從7步到1步：當傳統(tǒng)合成“此路不通”，藥明康德如何用光化學打開新門

在藥明康德的一棟實驗樓里，一群年輕人正圍著光反應設備做最后的調(diào)試。窗外是料峭春寒，窗內(nèi)，一盞特制的光源照亮了靜靜放置的反應器。

此時，一家公司正在焦急地等待消息。他們急需合成一種關(guān)鍵藥物中間體，卻卡在了關(guān)鍵反應步驟上，試遍了常規(guī)方案卻始終無法突破。他們將希望托付給了藥明康德。

等待終于迎來了回響。項目團隊通過運用光化學反應和其他創(chuàng)新技術(shù)的“組合拳”，僅用9個小時就完成了100克以上規(guī)模的精準制備，為后續(xù)研究奠定基礎。最終，原本預估需要4個多月的項目工期，被大幅縮短至僅10周。

當高質(zhì)量產(chǎn)物交付到客戶手中時，客戶項目負責人難掩興奮：“你們對光化學工藝的掌握和應用令人印象深刻，這項新技術(shù)為我們打開了實驗優(yōu)化的大門，不僅提高了產(chǎn)量，也讓規(guī)模放大成為可能。”

如今，這家客戶仍有多個后續(xù)項目選擇與藥明康德持續(xù)合作。

圖片來源：123RF

這個案例，是藥明康德二十多年來在一體化CRDMO賦能平臺上，憑借全面的化學技術(shù)和能力持續(xù)賦能新藥研發(fā)，贏得客戶信任的一個縮影。

對此，藥明康德研發(fā)化學服務部（Research Chemistry Services，RCS）光化學技術(shù)平臺負責人指出：“光化學的潛力讓我們看到，化學的邊界仍可被不斷拓展。在藥明康德，類似的賦能故事每天都在發(fā)生。依托公司全面、系統(tǒng)的化學技術(shù)與能力，我們能夠更有力地支持客戶攻克研發(fā)和生產(chǎn)難題，將前沿方法轉(zhuǎn)化為驅(qū)動新藥研發(fā)的切實動力，最終助力更多客戶的創(chuàng)新療法更快惠及患者。”

前瞻布局，擁抱光化學浪潮

二十一世紀初，合成化學家們開始嘗試駕馭一種溫和卻強大的能量——可見光。

2008年，普林斯頓大學David MacMillan教授團隊在《科學》雜志發(fā)表論文，證明可見光可以溫和地撬開化學鍵，生成以往難以駕馭的自由基。幾乎同一時段，威斯康星大學麥迪遜分校Tehshik Yoon教授團隊和密西根大學Corey Stephenson教授團隊也發(fā)現(xiàn)光催化在更多反應類型中的應用潛力。這些背靠背的研究共同為現(xiàn)代光氧化還原催化領(lǐng)域奠定了重要基礎。兩年后，MacMillan教授團隊又將光催化與手性催化結(jié)合，實現(xiàn)了對產(chǎn)物三維結(jié)構(gòu)的精準控制。

至此，合成化學家的工具箱里，從此多了一把名為“光”的鑰匙。

這把鑰匙很快打開了新世界的大門。2014年，MacMillan教授與同校的Abigail Doyle教授合作，創(chuàng)造性地將光催化與鎳催化結(jié)合，攻克了傳統(tǒng)方法難以高效地構(gòu)建C(sp3)-C(sp2)鍵難題。這一突破讓原本需要多步反應轉(zhuǎn)化才能使用的羧酸，可直接用于構(gòu)建復雜的藥物分子骨架，合成路徑大幅縮短，迅速引發(fā)產(chǎn)業(yè)界關(guān)注。

彼時，光氧化還原催化技術(shù)在學術(shù)界發(fā)展如火如荼，但在工業(yè)界仍是“燒杯里的魔術(shù)”——現(xiàn)象令人驚嘆，機理卻難以捉摸，更遑論規(guī)模化生產(chǎn)。

