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Preparing technology of erlotinib hydrochloride

A technology for the preparation of erlotinib hydrochloride, which is applied in the field of preparation of pharmaceutical compounds, can solve problems such as unfavorable post-processing and large environmental pollution, and achieve the effects of short reaction process route, simple and easy operation, and mild reaction conditions

Inactive Publication Date: 2012-07-18
REYOUNG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is unavoidable to use chlorination reagents that are prohibited by the country and have great environmental pollution, such as oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride and thionyl chloride, etc. These substances are not conducive to the post-treatment of industrial production

Method used

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  • Preparing technology of erlotinib hydrochloride
  • Preparing technology of erlotinib hydrochloride
  • Preparing technology of erlotinib hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The preparation process of erlotinib hydrochloride uses 2-nitro-4,5-bis(2-methoxyethoxy)benzonitrile as the starting material to obtain 2-amino-4 through nitro reduction, 5-two (2-methoxyethoxy) benzonitriles, then prepare according to the operational route (1), specifically comprising the following steps:

[0030] 1, the preparation of 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile

[0031] Mix and stir 2-nitro-4,5-bis(2-methoxyethoxy)benzonitrile (100g, 0.336mol), sodium dithionite (204g, 1.176mol) and water (1.7L), and heat to 50-55°C, continue to stir for 2 hours, quickly raise the temperature to 65-70°C, slowly add concentrated hydrochloric acid (450ml) dropwise, the temperature of the reaction solution drops to room temperature after the dropwise addition, adjust the pH value with 40% sodium hydroxide solution to 10, extracted with dichloromethane (3×75ml), the combined organic phases were washed with purified water (2×50ml) and saturated brine (1×50ml) successivel...

Embodiment 2

[0037] The preparation process of erlotinib hydrochloride uses 2-nitro-4,5-bis(2-methoxyethoxy)benzonitrile as the starting material to obtain 2-amino-4 through nitro reduction, 5-two (2-methoxyethoxyl) benzonitriles are prepared according to the operational route (2), specifically comprising the following steps:

[0038] 1, the preparation of 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile

[0039] The operation was the same as step 1 in Example 1 to obtain a brown-yellow solid (84.65 g, 94.06%).

[0040] 2, Preparation of Schiff base of 3-ethynylaniline

[0041] Add 3-ethynylaniline (32.6, 0.28mol), toluene (800ml), acetic acid (0.13ml) and DMF-DMA (60g, 0.505mol) into the reaction flask equipped with an oil-water separator, mix and stir, and heat to reflux for 3 After the reaction was completed, the solvent was distilled off to obtain an oily liquid (37.1 g, 0.257 mol). The next reaction was carried out directly without purification.

[0042] 3. Preparation of [6,7-bis(2-m...

Embodiment 3

[0048] The preparation process of erlotinib hydrochloride uses 2-nitro-4,5-bis(2-methoxyethoxy)benzonitrile as the starting material to obtain 2-amino-4 through nitro reduction, 5-two (2-methoxyethoxy) benzonitriles, then prepare according to the operational route (1), specifically comprising the following steps:

[0049] 1, the preparation of 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile

[0050] 2-nitro-4,5-di(2-methoxyethoxy)benzonitrile (100g, 0.336mol), iron powder (65.86g, 1.176mol) and water (1.7L) were mixed and stirred, heated to 50-55°C, continue to stir for 2 hours, quickly raise the temperature to 65-70°C, slowly add concentrated hydrochloric acid (450ml) dropwise, the temperature of the reaction solution drops to room temperature after the dropwise addition, adjust the pH value with 40% sodium hydroxide solution to 10, extracted with dichloromethane (3×75ml), and the combined organic phases were washed with purified water (2×50ml) and saturated brine (1×50ml) succ...

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Abstract

The invention relates to a preparing technology of erlotinib hydrochloride and belongs to the technical field of medical compound preparation. The preparing technology of erlotinib hydrochloride comprises the followings: 2-nitryl-4, 5-2 (2-methoxyethoxy) cyanophenyl is taken as a starting material and is reduced to obtain 2-amino-4, 5-2 (2-methoxyethoxy) cyanophenyl, and then erlotinib hydrochloride is synthetized through a route (1) or a route (2): (1) after being in reaction with DMF-DMA, 2-amino-4, 5-2 (2- methoethyl) cyanophenyl and 3-acetylenyl benzene are synthetized for obtaining erlotinib hydrochloride; (2) angiostatin is obtained through the reaction of the 2-amino-4,5-2 (2-methoxyethoxy) cyanophenyl and schiff base of 3-acetylenyl benzene, then acid is added to form salt, and the erlotinib hydrochloride is obtained. The preparing technology for erlotinib hydrochloride, provided by the invention, has the advantages of short reaction route, mild reaction conditions, and easiness and feasibility in operation, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation process of erlotinib hydrochloride, which belongs to the technical field of preparation of pharmaceutical compounds. Background technique [0002] The preparation process of erlotinib hydrochloride (CN200710172779) uses 3,4-dihydroxybenzaldehyde as the starting material through reduction, condensation, oxidation, alkoxylation, nitration, hydrolysis, nitro reduction, ring closure, chlorination and prophylaxis. Nuclear substitution yields erlotinib hydrochloride. [0003] The reaction scheme is as follows: [0004] [0005] The above preparation process first synthesizes 4-chloroquinazolone, and then reacts with 3-alkynyl aniline to obtain the final product. It is unavoidable to use chlorination reagents that are prohibited by the state and have great environmental pollution, such as oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride and thionyl chloride, etc. These substances are not conducive t...

Claims

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Application Information

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IPC IPC(8): C07D239/94
Inventor 何茂群苗得足杨祥龙王福生赵永坤
Owner REYOUNG PHARMA