从质疑到信赖：7步缩至3步，收率翻倍，药明康德如何以甾体化学能力赢得客户 | Bilingual

真正的答案，经得起反复叩问。在新药分子合成中，真正经得起检验的，不是一次成功的反应，而是一套经得起重复、经得起放大、经得起时间考验的可靠工艺。这，便是专业最朴素也最坚实的底色。

几年前，一家正在开发甾体药物的客户找到药明康德研发化学服务部（Research Chemistry Services，RCS），希望协助完成一个关键甾体分子的工艺开发。

客户提供的原始路线看似可行，实则暗藏局限：该路线共7步，总收率低，且存在严重的区域选择性问题——由于甾体分子具多个反应位点，副反应频发，导致目标产物难以精准获得。更严峻的是，该路线在实验室小试阶段尚可运行，一旦放大至十克级乃至百克级，便完全无法重现：反应失控、杂质增多、收率骤降。

客户的核心需求很明确：开发一条真正可用于工艺放大的可行路线。

面对这一挑战，RCS团队并未止步于局部优化，而是依托药明康德多年积累的甾体化学平台能力，迅速为客户设计了一条全新的合成路线。

值得一提的是，甾体化学与普通有机化学截然不同：起始原料种类相对有限，市场上可获得的常规甾体原料屈指可数，而客户所需的分子通常只能从其中几种核心原料出发；加之甾体分子本身结构复杂，反应位点多，立体选择性控制难度大，分离纯化困难重重。然而，团队凭借十多年甾体化学研究经验，以及累计完成超过10000个甾体分子的深厚知识储备，精准识别出关键反应位点，通过创新设计，成功解决了难题。

最终，团队交付的成果远超客户预期：总路线从7步缩短至3步，总收率也提升了两倍以上，且在小规模（十克级至百克级）验证中一次性通过，获得了客户的认可。

图片来源：123RF

然而，事情并未就此结束。两年后，客户突然联系RCS团队：他们在公斤级放大过程中遇到了反复的失败。客户的第一反应是——该工艺本身是否存在问题？

面对这一质疑，RCS团队并未急于辩解，而是冷静分析，与客户展开技术细节讨论。团队坚信自己开发的工艺的可靠性，并做出全面的验证实验：1 g x 2次验证，10 g x 2次验证，100 g x 2次验证，1000 g x 2次验证。团队以极高的执行效率，迅速、详实地完成了每一次验证，所有结果不仅重现两年前的数据，且证实了工艺稳定性和重现性均优于预期。

更令客户惊喜的是，RCS团队并未满足于简单的验证重复。在验证过程中，团队主动思考如何进一步优化工艺。两年前开发的工艺虽已大幅缩短路线，但每一步仍需分离纯化。在此基础上，团队引入连续工艺和析出工艺，将原本需要复杂分离纯化的步骤整合为一体化操作，实现连续工艺，直接析出产品。这一工艺改进使得百克级产品的制备周期从两周缩短至仅4天，效率大幅提升。

客户在收到验证结果后，给出了高度评价：“是你们出色的工作，让项目变得简单！这是一项卓越的成果。”这既是对RCS团队专业技术和能力的认可，更是对团队精益求精的专业态度的由衷赞赏。

两次合作——一次顺利开发，一次充分验证——让客户对药明康德RCS团队的甾体化学能力和工艺优化能力彻底信服。此后，客户主动升级为深度合作模式，与RCS共同挑战更高难度的甾体分子合成。

赋能甾体分子的背后：平台积淀与团队精神

回顾合作历程，药明康德RCS团队赢得客户信赖，绝非偶然。其甾体化学平台历经十余年深耕，已构建覆盖发现、优化到工艺开发与规模化生产的综合技术体系。平台累计完成10000余个甾体分子的合成，在复杂多手性中心构建与结构精准修饰方面积淀深厚。同时，平台建立了20余种甾体手性中心构建方法，并配套丰富的甾体高级中间体与定制化路线设计能力，可高效支持从Hit-to-Lead、新结构开发到聚焦化合物库构建等早期研究需求。

一直以来，甾体药物研发面临独特挑战——分子结构刚性强、区域与立体选择性要求高，工艺放大难度大。作为创新的赋能者，药明康德RCS基于多年的深厚技术积淀，能够迅速应对区域选择性差、放大不重现等棘手问题，并持续迭代优化。

针对甾体分子的结构特点，RCS团队通过路线开发、杂质与代谢物合成、同位素标记及绝对构型解析等能力，实现对候选分子的系统性研究与优化。同时，平台支持毫克级至公斤级的交付，并通过早期工艺开发与放大研究有效缩短开发周期。（如需了解药明康德研发化学服务或业务咨询，请点击文末“阅读原文”）

与此同时，甾体分子的应用也在持续拓展。这类分子正从“受体激动或拮抗”走向更复杂的功能调控，从单一治疗作用拓展至诊断、递送和新型分子模式。这些新方向也带来了新的研发挑战。

