從“不反應(yīng)”到“產(chǎn)量超預(yù)期”，藥明康德如何用電化學(xué)解開合成難題？| Bilingual

2025年的一個秋日，藥明康德研發(fā)化學(xué)服務(wù)部（RCS）收到一封客戶的郵件：他們急需設(shè)計并合成有生物活性的目標(biāo)分子，卻卡在了關(guān)鍵中間體環(huán)節(jié)，如果用傳統(tǒng)方法合成如同在“迷宮”中打轉(zhuǎn)，難以推進(jìn)。

基于此前與藥明康德長期合作建立的深度了解與信任，客戶抱著希望前來詢問：“聽你們說過有電化學(xué)技術(shù)平臺，能試試合成這個分子嗎？”

項目團(tuán)隊分析發(fā)現(xiàn)，從這個中間體到最終的目標(biāo)分子生成，還要約19～20步反應(yīng)。根據(jù)每一步的收率推算，該中間體的產(chǎn)量至少需要幾十克，才能撐起后續(xù)的反應(yīng)需求。

幾十克，對于普通分子的合成而言很容易；但在這類復(fù)雜分子的合成道路上，卻如同一座高不可攀的大山。

接到這一需求后，項目團(tuán)隊快速響應(yīng)。好消息是，“山”雖高，卻并不是“無路可走”。在此之前，公司內(nèi)部的電化學(xué)技術(shù)團(tuán)隊已經(jīng)積累了類似分子的合成技術(shù)知識與經(jīng)驗，更有全套的設(shè)備。

但挑戰(zhàn)也同樣尖銳——原來的分子沒有取代基，可客戶需要的中間體多帶了特殊的取代基，反應(yīng)性也因此天差地別。

面對難題，電化學(xué)團(tuán)隊沒有退縮。他們先按圖索驥，用行業(yè)已知方法測試，結(jié)果不出所料，反應(yīng)無法進(jìn)行、未得到目標(biāo)產(chǎn)物。

既然老路走不通，那就自己開辟一條新路。團(tuán)隊一頭扎進(jìn)實驗室，在已有知識基礎(chǔ)上自行探索，發(fā)現(xiàn)不同的反應(yīng)參數(shù)稍有偏差，結(jié)果便大相徑庭。于是，他們一點點調(diào)整電解質(zhì)的當(dāng)量和濃度等參數(shù)，在形形色色的電極中不斷篩選。經(jīng)歷幾天的試錯與推翻后，終于，更佳的反應(yīng)條件浮出水面。

團(tuán)隊科學(xué)家密切配合，僅一周時間，便完成了這個中間體分子的“闖關(guān)突圍”——從幾乎不反應(yīng)，到小試條件篩選、中試產(chǎn)物成功合成、再到幾十克規(guī)模放大產(chǎn)物的交付，以及后處理、分離和檢測工作，一氣呵成。

圖片來源：123RF

這超乎預(yù)料的速度與產(chǎn)量，讓客戶收獲了額外的驚喜。第二周，客戶隨即下達(dá)了第二批幾十克規(guī)模的放大項目，后續(xù)更多批次的放大項目也隨之而來。這一關(guān)鍵中間體滿足要求后，客戶需要的最終目標(biāo)分子也順利合成，并完成了初步測試。

此前，這家“老客戶”已經(jīng)見證了藥明康德的流動化學(xué)、金屬催化、光催化等技術(shù)平臺的能力，但與電化學(xué)“打交道”還是頭一回。這次，他們親眼見證了這柄“新利器”的鋒芒，信賴再添幾分。

從“冷門技術(shù)”到應(yīng)用“風(fēng)口”

在攻克上述難題的過程中，藥明康德電化學(xué)團(tuán)隊所用的技術(shù)全稱為“有機(jī)電化學(xué)合成技術(shù)”，是電化學(xué)學(xué)科的應(yīng)用領(lǐng)域之一。

