“以光为刃”，当传统工艺无解，药明康德如何将新药化学合成的鸿沟化为坦途？

在新药研发道路上，有时候决定成败的往往不是宏大的叙事，而是一次关键化学中间体的高效合成。这类中间体如同精密的齿轮，其结构的细微偏差，都可能导致后续进程的停滞。在药明康德的众多客户里，许多重要合作常常始于一个看似微小却至关重要的化学工艺节点。

故事要从一个棘手的分子骨架说起。

某公司在推进一个极具潜力的分子项目时，被一个关键的“路障”卡住了。项目急需构建一个复杂而精确的三维分子骨架。这个骨架，是整个药物分子的“心脏”，它的形状、空间结构都必须分毫不差。因此，只有成功构建出正确立体构型的核心骨架，才能构建出具有生物活性的复杂分子，进而有望推进临床，拯救生命。

然而，摆在他们面前的，是行业内传统分批工艺的“瓶颈”。

传统分批工艺生产模式是将所有原料按顺序投入反应容器中，在设定好的温度、压力下搅拌、反应。待反应结束，再进行分离提纯，得到产物。在这个项目中，如果采用传统合成路线，需经过5步反应，效率较低。而且，最终得到的产物里，只有一半是符合要求的立体构型，整体收率也不高。

更为棘手的是，传统分批工艺从实验室的克级探索放大到千克级生产时，横亘着一条难以逾越的“鸿沟”。这不是简单地把原料配方乘以1000就能解决的。规模放大后，反应体系的物理环境会发生变化，许多在烧瓶中运行良好的反应，一旦进入大釜，就可能面临效率下降、甚至失败风险。要解决这些挑战，就需要耗费更多时间和资源来重新摸索工艺条件。

面对难题，该公司第一时间联系上药明康德研发化学服务部（Research Chemistry Services，RCS）。这种信任并非凭空而来。它是十多年间，在多个合作项目里，由药明康德一次次专业、高效的服务交付，一点一滴积累起来的。

接到任务后，药明康德RCS团队迅速组建了由多个研发和生产基地专家构成的项目团队，一场与时间赛跑的技术攻坚就此拉开序幕。

如何破解分批工艺收率低、顺反选择性差，以及难以放大的“死结”？团队的目光投向了光化学工艺技术。

所谓光化学工艺，是利用特定波长的光能作为“精确的刻刀”，代替传统的热能或化学试剂，来精准切断或重组化学键，从而高效构建目标分子。这听起来似乎有些深奥，但光化学离我们的生活并不遥远，就像晾在阳台的彩色衣物，时间久了会慢慢褪色，其实是染料分子在太阳光的照射下发生了光化学反应；或是老式胶片相机按下快门的瞬间，胶片上的感光材料会因吸收光线而发生化学变化，最终定格下影像，也是光化学的典型应用。然而，当光化学技术应用于工业场景时，对设备、对人员的专业素养要求极高，它需要光能均匀、稳定地穿透反应体系，这在传统的反应釜中几乎无法实现。

为此，项目团队引入了一套高效的技术“组合拳”。

首先登场的是高通量实验（HTE），如果说分批工艺是在黑暗中一把把地尝试“钥匙”，那HTE就像同时启动了上百个微型“智能钥匙”，它能在极短时间内并行测试数百种反应条件——换一种光波长、试一种新催化剂、调一下浓度——过去需要几周甚至几个月的摸索，现在可将项目初期的摸索时间压缩到以天计，从而迅速锁定关键“配方”。

但仅找到“配方”还不够，关键是如何让它稳定、高效地运转起来，并适用于规模放大。于是，流动化学技术便登场亮相。

想象一下，不再让原料闷在反应容器里“不均匀光照”，而是将它们像输液一样，通过细细的管道持续泵入一个盘成线圈的透明“光隧道”。反应物一边匀速流动，一边接受管道外壁均匀的光照，真正实现了“边走边反应”。