图片来源：123RF

面对这一趋势，药明康德RCS团队将甾体化学与创新治疗模式开发深度结合，可支持基于甾体骨架的抗体偶联药物（ADC）、靶向蛋白降解剂、前药及氮芥类分子设计与合成。平台与分析服务、反应条件筛选、重结晶平台、流动化学、光氧化还原及电化学等技术协同运行，实现从分子创新到可放大生产的无缝衔接。通过整合长期经验、模块化技术能力与跨平台协同，甾体化学平台能够为客户提供稳定、高效且可扩展的化学赋能，助力复杂甾体及新型偶联分子的研发与转化。（如需了解药明康德研发化学服务或业务咨询，请点击文末“阅读原文”）

更重要的是，药明康德RCS团队始终敢于面对挑战、以专业能力服务客户。面对质疑，不回避、不推诿，而是用行动和结果回应；在已有良好成果的基础上，依然主动追求更好，将工艺从“好”做到“卓越”。这种精益求精的态度，也是团队赢得客户长期信赖的重要精神力量。

从首次合作路线开发，到后来的验证升级，再到如今的深度合作，药明康德用一次次超预期的交付，不断践行着团队“极致赋能”的承诺。这份承诺，不止于甾体。它贯穿于药明康德整个的一体化CRDMO平台，驱动公司在任何复杂分子与创新治疗模式面前，始终以专业与担当，持续助力客户的每一次突破。

From Doubt to Trust: How WuXi AppTec’s Steroid Chemistry Expertise Forged a Long-Term Partnership

True answers withstand repeated scrutiny. In the synthesis of new drug molecules, what truly stands the test of time is not a single successful reaction, but a reliable process that can be repeated, scaled up, and proven over time. This forms the most fundamental and solid foundation of true professionalism.

Several years ago, a client developing a steroidal drug candidate approached WuXi AppTec’s Research Chemistry Services (RCS) team for help with the process development of a key steroid molecule.

The client’s original route appeared feasible but had hidden limitations. It required seven steps, with an overall yield that was quite low. More critically, it suffered from significant regioselectivity issues—because steroid molecules contain multiple reactive sites, side reactions occur frequently, making it difficult to consistently obtain the desired product. Even more problematically, while the route worked at the laboratory scale, it was completely irreproducible when scaled up to the 10 to 100 gram scale, resulting in side reactions, increased impurities, and plummeted yields.

The client’s need was clear: to develop a viable route that could truly be used for scale-up.

Facing this challenge, the RCS team did not restrict its attempts to simple reaction optimization. Instead, relying on its years of accumulated expertise in steroid chemistry, it rapidly designed a brand-new synthetic route for the client.

It is worth noting that steroid chemistry is distinctly different from general organic chemistry. The types of starting materials are relatively limited, with only a handful of commercially available steroid precursors. The molecules requested by the client typically had to be derived from just one or two core starting materials. Furthermore, steroid molecules are structurally complex, featuring multiple reactive sites, making stereoselectivity difficult to control and purification challenging. However, leveraging over a decade of experience in steroid chemistry and a profound knowledge base built on synthesizing over 10,000 steroid molecules, the team accurately identified the critical reactive sites and solved the problem through innovative design.

Ultimately, the results delivered by the team far exceeded the client’s expectations. The route was shortened from seven steps to three, and the overall yield more than doubled. The process was validated at the tens-gram scale in a single run and was well recognized by the client.

Image Source: 123RF

However, the story did not end there. Two years later, the client suddenly contacted the RCS team, reporting repeated failures during kilogram-scale scale-up. The client's first reaction was to question whether there was an inherent flaw in the process itself.

Facing this doubt, the RCS team did not rush to defend their work. Instead, they calmly analyzed the situation and engaged in detailed technical discussions with the client. Firmly believing in the reliability of their developed process, the team conducted comprehensive validation experiments: 1 g × 2 runs, 10 g × 2 runs, 100 g × 2 runs, and 1000 g × 2 runs. With extremely high execution efficiency, the team quickly and meticulously completed each validation. The results not only reproduced the data from two years prior, but also confirmed that the process stability and reproducibility were better than expected.

To the client's pleasant surprise, the RCS team was not satisfied with merely repeating the validation. During the validation experiments, they proactively explored ways to further optimize the process. Although the route developed two years ago was significantly shorter, each step still required separation and purification. Building upon this, the team introduced continuous processing and precipitation techniques, integrating steps that previously required complex separation and purification into a single, continuous operation and direct product precipitation. This process improvement shortened the cycle time for hundred-gram-scale production from two weeks to just four days, significantly boosting efficiency.

Upon receiving the validation results, the client offered high praise: "It is your outstanding work that made the project simple! This is an excellent achievement." This was not only a recognition of the RCS team's technical expertise and capabilities, but also a sincere appreciation for their relentless pursuit of professional excellence.