作為全球一體化的CRDMO賦能平臺，藥明康德敏銳意識到這一創(chuàng)新技術(shù)在新藥研發(fā)領(lǐng)域的應用潛力，并開始提前布局。早在2008年，藥明康德就曾邀請MacMillan教授前往公司進行專題講座。

2016年，藥明康德在做足準備后正式搭建光催化條件篩選平臺，快速組建核心技術(shù)團隊，并面向公司內(nèi)部提供條件篩選服務。

萬事開頭難。十年前，在整個制藥產(chǎn)業(yè)，通過光催化合成分子都還處于起步階段。“那時市面上不像現(xiàn)在有這么多光波長、光催化試劑，光反應器更是寥寥無幾。第一次嘗試用光催化反應解決合成路線設計時，挑戰(zhàn)巨大。但化學團隊勇敢去嘗試。”該負責人回憶道，“起步時缺少適用的工業(yè)級光反應器，更別提篩選現(xiàn)成的光催化劑，一切幾乎從零開始。”

這支年輕的團隊并未被困難嚇退。沒有成熟光反應器，就找到工廠定制；沒有路徑，就通過海量實驗篩選催化劑、配體與反應參數(shù)……

功夫不負有心人。平臺成立的第一年，團隊就在一個項目中利用光催化反應，將C(sp2)-C(sp3)鹵鹵偶聯(lián)原始路線從4步縮短至2步，總收率提高8倍以上。而且，與傳統(tǒng)合成路線相比，光化學反應不僅避免了使用敏感的金屬試劑，也規(guī)避了存在安全風險的還原步驟。

隨著技術(shù)、方法和經(jīng)驗的積累，團隊在光催化平臺的應用上越發(fā)游刃有余。平臺成立的第二年，客戶的一個化合物項目需要在雜環(huán)鹵代物上引入烷基基團，而烷基羧酸底物化學性質(zhì)比較鈍化，不易發(fā)生脫羧反應。藥明康德團隊大膽嘗試了光化學C(sp3)-C(sp2)脫羧偶聯(lián)策略，通過對30多種鎳配體的篩選，成功找到光催化方法。最終，原本7步的合成路線被縮短為1步，項目周期從預計至少2周大幅縮短至4天。

“這是在光催化技術(shù)發(fā)展初期，也是在平臺發(fā)展初期，非常出色的一次設計和篩選。”該負責人自豪地說。

2019年，當MacMillan教授再次受邀來到藥明康德講座的時候，藥明康德在光化學應用領(lǐng)域的進度令他感到振奮——不到四年的時間里，藥明康德化學團隊已累計完成上萬個光化學反應。

迄今為止，公司光化學平臺已成功驗證并實施了數(shù)十種光化學反應類型。常見的C(sp2)-C(sp3)鹵鹵偶聯(lián)、C(sp3)-C(sp2)脫羧偶聯(lián)等反應類型，都已經(jīng)是藥明康德光化學平臺的成熟服務模塊之一。

突破“放大”之困：從克級到公斤級的跨越

在光化學工藝領(lǐng)域流傳著這樣一句話：“在燒瓶里讓一個光催化反應完美進行，是藝術(shù)；而讓它在工廠里以公斤級規(guī)模安全、經(jīng)濟地運行，完全是另一門工程學”。

自光催化可在高通量模式下運行后，光催化從“冷門技術(shù)”一躍成為合成化學家的“常規(guī)工具”。然而，規(guī)模化放大問題始終懸而未決。這既是光化學技術(shù)產(chǎn)業(yè)化的必經(jīng)之路，也是一道嚴峻的工程挑戰(zhàn)。

緊跟行業(yè)發(fā)展趨勢，藥明康德光化學團隊在經(jīng)歷了反應類型開發(fā)，反應參數(shù)探索，克級化合物庫合成探索之后，也開始著力攻克這一行業(yè)痛點。

憑借藥明康德在化學領(lǐng)域的全面能力和豐富經(jīng)驗，光化學團隊與流體化學團隊攜手開發(fā)流體放大方法。他們通過將高通量實驗（HTE）與流動化學（Flow）工藝深度結(jié)合，持續(xù)探索解決方案。

