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

这一小型企业创新技术转移研究第一阶段项目的更广泛的影响/商业潜力是促进天然和半合成产品的制造和商业化，即作为药物开发和其他工业应用的前体的核心卢帕烷三萜类化合物(白桦醇、白桦酸、羽扇豆醇、白桦醛)。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、艾滋病毒/艾滋病、2型糖尿病、结核病、代谢性疾病，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/或化学合成导致规模产量很低，成本超过10,000美元/公斤。该项目的基本潜力在于展示了使用某些选择性有机反应直接从白桦树外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。白桦树是一种可再生的自然资源，在北方气候中广泛存在。这种方法是新颖的，如果成功，可以显著提高产率，同时消除了多个复杂的合成步骤，从而提供了以前无法在商业数量上获得的大量三萜类化合物。第一阶段研究项目的技术目标是从白桦树外层树皮中发现的三萜类提取物开发一种主要是纯天然和半合成化学制造的新方法。该项目的具体目标是开发方法和流程，以1)提供商业数量的外层树皮，不含杂质和异物，2)开发从外层树皮中提取天然三萜类化合物(BBE)并去除有害污染物的过程。3)开发合成工艺，以将三萜提取物转化为具有用于药物开发的质量和纯度所需的半合成前体。这项研究将提供专门设计的树皮筛选、分离和致密工艺，以提供能够高效和经济地加工的纯材料。将开发提取方法来去除微量的单宁、色素、黄油和其他不需要的物质。从BBE直接直接半合成三萜类化合物的创新新方法将被开发出来，以导致三萜类化合物作为精细化学品的大规模生产工艺的建立。

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.