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Preparation method of erlotinib hydrochloride key intermediate

A technology of erlotinib hydrochloride and an intermediate, which is applied in the field of pharmaceutical compound synthesis, can solve problems such as the recovery and application of unfavorable solvents, and achieve the effects of easy mass production, good environmental protection and mild reaction conditions

Inactive Publication Date: 2014-04-09
ZHEJIANG APELOA KANGYU PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The total yield of this route is only 60%, and a large number of mixed solvents are used, which is not conducive to the recovery and application of solvents during industrial production

Method used

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  • Preparation method of erlotinib hydrochloride key intermediate
  • Preparation method of erlotinib hydrochloride key intermediate
  • Preparation method of erlotinib hydrochloride key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] A. Synthesis of compound (i)

[0057] Add methanesulfonyl chloride (250g), ethylene glycol monomethyl ether (97.8g) and dichloromethane (587mL), cool down to 0-5°C, slowly add KOH (144g) in batches, raise the temperature to about 25°C for 3 hours , TLC shows that the reaction is complete, add 1360g ice water, stir to dissolve, separate layers, extract the water layer with dichloromethane (645mL×2), combine the dichloromethane layers, wash with 635g water, wash with 20.5g1mol / L hydrochloric acid (pH95%;

[0058] B. Synthesis of compound (iii)

[0059] Compound (i) (194.2g), compound (ii) (111g), potassium carbonate (252.3g), toluene (2220mL) and tetrabutylammonium bromide (5g) were mixed, heated to reflux, reacted for 6 hours, HPLC It shows that the reaction is complete, cool down to room temperature, filter with suction, rinse with 370mL of toluene, wash the filtrate with 1110mL of water, extract the water layer with toluene (555mL×2), combine the toluene layers, wash ...

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Abstract

The invention discloses a preparation method of an erlotinib hydrochloride key intermediate 4-chloro-6,7-di(2-methoxyethoxy)quinazoline, which comprises the following steps: reacting the raw material ethyl 3,4-dihydroxybenzoate with ethyl 2-methoxysulfonate, nitrating, reducing, cyclizing and chlorinating to obtain the key intermediate 4-chloro-6,7-di(2-methoxyethoxy)quinazoline. The method has the advantages of mild reaction conditions, low cost, high purity and high total yield (up to 74.8%), and can easily implement industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical compounds, in particular to a method for preparing a key intermediate of erlotinib hydrochloride (4-chloro-6,7-bis(2-methoxyethoxy)quinazoline). Background technique [0002] 4-(3-ethynylphenylamino)-6,7-dimethoxyquinazoline hydrochloride (erlotinib hydrochloride, Erlotinib Hydrochloride, trade name: Tarceva, Tarceva) was originally developed by the American OSI Pharmaceutical Company (OSI Pharmaceuticals), a 4-aminophenylquinazoline oral antineoplastic drug, was first approved by the US FDA on November 18, 2004. It is a selective epidermal growth factor (EGFR) tyrosine kinase Preparations are mainly used clinically for the treatment of non-small cell lung cancer. [0003] [0004] Erlotinib hydrochloride molecular structure [0005] At present, most of the routes adopt the condensation reaction of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline and 3-aminophenylacetylene to prepare er...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/86
CPCC07D239/86
Inventor 冯立春黎伽伽
Owner ZHEJIANG APELOA KANGYU PHARMA
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