“HTE能在極短時間內(nèi)測試數(shù)百種反應條件，快速鎖定最佳‘配方’；Flow則通過連續(xù)化生產(chǎn)，穩(wěn)定批量地產(chǎn)出目標產(chǎn)物。”該負責人這樣比喻兩者的協(xié)作，“前者如同在家研發(fā)新菜譜，探索最佳組合；后者則像中央廚房，在百克級至公斤級的規(guī)模上驗證與固化工藝，最終為客戶交付一套完整、可放大的解決方案。”

通過“HTE+Flow”的深度協(xié)同，藥明康德的化學平臺每年都在穩(wěn)健拓展著可放大的流動光化學反應工藝類型，支持客戶解決從百克級至公斤級以上的放大反應需求，涵蓋條件篩選、參數(shù)影響探索、操作步驟穩(wěn)定以及后續(xù)流體放大等全流程。

目前公司光化學平臺已與流體化學團隊聯(lián)合開發(fā)了數(shù)十種流動光化學反應類型，并總結(jié)了多種放大方法，包括需要分步操作的難度較大的脫氧偶聯(lián)反應，涉及產(chǎn)氣的環(huán)丙烷化，涉及需要避免使用危險試劑的肼合成等。

“光催化對于特殊類型分子的合成不可或缺，甚至是不二之選。”該負責人對光催化合成藥物分子的未來潛力充滿信心。

從最初那間實驗室的“一束光”，到如今覆蓋數(shù)十種反應類型的光化學一體化平臺，藥明康德的光催化平臺走過了一條從0到1、從實驗室走向產(chǎn)業(yè)化的道路。

當下，“這束光”正以更成熟的姿態(tài)，照亮著更多復雜分子的合成之路。

以近年來新藥開發(fā)熱點領(lǐng)域——靶向蛋白降解劑（TPD）為例，這類分子結(jié)構(gòu)復雜且敏感，給化學合成和放大帶來諸多挑戰(zhàn)。而光催化技術(shù)憑借溫和、快速、無需加熱等特點，正在為這類復雜分子的合成提供新路徑。“目前，我們光化學平臺已經(jīng)成為合成TPD等復雜分子的關(guān)鍵技術(shù)手段之一，我們已能夠系統(tǒng)實現(xiàn)多種關(guān)鍵的TPD光催化反應類型。”該負責人表示。

“隨著光催化技術(shù)日益成熟，可用的反應類型更加豐富，團隊對何時采用光催化也愈發(fā)得心應手。”該負責人進一步補充道，“光催化為逆合成分析提供了更多可行的切斷方式，并展現(xiàn)了更豐富的化學鍵斷裂模式。它不僅使合成路線更簡潔高效，還能實現(xiàn)傳統(tǒng)方法難以完成的轉(zhuǎn)化，如脫羧偶聯(lián)、脫硼偶聯(lián)、NHP酯偶聯(lián)、含F(xiàn)官能團、以及近年來熱門的BCP環(huán)的引入和后續(xù)官能化等。在這些轉(zhuǎn)化中，光催化都是一種更高效、成功率更高的合成方法。”

持續(xù)精進，賦能創(chuàng)新未來

藥明康德光化學平臺建設和賦能能力的不斷完善，是公司全面化學能力的重要體現(xiàn)，也是公司CRDMO全球賦能平臺在創(chuàng)新浪潮中的一個縮影。

二十多年來，藥明康德打造的全球一體化、端到端的CRDMO賦能平臺，已構(gòu)建起包括光化學、電化學、流動化學、酶催化等等在內(nèi)的全方位化學技術(shù)能力。這些不斷精進的全面化學能力，成為高質(zhì)量、高效率交付的重要支撐，贏得了全球眾多客戶的長期信任。