這項技術(shù)其實起源很早，但在近幾十年的發(fā)展卻一度沉寂。早在19世紀(jì)上半葉，法拉第（Faraday，“電學(xué)之父”）和科爾貝（Kolbe）就點亮了有機(jī)電化學(xué)的星火；20世紀(jì)，馬庫斯（Marcus）的“電子轉(zhuǎn)移理論”進(jìn)一步為其完善了底層原理。然而，受限于電極材料和設(shè)備進(jìn)展緩慢，這一技術(shù)長期坐著“冷板凳”，發(fā)展速度明顯不及光催化和金屬催化。

直到2017年前后，在可持續(xù)發(fā)展、“綠色化學(xué)”理念與新能源浪潮的推動下，電極材料、催化劑與反應(yīng)設(shè)備紛紛換代升級，這一技術(shù)終于在沉寂中抬頭。到2020年，該領(lǐng)域的相關(guān)論文數(shù)量相比2010年已然翻倍。同年，巴蘭（Baran）課題組發(fā)表了一篇重要論文，這相當(dāng)于一份標(biāo)準(zhǔn)化的有機(jī)電化學(xué)合成“用戶操作指南”，點燃了學(xué)術(shù)界的熱情。產(chǎn)業(yè)界也聞風(fēng)而動，2022年的一項調(diào)查顯示，全球17家大型藥企中已有15家在積極應(yīng)用或探索該技術(shù)。

實際上，在風(fēng)口來臨之前，藥明康德已有十余年電化學(xué)技術(shù)應(yīng)用經(jīng)驗，但僅限于Shono氧化這種經(jīng)典反應(yīng)。2022年，基于對行業(yè)趨勢的洞察，藥明康德開始加大對電化學(xué)技術(shù)平臺的投入。

“電化學(xué)不管是對傳統(tǒng)化學(xué)，還是對光化學(xué)等新技術(shù)，都是很好的補充。提早建設(shè)相關(guān)能力，我們就能提早探索它的優(yōu)勢與潛力，當(dāng)未來客戶項目來臨時，我們便能擁有更多可選擇的工具、應(yīng)對更加游刃有余。如果等客戶有了更多需求再建，那就來不及了。”藥明康德RCS電化學(xué)平臺負(fù)責(zé)人的這番話，道出了藥明康德對各類創(chuàng)新技術(shù)應(yīng)用的遠(yuǎn)見和擔(dān)當(dāng)。

冷門利器初顯“鋒芒”，已開發(fā)出幾十余種反應(yīng)類型

2022年，藥明康德RCS團(tuán)隊基于過去積累的經(jīng)驗，很快完成了實驗設(shè)備和流程搭建，引入國際通用的電化學(xué)反應(yīng)器，并建立了自主篩選反應(yīng)參數(shù)的能力，從而更好地為客戶提供條件篩選和放大支持服務(wù)。

在這個過程中，團(tuán)隊開展了大量研發(fā)嘗試，不僅復(fù)現(xiàn)了文獻(xiàn)報道的反應(yīng)，還在未知領(lǐng)域自主探索，豐富電化學(xué)實操經(jīng)驗，以及與其他技術(shù)平臺“打配合”的經(jīng)驗。當(dāng)年之內(nèi)，團(tuán)隊就憑借這一新技術(shù)完成了客戶分子項目的交付。

到了2025年，也就是三年后，電化學(xué)反應(yīng)數(shù)相比初期已呈爆發(fā)式增長。團(tuán)隊漸漸發(fā)現(xiàn)，這柄“新利器”能“切開”一些其他化學(xué)技術(shù)無可奈何的“死結(jié)”：面對當(dāng)下熱門的靶向蛋白降解（TPD）分子合成，在鹵鹵偶聯(lián)反應(yīng)中使出電化學(xué)這招，成功率很高，幾十克規(guī)模的合成不再是難題；對于帶著大位阻的BCP環(huán)NHP酯與芳香鹵代物的棘手反應(yīng)，平臺一年能護(hù)航幾十個此類項目的交付；至于那些位阻型大環(huán)張力NHP酯偶聯(lián)反應(yīng)，電化學(xué)平臺更有“化險為夷”的潛力，一年能“挽救”幾十個采用光催化折戟的項目分子。