在这条精心设计的“光隧道”上，光照条件均匀稳定，反应路径精准可控。原本需要5步、多批次投放、多次分离、转移的复杂过程，如今像一条流水线，仅需1步连贯完成。

结果是令人惊喜的——产物收率良好，顺式选择性极高。更难得的是，项目团队仅用了9个小时，就完成了100克以上规模的精准制备，这意味着该工艺路线已成功跨越实验室研究阶段，具备了直接为后续毒理研究、临床试验提供足量药物的能力，也为未来更大规模化生产奠定了坚实的技术基础。这种效率与质量的双重提升，使得原本预估需要4个多月的项目工期，被大幅缩短至仅10周。

当项目团队将高质量的产物交付到客户手中时，客户的项目负责人难掩兴奋，高度赞赏道：“你们对光化学工艺的掌握和应用令人印象深刻，新的技术为我们打开了路线优化的大门，不仅提高了产量，也让规模放大成为可能。”

如今，这家客户仍有多个后续项目与药明康德持续合作。

图片来源：123RF

这不仅是药明康德光化学平台一次高质量的服务交付，更是公司“让天下没有难做的药，难治的病”这一愿景在微观层面的生动注脚。这一成功的赋能案例，不仅彰显了药明康德在光化学领域的技术深度，更是公司全面化学能力的坚实印证，是公司CRDMO全球赋能平台在创新浪潮中的一个典型缩影。

回首二十余载，药明康德构建的一体化、端到端CRDMO赋能平台，早已超越了单纯的技术叠加。公司将光化学、电化学、流动化学、酶催化等一系列创新技术融会贯通，以更好地赋能全球合作伙伴。因为，每一次分子的合成，背后都是满怀期待的科学家和客户，以及等待救治的患者。正是这份敬畏与担当，驱动公司支持全球数千家合作伙伴破解研发挑战，加速新药从分子走向临床的过程，让创新疗法突破瓶颈，推动更多新药、好药早日问世。

Light and Flow: How WuXi AppTec Bridges the Gap in Novel Drug Chemical Synthesis

In the journey of new drug development, success or failure often hinges on the efficient synthesis of a single, critical chemical intermediate—far more than on grand narratives. Among WuXi AppTec’s many customers, numerous significant collaborations begin at what may seem like a minor but is in fact a pivotal point in the chemical process.

The story starts with a challenging molecular scaffold.

A company was advancing a highly promising molecule when it hit a critical roadblock. The project urgently required the construction of a complex and precise three-dimensional molecular scaffold. This scaffold was the “heart” of the drug molecule; its shape and spatial structure had to be flawless. Therefore, successfully constructing this core scaffold with correct stereo configuration was the only way to build a biologically active complex molecule, ultimately advancing it toward clinical trials and the potential to save lives.

However, the team faced a bottleneck inherent to traditional batch processing.

In traditional batch processing, all raw materials are sequentially added to a reaction vessel, stirred, and reacted under set temperature and pressure conditions. Once the reaction is complete, the product is isolated and purified.For this project, the conventional synthetic route would have required five reaction steps, resulting in low efficiency. Moreover, only about half of the final product possessed the required stereo configuration, and the overall yield was low.

An even greater challenge was the significant gap between gram-scale laboratory exploration and kilogram-scale production using traditional batch methods. This scaling-up process is not a simple matter of multiplying the recipe by a factor of 1000. When a process is scaled up, the physical environment of the reaction system changes. Many reactions that work smoothly in a flask may face decreased efficiency or even fail when transferred to a large reactor. Overcoming these challenges would require substantial additional time and resources to re-optimize the process conditions.

Faced with this challenge, the company immediately contacted WuXi AppTec’s Research Chemistry Services (RCS) team. This trust was not built overnight. It has been accumulated over more than a decade through multiple collaborative projects, earned through consistent delivery of professional and efficient services.

Upon receiving the task, the RCS team quickly pulled together experts from multiple sites—kicking off a race against time to tackle the technical challenge.