根據(jù)2025年藥明康德投資者開放日上披露的數(shù)據(jù)，其研發(fā)化學服務部已經(jīng)與超過980個客戶合作5年以上，與280個客戶合作10年以上，與10多家客戶合作超過20年。這些數(shù)字，是客戶長期信任的見證，更是藥明康德對“賦能全球創(chuàng)新”這一使命堅定踐行的回響。

從最初那間實驗室里點亮的第一盞燈，到如今覆蓋數(shù)十種反應類型、并與各類創(chuàng)新化學技術(shù)融會貫通，藥明康德光化學平臺的進化之路，折射出的不僅是技術(shù)邊界的拓展，更是公司二十余年來“跟隨科學、跟隨客戶”的堅守——將每一個看似微小的反應，淬煉為可被信賴的解決方案。

當全球越來越多的復雜分子在光照下高效合成，當傳統(tǒng)方法難以實現(xiàn)的化學空間被成功解鎖，我們看到的不僅是技術(shù)突破，更是藥明康德對客戶的堅定承諾——用更綠色、更高效的化學，點亮創(chuàng)新的希望。

From Bottleneck to Breakthrough: How WuXi AppTec Translates Photochemistry into Real-World Drug Development Impact

In one of WuXi AppTec’s laboratory buildings, a group of young researchers gathered around a photoreactor, making final adjustments. Outside, a lingering spring chill hung in the air; inside, a custom-built light source illuminated a reactor vessel sitting quietly.

At that moment, a client company was anxiously awaiting news. They needed to synthesize a key pharmaceutical intermediate but had hit a wall at a critical reaction step. Having exhausted all conventional methods without success, they turned to WuXi AppTec.

The wait finally paid off.The project team, leveraging a combination of photochemical reactions and other technologies, completed a synthesis at a scale exceeding 100 grams in just nine hours, laying the groundwork for subsequent research. Ultimately,the overall project timeline, initially estimated at over four months, was drastically shortened to just ten weeks.

When the high-quality product was delivered to the client, their project lead excitedly commented: “Your teams' use of photochemistry including flow chemistry has really opened the doors to new optimization and has increased the yields on many projects as well as making many scale ups feasible.”

Today, the client continues to partner with WuXi AppTec on several follow-up projects.

Image source: 123RF

This case serves as a microcosm of how WuXi AppTec, over more than two decades, has leveraged its comprehensive chemistry capabilities within its integrated CRDMO platform to enable R&D and manufacturing and earn customer trust.

Commenting on this, the head of the Photochemistry Technology Platform at WuXi AppTec’s Research Chemistry Services team noted: “The potential of photochemistry shows us that the boundaries of chemistry can still be pushed further. At WuXi AppTec, similar enabling stories unfold every day. Leveraging the company's comprehensive and systematic chemical technologies and capabilities, we can more effectively support clients in overcoming R&D and manufacturing challenges, and ultimately help more customers to bring innovative therapies to patients faster.”

Future-Oriented Strategy: Riding the Wave of Photochemistry

In the early 2000s, synthetic chemists began exploring the potential of a mild yet powerful energy source: visible light.

In 2008, Professor David MacMillan’s team at Princeton University published a paper in Science demonstrating that visible light could gently pry open chemical bonds to generate previously difficult-to-handle radicals. Around the same time, research groups led by Professor Tehshik Yoon at the University of Wisconsin-Madison and Professor Corey Stephenson at the University of Michigan also discovered the potential of photocatalysis in various reaction types.These parallel studies collectively laid the essential groundwork for modern photoredox catalysis.Two years later, Professor MacMillan's team combined photocatalysis with asymmetric catalysis, achieving precise three-dimensional control over product structure.

With that, synthetic chemists gained a new tool: light.

This key swiftly unlocked a new world. In 2014, Professor MacMillan collaborated with Professor Abigail Doyle, also at Princeton, to creatively merge photocatalysis and nickel catalysis, overcoming the challenge of efficiently constructing C(sp3)-C(sp2) bonds—a feat difficult with traditional methods. This breakthrough enabled carboxylic acids, which previously required multi-step transformations to be used, to directly build complex drug molecular frameworks, significantly shortening synthetic routes and quickly capturing the attention of the industry.

