Organic Process Research & Development最新文献

Determining the Influence of Particle Size and Surface Area on the Measured Minimum Ignition Energy of Pharmaceutical Powders 测定粒径和表面积对药粉最小点火能的影响

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-05-15 DOI: 10.1021/acs.oprd.5c00052

Rafaela Costa Carmona, Rachel Duong, John F. Gamble, Lauren N. Grant, Helen Hughes, Simon Shun Wang Leung, Michael Tobyn, Linda Zheng

Dust explosions constitute a significant risk in many industries. To identify materials for which mitigation strategies are required, information about the relative risk for each material is required. Such information will include characteristics such as the minimum ignition energy (MIE), but material availability represents a significant challenge for the pharmaceutical industry at early stages of development. These challenges contrast with the relatively high material requirements for risk characterization. To this end, there is significant interest in the application of models to predict MIE. The aims of this study were 2-fold. The first stage was to assess the predictive strength of a published MIE prediction model for a range of pharmaceutical powders. The second stage of the study was to investigate the role of particle size for a series of samples of ‘constant chemistry’ and varying size. The results demonstrate that the model provided ‘safe’ results for half the materials tested while the accuracy of the model was unsatisfactory. The results showed that the risk was often overestimated; thereby, the work required for safety mitigation would not add value to the process, or underestimated, raising the risk of inadequate safety mitigation. When the chemistry of the materials was maintained constant, significant differences in the relationship of particle size and surface area with the measured MIE were demonstrated. Overall, the work suggests that the relative influence of chemistry and particle properties on MIE shows notable differences between materials, thereby affecting the ability of the assessed model to accurately predict MIE.

粉尘爆炸在许多工业中构成重大危险。为确定需要采取缓解战略的材料，需要了解每种材料的相对风险。这些信息将包括诸如最小点火能量（MIE）等特征，但材料的可用性对于制药工业在早期发展阶段来说是一个重大挑战。这些挑战与风险表征相对较高的材料要求形成对比。为此，人们对应用模型来预测MIE非常感兴趣。这项研究的目的有两个方面。第一阶段是评估已发表的MIE预测模型对一系列药物粉末的预测强度。研究的第二阶段是研究一系列“恒定化学”和不同大小的样品中粒径的作用。结果表明，该模型为一半的测试材料提供了“安全”的结果，而模型的准确性令人不满意。结果表明，风险往往被高估；因此，安全缓解所需的工作不会为该过程增加价值，或被低估，从而增加了安全缓解不足的风险。当材料的化学性质保持不变时，粒径和表面积与测量的MIE之间的关系存在显著差异。总的来说，这项工作表明，化学和颗粒性质对MIE的相对影响在材料之间表现出显著差异，从而影响了评估模型准确预测MIE的能力。

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引用次数: 0

A Concise Flow Synthesis of the IKZF2 Glue Degrader DKY709 IKZF2型胶水降解剂DKY709的简洁流动合成

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-05-15 DOI: 10.1021/acs.oprd.4c00476

Xu You, Xu-Lun Huang, Hailong Ren, Chunrui Wu, Dahai Wang

DKY709, a protein degrader targeting Helios (IKZF2), was efficiently synthesized via flow chemistry. The synthetic sequence comprised a visible-light-induced benzyl bromination, an amination–cyclization cascade, a photoinduced C(sp²)–C(sp³) coupling, and a high-temperature, high-pressure de-Boc/alkylation. Each reaction was systematically optimized under continuous-flow or stop-flow conditions to identify crucial parameters. The overall yield was substantially increased from 4.3% to 22.8% using commercially available starting materials, while the number of synthetic steps was reduced from five to four. The scalability of each reaction step was validated, and the direct use of intermediates in subsequent steps minimized workup complexity.

