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Preparation method of 6-nitro-4-substituted aminoquinazoline derivative

A thiazole and compound technology, applied in the field of pharmaceutical intermediate chemistry, can solve the problems of complicated preparation process, many isomer by-products, unfavorable product purification, valilitinib quality assurance, etc., and achieves high reactivity and stable raw materials. Good performance and specific effect of amidation reaction selectivity

Active Publication Date: 2019-12-17
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The preparation process of 6-amino-4-[4-(thiazol-2-yl) methoxy-3-chlorophenyl] aminoquinazoline involved in synthetic route 3 is tedious, and the Dimroth rearrangement reaction isomer vice There are many products, which is not conducive to product purification and quality assurance of valitinib

Method used

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  • Preparation method of 6-nitro-4-substituted aminoquinazoline derivative
  • Preparation method of 6-nitro-4-substituted aminoquinazoline derivative
  • Preparation method of 6-nitro-4-substituted aminoquinazoline derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0051] Example 1: Preparation of N-[4-(thiazol-2-yl)methoxy-3-chlorophenyl]-2-chloro-5-nitrobenzamide (Ⅲ1)

[0052] In the 1000 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser, add 500 grams of toluene, 43.1 grams (0.2 moles) of methyl 2-chloro-5-nitrobenzoate (Ⅱ1), 48.1 grams (0.2 moles ) 4-(thiazol-2-yl)methoxy-3-chloroaniline, 5.0 g of ammonium chloride, stirred and reacted at 95 to 100° C. for 5 hours, and distilled off the produced methanol. Cool to 20-25°C, add 50 grams of water, separate layers, distill the organic phase, recycle the solvent toluene, and recrystallize the residue with methyl tert-butyl ether to obtain 81.8 grams of N-[4-(thiazol-2-yl)methanol Oxy-3-chlorophenyl]-2-chloro-5-nitrobenzamide (Ⅲ1), yield 96.5%, liquid phase purity 99.7%.

Embodiment 2

[0053] Example 2: Preparation of N-[4-(thiazol-2-yl)methoxy-3-chlorophenyl]-2-bromo-5-nitrobenzamide (Ⅲ2)

[0054] In the 500 milliliter four-neck flask that is connected with stirring, thermometer, reflux condenser, add 250 grams of toluene, 26.0 grams (0.1 moles) of methyl 2-bromo-5-nitrobenzoate (II2), 24.1 grams (0.1 moles ) 4-(thiazol-2-yl)methoxy-3-chloroaniline, 3.5 g of zinc chloride, stirred and reacted at 90 to 95° 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, recover the solvent toluene, and recrystallize the residue with methyl tert-butyl ether to obtain 45.3 grams of N-[4-(thiazol-2-yl)methanol Oxy-3-chlorophenyl]-2-bromo-5-nitrobenzamide (Ⅲ2), yield 96.7%, liquid phase purity 99.3%.

Embodiment 3

[0055] Example 3: Preparation of N-[4-(thiazol-2-yl)methoxy-3-chlorophenyl]-2-chloro-5-nitrobenzamide (Ⅲ1)

[0056] In a 500 ml four-neck flask connected with stirring, a thermometer, and a reflux condenser, add 250 g of xylene, 23.0 g (0.1 mole) of ethyl 2-chloro-5-nitrobenzoate (II3), 24.1 g (0.1 mol) 4-(thiazol-2-yl)methoxy-3-chloroaniline, 3.0 g of ammonium chloride, stirred at 105 to 110° C. for 4 hours, and distilled off the ethanol produced. Cool to 20-25°C, add 20 grams of water, separate layers, distill the organic phase, recover the solvent xylene, and recrystallize the residue with methyl tert-butyl ether to obtain 41.1 grams of N-[4-(thiazol-2-yl) Methoxy-3-chlorophenyl]-2-chloro-5-nitrobenzamide (Ⅲ1), yield 96.9%, liquid phase purity 99.5%.

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Abstract

The invention provides a preparation method of a 6-nitro-4-substituted aminoquinazoline derivative. The method comprises the following steps: carrying out an amidation reaction on 2-halo-5-nitrobenzoate and 4-(thiazole-2-yl)methoxy-3-chloroaniline in the presence of a catalyst to obtain N-[4-(thiazol-2-yl)methoxy-3-chlorphenyl]-2-halo-5-nitrobenzamide, and carrying out substitution and condensation reactions on the N-[4-(thiazol-2-yl)methoxy-3-chlorphenyl]-2-halo-5-nitrobenzamide and a formamidine salt through a one-pot process in the presence of an acid-binding agent to obtain 6-nitro-4-[4-(thiazol-2-yl)methoxy-3-chlorphenyl]aminoquinazoline. The method has the advantages of cheap and easily available raw materials, good raw material stability, high reaction selectivity, easiness in operation of the reactions, and high yield and high purity of the product.

Description

technical field [0001] The invention relates to a preparation method of 6-nitro-4-substituted aminoquinazoline derivatives, in particular to 6-nitro-4-[4-(thiazol-2-yl)methoxy-3-chlorobenzene The preparation method of base] aminoquinazoline is used for preparing valitinib, and belongs to the chemical technology field of pharmaceutical intermediates. Background technique [0002] Varlitinib, the chemical name is (R)-N4-[3-chloro-4-(thiazol-2-ylmethoxy)phenyl]-N6-(4-methyl-4,5- Dihydrooxazol-2-yl)quinazoline-4,6-diamine, a potent small molecule reversible pan-HER inhibitor, was developed by Array Biopharmaceuticals and acquired by Singapore ASLAN Pharmaceuticals Its global development and commercialization ownership, research and development for multiple indications including biliary tract cancer, gastric cancer, metastatic breast cancer and metastatic colorectal cancer. [0003] [0004] Regarding the preparation method of valitinib, the patent CN102432552 applied by the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 于大伟戚聿新周立山孙玉龙
Owner XINFA PHARMA
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