At that time, photoredox catalysis was flourishing in academia but remained a “test-tube magic trick” in industry—impressive to observe but difficult to control, let alone scale up for production.

As a global, integrated CRDMO platform, WuXi AppTec keenly recognized the potential of this innovative technology for drug discovery and began its strategic investments.

In 2016, after thorough preparation, WuXi AppTec formally established a photocatalysis condition screening platform, quickly assembled a core technical team and began to offer condition screening services internally.

The initial phase was challenging. A decade ago, the use of photocatalysis for molecular synthesis was still nascent across the pharmaceutical industry. “At that time, the market didn’t have the range of light wavelengths and photocatalytic reagents that are available today, and photoreactors were extremely rare. The first attempt to use a photocatalytic reaction to solve a synthetic route design was immensely challenging. But our team was courageous in trying,” the platform head recalled. “At the start, we lacked suitable industrial-grade photoreactors, let alone ready-made photocatalytic catalysts to screen. It was like starting from scratch.”

This young team remained determined. In the absence of commercially available photoreactors, they collaborated with manufacturing partners to custom-build their own. Even without a defined pathway, they examined catalysts, ligands, and reaction parameters through extensive experimental research.

Their perseverance paid off. In the platform's first year, the team applied photocatalysis to a project involving C(sp2)-C(sp3) cross-coupling process, shortening the original four-step route to just two steps and increasing the overall yield by over eightfold.Furthermore, compared to traditional synthetic routes, the photochemical approach avoided the use of sensitive reagents and eliminated a reduction step that posed safety risks.

As expertise in technology, methods, and experience grew, the team became increasingly adept at applying the photocatalytic platform. In its second year, a client required the introduction of alkyl groups onto heterocyclic halides for a compound project. However, the alkyl carboxylic acid substrates were relatively unreactive and displayed resistance to decarboxylation. The RCS team applied a photochemical C(sp3)-C(sp2) decarboxylative coupling strategy. After screening over 30 nickel ligands, they successfully identified a photocatalytic method. The result: the original seven-step synthetic route was condensed into a single step, and the project timeline, initially projected to be at least two weeks, was shortened to just four days.

“This example illustrated the potential of reaction design and screening in the early stage of photocatalytic technology development.” The platform head stated.

In 2019, when Professor MacMillan was invited to give a lecture at WuXi AppTec, he was impressed by the company’s progress in photochemical applications—in less than four years, WuXi AppTec had successfully carried out more than 10,000 photochemical reactions.

To date, WuXi AppTec's photochemistry platform has successfully validated and implemented dozens of photochemical reaction types. Now, routine reactions such as C(sp2)-C(sp3) cross-coupling and C(sp3)-C(sp2) decarboxylative coupling are mature service modules within WuXi AppTec's photochemistry platform.

Overcoming the Scale-Up Challenge: Bridging the Gap from Grams to Kilograms

A well-known saying in the field of photochemical process development goes:“Getting a photocatalytic reaction to work perfectly in a flask is an art; making it run safely and economically at the kilogram scale in a plant is an entirely different engineering discipline.”

As photocatalysis became operable in high-throughput modes, it rapidly evolved from a specialized technique into a conventional tool for synthetic chemists. However, the challenge of scaling up remained unresolved. This issue represents not only a necessary step for the industrialization of photochemistry but also a significant engineering hurdle.

Following industry trends, WuXi AppTec’s photochemistry team, after focusing on reaction type development, parameter exploration, and gram-scale synthesis for compound libraries, turned its attention to tackling this industry-wide pain point.

Leveraging WuXi AppTec's comprehensive capabilities and extensive experience in chemistry,the photochemistry team collaborated with the flow chemistry team to develop methods for scaling up flow photochemistry. They continuously explored solutions by deeply integrating high-throughput experimentation (HTE) with flow chemistry.

