Highly efficient synthesis of fatty acid dopamides
Highly efficient synthesis of fatty acid dopamides
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DOI：
10.1080/00304949809355327
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发表时间：
1998-12-01
影响因子：
1.5
通讯作者：
Matuszewska, I
中科院分区：
文献类型：
--
作者：
Czarnocki, Z;Matuszewska, MP;Matuszewska, I
在过去的十年中，长链多不饱和酸和生物重要胺的酰胺引起了相当大的兴趣，特别是与生物活性衍生物的合成有关。用于制备这些化合物的许多方法是费力的，并且以差到中等的产率得到产物。12由于对一系列脂肪酸多巴胺的合成及其可能的神经传递性质感兴趣，我们用“混合酸酐”方法进行了研究。然而，在我们的手中，该方法得到了一种复杂的产物混合物，从中只能分离出痕量的所需酰胺。这一事实鼓励我们为此目的研究其他可能的方法。本文介绍了广泛应用于肽化学的苯并三唑基三（二甲氨基）磷鎓六氟磷酸盐（BOP试剂）的应用。BOP介导的受保护氨基酸和肽的偶联已被证明是与不稳定或敏感组分反应的首选方法。已知多巴胺和多顺式不饱和脂肪酸易于发生氧化或异构化副反应。因此，我们预期在非常温和的条件下BOP介导的偶联将使所有不期望的转化最小化。在我们的程序中，将盐酸多巴胺与等摩尔量的脂肪酸和BOP试剂在无水THF中混合。在0 °下加入过量的甲胺，然后进行标准的萃取后处理和柱色谱纯化，得到所需的酰胺1-5（Organic Preparations and Procedures Inc.，1998）。699
Amides of long-chain polyunsaturated acids and biologically important amines have attracted considerable interest in the last decade, especially in connection with the synthesis of biologically active derivatives.’The many methods used for the preparation of these compounds are laborious and give products in poor to medium yields.’12 Having been interested in the synthesis of a series of fatty acid dopamides in connection with their possible neurotransmissing properties,’, 2 we investigated with the “mixed anhydride” procedure. Ia In our hands, however, the method gave a complex mixture of products from which only a trace amounts of the desired amides could be isolated. This fact encouraged us to investigate other possible methodologies for this purpose. We turned our attention to the use of benzotriazol-1-yloxy-tris (dimethy1amino) phosphonium hexafluorophosphate (BOP reagent) which is widely used in peptide chemi~ try.~ A BOP-mediated coupling of protected aminoacids and peptides has proven to be the method of choice for the reactions with unstable or sensitive components. Dopamine and poly-cis-unsaturated fatty acids are known to be prone to oxidation or isomerization side-reactions. We thus anticipated that BOP-mediated coupling under very mild conditions would minimize all undesired transformations. In our procedure, dopamine hydrochloride was mixed with an equimolar amounts of fatty acid and BOP reagent in dry THF. Addition of an excess of methylamine at 0” followed by standard extractive work-up and purification by column chromatography, gave the desired amides 1-5 in good1998 by Organic Preparations and Procedures Inc. 699