利用流动化学高效合成了一种靶向Helios的蛋白质降解物DKY709 （IKZF2）。该合成序列包括一个可见光诱导的苄基溴化反应、一个氨基环化级联反应、一个光诱导的C(sp2) -C （sp3）偶联反应和一个高温高压的脱boc /烷基化反应。在连续流或停流条件下对每个反应进行系统优化，以确定关键参数。使用市售原料，总收率从4.3%大幅提高到22.8%，而合成步骤从5个减少到4个。验证了每个反应步骤的可扩展性，并在后续步骤中直接使用中间体，最大限度地降低了作业的复杂性。

引用次数: 0

Development of a Manufacturing Process for S-892216 Part II: Improvements Toward Commercially Feasible Process S-892216制造工艺的开发，第二部分：对商业可行工艺的改进

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-05-15 DOI: 10.1021/acs.oprd.5c00072

Thien Phuc Le, Takahiro Kawajiri, Naoto Sahara, Go Kato, Masahiro Hosoya, Tadashi Oohara, Kazushi Agura, Takafumi Ohara, Satoshi Goda

In this study, we described developing a refined manufacturing process for S-892216, a second-generation COVID-19 therapeutic agent currently under development. The focus of this research was on the feasibility of commercial manufacturing. In particular, we developed a manufacturing process that facilitates the stable acquisition of a specific crystal form for intermediate or maximum reaction efficiency using flow chemistry, eliminating the need for excessive extraction, concentration, and purification operations. Compared to the first-generation process used during early phase clinical trials, the overall yields (increasing from 41% to 62%) and PMI values (decreasing from 323 to 210) improved significantly. These advancements underscore the potential of the second-generation process for S-892216 to strengthen the supply chain of COVID-19 therapeutics.

在本研究中，我们描述了目前正在开发的第二代COVID-19治疗剂S-892216的精炼制造工艺。这项研究的重点是商业生产的可行性。特别是，我们开发了一种制造工艺，可以使用流动化学技术稳定地获得特定的晶体形式，以达到中间或最大的反应效率，从而消除了过度提取、浓缩和纯化操作的需要。与早期临床试验中使用的第一代工艺相比，总体收率（从41%增加到62%）和PMI值（从323降低到210）显著提高。这些进展凸显了S-892216第二代工艺在加强COVID-19治疗药物供应链方面的潜力。

引用次数: 0

Cu-Catalyzed Coupling of Aryl Halides Utilizing Ammonia and Hydroxypicolinamide Ligands 利用氨和羟基喹啉酰胺配体铜催化芳基卤化物的偶联

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-05-15 DOI: 10.1021/acs.oprd.5c00101

David J. Bernhardson, Ian Hotham, Liam S. Sharninghausen, Robert A. Singer, Daniel W. Widlicka

The hydroxypicolinamide family of ligands has previously demonstrated utility in Cu-catalyzed C–N couplings and hydroxylation of heteroaryl halides. The application of these ligands has been extended to the coupling of ammonia with aryl bromides and iodides using the dimethoxy picolinamide scaffold ligand. By tailoring reaction conditions, Cu-DMPS provides high reactivity and selectivity toward amination over hydroxylation. Utilizing aqueous ammonia or anhydrous ammonia with K₃PO₄ in MeOH provides robust conversion of bromides and iodides to the corresponding aryl amines. Additionally, this catalytic system gives efficient C–N couplings with simple primary amines by using the same general reaction conditions.

羟基喹啉酰胺家族的配体已经在cu催化的C-N偶联和杂芳基卤化物的羟基化中得到证实。这些配体的应用已经扩展到使用二甲氧基吡啶酰胺支架配体将氨与芳基溴化物和碘化物偶联。通过调整反应条件，Cu-DMPS提供高反应活性和选择性胺化羟基化。在MeOH中使用含K3PO4的水氨或无水氨，可将溴化物和碘化物转化为相应的芳基胺。此外，该催化体系在相同的一般反应条件下与简单伯胺进行了高效的C-N偶联。

引用次数: 0

Enabling the First Scale-Up of the Selective HER2 Inhibitor BI-4142 选择性HER2抑制剂BI-4142的首次规模化应用