有業(yè)內(nèi)人士稱電化學(xué)是“黑科技”，因為它在完成高難度反應(yīng)的同時，過程和用具卻往往十分樸素。比如在一個客戶項目中，藥明康德團(tuán)隊用價廉易得的雙羧酸當(dāng)原料，用成本相對低廉的RVC電極換下傳統(tǒng)的貴金屬鉑電極，通過電化學(xué)技術(shù)脫羧偶聯(lián)構(gòu)建C(sp3)-C(sp3)鍵，高效合成了一種非天然β-氨基酸，將原本需7步的合成路線，“抄近道”縮減至1步，收率更從21%躍升至74%，實現(xiàn)了快速的毫克級制備。

圖片來源：123RF

隨著成功案例的積累，越來越多以電化學(xué)為核心的賦能合作項目紛至沓來。如今，藥明康德電化學(xué)平臺每年能穩(wěn)穩(wěn)交付數(shù)百個分子。藥明康德在多個基地均有電化學(xué)實驗室和人員，已開發(fā)出幾十余種電化學(xué)反應(yīng)類型，單個反應(yīng)可操作規(guī)模從百毫克級別到200克規(guī)模以上都能覆蓋。

以“合成工具箱”，更好地賦能創(chuàng)新

在藥明康德的CRDMO賦能體系中，電化學(xué)與流動化學(xué)、金屬催化、光催化等技術(shù)一起，共同構(gòu)成了一個功能多樣、全面的“合成工具箱”。

以電化學(xué)與光化學(xué)為例：它們均是通過激發(fā)電子流動來實現(xiàn)分子的氧化還原與“移花接木”，但各有專長、互為補充。光化學(xué)發(fā)展更為成熟，可催化反應(yīng)類型更多；電化學(xué)則在某些特定的反應(yīng)中優(yōu)勢獨特：它操作簡便，實驗人員無需準(zhǔn)備苛刻的無水無氧環(huán)境；它條件溫和，能省去繁瑣的基團(tuán)保護(hù)步驟，縮短流程，從而提高收率；且反應(yīng)后雜質(zhì)少，目標(biāo)產(chǎn)物的提純更容易。

在熱門的C(sp2)-C(sp3)和C(sp3)-C(sp3)鍵的構(gòu)建中，光化學(xué)是常用“主力”，電化學(xué)則是有力的“補位”，兩者協(xié)同拓寬了合成的可能性。比如有一些分子，采取常用的光催化方式收率非常低，經(jīng)電化學(xué)嘗試后，收率顯著提升，已經(jīng)足以成功交付用于下一步生物測試。尤其是能為分子帶來高sp3雜化特征的C(sp3)-C(sp3)鍵，近年研究發(fā)現(xiàn)其與藥物后期研究的成功率息息相關(guān)，因此它的高效構(gòu)建也成為行業(yè)致力追求的目標(biāo)，而近年興起的電化學(xué)催化脫羧偶聯(lián)（rAP-Kolbe/dDCC）技術(shù)，正是構(gòu)建這類分子結(jié)構(gòu)的創(chuàng)新方法之一，能“鍛造”出許多在傳統(tǒng)反應(yīng)中難以獲得的高價值模塊結(jié)構(gòu)。

對于大位阻分子，電化學(xué)也可以幫光化學(xué)破局，讓“光照不到的反應(yīng)死角”無處遁形，從而破解大位阻C(sp2)-C(sp3)鹵鹵偶聯(lián)、NHP酯偶聯(lián)，乃至大位阻烷基醚的合成困局。

此外，電化學(xué)還能在這些方面“大顯身手”：在C-N/C-O鍵的構(gòu)建上，電化學(xué)是對金屬催化的補充；面對加壓、危險試劑、氣體等特殊反應(yīng)，電化學(xué)更能以溫和的方式化解風(fēng)險。

