Process Research and Scale-Up Synthesis of 3-(4-Isobutyl-2-methylphenyl)propanal, a Safe and Uniquely Performing Perfumery Ingredient,Organic Process Research & Development

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Process Research and Scale-Up Synthesis of 3-(4-Isobutyl-2-methylphenyl)propanal, a Safe and Uniquely Performing Perfumery Ingredient
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-11-24 , DOI: 10.1021/acs.oprd.0c00421
Martin A. Lovchik ₁ , Chi-Lam Tse ₁ , Simon Ellwood ₁

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Ever since the beginning of modern perfumery, muguet (lily-of-the-valley) notes have been sought after and are now found in varying doses in practically every perfume composition, accounting for the warm, soft, and comforting facets of many fragrances. Over the past decades, Lilial and Bourgeonal have evolved to become popular and inexpensive ingredients to satisfy the high demand of such floral odors. However, the search continues for more performing ingredients, especially in this odor family. Through this effort, 3-(4-isobutyl-2-methylphenyl)propanal (Nympheal) was identified as a modern, more performing, and benign alternative to the traditional ingredients. In particular, it outperforms Lilial in a sense that it has a linden blossom, a floral aldehydic odor considered to be more natural in its character. This paper details the challenge to design an efficient synthesis for the multi-kilogram production of the fragrance ingredient Nympheal. The methyl group, strategically placed in the 2-position to ensure the biological safety of the ingredient, also introduced a level of asymmetry into the molecule resulting in regiochemical challenges to identifying potential synthetic routes. Route scouting for this initial scale-up was performed using 1-isobutyl-3-methylbenzene as a feedstock made by continuous dehydrogenation of a mixture of 3- and 5-isobutyl-1-methylcyclohex-1-ene. Different routes were explored for introduction of the propanal moiety including carbonylation, Heck reaction, and Friedel–Crafts reaction. Ultimately, 3.3 kg of Nympheal was prepared by electrophilic bromination of 1-isobutyl-3-methylbenzene, followed by reaction with magnesium and dimethylformamide to give the corresponding benzaldehyde, which was then reacted with ethyl vinyl ether by the procedure from Muller-Cunradi–Pierroh and hydrogenated to give the desired product.

中文翻译：

安全且性能独特的香料成分3-（4-异丁基-2-甲基苯基）丙醛的工艺研究和按比例放大合成

自现代香水制造开始以来，人们就一直在寻找味ue（山谷中的香气）香精，如今在几乎每种香精成分中都以不同的剂量发现了香精，这是许多香水温暖，柔和和令人愉悦的一个方面。在过去的几十年中，Lilial和Bourgeonal已经发展成为一种流行且便宜的成分，可以满足此类花香的高需求。但是，仍在寻找性能更强的成分，尤其是在该气味家族中。通过这种努力，3-（4-异丁基-2-甲基苯基）丙醛（Nympheal）被认为是现代，更有效和良性的传统成分替代品。尤其是从某种意义上说，它的表现优于Lilial，具有a树花的花香，这种花香的醛香气味被认为更自然。本文详细介绍了设计有效合成香精成分Nympheal的多千克产品所面临的挑战。为了确保成分的生物安全性，在策略上放置在2位上的甲基基团还向分子内引入了一定程度的不对称性，从而导致了区域化学挑战，难以确定潜在的合成途径。使用1-异丁基-3-甲基苯作为原料，通过3-和5-异丁基-1-甲基环己-1-烯的混合物连续脱氢制得的原料，进行最初的规模放大。探索了引入丙醛部分的不同途径，包括羰基化，Heck反应和Friedel-Crafts反应。最终，通过1-异丁基-3-甲基苯的亲电溴化反应制备了3.3千克的Nympheal，

更新日期：2020-12-18

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