Through these two collaborations, the client was completely convinced by the RCS team’s capability in steroid chemistry and process optimization. Following this, the client voluntarily upgraded the partnership into a deep collaboration model, tackling even more challenging steroid molecule syntheses with RCS.

Behind the Enablement of Steroid Molecules: Platform Heritage and Team Spirit

Looking back at the collaboration, it is no coincidence that the WuXi AppTec RCS team won the client's trust. With over a decade of deep involvement, its steroid chemistry platform has built comprehensive technical expertise covering discovery, optimization, process development, and large-scale manufacturing. The platform has accumulated experience from the syntheses of over 10,000 steroid molecules, possessing a profound knowledge base in constructing complex multi-chiral centers and performing precise structural modifications. Furthermore, the platform has established over 20 methods for constructing steroid chiral centers, supported by a rich inventory of advanced steroid intermediates and customized route design capabilities, efficiently enabling steroid drug early discovery efforts including Hit-to-Lead, novel structure development and focused library construction. 

Steroid drug research and development has always faced unique challenges: high structural rigidity, high demands for regio- and stereoselectivity, and high difficulty in scale-up. As an enabler, WuXi AppTec’s RCS draws on years of technical expertise to rapidly address thorny issues such as poor regioselectivity and irreproducibility during scale-up, while continuously iterating and optimizing.

Tailoring to the structural characteristics of steroid molecules, the RCS team can achieve systematic research and optimization of candidate molecules through expertise in route development, impurity and metabolite synthesis, isotope labeling, and absolute configuration determination. Meanwhile, the platform supports deliveries ranging from milligrams to kilograms and effectively shortens the development cycle through integration of early process development and scale-up production.

At the same time, the application of steroid molecules continues to expand. These molecules are moving from “receptor agonism or antagonism” to more complex functional regulation, and expanding from single therapeutic effects to diagnostics, drug delivery, and other novel molecular modalities. These new directions, in turn, bring new R&D challenges.

Image Source: 123RF

In response to this trend, the RCS team deeply integrates steroid chemistry with the development of innovative therapeutic modalities, supporting the design and synthesis of steroid skeleton-based antibody-drug conjugates (ADCs), targeted protein degraders, prodrugs, and nitrogen mustard molecules. The platform operates synergistically with analytical services, reaction condition screening, crystallization, flow chemistry, and photoredox and electrochemistry technologies, ensuring a seamless transition from candidate discovery to scalable production. By integrating long-term experience, modular technical capabilities, and cross-platform synergy, the steroid chemistry platform provides clients with stable, efficient, and scalable synthetic solutions, accelerating the R&D of complex steroids and novel conjugate molecules.

More importantly, the RCS team at WuXi AppTec always dares to face challenges and supports clients with professional expertise. In the face of doubt, they do not evade or shift blame; instead, they respond with action and results. Building on already solid achievements, they proactively strive for better, elevating the process from “good” to “excellent.” This relentless pursuit of excellence is a crucial spiritual driving force behind the team's ability to win clients' long-term trust.

From the initial route development to the subsequent validation and upgrade, and now to deep collaboration, WuXi AppTec has consistently fulfilled the team's promise of "strive for excellence" through deliveries that repeatedly exceed expectations. This commitment extends far beyond steroids. It permeates WuXi AppTec’s entire integrated CRDMO platform, driving the company to consistently support every breakthrough of its clients with professionalism and dedication, no matter the complexity of the molecule or the novelty of the therapeutic modality.

Key messages:

• In one case, WuXi AppTec’s RCS team reduced a client’s steroid synthesis route from 7 steps to 3, while more than doubling the overall yield—a clear demonstration of the team’s deep expertise in steroid chemistry. During the verification phase, the team proactively introduced continuous processing and direct precipitation techniques, cutting the production time for 100 g of product from two weeks to just 4 days. This “good to excellent” mindset turned a client into a long-term partner.

• WuXi AppTec RCS’s steroid chemistry platform, established more than ten years ago, has synthesized over 10,000 steroid molecules and developed more than 20 methods for chiral center construction. This accumulated knowledge base, combined with integrated capabilities—including flow chemistry, recrystallization, ADC, targeted degradation—enables rapid, scalable solutions for even the most challenging steroid projects.

• Steroid drug development faces unique challenges—rigid molecular structures, high demands for regio- and stereoselectivity, and scale-up difficulties. Leveraging years of expertise, WuXi AppTec’s RCS team systematically optimizes candidates through route development, impurity synthesis, isotope labeling, and absolute configuration determination, supporting synthesis and delivery from milligram to kilogram scales.

• The client’s journey from doubt to deep collaboration was won not by promises but by repeated delivery that combined speed with uncompromising quality. This reflects WuXi AppTec’s commitment to “strive for excellence” across its entire CRDMO platform.

  
  

For more information about WuXi AppTec’s Research Chemistry Services or business collaboration inquiries, please click “Read More” at the end of this article.

免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。