在新藥研發(fā)道路上，有時(shí)候決定成敗的往往不是宏大的敘事，而是一次關(guān)鍵化學(xué)中間體的高效合成。這類中間體如同精密的齒輪，其結(jié)構(gòu)的細(xì)微偏差，都可能導(dǎo)致后續(xù)進(jìn)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(gè)看似微小卻至關(guān)重要的化學(xué)工藝節(jié)點(diǎn)。

故事要從一個(gè)棘手的分子骨架說(shuō)起。

某公司在推進(jìn)一個(gè)極具潛力的分子項(xiàng)目時(shí)，被一個(gè)關(guān)鍵的“路障”卡住了。項(xiàng)目急需構(gòu)建一個(gè)復(fù)雜而精確的三維分子骨架。這個(gè)骨架，是整個(gè)藥物分子的“心臟”，它的形狀、空間結(jié)構(gòu)都必須分毫不差。因此，只有成功構(gòu)建出正確立體構(gòu)型的核心骨架，才能構(gòu)建出具有生物活性的復(fù)雜分子，進(jìn)而有望推進(jìn)臨床，拯救生命。

然而，擺在他們面前的，是行業(yè)內(nèi)傳統(tǒng)分批工藝的“瓶頸”。

傳統(tǒng)分批工藝生產(chǎn)模式是將所有原料按順序投入反應(yīng)容器中，在設(shè)定好的溫度、壓力下攪拌、反應(yīng)。待反應(yīng)結(jié)束，再進(jìn)行分離提純，得到產(chǎn)物。在這個(gè)項(xiàng)目中，如果采用傳統(tǒng)合成路線，需經(jīng)過(guò)5步反應(yīng)，效率較低。而且，最終得到的產(chǎn)物里，只有一半是符合要求的立體構(gòu)型，整體收率也不高。

更為棘手的是，傳統(tǒng)分批工藝從實(shí)驗(yàn)室的克級(jí)探索放大到千克級(jí)生產(chǎn)時(shí)，橫亙著一條難以逾越的“鴻溝”。這不是簡(jiǎn)單地把原料配方乘以1000就能解決的。規(guī)模放大后，反應(yīng)體系的物理環(huán)境會(huì)發(fā)生變化，許多在燒瓶中運(yùn)行良好的反應(yīng)，一旦進(jìn)入大釜，就可能面臨效率下降、甚至失敗風(fēng)險(xiǎn)。要解決這些挑戰(zhàn)，就需要耗費(fèi)更多時(shí)間和資源來(lái)重新摸索工藝條件。

面對(duì)難題，該公司第一時(shí)間聯(lián)系上藥明康德研發(fā)化學(xué)服務(wù)部（Research Chemistry Services，RCS）。這種信任并非憑空而來(lái)。它是十多年間，在多個(gè)合作項(xiàng)目里，由藥明康德一次次專業(yè)、高效的服務(wù)交付，一點(diǎn)一滴積累起來(lái)的。

接到任務(wù)后，藥明康德RCS團(tuán)隊(duì)迅速組建了由多個(gè)研發(fā)和生產(chǎn)基地專家構(gòu)成的項(xiàng)目團(tuán)隊(duì)，一場(chǎng)與時(shí)間賽跑的技術(shù)攻堅(jiān)就此拉開(kāi)序幕。

如何破解分批工藝收率低、順?lè)催x擇性差，以及難以放大的“死結(jié)”？團(tuán)隊(duì)的目光投向了光化學(xué)工藝技術(shù)。

所謂光化學(xué)工藝，是利用特定波長(zhǎng)的光能作為“精確的刻刀”，代替?zhèn)鹘y(tǒng)的熱能或化學(xué)試劑，來(lái)精準(zhǔn)切斷或重組化學(xué)鍵，從而高效構(gòu)建目標(biāo)分子。這聽(tīng)起來(lái)似乎有些深?yuàn)W，但光化學(xué)離我們的生活并不遙遠(yuǎn)，就像晾在陽(yáng)臺(tái)的彩色衣物，時(shí)間久了會(huì)慢慢褪色，其實(shí)是染料分子在太陽(yáng)光的照射下發(fā)生了光化學(xué)反應(yīng)；或是老式膠片相機(jī)按下快門(mén)的瞬間，膠片上的感光材料會(huì)因吸收光線而發(fā)生化學(xué)變化，最終定格下影像，也是光化學(xué)的典型應(yīng)用。然而，當(dāng)光化學(xué)技術(shù)應(yīng)用于工業(yè)場(chǎng)景時(shí)，對(duì)設(shè)備、對(duì)人員的專業(yè)素養(yǎng)要求極高，它需要光能均勻、穩(wěn)定地穿透反應(yīng)體系，這在傳統(tǒng)的反應(yīng)釜中幾乎無(wú)法實(shí)現(xiàn)。