據(jù)RCS電化學(xué)平臺負(fù)責(zé)人介紹，面對合成路上的“攔路虎”，團(tuán)隊往往會優(yōu)先拿出成熟的技術(shù)，如果遇到阻礙，再果斷切換電化學(xué)等可能有希望的技術(shù)。而對于已有經(jīng)驗的電化學(xué)優(yōu)勢反應(yīng)，也會同時嘗試多種技術(shù)，最終為客戶提供更豐富的放大選擇。

這種一體化“工具箱”式的協(xié)作，讓越來越多復(fù)雜分子的合成成為可能，并順利邁入后續(xù)階段，推動客戶項目穩(wěn)步向前。尤其對于需要把握關(guān)鍵時間節(jié)點、試錯空間較低的小型生物科技公司這樣的客戶而言，這種全面、穩(wěn)定的能力，可以“挽救”更多傳統(tǒng)方法望而卻步的分子，更好地為客戶的前沿創(chuàng)新的小分子或復(fù)雜分子項目保駕護(hù)航。

圖片來源：123RF

藥明康德電化學(xué)平臺的發(fā)展歷程，是公司全面化學(xué)能力的生動側(cè)寫。正是這些深耕厚植、由專而全的技術(shù)工具，鋪就了公司的一體化CRDMO賦能平臺這片繁茂森林。

如今，藥物分子量越來越大，合成難度越來越高，新型分子由于結(jié)構(gòu)的復(fù)雜性，其分子量、合成難度以及合成步驟更是顯著增長。但對能力全面的一體化CRDMO平臺而言，這意味著更多機(jī)遇。在創(chuàng)新的浪潮中，藥明康德深知，提早布局新能力、精益求精地打磨每一項技術(shù)能力，方能打造出更全面的“工具箱”式的一體化平臺，更好地賦能全球創(chuàng)新。

未來，藥明康德將繼續(xù)跟隨科學(xué)發(fā)展、跟隨客戶需求，跟隨分子進(jìn)程，持續(xù)夯實技術(shù)平臺能力和規(guī)模，助力全球創(chuàng)新者突破新藥研發(fā)瓶頸，加速客戶的更多新療法從實驗室脫穎而出、來到患者身邊。

了解藥明康德研發(fā)化學(xué)服務(wù)部如何賦能藥物研發(fā)，請長按掃描上方二維碼，與藥明康德研發(fā)化學(xué)服務(wù)部聯(lián)系

From “No Reaction” to “Better-Than-Expected Production”: How WuXi AppTec Uses Electrochemistry to Solve Synthetic Bottleneck?

On an autumn day of 2025, WuXi AppTec’s Research Chemistry Services (RCS) received an email from a customer: they needed to design and synthesize a bioactive target molecule but were stuck at a key intermediate step, and using conventional routes was hard to move forward.

Based on years of collaboration and trust, they asked the RCS team, “We heard you have an electrochemistry platform. Could you try to synthesize this molecule?”

The project team traced the synthesis from the intermediate to the target molecule and counted roughly 19–20 additional steps. Based on the expected yields for each step, the intermediate would require at least several tens of grams to sustain downstream work. For many simple syntheses, producing tens of grams is trivial, but for this class of complex molecules, it presents a high level of difficulty.

The team responded quickly. WuXi AppTec’s in-house electrochemistry team had previously accumulated relevant knowledge, experience, and a complete set of equipment. The challenge was significant: the intermediate previously synthesized in-house bore no substituents, whereas the customer’s target intermediate was expected to carry a specific substituent that notably altered reactivity.

The electrochemistry team first followed protocols guided by existing knowledge, but as expected, the reactions failed to produce the desired product. Rather than retreat, they decided to open a new path. Building on prior knowledge, they launched an intensive experimental campaign and found that small deviations in parameters led to much different outcomes. They methodically adjusted parameters including electrolyte equivalents and concentrations, and screened a variety of electrodes. After several days of iterative trial and error, optimized conditions emerged.