How could they solve the intertwined problems of low yield, poor cis-trans selectivity, and the difficulty of scaling up the batch process? The team’s focus turned to photochemistry.

Photochemistry uses light energy of a specific wavelength as a “precision chisel,” replacing traditional thermal energy or chemical reagents to precisely break or reform chemical bonds, efficiently constructing the target molecule.While this might sound complex, photochemistry is not far from our daily lives. For example, colored clothes left to dry on a balcony slowly fade over time because the dye molecules undergo photochemical reactions under sunlight. Similarly, when a vintage film camera shutter clicks, the photosensitive material on the film absorbs light and undergoes a chemical change, capturing the image—a classic application of photochemistry. However, applying photochemistry in an industrial setting demands highly specialized equipment and expertise. It requires the light energy to penetrate the reaction system uniformly and stably, a feat nearly impossible in traditional reaction vessels.

To address this, the project team implemented a powerful combination of technologies.

The first was High-Throughput Experimentation (HTE). If batch processing is like trying keys one by one in the dark, HTE is like activating hundreds of miniature “smart keys” simultaneously. It allows hundreds of reaction conditions—varying the light wavelength, trying a new catalyst, adjusting the concentration—to be tested in parallel within a very short time. What used to take weeks or even months of exploration could now be compressed into days, enabling the team to rapidly lock in a critical “formula.”

But finding the formula was only half the battle. The key was to make it run stably, efficiently, and in a scalable manner. This is where flow chemistry came into play.

Imagine, instead of having the raw materials confined in a reactor with uneven light exposure, they were continuously pumped like an intravenous drip through a narrow tube coiled into a transparent “light tunnel.” As the reactants flowed at a constant rate, they received uniform illumination from the outside of the tube wall, truly achieving “reaction on the go.”

Within this precisely engineered “light tunnel,” the light exposure was consistent and stable, and the reaction pathway was precisely controlled.The original complex process requiring five steps, multiple batch additions, and multiple separations and transfers was streamlined like an assembly line, completed in continuous flow in one step.

The results were remarkable: excellent product yield, exceptionally high cis-selectivity, andprecise preparation of over 100 grams in just nine hours. This demonstrated that the process had successfully crossed the laboratory research stage, enabling the possibility to directly supply sufficient quantity of the drug candidate for subsequent toxicology studies and clinical trials, and laying a solid technical foundation for future large-scale production.This dual improvement in efficiency and quality shortened the project timeline significantly, from an estimated over four months to just ten weeks.

When the project team delivered the high-quality product to the client, the client’s project lead couldn’t hide their excitement. "The photochemical process had opened the door to route optimization for us, not only increasing yield but also making it possible to scale-up."

Since then, this client has continued to collaborate with WuXi AppTec on multiple subsequent projects.

Image source: 123RF

This case represents more than just a high-quality service delivery by WuXi AppTec’s photochemistry platform; it is a tangible microcosm of the company’s vision: “Every drug can be made, and every disease can be treated.” This successful enabling story not only highlights WuXi AppTec’s technical depth in the field of photochemistry but also stands as a solid testament to its comprehensive chemistry capabilities, serving as a quintessential example of its global CRDMO enabling platform in action amidst a wave of innovation.

Looking back over more than two decades, WuXi AppTec’s integrated, end-to-end CRDMO enabling platform has gone beyond a mere collection of technologies. The company has integrated and mastered a suite of innovative technologies—including photochemistry, electrochemistry, flow chemistry, enzymatic catalysis, and beyond—to better enable its global partners. Behind every synthesis of a molecule, what we see are scientists and clients full of anticipation, as well as patients waiting for treatment. It is this sense of respect and responsibility that drives the company to support thousands of customers worldwide in tackling R&D challenges, accelerating the journey of new drugs from molecule to clinical, breaking through bottlenecks in innovative therapies, and helping bring more new and better medicines to patients faster.

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。