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Preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline

A technology of methoxyethoxy and quinazoline, which is applied in the field of drug preparation, can solve the problems of high price of ethyl 3,4-dihydroxybenzoate, difficulty in obtaining raw materials, high production cost, etc., and achieve good industrial application Prospects, raw materials and reagents are cheap and easy to obtain, and the effect of low production cost

Inactive Publication Date: 2012-12-19
ZHEJIANG SCI-TECH UNIV
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The disadvantage of this route is that the raw material 3,4-dihydroxybenzoic acid ethyl ester is expensive and rare, and expensive platinum dioxide is used when reducing the nitro group, and the production cost is relatively high
[0018] The raw material 3,4-dihydroxynitrobenzene used in this route is obtained through the nitration of catechol in the preparation. This process is dangerous, so the raw material is not easy to obtain; Completed under radiation conditions, it is difficult to use in industrial production; finally, this route uses ammonium cerium nitrate for the oxidation of quinazoline, and a large amount of waste water is likely to be generated during the synthesis, resulting in environmental pollution

Method used

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  • Preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline
  • Preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline

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preparation example Construction

[0040] The raw material 3,4-bis-(2-methoxyethoxy)-benzaldehyde used in the present invention can be prepared by 3,4-dihydroxybenzaldehyde according to literature [Heterocyces, 2007,71 (1), 39-48] Easy to make. The steps of the preparation method of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline are as follows:

[0041] a. Dissolve 3,4-bis-(2-methoxyethoxy)-benzaldehyde in an organic solvent, add concentrated nitric acid with a concentration of 40-90% by mass at 0°C to 20°C, and then React at 20-80°C for 3-10 hours. After the reaction is completed, add water, extract with toluene, wash, dry, and concentrate to obtain 4,5-bis-(2-methoxyethoxy)-2-nitrobenzaldehyde. The molar ratio of concentrated nitric acid to 3,4-di-(2-methoxyethoxy)-benzaldehyde is 1~10:1;

[0042] b. 4,5-bis-(2-methoxyethoxy)-2-nitrobenzaldehyde dissolved in an organic solvent, at 20-80°C and with a mass percent concentration of 10-50% permanganese Potassium acid aqueous solution was reacted for 2 to 10 ho...

Embodiment 1

[0055] (1) Preparation of 4,5-bis-(2-methoxyethoxy)-2-nitrobenzaldehyde

[0056] Add 180g (0.708mol) 3,4-bis-(2-methoxyethoxy)-benzaldehyde, 200ml glacial acetic acid to a 2000ml reaction flask, add 206ml (2.975mol) 65% concentrated nitric acid dropwise at 15°C, After dropping, gradually raise the temperature to 50°C and react for 6 hours. After the reaction is completed, cool to room temperature, add 500ml of water to the reaction bottle, extract twice with 500ml of toluene, and wash the separated toluene layer twice with 1mol / L sodium carbonate aqueous solution. Dry over sodium sulfate, evaporate the solvent, and recrystallize the residue with 1:1 methanol-water to obtain bright yellow crystal 4,5-bis-(2-methoxyethoxy)-2-nitrobenzaldehyde 180g, yield 85%.

[0057] (2) Preparation of 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoic acid

[0058] Add 180g (0.6mol) of 4,5-bis-(2-methoxyethoxy)-2-nitrobenzaldehyde and 200ml of acetone into a 2000ml reaction bottle, and add 1000g of hi...

Embodiment 2

[0068] (1) Preparation of 4,5-bis-(2-methoxyethoxy)-2-nitrobenzaldehyde

[0069] Add 180g (0.708mol) 3,4-bis-(2-methoxyethoxy)-benzaldehyde and 200ml propionic acid to a 2000ml reaction flask, add 49ml (0.708mol) 65% concentrated nitric acid dropwise at 15°C, After dropping, gradually raise the temperature to 50°C and react for 6 hours. After the reaction is completed, cool to room temperature, add 500ml of water to the reaction bottle, and extract twice with 500ml of toluene. The separated toluene layer is washed twice with 1mol / L sodium carbonate solution. Dry over sodium sulfate, evaporate the solvent, and recrystallize the residue with 1:1 methanol-water to obtain 105.8 g of bright yellow crystal 4,5-bis-(2-methoxyethoxy)-2-nitrobenzaldehyde. The rate is 50%.

[0070] (2) Preparation of 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoic acid

[0071] Add 105g (0.35mol) of 4,5-bis-(2-methoxyethoxy)-2-nitrobenzaldehyde and 200ml dioxane to a 2000ml reaction bottle, dissolve and add ...

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Abstract

The invention discloses a preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline. The process flow of the method is as follows: A, 3,4-bis(2-methoxyethoxy)benzaldehyde undergoes nitration to produce 4,5-bis(2-methoxyethoxy)-2-nitrobenzaldehyde; B, oxidation is carried out so as to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzoic acid; C, esterification is carried out so as to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate; D, reduction is carried out so as to obtain 4,5-bis(2-methoxyethoxy)-2-aminobenzoate; E, cyclization is carried out so as to obtain 6,7-bis(2-methoxyethoxy)-4(3H)-quinazolinone; and F, chlorination is carried out so as to obtain 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline. The preparation method provided in the invention has the advantages of a concise and practical synthetic route, high yield and a good industrial application prospect.

Description

technical field [0001] The invention relates to a preparation method of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline, which belongs to the technical field of medicine preparation. Background technique [0002] 4-Chloro-6,7-bis-(2-methoxyethoxy)-quinazoline is the key intermediate of the new anti-tumor drug erlotinib hydrochloride, and its structural formula is as formula 1: [0003] [0004] Formula 1 [0005] Erlotinib hydrochloride, the chemical name is N-(3-ethynylbenzene)-6,7-bis(methoxyhexyloxy)-4-quinazolinamine hydrochloride, its structural formula is shown in formula 2, It is a new drug for the treatment of non-small cell lung cancer and advanced pancreatic cancer jointly developed by Roche, OSI Biopharmaceutical Company and Genentech Pharmaceutical Company. It was approved by FDA in 2004 and launched in the United States in 2005. [0006] [0007] Formula 2 [0008] The mechanism of action of erlotinib hydrochloride is that it can competitively bind to th...

Claims

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Application Information

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IPC IPC(8): C07D239/86
Inventor 朱锦桃张俊李星孙丽文
Owner ZHEJIANG SCI-TECH UNIV
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