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Preparation method of 6-substituted furyl-4-substituted aminoquinazoline derivatives and key intermediates thereof

A technology of aminoquinazoline and furanyl, applied in the field of medicinal chemistry, can solve the problems of poor stability of 2-formylfuran-5-boronic acid, unfavorable industrial production, poor stability of raw materials, etc., and achieve high yield and selectivity , low cost, less side effects

Active Publication Date: 2020-11-20
XINFA PHARMA
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Problems solved by technology

[0018] Chinese patent CN102295638 aims at the problem of poor stability of the raw material 2-formylfuran-5-boronic acid used, and proposes a "one-pot method" preparation method of lapatinib di-p-toluenesulfonate
[0021] The above routes all have the problems of high price of raw materials 6-iodoquinazoline derivatives and 2-formylfuran-5-boronic acid, poor raw material stability and poor product purity, which are not conducive to industrial production

Method used

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  • Preparation method of 6-substituted furyl-4-substituted aminoquinazoline derivatives and key intermediates thereof
  • Preparation method of 6-substituted furyl-4-substituted aminoquinazoline derivatives and key intermediates thereof
  • Preparation method of 6-substituted furyl-4-substituted aminoquinazoline derivatives and key intermediates thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0084] Example 1: Preparation of 6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline (Ⅳ)

[0085] Step (1): Preparation of N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-2-bromo-5-cyanobenzamide (Ⅲ1)

[0086] In a 500 ml four-neck flask connected with stirring, a thermometer, and a reflux condenser, add 350 grams of toluene, 48.0 grams (0.2 moles) of methyl 2-bromo-5-cyanobenzoate (II1), 50.5 grams (0.2 moles ) 3-chloro-4-(3-fluorobenzyloxy)aniline, 1.5 g of ammonium chloride, stirred at 95 to 100° C. for 5 hours, and distilled off the produced methanol. Cool to 20-25°C, add 20 grams of water, separate layers, distill the organic phase to recover the solvent toluene, and recrystallize the residue with methyl tert-butyl ether to obtain 87.9 grams of N-[3-chloro-4-(3-fluorobenzyl Oxy)phenyl]-2-bromo-5-cyanobenzamide (Ⅲ1), yield 95.6%, liquid phase purity 99.8%.

[0087] Step (2): Preparation of 6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline (IV)

[00...

Embodiment 2

[0090] Example 2: Preparation of 6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline (Ⅳ)

[0091] Step (1): Preparation of N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-2-chloro-5-cyanobenzamide (Ⅲ2)

[0092] In a 500 ml four-neck flask connected with stirring, a thermometer, and a reflux condenser, add 350 grams of toluene, 42.0 grams (0.2 moles) of ethyl 2-chloro-5-cyanobenzoate (II2), 50.5 grams (0.2 moles ) 3-chloro-4-(3-fluorobenzyloxy)aniline, 2.0 g of zinc chloride, stirred and reacted at 95 to 100° C. for 5 hours, and distilled off the ethanol produced. Cool to 20-25°C, add 20 grams of water, separate layers, distill the organic phase to recover the solvent toluene, and recrystallize the residue with methyl tert-butyl ether to obtain 79.9 grams of N-[3-chloro-4-(3-fluorobenzyl Oxy)phenyl]-2-chloro-5-cyanobenzamide (Ⅲ2), yield 96.3%, liquid phase purity 99.7%.

[0093] Step (2): Preparation of 6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline (I...

Embodiment 3

[0095] Embodiment 3: the preparation of lapatinib (program A)

[0096] Step (1): Preparation of 6-(furan-2-yl)-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline (Ⅴ)

[0097] Into a 500 ml four-neck flask connected with a stirring, thermometer, constant pressure dropping funnel and reflux condenser, add 100 g of tetrahydrofuran, 1.6 g of metal magnesium powder, 0.4 g of 1,2-dibromoethane, 1 millet grain size iodine, 30-45 ° C to initiate the reaction, and then between 40-45 ° C, dropwise add a mixed solution of 10.5 grams (0.06 moles) of 1,1-dimethoxy-3-bromopropane and 100 grams of tetrahydrofuran, about 2 The dropwise addition was completed within 1 hour, and then the reaction was stirred at 40-45°C for 2 hours. After cooling to 20-25°C, transfer the obtained Grignard reagent liquid to a constant pressure dropping funnel for use. In another 500 ml four-neck flask connected with stirring, thermometer and reflux condenser, 100 g of tetrahydrofuran, 20.2 g (0.05 mole) o...

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Abstract

The invention relates to a preparation method of a 6-substituted furanyl-4-substituted aminoquinazoline derivative and a key intermediate thereof. 2-halo-5-cyanobenzoate and 3-chloro-4-(3-fluorobenzyloxy)aniline are used as raw materials, and 6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline is obtain through an amidation reaction, a formamidine salt substitution reaction and a condensation reaction; then 6-(furan-2-yl)-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline or 6-(5-formylfuran-2-yl)-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline are obtained througha Grignard reaction and an acidification reaction; and then lapatinib or selatinib are prepared through a Mannich reaction or imidization and a reductive amination reaction. The preparation method hasthe advantages that the raw materials are cheap and are easily available, selectivity of the reaction is high, purity of the product is high, and industrial production is facilitated.

Description

technical field [0001] The present invention relates to a preparation method of 4-substituted aminoquinazoline derivatives, in particular to 6-substituted furyl-4-substituted aminoquinazoline derivatives and their key intermediate 6-cyano-4-substituted amino The preparation method of quinazoline belongs to the technical field of medicinal chemistry. Background technique [0002] Lapatinib is a dual inhibitor of epidermal growth factor receptor (ErbB1) and human epidermal factor receptor-2 (ErbB2) developed by GlaxoSmithKline. On the 14th, it was reviewed and approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of advanced or metastatic breast cancer. The chemical name of lapatinib is 4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]amino-6-{5-[(2-(thymphenyl)ethylamino)methyl] Furan-2-yl}quinazoline or N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-{5-[(2-(methylsulfonyl)ethylamino) Methyl]furan-2-yl}quinazolin-4-amine. [00...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94C07D405/04
CPCC07D239/94C07D405/04
Inventor 崔庆荣王保林徐欣常仁义
Owner XINFA PHARMA
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