Working in close coordination,the electrochemistry team achieved rapid progression within one week: they progressed from virtually no reaction to lab-scale condition screening, succeeded in pilot-scale synthesis, and scaled up to deliver tens of grams of production—followed by downstream work on purification, separation, and analysis—just in one continuous effort. The unexpectedly rapid timeline and production delighted the customer. The following week, the customer placed a second tens-of-grams scale requirement, and further scale-up batches followed. With the key intermediate secured, the final target molecule was successfully synthesized and passed preliminary testing.

Image source: 123RF

Previously, the customer had seen WuXi AppTec’s capabilities in multiple synthetic technologies including flow chemistry, metal catalysis, and photochemistry, but this was their first direct collaboration on electrochemistry. During this project they witnessed the new platform’s effectiveness and gained confidence in the company’s capabilities.

Long Overlooked, a Niche Tool Finds Its Moment

In the process of tackling the above challenge, organic electrochemical synthesis is the applied branch of electrochemistry used by the team.

Although the field traces back to early pioneers—Faraday and Kolbe in the 19th century—and later theoretical advances such as Marcus’s electron-transfer theory, progress was limited by electrode materials and equipment for many decades. As a result, electrochemistry lagged behind photocatalysis and metal catalysis.

Around 2017, driven by sustainability and green-chemistry goals and improvements in electrode materials, catalysts, and reactors, the field began to revive. By 2020, the number of publications in synthetic electrochemistry had doubled compared with 2010. In the same year, Phil S. Baran’s group published an important paper, which served as a “user guide” for organic electrochemical synthesis and fueled the academic community’s enthusiasm for synthetic electrochemistry. Industry responded as well: a 2022 survey found that 15 of 17 large pharmaceutical companies were actively applying or exploring electrochemical methods.

In fact, before this niche tool found its moment, WuXi AppTec had applied electrochemistry in limited contexts—classical Shono oxidation—for over a decade. Based on insights into industry trends, the company increased investment in the electrochemistry platform in 2022.

“Whether for traditional chemistry or for newer methods such as photochemistry, electrochemistry serves as a strong complement. By building related capabilities early, we can begin to explore its advantages and potential in advance; when customer demands arise, we will be better prepared, since we have more tools to choose from. If we wait until customers demand it before we start building, it will place ourselves at a reactive position.” said the head of the electrochemistry platform, whose remarks reveal WuXi AppTec’s strategic vision and sense of responsibility in applying various innovative technologies.

The Niche Tool Began to Show Its Edge: Dozens of Reaction Types Have Been Developed

In 2022, the electrochemistry team quickly established equipment, workflows, including adoption of internationally used electrochemical reactors, and developed an in-house capability for parameter screening, thereby enabling partners in condition screening and scale?up. That year the team carried out extensive research efforts, reproduced literature reactions and explored new transformations, expanded their practical operating experience in electrochemistry and cross-platform collaboration skills. Within that year, the team had delivered multiple client projects by leveraging this new technology.

By 2025—three years later—the number of electrochemical reactions the team handled had grown significantly. The platform exhibited a distinct advantage in complex synthesis challenges that other techniques struggled with. For example, in targeted protein degradation (TPD) molecule synthesis, applying electrochemistry to reductive homocoupling of alkyl and aryl halides produced high success rates and made tens-of-grams syntheses routine. The platform supported dozens of projects annually for tricky reactions between highly sterically hindered BCP-derived NHP esters and aryl halides, and it showed particular promise for coupling reactions of sterically hindered, strained-ring NHP esters, where photocatalysis methods sometimes fail. Each year, it can rescue dozens of project molecules that stalled under photochemistry approaches.