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-05-14 DOI: 10.1021/acs.oprd.5c00127

Eugene Chong, Ruoshi Li, Weitong Dong, Maxim Chevliakov, Thomas G. Tampone, Yongda Zhang, Bo Qu, Nizar Haddad, Jon C. Lorenz, Max Sarvestani, Thuraya Omar, Huayu Li, Joe J. Gao, Donghong A. Gao, Scott Pennino, Ling Wu, Earl Spinelli, Steven Yao, Heewon Lee, Frederic Buono, Jinhua J. Song, Birgit Wilding

The enabling synthesis of the first route to HER2 inhibitor BI-4142 (1) to deliver a drug substance in kilogram quantity is reported. The synthetic route involves (1) a fit-for-purpose synthesis of pyrimido[5,4-d]pyrimidine 2; (2) a high yielding, scalable synthesis of aniline 3; (3) a safer sodium tungstate-catalyzed sulfide oxidation; (4) S_NAr reactions to form C–N bonds; and (5) amidation via Schotten–Baumann conditions. With the speed of delivery prioritized, a purification protocol using silica gel filtration and crystallizations was developed in time to control the quality of API. The overall yield of the delivery route was improved from 22% to 46% over a prior route starting from 2.

据报道，能够合成HER2抑制剂BI-4142(1)的第一种途径，以递送公斤数量的药物。合成路线包括(1)符合目的的嘧啶[5,4-d]嘧啶2的合成；(2)高效、规模化的苯胺3合成；(3)更安全的钨酸钠催化硫化物氧化；(4) SNAr反应形成C-N键；(5) Schotten-Baumann条件修正。以输送速度为优先，及时制定了硅胶过滤结晶纯化方案，控制原料药的质量。与之前从2点开始的配送路线相比，配送路线的总收益率从22%提高到46%。

引用次数: 0

Scalable Membrane Enabled One-Pot Liquid-Phase Oligonucleotide Synthesis 可扩展膜支持一锅液相寡核苷酸合成

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-05-13 DOI: 10.1021/acs.oprd.5c00117

Ronan Kelly, Catalina Parga, Steven Ferguson

In this article, a new one-pot liquid-phase oligonucleotide synthesis (OP-LPOS) route enabled by organic solvent resistant (OSR) ceramic membranes is described. This approach was demonstrated through the synthesis of 6mer and 18mer 2’-OMe phosphorothioate oligonucleotides with high stepwise filtration yields (97–100%), and high crude purity (∼72% for 18mer) using just 1.5 equiv of phosphoramidites. Ceramic organic solvent nanofiltration (OSN) and ultrafiltration (OSU) membranes were used to selectively retain the growing oligonucleotide, which is reversibly tethered to a 4-arm branched PEG support, facilitating lower molecular weight reaction byproducts to permeate to waste. This is the first application of ceramic ultrafiltration membranes in such an application, which enables purification of intermediate products in just 5 diavolumes with high permeance (13 Lm^–2 h^–1 bar^–1). We employ a one-pot approach that integrates sequential coupling, sulfurization, and detritylation steps, followed by a single membrane purification step per chain extension cycle. Analysis of the methodology indicates that the homogeneous reactions and separation performance, which use commercially available reagents and highly scalable membrane systems, represent a promising alternative to solid-phase oligonucleotide synthesis (SPOS) for large-scale manufacturing of therapeutic oligonucleotides. Furthermore, the combination of OP-LPOS with membrane separation increases intermediate product purity and yield. It reduces the number of unit operations, cycle times, and process mass intensity (PMI) compared to the previous state-of-the-art membrane-based LPOS.

