“以光為刃”，當傳統工藝無解，藥明康德如何將新藥化學合成的鴻溝化為坦途？

在新藥研發道路上，有時候決定成敗的往往不是宏大的敘事，而是一次關鍵化學中間體的高效合成。這類中間體如同精密的齒輪，其結構的細微偏差，都可能導致后續進程的停滯。在藥明康德的眾多客戶里，許多重要合作常常始于一個看似微小卻至關重要的化學工藝節點。

故事要從一個棘手的分子骨架說起。

某公司在推進一個極具潛力的分子項目時，被一個關鍵的“路障”卡住了。項目急需構建一個復雜而精確的三維分子骨架。這個骨架，是整個藥物分子的“心臟”，它的形狀、空間結構都必須分毫不差。因此，只有成功構建出正確立體構型的核心骨架，才能構建出具有生物活性的復雜分子，進而有望推進臨床，拯救生命。

然而，擺在他們面前的，是行業內傳統分批工藝的“瓶頸”。

傳統分批工藝生產模式是將所有原料按順序投入反應容器中，在設定好的溫度、壓力下攪拌、反應。待反應結束，再進行分離提純，得到產物。在這個項目中，如果采用傳統合成路線，需經過5步反應，效率較低。而且，最終得到的產物里，只有一半是符合要求的立體構型，整體收率也不高。

更為棘手的是，傳統分批工藝從實驗室的克級探索放大到千克級生產時，橫亙著一條難以逾越的“鴻溝”。這不是簡單地把原料配方乘以1000就能解決的。規模放大后，反應體系的物理環境會發生變化，許多在燒瓶中運行良好的反應，一旦進入大釜，就可能面臨效率下降、甚至失敗風險。要解決這些挑戰，就需要耗費更多時間和資源來重新摸索工藝條件。

面對難題，該公司第一時間聯系上藥明康德研發化學服務部（Research Chemistry Services，RCS）。這種信任并非憑空而來。它是十多年間，在多個合作項目里，由藥明康德一次次專業、高效的服務交付，一點一滴積累起來的。

接到任務后，藥明康德RCS團隊迅速組建了由多個研發和生產基地專家構成的項目團隊，一場與時間賽跑的技術攻堅就此拉開序幕。

如何破解分批工藝收率低、順反選擇性差，以及難以放大的“死結”？團隊的目光投向了光化學工藝技術。

所謂光化學工藝，是利用特定波長的光能作為“精確的刻刀”，代替傳統的熱能或化學試劑，來精準切斷或重組化學鍵，從而高效構建目標分子。這聽起來似乎有些深奧，但光化學離我們的生活并不遙遠，就像晾在陽臺的彩色衣物，時間久了會慢慢褪色，其實是染料分子在太陽光的照射下發生了光化學反應；或是老式膠片相機按下快門的瞬間，膠片上的感光材料會因吸收光線而發生化學變化，最終定格下影像，也是光化學的典型應用。然而，當光化學技術應用于工業場景時，對設備、對人員的專業素養要求極高，它需要光能均勻、穩定地穿透反應體系，這在傳統的反應釜中幾乎無法實現。

為此，項目團隊引入了一套高效的技術“組合拳”。

首先登場的是高通量實驗（HTE），如果說分批工藝是在黑暗中一把把地嘗試“鑰匙”，那HTE就像同時啟動了上百個微型“智能鑰匙”，它能在極短時間內并行測試數百種反應條件——換一種光波長、試一種新催化劑、調一下濃度——過去需要幾周甚至幾個月的摸索，現在可將項目初期的摸索時間壓縮到以天計，從而迅速鎖定關鍵“配方”。

但僅找到“配方”還不夠，關鍵是如何讓它穩定、高效地運轉起來，并適用于規模放大。于是，流動化學技術便登場亮相。

想象一下，不再讓原料悶在反應容器里“不均勻光照”，而是將它們像輸液一樣，通過細細的管道持續泵入一個盤成線圈的透明“光隧道”。反應物一邊勻速流動，一邊接受管道外壁均勻的光照，真正實現了“邊走邊反應”。

在這條精心設計的“光隧道”上，光照條件均勻穩定，反應路徑精準可控。原本需要5步、多批次投放、多次分離、轉移的復雜過程，如今像一條流水線，僅需1步連貫完成。

結果是令人驚喜的——產物收率良好，順式選擇性極高。更難得的是，項目團隊僅用了9個小時，就完成了100克以上規模的精準制備，這意味著該工藝路線已成功跨越實驗室研究階段，具備了直接為后續毒理研究、臨床試驗提供足量藥物的能力，也為未來更大規模化生產奠定了堅實的技術基礎。這種效率與質量的雙重提升，使得原本預估需要4個多月的項目工期，被大幅縮短至僅10周。

當項目團隊將高質量的產物交付到客戶手中時，客戶的項目負責人難掩興奮，高度贊賞道：“你們對光化學工藝的掌握和應用令人印象深刻，新的技術為我們打開了路線優化的大門，不僅提高了產量，也讓規模放大成為可能。”

如今，這家客戶仍有多個后續項目與藥明康德持續合作。

圖片來源：123RF

這不僅是藥明康德光化學平臺一次高質量的服務交付，更是公司“讓天下沒有難做的藥，難治的病”這一愿景在微觀層面的生動注腳。這一成功的賦能案例，不僅彰顯了藥明康德在光化學領域的技術深度，更是公司全面化學能力的堅實印證，是公司CRDMO全球賦能平臺在創新浪潮中的一個典型縮影。

回首二十余載，藥明康德構建的一體化、端到端CRDMO賦能平臺，早已超越了單純的技術疊加。公司將光化學、電化學、流動化學、酶催化等一系列創新技術融會貫通，以更好地賦能全球合作伙伴。因為，每一次分子的合成，背后都是滿懷期待的科學家和客戶，以及等待救治的患者。正是這份敬畏與擔當，驅動公司支持全球數千家合作伙伴破解研發挑戰，加速新藥從分子走向臨床的過程，讓創新療法突破瓶頸，推動更多新藥、好藥早日問世。

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.

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