Electrochemistry is noted by industry observers as a highly effective yet easily deployable approach, capable of driving challenging reactions with simple apparatus. Take one customer project, for example,the team used inexpensive and readily available dicarboxylic acids and a relatively lower-cost RVC (reticulated vitreous carbon) electrode instead of costly platinum.Through electrochemical decarboxylative coupling, they built a C(sp3)–C(sp3) bond to synthesize a non-natural β-amino acid efficiently,streamlining the original 7-step synthesis route into just one step, and raising yield from 21% to 74% for rapid milligram-scale preparation.

Image source：123RF

As successful cases accumulated, a growing number of electrochemistry-driven collaborative initiatives are pouring in. Today, the platform reliably delivers hundreds of molecules per year. WuXi AppTec maintains electrochemistry labs and scientists across multiple sites and has developed dozens of electrochemical reaction types. Individual reactions are operable from sub-100 mg scales up to over 200 g.

Leveraging the "Synthesis Toolbox" to Better Enable Innovation

The electrochemistry platform forms part of WuXi AppTec’s CRDMO “synthesis toolbox”, alongside flow chemistry, metal catalysis, and photochemistry. These technologies are complementary, and the “toolbox” approach broadens synthetic options for partners.

For example, electrochemistry and photochemistry both drive electron flow to accomplish oxidation–reduction transformations. The two are highly complementary, while each excels in different niches. Photochemistry is a well-developed area, and offers a wider range of reaction types; electrochemistry, however, has advantages in specific reactions: it is operationally simple (often avoiding rigorous anhydrous or oxygen-free conditions); uses mild conditions that can eliminate group-protecting steps and shorten sequences, thus significantly improving yields; and typically produces fewer impurities, easing purification.

For constructing C(sp2)–C(sp3) and C(sp3)–C(sp3) bonds, photochemistry is often the primary tool while electrochemistry provides powerful support. Some molecules that give low yields with photocatalysis methods show significant yield improvements under electrochemical approaches, enabling successful delivery for downstream biological testing. For example, high-sp3 fragments are increasingly linked to clinical success, so efficient methods for building C(sp3)–C(sp3) bonds are highly demanded; recently developed electrochemical decarboxylative coupling (rAP-Kolbe/dDCC) is one such innovation that accesses valuable modules difficult to obtain conventionally.

Electrochemistry can also supplement photochemistry for sterically hindered systems, resolving “dark” reaction pockets where photochemistry driven methods are ineffective. It aids in challenging cross-electrophile coupling for sterically hindered C(sp2)–C(sp3) bond formation, NHP ester couplings, and synthesis of sterically hindered alkyl ethers. Additionally, electrochemical methods can complement metal catalysis in constructing C–N and C–O bonds, and they offer milder solutions for reactions that would otherwise require pressure, hazardous reagents, or gases.

The electrochemistry platform leader notes that when synthesis encounters a barrier, the team first applies mature methods and then, if needed, decisively switches to electrochemistry or runs multiple approaches in parallel to give customers more scalable options. This “toolbox” integration makes many complex syntheses feasible and helps projects progress to later stages, especially for small biotech customers who must meet tight timelines with limited opportunity for trial and error. For such customers, a comprehensive, reliable capability enables them to rescue molecules that conventional synthesis leaves behind, thus de-risking and better advancing early-stage innovation.

Image source: 123RF

WuXi AppTec’s electrochemistry platform development mirrors the company’s broader chemical capability: methodical, cumulative work that builds an integrated CRDMO enabling platform.

Nowadays, as new modalities grow larger and more complex, synthesis becomes harder and routes lengthen; for a broadly capable integrated end-to-end CRDMO platform, these trends represent an opportunity. WuXi AppTec believes that early investment and continuous refinement of technical capabilities are essential to building a comprehensive integrated “technology toolbox” that enables global innovators.

In the future, WuXi AppTec will continue to align with scientific progress, respond to evolving customer needs, keep pace with advances in molecular complexity, and continuously scale capabilities and infrastructure, to enable global innovators in overcoming new drug development bottlenecks, and support their efforts to bring innovative treatments from the lab to patients.

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