本文介绍了一种利用有机耐溶剂陶瓷膜进行液相寡核苷酸合成（OP-LPOS）的新途径。该方法通过合成6mer和18mer 2 ' -OMe磷硫代寡核苷酸得到了证明，该方法具有高逐步过滤率（97-100%）和高粗纯度（18mer为72%），仅使用1.5等量的磷酰胺。采用陶瓷有机溶剂纳滤（OSN）和超滤（OSU）膜选择性保留生长的寡核苷酸，并将其可逆地拴在四臂支链PEG载体上，促进低分子量反应副产物渗透到废物中。这是陶瓷超滤膜在此类应用中的首次应用，它可以在5双体积内以高渗透率（13 Lm-2 h-1 bar-1）净化中间产物。我们采用一锅方法，整合了顺序偶联，硫化和脱三烷基化步骤，然后是每个链延伸循环的单个膜净化步骤。方法分析表明，均相反应和分离性能，使用市售试剂和高度可扩展的膜系统，代表了一个有前途的替代固相寡核苷酸合成（SPOS）大规模生产治疗性寡核苷酸。此外，OP-LPOS与膜分离相结合，提高了中间产物的纯度和收率。与之前最先进的基于膜的LPOS相比，它减少了单元操作的数量、周期时间和过程质量强度（PMI）。

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引用次数: 0

Green Chemistry Articles of Interest to the Pharmaceutical Industry 制药工业感兴趣的绿色化学文章

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-05-10 DOI: 10.1021/acs.oprd.5c00050

Melissa A. Ashley, Miles H. Aukland, Marian C. Bryan, Megan A. Cismesia, Theresa Dutschei, Oliver D. Engl, Pascal S. Engl, Álvaro Enríquez García, Alejandro Gimenez Molina, Vanessa Harawa, George Karageorgis, Shazia Keily, Christopher B. Kelly, Alexandre Leclair, Johnny W. Lee, Wei Li, Matthew Osborne, Jan Pawlas, Paul F. Richardson, Samuel C. Scott, Alan Steven, Balaram S. Takale, Mingshuo Zeng

This article has not yet been cited by other publications.

这篇文章尚未被其他出版物引用。

引用次数: 0

Preparation of Furazan Carboxylates from Enamines by a Nitrosation–Oxidative Cyclization Sequence 胺基亚硝化-氧化环化法制备呋喃唑羧酸酯

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-05-09 DOI: 10.1021/acs.oprd.5c00119

Connor L. Martin, Matthew E. Martinez

We report a telescoped nitrosation–oxidative cyclization sequence for preparing furazan (1,2,5-oxadiazole) carboxylic esters from the corresponding enamines. This method is mainly suitable for preparing furazan carboxylates substituted with aromatic rings. Preliminary process safety screening shows that our method offers advantages compared to the common dioxime dehydration method for preparing furazans.

我们报道了从相应的胺制备呋喃唑（1,2,5-恶二唑）羧酸酯的缩合亚硝化-氧化环化序列。该方法主要适用于制备芳环取代呋喃赞羧酸酯。初步的工艺安全性筛选表明，与常见的二肟脱水法制备呋喃脲相比，本方法具有优势。

引用次数: 0

Development of a Broadly Applicable Enzymatic Ligation Process for the Production of Single Guide RNAs 一种广泛应用于生产单个引导rna的酶连接工艺的发展

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-05-05 DOI: 10.1021/acs.oprd.4c00502

Martina Bigatti, André Moser, Bas Dierssen, Shtjefen Frrokaj, Elena Covato, Christophe Pfleger, Joerg Lill, Yael Leiser, Joël Zuber, Andreas Staempfli, Filippo Sladojevich, Stefan G. Koenig

In this manuscript, we present a robust chemo-enzymatic approach for the production of single guide RNAs (sgRNAs), essential reagents for CRISPR-Cas9-based cell and gene therapy applications currently under development. Our method leverages ligase-mediated assembly of two RNA fragments, each synthesized using standard solid-phase chemistry. This versatile process has been applied, without modification, to produce a variety of GMP-grade sgRNAs, supporting our clinical ex vivo cell therapy pipeline. We demonstrate that our approach consistently achieves higher purity (10–15% improvement in LC-UV area%) and significantly greater yield (3–4 times higher) compared to traditional linear solid-phase synthesis, which is commonly used for sgRNA production. Importantly, the process utilizes T4 RNA ligase 2, a natural, nonengineered enzyme, which can be easily sourced from several vendors. We believe that openly sharing this method will drive significant progress in the development of cell and gene therapies, enabling the production of higher-quality sgRNAs at lower cost, ultimately improving accessibility and treatment outcomes for patients.

