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Preparation method of tarceva

A methoxyethoxy and intermediate technology, applied in the field of preparation of tasewa, can solve the problems of carbonization and deterioration of reactants, incomplete or polynitration, uncontrollable temperature, etc., and achieves mild conditions, high selectivity, high The effect of easy large-scale industrial production

Active Publication Date: 2012-01-18
JIANGSU HUIFENG BIO AGRI CO LTD
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Problems solved by technology

It is found through experimental research that the method releases heat violently, and the temperature cannot be controlled after amplification; the reaction is extremely prone to incomplete or multi-nitration phenomenon, and concentrated sulfuric acid will cause carbonization and deterioration of some reactants; the reaction product is dark brown oily liquid with low content. and not suitable for purification

Method used

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  • Preparation method of tarceva
  • Preparation method of tarceva

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Experimental program
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Embodiment 1

[0032] Embodiment 1, the preparation of intermediate 1 methanesulfonic acid (2-methoxyethyl ester)

[0033]Add 0.25L ethylene glycol monomethyl ether and 0.25L triethylamine into the reaction flask, and add 0.20L p-methanesulfonyl chloride in batches under ice-salt bath cooling, keeping the internal temperature not exceeding 5°C. After the addition, keep warm at 5-10°C for 5 hours, filter, slowly pour the reaction solution into 2.5L ice water for dilution, extract 3 times with ethyl acetate (1.0L×3), combine the organic phases, and dilute with 3% dilute hydrochloric acid (v / v) wash 3 times (0.3L×3), wash once with water (0.3L), wash once with saturated sodium chloride solution (0.3L), and dry over anhydrous sodium sulfate. The desiccant was filtered off, concentrated and evaporated to remove the solvent to obtain a white transparent oily liquid, which was identified as methanesulfonic acid (2-methoxyethyl ester) (intermediate 1) by NMR H spectrum, yield: 98%, detected by HPLC,...

Embodiment 2

[0034] Embodiment 2, intermediate 23, the preparation of 4-two (2-methoxyethoxy) ethyl benzoate

[0035] In a three-necked flask with mechanical stirring, add 18.2g of ethyl 3,4-dihydroxybenzoate (0.1mol), 110ml of water, 100ml of DMF and 30g of potassium carbonate, heat to 90-95°C, and dropwise add 38g of intermediate Compound 1 methanesulfonic acid (2-methoxyethyl ester) (0.25mol), after the addition was complete, the mixture was stirred for another 4 hours and 30 minutes, and stopped. The reaction solution was slowly added dropwise to 800ml of water under stirring to obtain a relatively dispersed solid, which was dried to obtain 228.4g of an intermediate with a yield of 95%. The purity was 99.2% by HPLC detection.

Embodiment 3

[0036] Embodiment 3, intermediate 33, the preparation of 4-bis(2-methoxyethoxy)-5-aminobenzoic acid ethyl ester

[0037] Add 25.7g (86mmol) intermediate 23,4-bis(2-methoxyethoxy)ethyl benzoate and 100ml ethyl acetate to the reaction flask, cool to 0°C in an ice-salt bath and slowly add 200ml Containing the ethyl acetate solution of 34ml fuming nitric acid, after the dropwise addition is completed, the stirring reaction was continued for about 1 hour. After the reaction was completed, 400ml of water was added to dilute, the layers were separated, and the lower layer was extracted with 50ml×3 ethyl acetate, and the organic layers were combined. Wash twice with water (50ml×2), and dry over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation to obtain an oily substance. The resulting oil was added to the reaction kettle, and then 250ml of absolute ethanol and 0.5g of 5% Pd / C catalyst were added. Under the protection of nitrogen, hydrogen gas was introduced...

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Abstract

The invention provides a preparation method of tarceva. According to the invention, 3,4-ethyl dihydroxybenzoate is adopted as an initial raw material, and is subject to a reaction with ethylene glycol mono-methyl ether; the product is processed through nitrification, reduction, cyclic condensation, and halogenation; the product is then subject to a reaction with 3-aminophenylacetylene; and dry hydrogen chloride gas is delivered in, such that tarceva is produced. The technical scheme provided by the invention is advantaged in that: the reaction condition is mild, the yield of the processing line is high, and the post-treatment is convenient. Therefore, the method is suitable for industrialized productions.

Description

technical field [0001] The invention relates to a preparation method of Tarceva. Background technique [0002] It is jointly developed by Genetech, OSI and Roche and produced by Roche (Roche). It is an innovative drug for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has failed at least one chemotherapy regimen. 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. In 2005, the FDA also approved the combination of Seva and gemcitabine for the treatment of advanced pancreatic cancer, becoming the first approved drug for the treatment of advanced pancreatic cancer in the past 10 years. [0003] Taseva is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TK). It inhibits the phosphorylation reaction by competing with adenosine triphosphate to bind to the catalytic part of the intracellular region of the receptor tyrosine kinase, thereby ...

Claims

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Application Information

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IPC IPC(8): C07D239/94
Inventor 仲汉根宋芳
Owner JIANGSU HUIFENG BIO AGRI CO LTD
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