Preparation method of erlotinib hydrochloride

A technology of erlotinib hydrochloride and amino hydrochloride, applied in the field of N--6, can solve the problems of large reaction irritation and pollution, poor stability of substitution reagents, strong irritation, etc., and achieves simple and cheap raw materials, The effect of avoiding side effects and improving safety

Active Publication Date: 2010-06-16
BIOCOMPOUNDS PHARMACEUTICAL INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The substitution reagent has poor stability, strong irritation, and often contains dihaloethane impurities, which will react with the hydroxyl group on the parent ring at the same time to form impurities
Moreover, there are not many suppliers, such as self-preparation, the reaction is more irritating and polluting, special distillation is required, and the yield is low

Method used

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  • Preparation method of erlotinib hydrochloride
  • Preparation method of erlotinib hydrochloride
  • Preparation method of erlotinib hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Preparation of Intermediate I:

[0077] Add 10.0L of water, 0.64kg of chloral hydrate, and 9.1kg of anhydrous sodium sulfate into the reaction kettle, and raise the temperature to 30°C for use. Dissolve 0.53kg of 3,4-dimethoxyaniline and 0.78kg of hydroxylamine hydrochloride in 6L of 6.23% dilute hydrochloric acid (v / v), and stir to clarify. Control the temperature below 30°C, add the solution dropwise into the reaction kettle, raise the temperature to 70°C after dropping, and react for 4 hours. TLC monitoring (developer: petroleum ether / ethyl acetate = 2 / 1), filtered after the reaction was complete, washed the filter cake three times with water (0.5L×3), recrystallized with 2.0L ethanol, and filtered. The obtained solid was air-dried at 70° C. for 6 hours to obtain 0.43 kg of an off-white solid, which was the product, and the yield was 55.0%. The H-NMR spectrum identified the product as 2-oximino-N-(3,4-dimethoxyphenyl)acetamide.

[0078] Preparation of Intermediate...

Embodiment 2

[0097] Preparation of Intermediate I:

[0098] Add 5.0L of water, 0.86kg of chloral hydrate, and 5.0kg of anhydrous sodium sulfate into the reaction kettle, and raise the temperature to 40°C for use. Dissolve 0.53 kg of 3,4-dimethoxyaniline and 0.96 kg of hydroxylamine hydrochloride in 6 L of 10% dilute hydrochloric acid (v / v), and stir to clarify. Control the temperature below 40°C, add the solution dropwise to the reaction kettle, heat up to 100°C to reflux after dropping, and react for 3 hours. TLC monitoring (developer: petroleum ether / ethyl acetate = 2 / 1), filtered after the reaction was complete, washed the filter cake three times with water (0.5L×3), recrystallized with 2.5L ethanol, and filtered. The obtained solid was air-dried at 70° C. for 6 hours to obtain 0.40 kg of an off-white solid, which was the product, and the yield was 51.6%. The H-NMR spectrum identified the product as 2-oximino-N-(3,4-dimethoxyphenyl)acetamide.

[0099] Preparation of Intermediate II: ...

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Abstract

The invention provides a preparation method of erlotinib hydrochloride. The method comprises the following steps: taking 6,7-dimethoxy-3,4-dihydro-quinazoline as an initial raw material, chlorinating directly, then reacting with 3-aminophenylacetylene, afterwards removing methyl on the positions of 6 and 7 and finally introducing a methoxyethyl side chain to generate the erlotinib hydrochloride. The invention has the technological lines of mild reaction condition, no need of high temperature, deep cooling, energy saving and environment friendliness; the whole line has better yield and quality; and the reaction steps are little, the reaction is stable and controllable, the postprocessing is very simple and convenient, and the industrialized production is easy.

Description

technical field [0001] The present invention relates to a preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-aminoquinazoline hydrochloride (erlotinib hydrochloride) method. Background technique [0002] Erlotinib Hydrochloride (Erlotinib Hydrochloride), jointly developed by Genetech, OSI, and Roche, and produced by Roche (Roche), is used to treat locally advanced or metastatic non-small cell lung cancer that has failed at least one chemotherapy regimen (NSCLC) innovative medicine. It was approved by the US FDA in November 2004, approved by the European Union in September 2005, and launched in China in April 2006. FDA also approved the combination of erlotinib and gemcitabine for the treatment of advanced pancreatic cancer in 2005, becoming the first approved drug for the treatment of advanced pancreatic cancer in the past 10 years. [0003] Erlotinib hydrochloride is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TK). It inhibits the phos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
Inventor 孙婧吕伟张五军张平李倩康立涛
Owner BIOCOMPOUNDS PHARMACEUTICAL INC
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