The preparation method of erlotinib hydrochloride key intermediate

A technology of acetic acid and nitric acid, applied in the field of medicinal chemistry, can solve the problems of reduced purity, increased side reactions, and increased waste liquid treatment costs.

Active Publication Date: 2021-07-06
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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  • The preparation method of erlotinib hydrochloride key intermediate
  • The preparation method of erlotinib hydrochloride key intermediate
  • The preparation method of erlotinib hydrochloride key intermediate

Examples

Experimental program
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example 1

[0024] Add glacial acetic acid (70L), acetic anhydride (10L) and ethyl 3,4-bis(2-methoxyethoxy)benzoate (23kg, 77.1mol) into a 200L reactor, slowly add nitric acid ( 12L, 269.85mol). Another concentrated sulfuric acid (200ml, 3.85mol) was diluted in glacial acetic acid (2L). 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 br...

example 2

[0027] Add glacial acetic acid (80L), acetic anhydride (15L) and ethyl 3,4-bis(2-methoxyethoxy)benzoate (27kg, 90.5mol) into a 200L reactor, slowly add nitric acid ( 14L, 316.75mol). Another concentrated sulfuric acid (10ml, 0.18mol) 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 bri...

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 a preparation method of a key intermediate of erlotinib hydrochloride, in particular to the preparation of 2-nitro- The method for 4,5-bis(2-methoxyethoxy) ethyl benzoate, the method comprises in the presence of the vitriol oil of catalytic amount, with acetic acid and acetic anhydride as solvent, 3,4-bis(methyl) Oxyethoxy) ethyl benzoate reacts with concentrated nitric acid. The invention has mild reaction conditions, fast reaction rate, high conversion rate and purity, safe and environmentally friendly process, and is easy to carry out industrialized production.

Description

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

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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