STTR Phase I: Semisynthetic Manufacturing of Core Natural Triterpenoids from Outer Birch Bark Extract

这一小企业创新技术转让研究第一阶段项目的更广泛影响/商业潜力是促进天然和半合成产品的生产和商业化，即核心羽扇烷三萜类化合物（桦木醇，桦木酸，羽扇豆醇，桦木醛）作为药物开发和其他工业应用的前体。研究表明，这些三萜类化合物可用于预防和治疗癌症、慢性炎症、HIV/AIDS、2型糖尿病、结核病、代谢疾病以及下一代抗菌剂和疫苗佐剂。不幸的是，这些化合物的复杂分离和/或化学合成导致低规模产率，成本超过10，000美元/kg。该项目的基本潜力在于展示使用某些选择性有机反应直接从桦树外层树皮中发现的天然提取物的复杂成分中生产这些高价值化合物，桦树是一种可再生的自然资源，广泛存在于北方气候中。这种方法是新颖的，如果成功的话，可以导致显着更高的产率，同时消除多个复杂的合成步骤，从而提供了大量的三萜类化合物的多样性，这是以前无法获得的商业数量。第一阶段研究项目的技术目标是开发一种新的纯天然和半合成化学品制造方法，从桦树外层树皮中发现的三萜类化合物提取物。该项目的具体目标是开发方法和工艺，以1）提供商业数量的无杂质和异物的外树皮，2）开发从外树皮中提取天然三萜类化合物（BBE）并去除不需要的污染物的工艺。3)开发合成工艺，将三萜提取物转化为具有药物开发所需质量和纯度的半合成前体。这项研究将提供专门设计的树皮筛选，分离和致密化过程，以提供一种可以有效和经济地加工的纯材料。将开发提取方法以去除单宁、色素、木栓质和其他不需要的物质。 将开发直接从BBE直接半合成生产三萜类化合物的创新新方法，以创建作为精细化学品的三萜类化合物的大规模生产工艺。

The broader impact/commercial potential of this Small Business Innovation Technology Transfer Research Phase I project is to facilitate the manufacturing and commercialization of natural and semi-synthetic products namely core lupane triterpenoids (betulin, betulinic acid, lupeol, betulinic aldehyde) as precursors for drug development and other industrial applications. Research shows that these triterpenoids can be useful agents for prevention and treatment of cancer, chronic inflammation, HIV/AIDS, type 2 diabetes, tuberculosis, metabolic disease, as well as next generation antimicrobials, and vaccine adjuvants. Unfortunately, the complex isolation and/or chemical synthesis of these compounds has resulted in low scale yields at costs of more than US$10,000/kg. The fundamental potential of this project lies in the demonstration of the use of certain selective organic reactions to produce these high value compounds straight from the complex composition of the natural extract found in the outer bark of the birch tree, a renewable, natural resource found extensively throughout the northern climates. This approach is novel and if successful, can result in significantly higher yields while eliminating multiple complex synthesis steps, thus providing a large diversity of triterpenoids that were previously not available in commercial quantities. The technical objective in Phase I research project is the development of a principally new way of pure natural and semi-synthetic chemical manufacturing from the triterpenoid extract found in the outer bark of the birch tree. The specific objectives of this project are to develop the methods and processes to 1) provide commercial quantities of outer bark, free from impurities and foreign matter, 2) develop the processes to extract the natural triterpenoids (BBE) from the outer bark and remove unwanted contaminants. 3) Develop the synthesis processes to convert the triterpene extract to the semi-synthetic precursors necessary with the quality and purity to be used for drug development. This research will provide specially designed processes of bark screening, separation and densification to provide a pure material that can be efficiently and economically processed. Extraction methods will be developed to remove traces of tannins, pigments, suberin, and other unwanted materials. Innovative new ways for the straight semisynthetic production of the triterpenoids directly from BBE, will be developed to lead to the creation of a large scale production process for triterpenoids as fine chemicals.