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New preparation method of lapatinib

A compound and reaction technology applied in the field of synthesis of small molecule targeted drug lapatinib

Active Publication Date: 2011-12-28
QILU PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] The technical problem to be solved by this invention is to overcome the problems existing in the synthetic lapatinib method of the prior art, and to provide a method for the synthesis of lapatinib with at least one of the following advantages: avoid the use of high toxicity and / or Environmentally harmful solvents and / or reagents, short reaction route, short operation time, stable reactants and intermediates in the reaction system, no complicated purification process or simple purification process, less organic solvent and / or reagent usage, suitable for industrial production etc.

Method used

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preparation example Construction

[0107] In the preparation method of the present invention, the reducing agent is selected from sodium triacetoxyborohydride, sodium borohydride and potassium borohydride, among which sodium triacetoxyborohydride is preferred.

[0108] In the preparation method of the present invention, the reaction temperature used to generate transition intermediate 1 is 0-80°C; the reaction temperature used to generate transition intermediate 2 is 40°C-130°C; the imine is reduced to obtain lapatidine The reaction temperature used by Nietzsche is -20~40℃.

[0109] In the preparation method of lapatinib described in the present invention, each starting material can make full use of each functional group on the chemical structure during the reaction process, and react to obtain the desired final product. Specifically, the amino group in compound II reacts with the aldehyde group in compound III to form an imine, which avoids the instability caused by the oxidation of the aldehyde group at high ...

Embodiment 1

[0117] Add 10L N,N-dimethylformamide to the 20L reactor, then add the starting material compound II 352g (1.485mol), compound III 194g (1.386mol), compound IV 500g (0.990mol), triethylamine 1500g, (dppf)PdCl 2 10g, stirred evenly, under nitrogen protection, stirred at 25 ° C, TLC analysis of raw material compound III after the reaction was complete, the temperature was raised to reflux reaction, TLC analysis of the raw material compound IV after the reaction was complete, cooled to room temperature, added sodium triacetoxyborohydride 630g (2.97 mol), stirring reaction at room temperature, TLC analysis transition intermediate 2 after the complete reaction, suction filtration, adding 20L dichloromethane to the filtrate, washing with 10L 1N sodium hydroxide solution, washing with 20L saturated sodium chloride solution, drying over anhydrous sodium sulfate , suction filtration, the filtrate was added under stirring and 750g (3.94mol) p-toluenesulfonic acid was added, crystallized ...

Embodiment 2

[0119] Add 10L ethanol to the 20L reactor, then add the starting material compound II 352g (1.485mol), compound III 194g (1.386mol), compound IV500g (0.990mol), triethylamine 1500g, (dppf)PdCl 2 10g, stirred evenly, under nitrogen protection, stirred at room temperature, after TLC analysis raw material III reacted completely, was heated to reflux reaction, after TLC analyzed raw material IV reacted completely, cooled to room temperature, added triacetoxy sodium borohydride 630g (2.97mol), Stir the reaction at room temperature, TLC analysis transition intermediate 2 After the reaction is complete, filter with suction, add 750g (3.94mol) p-toluenesulfonic acid to the filtrate under stirring, crystallize at room temperature, filter with suction, and dry in the air to obtain lapatinib p-toluenesulfonic acid Salt 725g, yield 79.2%, HPLC purity 98.35%.

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Abstract

The invention provides a novel method for preparing lapatinib. Specifically, the method for preparing a compound shown in a formula I or medicinal salt thereof comprises the following steps of: (1) reacting a compound shown in a formula II or salt thereof and a compound shown in a formula III at the first temperature; (2) reacting a reaction product obtained in the step (1) and a compound shown in a formula IV in reaction liquid in the step (1) at the second temperature; (3) adding a reducing agent into reaction liquid in the step (2) to reduce the reaction product obtained in the step (2) to obtain the compound shown in the formula I; and optionally (4) reacting the compound shown in the formula I and obtained in the step (3) and acid to obtain medicinal salt of the compound shown in the formula I. The method is high in yield, and can overcome one or more disadvantages of the conventional method and the purity of a product is high.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a synthetic small molecule targeted drug lapatinib, namely N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- The preparation method of [5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinolineamine. Background technique [0002] Lapatinib (structural formula I), namely N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl) Ethyl]amino}methyl)-2-furyl]-4-quinolinamine is a small molecule targeted drug currently used in the treatment of breast cancer. The structural formula of lapatinib is as follows: [0003] [0004] A preparation method of lapatinib has been reported in WO9935146A1, which is summarized in the following reaction scheme 1: [0005] [0006] Reaction route 1, [0007] A highly toxic organotin reagent was used in the above reaction It has high risks to the safety of production, drug safety and environmental protection. [0008] In ad...

Claims

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Application Information

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IPC IPC(8): C07D405/04
CPCC07D239/94C07D405/04
Inventor 王晶翼林栋冷传新张进张占涛范传文朱屹东张明会
Owner QILU PHARMA
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