base and 2-(thysulfonyl)ethylamine hydrochloride in a second organic solvent, and reacting to obtain a lapatinib intermediate or its analogue, the The lapatinib intermediate or its analogue...

Embodiment 1

[0065] Preparation of 5-iodo-2-aminobenzoic acid:

[0066] Anthranilic acid (10mmol, 1.37g), sodium periodate (10mmol, 2.14g) and sodium chloride (10mmol, 1.90g) were dissolved in 30mL of acetic acid aqueous solution (27mL of acetic acid, 3mL of water), and then slowly Add an aqueous solution (10mL) of potassium iodide (20mmol, 1.18g), and control the temperature within 50°C. After the addition, the reaction is stirred at room temperature for 8 hours, and then the reaction is stopped. The reaction system is poured into ice water, suction filtered, and the upper layer is filtered. The cake was eluted with a large amount of water and a small amount of ethanol, and the solid obtained by suction filtration was vacuum-dried at 60°C to finally obtain 2.52g of 5-iodo-2-aminobenzoic acid, yield: 95.7%. 1 HNMR (300MHz, DMSO-d 6 )δ9.50-8.13 (s, 2H), 7.91 (s, 1H), 7.45 (d, J=7.8Hz, 1H), 6.61 (d, J=7.8Hz, 1H). The reaction formula of the above-mentioned process is as follows:

[0067] ...

Embodiment 2

[0097] Preparation of 4-fluoro-benzyl alcohol:

[0098] Dissolve p-fluorobenzaldehyde (10mmol, 1.24g) in 25ml of methanol, then add sodium borohydride (10mmol, 0.37g) in batches, after the addition, the reaction system continues to react at room temperature for 6 hours, stop the reaction, and spin off the methanol , add water, then extract with ethyl acetate, dry over anhydrous sodium sulfate, spin off the solvent to obtain 1.19g of colorless liquid, yield: 94%, that is, 4-fluoro-benzyl alcohol, the reaction formula of the above process is as follows:

[0099]

[0100] Preparation of 2-chloro-1-(4-fluoro-benzyloxy)-4-nitrobenzene:

[0101] After dissolving 1,2-dichloro-4-nitrobenzene (5mmol, 0.960g) and p-fluorobenzyl alcohol (6mmol, 0.75g) prepared in Example 1 with DMF (5mL), then slowly Sodium hydride (7.5mmol, 180mg) was added slowly, after the addition, the reaction system was continued to react for 2 hours, the reaction was stopped, and then the system was poured int...

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Abstract

The invention discloses a compound preparation method, which comprises the following steps: a) a compound disclosed in formula I and 4-chlorine-6-iodine-quinazoline are in backflow reaction in isopropanol; b) kieselguhr, stannous chloride, trifluoroacetic acid, H2PdCl4 and polyvinylpyrrolidone are mixed in water and heated to 100-150 DEG C, and a Pd catalyst is obtained after reaction; c) the products obtained in step a), the Pd catalyst, 5-formyl furanboronic acid and K2CO3 are mixed to be reacted in a first organic solvent; and d) reaction products obtained in step c), organic base and 2-(methyl sulfone) ethylamine hydrochloride are mixed in a second organic solvent, and lapatinib basic groups or analogues thereof are obtained after reaction. The heterogeneous Pd catalyst is adopted, and because the heterogeneous Pd catalyst is easy to recycle, the preparation method provided by the invention protects the environment at the time of saving raw materials. Formula (I) is disclosed in the specification.

Description

technical field [0001] The invention relates to the technical field of chemical industry and pharmacy, more specifically, to a preparation method of a lapatinib intermediate and analogues thereof. Background technique [0002] With the development of human society and economy and the advancement of science and technology, people's research on diseases has also made great progress. Even so, diseases such as cancer and tumors are still the greatest threats to human life and health. [0003] As an antitumor drug, the chemical name of lapatinib (lapatinib) is N-(3-chloro-4-((3-fluorophenyl)methoxy)phenyl)-6-(5-(( (2-(methylsulfonyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine di-p-toluenesulfonate, which was approved for marketing by the US FDA in March 2007, is a The 4-anilinoquinazoline receptor tyrosine kinase inhibitor can effectively cut off the downstream signal transmission of tyrosine kinase, thereby stopping the rapid growth of cancer cells, thereby effectively slow...

Claims

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Application Information

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IPC IPC(8): C07D405/04
CPCY02P20/584
Inventor 汪志勇万常峰王晔
Owner UNIV OF SCI & TECH OF CHINA
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