為此，項(xiàng)目團(tuán)隊(duì)引入了一套高效的技術(shù)“組合拳”。

首先登場(chǎng)的是高通量實(shí)驗(yàn)（HTE），如果說(shuō)分批工藝是在黑暗中一把把地嘗試“鑰匙”，那HTE就像同時(shí)啟動(dòng)了上百個(gè)微型“智能鑰匙”，它能在極短時(shí)間內(nèi)并行測(cè)試數(shù)百種反應(yīng)條件——換一種光波長(zhǎng)、試一種新催化劑、調(diào)一下濃度——過(guò)去需要幾周甚至幾個(gè)月的摸索，現(xiàn)在可將項(xiàng)目初期的摸索時(shí)間壓縮到以天計(jì)，從而迅速鎖定關(guān)鍵“配方”。

但僅找到“配方”還不夠，關(guān)鍵是如何讓它穩(wěn)定、高效地運(yùn)轉(zhuǎn)起來(lái)，并適用于規(guī)模放大。于是，流動(dòng)化學(xué)技術(shù)便登場(chǎng)亮相。

想象一下，不再讓原料悶在反應(yīng)容器里“不均勻光照”，而是將它們像輸液一樣，通過(guò)細(xì)細(xì)的管道持續(xù)泵入一個(gè)盤(pán)成線圈的透明“光隧道”。反應(yīng)物一邊勻速流動(dòng)，一邊接受管道外壁均勻的光照，真正實(shí)現(xiàn)了“邊走邊反應(yīng)”。

在這條精心設(shè)計(jì)的“光隧道”上，光照條件均勻穩(wěn)定，反應(yīng)路徑精準(zhǔn)可控。原本需要5步、多批次投放、多次分離、轉(zhuǎn)移的復(fù)雜過(guò)程，如今像一條流水線，僅需1步連貫完成。

結(jié)果是令人驚喜的——產(chǎn)物收率良好，順式選擇性極高。更難得的是，項(xiàng)目團(tuán)隊(duì)僅用了9個(gè)小時(shí)，就完成了100克以上規(guī)模的精準(zhǔn)制備，這意味著該工藝路線已成功跨越實(shí)驗(yàn)室研究階段，具備了直接為后續(xù)毒理研究、臨床試驗(yàn)提供足量藥物的能力，也為未來(lái)更大規(guī)模化生產(chǎn)奠定了堅(jiān)實(shí)的技術(shù)基礎(chǔ)。這種效率與質(zhì)量的雙重提升，使得原本預(yù)估需要4個(gè)多月的項(xiàng)目工期，被大幅縮短至僅10周。

當(dāng)項(xiàng)目團(tuán)隊(duì)將高質(zhì)量的產(chǎn)物交付到客戶手中時(shí)，客戶的項(xiàng)目負(fù)責(zé)人難掩興奮，高度贊賞道：“你們對(duì)光化學(xué)工藝的掌握和應(yīng)用令人印象深刻，新的技術(shù)為我們打開(kāi)了路線優(yōu)化的大門(mén)，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(gè)后續(xù)項(xiàng)目與藥明康德持續(xù)合作。

圖片來(lái)源：123RF

這不僅是藥明康德光化學(xué)平臺(tái)一次高質(zhì)量的服務(wù)交付，更是公司“讓天下沒(méi)有難做的藥，難治的病”這一愿景在微觀層面的生動(dòng)注腳。這一成功的賦能案例，不僅彰顯了藥明康德在光化學(xué)領(lǐng)域的技術(shù)深度，更是公司全面化學(xué)能力的堅(jiān)實(shí)印證，是公司CRDMO全球賦能平臺(tái)在創(chuàng)新浪潮中的一個(gè)典型縮影。

回首二十余載，藥明康德構(gòu)建的一體化、端到端CRDMO賦能平臺(tái)，早已超越了單純的技術(shù)疊加。公司將光化學(xué)、電化學(xué)、流動(dòng)化學(xué)、酶催化等一系列創(chuàng)新技術(shù)融會(huì)貫通，以更好地賦能全球合作伙伴。因?yàn)椋恳淮畏肿拥暮铣桑澈蠖际菨M懷期待的科學(xué)家和客戶，以及等待救治的患者。正是這份敬畏與擔(dān)當(dāng)，驅(qū)動(dòng)公司支持全球數(shù)千家合作伙伴破解研發(fā)挑戰(zhàn)，加速新藥從分子走向臨床的過(guò)程，讓創(chuàng)新療法突破瓶頸，推動(dòng)更多新藥、好藥早日問(wèn)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 “l(fā)ight 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 “l(fā)ight 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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