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Erlotinib hydrochloride key intermediate preparation method

A technology of acetic acid and nitric acid, which is applied in the field of medicinal chemistry, can solve the problems of increased side reactions, reduced purity, and unsuitability for large-scale industrial production, and achieves the effects of reducing the generation of waste liquid, facilitating industrial production, and strong production operability

Active Publication Date: 2017-07-04
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When repeating this nitration method, find that this nitration condition is too strong and cause three comparatively serious problems, 1. because the amount of concentrated sulfuric acid is bigger, when concentrated sulfuric acid adds reaction solution, very easily cause raw material 3,4-bis(2-methoxy 2. The reaction temperature when nitric acid is added dropwise is difficult to control, and the temperature is very easy to rapidly rise to more than 100°C, causing a sharp increase in side reactions, reducing the purity of the reaction to 60%, and the yield to 60%. 45%; 3. Due to the large amount of concentrated sulfuric acid used, this method needs to consume a large amount of alkaline water when treating the waste liquid, resulting in a large amount of waste water, increasing the cost of waste liquid treatment and not being environmentally friendly
The above three reasons cause this nitrification method to be unsuitable for carrying out industrialized large-scale production

Method used

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  • Erlotinib hydrochloride key intermediate preparation method
  • Erlotinib hydrochloride key intermediate preparation method
  • Erlotinib hydrochloride key intermediate preparation method

Examples

Experimental program
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Effect test

example 1

[0024] Glacial acetic acid (70L), acetic anhydride (10L) and 3,4-bis(2-methoxyethoxy) ethyl benzoate (23kg, 77.1mol) were added in the 200L reactor, and nitric acid ( 12L, 269.85 mol). Another concentrated sulfuric acid (200 ml, 3.85 mol) was diluted in glacial acetic acid (2 L). After the nitric acid was added dropwise, the diluted concentrated sulfuric acid glacial acetic acid solution was slowly added dropwise to the reaction kettle, the dropping was completed, and the temperature was raised to 40° C. to react for 2 hours. After the reaction is completed, the reaction solution is cooled to 20° C., slowly poured into the mixed solution of ice water (80L) and dichloromethane (80L) under stirring, the dichloromethane layer of the lower layer is separated, and the water layer of the upper layer is added with dichloromethane. (80L) extracted once, the lower organic layer was released, and the organic phases were combined. The organic phase was washed successively with purified...

example 2

[0027] Glacial acetic acid (80L), acetic anhydride (15L) and 3,4-bis(2-methoxyethoxy) ethyl benzoate (27kg, 90.5mol) were added in the 200L reactor, and nitric acid ( 14L, 316.75 mol). Another concentrated sulfuric acid (10 ml, 0.18 mol) was diluted in glacial acetic acid (1 L). After the nitric acid was added dropwise, the diluted concentrated sulfuric acid glacial acetic acid solution was slowly added dropwise to the reaction kettle, the dropping was completed, and the temperature was raised to 40° C. to react for 2 hours. After the reaction is completed, the reaction solution is cooled to 20° C., slowly poured into the mixed solution of ice water (80L) and dichloromethane (80L) under stirring, the dichloromethane layer of the lower layer is separated, and the water layer of the upper layer is added with dichloromethane. (80L) extracted once, the lower organic layer was released, and the organic phases were combined. The organic phase was washed successively with purified ...

example 3

[0029]Add glacial acetic acid (80L), acetic anhydride (15L) and ethyl 3,4-bis(2-methoxyethoxy)benzoate (25kg, 83.8mol) into a 200L reactor, and slowly add nitric acid ( 13 L, 293.3 mol). Another concentrated sulfuric acid (460ml, 8.4mol) was diluted in glacial acetic acid (1L). After the addition of nitric acid is completed, the diluted concentrated sulfuric acid solution in glacial acetic acid is slowly added dropwise to the reaction kettle. After the drop is complete, the temperature is raised to 40°C for 2 hours. After the reaction is complete, cool the reaction solution to 20°C, slowly pour it into a mixture of ice water (80L) and dichloromethane (80L) while stirring, separate the lower dichloromethane layer, and add dichloromethane to the upper water layer (80L) extracted once, the lower organic layer was released, and the organic phases were combined. The organic phase was washed successively with purified water (80 L), aqueous sodium bicarbonate (100 L), and saturated...

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Abstract

The present invention relates to an erlotinib hydrochloride key intermediate preparation method, particularly to a method for high reaction rate, high purity and high yield preparation of 2-nitro-4,5-bis(2-methoxyethoxy) ethyl benzoate from 3,4-bis(methoxyethoxy)ethyl benzoate, wherein in the presence of a catalytic amount of concentrated sulfuric acid, 3,4-bis(methoxyethoxy)ethyl benzoate and concentrated sulfuric acid are subjected to a reaction by using acetic acid and acetic anhydride as a solvent. According to the present invention, the method has characteristics of mild reaction condition, rapid reaction rate, high conversion rate, high product purity, safety and environmental protection, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of 2-nitro-4,5-bis(2-methoxyethoxy) ethyl benzoate, a key intermediate of erlotinib hydrochloride. Background technique [0002] Erlotinib Hydrochloride, trade name Tarceva, was developed by OSI Pharmaceuticals in the United States, and later approved by Roche Pharmaceuticals in November 2004, September 2005 and April 2006 in the United States, A tinib-type antitumor drug approved for marketing in Europe and China. As a small molecule compound, erlotinib hydrochloride belongs to the epidermal growth factor receptor (EGFR) family of tyrosine kinase inhibitors, and is suitable for locally advanced or metastatic non-small cell lung cancer after failure of at least one chemotherapy regimen in the past (NSCLC) treatment. Erlotinib hydrochloride is also a targeted drug preparation, which can target specific lesions and accumulate or release active ingredients a...

Claims

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Application Information

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IPC IPC(8): C07C201/08C07C205/59
CPCC07C201/08C07C205/59
Inventor 陈绍磊张小兵季荣涛
Owner JIANGSU HANSOH PHARMA CO LTD
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