Preparation method of targeted drug AZD3759 intermediate

A technology of AZD3759 and intermediates, which is applied in the field of preparation of targeted drug AZD3759 intermediates, can solve the problems of highly toxic and unsafe phosphorus oxychloride, complex synthesis routes, expensive palladium carbon and the like, and achieves easy industrial production and process steps. Simple, easy-to-use effects

Active Publication Date: 2019-12-20
山东四环药业股份有限公司
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0006] This synthetic route prepares 4-[(3-chloro-2-fluorophenyl)amino]-6-acetoxy-7-methoxyquinazoline to first use phosphorus oxychloride to convert 4-hydroxyl-6-acetyl Oxy-7-methoxyquinazoline is chlorinated, and then reacted with 3-chloro-2-fluoroaniline to generate 4-[(3-chloro-2-fluorophenyl)amino]-6-acetoxy-7 -Methoxyquinazoline, the synthetic route is complex and difficult to handle, it produces a large amount of acid water, and phosphorus oxychloride is highly toxic and unsafe
This synthetic route also adopts palladium-carbon hydrogenation to reduce the nitro group of 3-hydroxyl-4-methoxy-6-nitrobenzoic acid to amino group, palladium-carbon is expensive, and the production cost is high; high-pressure reaction has certain danger

Method used

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  • Preparation method of targeted drug AZD3759 intermediate
  • Preparation method of targeted drug AZD3759 intermediate
  • Preparation method of targeted drug AZD3759 intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0044] Embodiment 1: Preparation of 2-nitro-4-methoxy-5-hydroxybenzoic acid

[0045]

[0046]Dissolve 118g of sodium hydroxide in 400g of water, add 118g of 6-nitroveratronic acid, heat up to 100°C, keep warm for 6 hours, pour the system into 1160g of dilute hydrochloric acid, pH<2, cool down to room temperature, filter, and wash with water , and dried to obtain 108 g of a yellow solid, which is 2-nitro-4-methoxy-5-hydroxybenzoic acid, with a molar yield of 97.6% and a purity of 99%.

[0047] ESI-MS: m / z([M-H] - ) is 212.0, such as figure 1 shown.

Embodiment 2

[0048] Embodiment 2: Preparation of 2-amino-4-methoxy-5-hydroxybenzoic acid

[0049]

[0050] Add 100g of 2-nitro-4-methoxy-5-hydroxybenzoic acid to 500g of methanol, add 20g of a mixture of ferric chloride hexahydrate: active carbon=1:10 in mass ratio, rise to reflux, and add 40% dropwise Hydrazine hydrate 115g, keep reflux for 4h after dripping, after the reaction is completed, drop to room temperature, filter to remove the catalyst, and concentrate the solution to dryness to obtain 80g of off-white solid, which is 2-amino-4-methoxyl-5-hydroxybenzoic acid, molar yield The yield is 93.1%, and the purity is 99%.

Embodiment 3

[0051] Embodiment 3: the preparation of 4,6-dihydroxy-7-methoxyquinazoline

[0052]

[0053] Add 80g of 2-amino-4-methoxy-5-hydroxybenzoic acid and 90g of methylamine acetate to 450g of ethylene glycol methyl ether, raise the temperature to 110°C, keep it warm for 6h, after the reaction is complete, concentrate to dryness under reduced pressure, add 450g Water, 50g of ammonia water, stirred at room temperature for 2h, filtered, and dried at 50°C for 6h to obtain 71g of brown solid, namely 4,6-dihydroxy-7-methoxyquinazoline, with a molar yield of 84.6% and a purity of 99.2%.

[0054] ESI-MS: m / z([M-H]-) is 191.0, such as figure 2 shown.

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Abstract

The invention discloses a preparation method of a targeted drug AZD3759 intermediate, which comprises the following steps of: firstly, 6-nitro veratric acid is hydrolyzed under alkaline conditions toobtain 2-nitro-4-methoxy-5-hydroxybenzoic acid, the 2-nitro-4-methoxy-5-hydroxybenzoic acid is then reduced by hydrazine hydrate under the action of catalyst ferric chloride hexahydrate activated carbon mixture to obtain 2-amino-4-methoxy-5-hydroxybenzoic acid, 2-amino-4-methoxy-5-hydroxybenzoic acid is reacted with formamidine acetate to obtain 4,6-dihydroxy-7-methoxyquinazoline, 4,6-dihydroxy-7-methoxyquinazoline is reacted with acetyl chloride under alkaline conditions to obtain 4-hydroxyl-6-acetoxy-7-methoxyquinazoline, finally 4-hydroxyl-6-acetoxy-7-methoxyquinazoline is reacted with 3-chlorine-2-fluoroaniline by Mitsunobu reaction under the action of triphenylphosphine and azo reagent to obtain 4-[(3-chloro-2-fluorophenyl)amino]-6-acetoxy-7-methoxyquinazoline. The invention reduces the synthesis steps, reduces the use of harmful compounds, reduces the production cost and optimizes the production operation.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of an intermediate of targeted drug AZD3759. Background technique [0002] AZD3759 is a targeted drug developed by AstraZeneca that targets EGFR in lung cancer and targets brain metastases. AZD3759 is mainly designed to effectively cross the blood-brain barrier to address the central nervous system (CNS) of EGFRm+ non-small cell lung cancer patients. ) transfer. 4-[(3-chloro-2-fluorophenyl)amino]-6-acetoxy-7-methoxyquinazoline is an important intermediate for the preparation of AZD3759, and its structural formula is as follows: [0003] [0004] At present, the synthetic route of 4-[(3-chloro-2-fluorophenyl) amino]-6-acetoxy-7-methoxyquinazoline mainly adopts the synthetic route reported by CN105209456A, which is based on 6-nitrate Base veratronic acid as raw material, hydrolysis under alkaline conditions, palladium carbon hydrog...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/44
CPCC07D241/44
Inventor 朱玉正宁尚恩王金兵张晓君
Owner 山东四环药业股份有限公司
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