在这篇论文中，我们提出了一种强大的化学酶促方法，用于生产单导rna (sgRNAs)，这是目前正在开发的基于crispr - cas9的细胞和基因治疗应用的基本试剂。我们的方法利用连接酶介导的两个RNA片段的组装，每个片段都使用标准固相化学合成。这种通用工艺已被应用于生产各种gmp级sgrna，支持我们的临床体外细胞治疗管道。我们证明，与通常用于sgRNA生产的传统线性固相合成相比，我们的方法始终能够获得更高的纯度（LC-UV面积提高10-15% %）和显着更高的收率（提高3-4倍）。重要的是，该过程使用T4 RNA连接酶2，这是一种天然的，非工程酶，可以很容易地从几个供应商处获得。我们相信，公开分享这种方法将推动细胞和基因疗法的发展取得重大进展，从而以更低的成本生产更高质量的sgrna，最终改善患者的可及性和治疗效果。

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引用次数: 0

Development of a Broadly Applicable Enzymatic Ligation Process for the Production of Single Guide RNAs 一种广泛应用于生产单个引导rna的酶连接工艺的发展

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-05-05 DOI: 10.1021/acs.oprd.4c0050210.1021/acs.oprd.4c00502

Martina Bigatti, André Moser, Bas Dierssen, Shtjefen Frrokaj, Elena Covato, Christophe Pfleger, Joerg Lill, Yael Leiser, Joël Zuber, Andreas Staempfli, Filippo Sladojevich* and Stefan G. Koenig*,

In this manuscript, we present a robust chemo-enzymatic approach for the production of single guide RNAs (sgRNAs), essential reagents for CRISPR-Cas9-based cell and gene therapy applications currently under development. Our method leverages ligase-mediated assembly of two RNA fragments, each synthesized using standard solid-phase chemistry. This versatile process has been applied, without modification, to produce a variety of GMP-grade sgRNAs, supporting our clinical ex vivo cell therapy pipeline. We demonstrate that our approach consistently achieves higher purity (10–15% improvement in LC-UV area%) and significantly greater yield (3–4 times higher) compared to traditional linear solid-phase synthesis, which is commonly used for sgRNA production. Importantly, the process utilizes T4 RNA ligase 2, a natural, nonengineered enzyme, which can be easily sourced from several vendors. We believe that openly sharing this method will drive significant progress in the development of cell and gene therapies, enabling the production of higher-quality sgRNAs at lower cost, ultimately improving accessibility and treatment outcomes for patients.

在这篇论文中，我们提出了一种强大的化学酶促方法，用于生产单导rna (sgRNAs)，这是目前正在开发的基于crispr - cas9的细胞和基因治疗应用的基本试剂。我们的方法利用连接酶介导的两个RNA片段的组装，每个片段都使用标准固相化学合成。这种通用工艺已被应用于生产各种gmp级sgrna，支持我们的临床体外细胞治疗管道。我们证明，与通常用于sgRNA生产的传统线性固相合成相比，我们的方法始终能够获得更高的纯度（LC-UV面积提高10-15% %）和显着更高的收率（提高3-4倍）。重要的是，该过程使用T4 RNA连接酶2，这是一种天然的，非工程酶，可以很容易地从几个供应商处获得。我们相信，公开分享这种方法将推动细胞和基因疗法的发展取得重大进展，从而以更低的成本生产更高质量的sgrna，最终改善患者的可及性和治疗效果。

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