“HTE can test hundreds of reaction conditions in a very short time, quickly identifying the optimal formulation; flow chemistry, through continuous processing, enables stable, batch production of the target compound,” the platform head explained, drawing an analogy. “It’s like developing a new recipe at home to find the best combination, and then using a central kitchen to validate and solidify the process at a pilot scale from hundreds of grams to kilograms, ultimately delivering a complete, scalable solution to the client.”

Leveraging the deep synergy of HTE and flow chemistry, WuXi AppTec's chemistry platform widens the scope of scalable flow photochemical processes year by year. It supports clients in addressing scale-up needs from hundreds of grams to over a kilogram, covering the entire workflow from condition screening and parameter impact studies to process stabilization and subsequent flow scale-up.

At present, the company’s photochemistry team has been working in conjunction with the flow chemistry team to develop dozens of flow photochemical reaction types. Additionally, they established a variety of scale-up methods. These include challenging deoxygenative coupling reactions requiring meticulous steps, as well as gas-generating cyclopropanations and hydrazine synthesis involving hazardous reagents.

“For certain types of molecules, photocatalysis offers a synthetic route that may be more efficient or, in some cases, not readily achievable with conventional methods,”the platform head remarked, expressing strong confidence in the future potential of photocatalytic synthesis for pharmaceutical molecules.

From the initial “beam of light” in that early laboratory to today’s integrated photocatalysis platform covering dozens of reaction types, WuXi AppTec’s photocatalytic capabilities have traversed a path from zero to one, from laboratory research to industrial application.

Today, photocatalysis is increasingly applied to the synthesis of complex molecules with greater maturity.

Consider targeted protein degraders (TPDs), a recent focus in drug development. These molecules often feature complex and sensitive structures, posing significant challenges for chemical synthesis and scale-up. Photocatalysis, with its mild, rapid, and heating-free characteristics, is offering new pathways for synthesizing such complex molecules.“Currently, our photochemistry platform has become one of the key technological approaches for synthesizing complex molecules like TPDs. We can now systematically execute a variety of critical photocatalytic reactions for TPDs,” remarked the platform head.

“As photocatalysis technology continues to evolve, with the diversification of available reaction types, our team has become skilled in determining its effective applications,” further elaborated the platform head. “Photocatalysis allows for feasible disconnection strategies in retrosynthetic analysis and provides the opportunity for a broader array of bond cleavage modes. This technique not only enhances the conciseness and effectiveness of synthesis but also aids in executing transformations that could be challenging or unfeasible using traditional methods. These include decarboxylative coupling, deboronative coupling, NHP ester coupling, the incorporation of fluorinated functional groups, and the recent incorporation of bicyclo[1.1.1]pentane (BCP) rings followed by functionalization. In these transformations, photocatalysis serves as a synthetic method that yields more effective outcomes and achieves a higher success rate.”

Ongoing Enhancement: Enabling Innovative Futures

The evolution of WuXi AppTec's photochemistry platform capabilities reflect the company's comprehensive chemical expertise and serves as a microcosm of its global CRDMO enabling platform amid ongoing waves of innovation.

Over the past two decades, WuXi AppTec has established an integrated, end-to-end CRDMO platform encompassing a wide range of chemistry technologies and capabilities, including photochemistry, electrochemistry, flow chemistry, and enzymatic catalysis. These continuously refined and comprehensive chemical capabilities provide the essential support for high-quality, efficient delivery, earning the long-term trust of numerous clients worldwide.

According to data disclosed at 2025 WuXi AppTec Investor Day,its RCS team has collaborated with over 980 clients for more than five years, with 280 clients for over a decade, and with more than ten clients for over twenty years.These figures stand as a testament to enduring client trust and reflect the fulfillment of WuXi AppTec's mission to “enable global innovation.”

From the first light switched on in that initial laboratory to today's integrated platform encompassing dozens of reaction types with various innovative chemical technologies, the evolution of WuXi AppTec's photochemistry platform mirrors not only the expansion of technological frontiers but also the company’s more than two decades commitment to “following the science, following the customer”—transforming seemingly minor reactions into reliable, trustworthy solutions.

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