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Method for preparing Erlotinib intermediate

A technology of erlotinib and intermediates, which is applied in the field of pharmaceutical compound synthesis, can solve the problems of decreased product yield and purity, great influence, and high cost of intermediates, and achieves mild reaction conditions, few reaction steps, and low production costs. Effect

Active Publication Date: 2012-04-18
TIANJIN WEIJIE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] People such as Jyothi Prasad mentioned in the patent (WO200706091) that this synthetic route is greatly affected by the substrate during the nitration reaction. When the number of substrates increases, the yield and purity of the product will drop significantly, and the reduction of nitro When using an expensive catalyst, this will lead to a higher cost of the intermediate
[0008] In addition, the reduction reaction is carried out under a high pressure of 5.0 MPa, so the safety is poor
In addition, the temperature during the cyclization reaction is as high as 170 ° C, these conditions are not conducive to industrial production

Method used

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  • Method for preparing Erlotinib intermediate
  • Method for preparing Erlotinib intermediate
  • Method for preparing Erlotinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] 1) Preparation of 4,5-bis(2-methoxyethoxy)-2-aminobenzamide (III)

[0026] Dissolve 12.5g (42mmol) of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile (II) in 100ml of isopropanol, add 0.5g of 5% palladium on carbon and hydrate Hydrazine 14.8g, heated to 50°C, reacted for 5-6 hours, cooled, filtered, and desolvated in vacuo to obtain a yellow viscous solid, which was recrystallized from absolute ethanol to obtain 10.7g of 4,5-bis(2-methoxyl group) as a yellow solid Ethoxy)-2-aminobenzamide (III) in 90% yield.

[0027] 2) Preparation of N'-(2-carbamoyl-4,5-bis(2-methoxyethoxyphenyl))-N,N-dimethylformamidine (IV)

[0028] 6g (21mmol) of 4,5-bis(2-methoxyethoxy)-2-aminobenzamide (III) was added to 60ml of toluene, 6g of DMF-DMA was added, 0.05ml of acetic acid was added dropwise, and the mixture was heated to 60°C, reacted for 2 hours, cooled and filtered to obtain N'-(2-carbamoyl-4,5-bis(2-methoxyethoxyphenyl))-N,N-dimethyl as a white solid Formamidine (IV) 6.98 g, yield 9...

Embodiment 2

[0032] 1) Preparation of 4,5-bis(2-methoxyethoxy)-2-aminobenzamide (III)

[0033] Dissolve 29.61 g (0.1 mol) of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile (II) in 250 ml of absolute ethanol, add 1.0 g of 5% palladium on carbon and Hydrazine hydrate 35g, heated to reflux, reacted for 4 hours, cooled, filtered, desolvated in vacuo to obtain a yellow viscous solid, recrystallized from absolute ethanol to obtain 24.48g of yellow solid 4,5-bis(2-methoxyethoxy) )-2-aminobenzamide (III) in 87% yield.

[0034] 2) Preparation of N'-(2-carbamoyl-4,5-bis(2-methoxyethoxyphenyl))-N,N-dimethylformamidine (IV)

[0035] 21.3g (75mmol) of 4,5-bis(2-methoxyethoxy)-2-aminobenzamide (III) was added to 210ml of dichloromethane, 21g of DMF-DMA was added, 2ml of acetic acid was added dropwise, Heated to reflux, reacted for 3 hours, cooled and filtered to obtain N'-(2-carbamoyl-4,5-bis(2-methoxyethoxyphenyl))-N,N-di as a white solid Methylformamidine (IV) 24.1 g, yield 95%.

[0036] 3) Preparat...

Embodiment 3

[0038] Example 3: Preparation of 6,7-bis-(2-methoxyethoxy)-3H-quinazolin-4-one (I)

[0039] Add 6g (21mmol) of 4,5-bis(2-methoxyethoxy)-2-aminobenzamide (III) to 60ml of toluene, add 6g of DMF-DMA, dropwise add 1ml of acetic acid, and heat to 60 ℃, reacted for 8 hours, cooled and filtered to obtain 5.6 g of 6,7-bis-(2-methoxyethoxy)-3H-quinazolin-4-one (I) as a white solid with a yield of 90 %.

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Abstract

The invention discloses a method for preparing an Erlotinib intermediate. 4,5-bi(2-methoxyethoxy)-2-nitrobenzonitrile (II) serves as a raw material in an organic solvent; and the method comprises the following steps of: reducing nitro by hydration hydrazine in the presence of a palladium carbon catalyst and performing addition on cyan to obtain a compound 4,5-bi(2-methoxyethoxy)-2-aminobenzamide (III); adding the compound (III) to DMF-DMA under the condition of acid catalysis so as to obtain a compound IV; and further cyclizing the compound IV to obtain the Erlotinib intermediate. The method for preparing the Erlotinib intermediate has the advantages of fewer needed reaction steps, mild reaction condition, high yield, and no expensive raw materials, so the production cost is low. Therefore, the method for preparing the Erlotinib intermediate is suitable for industrialized production. The method has the following synthetic route.

Description

technical field [0001] The invention relates to the field of pharmaceutical compound synthesis, in particular to 6,7-bis-(2-methoxyethoxy)-3H-quinoline, a key intermediate of a drug erlotinib for treating non-small cell lung cancer The preparation method of oxazolin-4-one. Background technique [0002] The chemical name of erlotinib is N-(3-ethynylphenyl)-[6,7-bis(2-methoxyethoxy)]quinazolin-4-amine, and the trade name is Tarceva ( Tarceva), originally developed by OSI Pharmaceuticals, was first listed in the United States in November 2004, and was approved for marketing in Switzerland, the first European country on March 22, 2005, for the treatment of localized advanced or metastatic disease that has failed at least one chemotherapy. Non-small cell lung cancer, its chemical structural formula is as follows: [0003] [0004] The synthetic route of the key intermediate 6,7-bis-(2-methoxyethoxy)-3H-quinazolin-4-one (I) used in the preparation of erlotinib was mainly prov...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/88
Inventor 宋洪海赵连营施欢乐陈继德
Owner TIANJIN WEIJIE TECH