酵素を利用したシクロヘキサンメタノール誘導体の酸化方法の検討

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  • コウソ オ リヨウ シタ シクロヘキサンメタノール ユウドウタイ ノ サンカ ホウホウ ノ ケントウ
  • Study of enzymatic oxidation of cyclohexanemethanol derivatives

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Tranexamic acid has been widely used as a medication and in cosmetics since it was first approved in Japan in 1965. One of the synthetic methods uses 1,4-cyclohexanedimethanol as a starting material and underwent through four steps: (1) monotosylation, (2) azidation, (3) oxidation, and (4) amination. In the third step, where a hydroxyl group is converted to carboxylic acid, strong oxidant is required. Traditionally, this process uses Jones reagent, which contains toxic hexavalent chromium. However, hexavalent chromium is highly toxic and carcinogenic, raising concerns about its impact on human health and the environment. To address this issue, this study focused on a choline oxidase enzyme derived from Arthrobacter mangrovi. A modified version of this enzyme, where six specific amino acids were substituted, has been reported to have increased substrate specificity for primary alcohols. This makes it a potential alternative to hexavalent chromium for the carboxylation step in tranexamic acid synthesis. After purifying the mutant choline oxidase, its oxidation activity was measured. Results showed that while activity toward choline decreased, activity toward cyclohexanemethanol increased by 73 times, and activity toward 1,4-cyclohexanedimethanol increased by 156 times. Gas-liquid chromatography (GLC) analysis of the products revealed partial oxidation to aldehydes for cyclohexanemethanol. For 1,4-cyclohexanedimethanol, the analysis suggested the formation of an unknown product. These findings indicate that this enzyme reaction has the potential for use in the third step of tranexamic acid synthesis as a safer and more environmentally friendly alternative to hexavalent chromium.

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