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Isolation of highly pure erlotinib hydrochloride by recrystallization after nucleophilic substitution of an impurity with piperazine

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Abstract

Optimized synthesis and purification of erlotinib hydrochloride (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine hydrochloride) were studied. Highly polar piperazine was used in a nucleophilic substitution reaction with the chlorinated intermediate byproduct N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. As a result, N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was completely transformed to N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The polarity of N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was changed, and its molecule was enlarged. It was easy to remove this larger, more polar, compound by recrystallization. Highly pure erlotinib hydrochloride was obtained with low impurity content (<1 %). The purity of erlotinib hydrochloride was >99.9 %.

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Authors and Affiliations

  1. Zhejiang Better Pharmaceuticals Co., Ltd, Shaoxing, 312071, People’s Republic of China

    Gengzhen Zhang

  2. R&D, Hangzhou Wahaha Group, Hangzhou, 310018, People’s Republic of China

    Linlin Zha

  3. Department of Chemistry, Zhejiang University, Hangzhou, 310028, People’s Republic of China

    Linlin Zha

Authors
  1. Gengzhen Zhang
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  2. Linlin Zha
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Correspondence to Linlin Zha.

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Zhang, G., Zha, L. Isolation of highly pure erlotinib hydrochloride by recrystallization after nucleophilic substitution of an impurity with piperazine. Res Chem Intermed 39, 2303–2309 (2013). https://doi.org/10.1007/s11164-012-0757-9

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  • DOI: https://doi.org/10.1007/s11164-012-0757-9

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