Development of a Continuous Flow Grignard Reaction to Manufacture a Key Intermediate of Ipatasertib
The development and scale-up of a continuous flow Grignard reaction to manufacture a key intermediate for Ipatasertib is described. Using cascaded continuous stirred tank reactors, the process improved yield (80% vs 61%), robustness, and product quality, enabling efficient, scalable pharmaceutical manufacturing with enhanced process control.
"To gain deeper process understanding, at-line analytical samples were taken in CSTR2 and CSTR3 using Mettler Toledo EasySampler devices at a 30 min frequency and offline samples of the crude organic layer for each DoE run prior to distillation for HPLC analysis."
Kaldre, D., Stocker, S., Linder, D., Reymond, H., Schuster, A., Lamerz, J., Hildbrand, S., Püntener, K., Berry, M., & Sedelmeier, J. (2024). Development of a continuous flow Grignard reaction to manufacture a key intermediate of Ipatasertib. Organic Process Research & Development, 28(7), 1576–1586. https://doi.org/10.1021/acs.oprd.4c00123
Synthesis of a Highly Functionalized Quinazoline Organozinc toward KRAS G12C Inhibitor Divarasib (GDC-6036), Enabled through Continuous Flow Chemistry
The development and scale-up is described of a continuous flow process for synthesizing a quinazoline organozinc intermediate, a key precursor for the KRAS G12C inhibitor divarasib (GDC-6036). The synthesis involves a halogen–metal exchange using the Grignard reagent i-PrMgCl·LiCl (isopropylmagnesium chloride–lithium chloride complex). This Grignard reagent reacts with bromoquinazoline to form a quinazoline organomagnesium intermediate. The challenges of instability of organomagnesium intermediates at higher temperatures were addressed by using a plug flow reactor (PFR) for precise temperature and residence time control, followed by a continuous stirred tank reactor (CSTR) to manage precipitates.
“In situ FTIR spectroscopic analysis and RC1 calorimetric data acquired during batch reactions performed at −20 °C showed near instantaneous Br−Mg exchange reaction and no evidence of significant i-PrMgCl·LiCl accumulation. This suggests that efficient mass transfer would likely have a larger impact on the reaction rate than underlying kinetics for this metalation step, so a reasonable minimum residence time of 15s was selected to allow for complete and reliable mixing of the reagent streams and ensure complete conversion to 2.”
Kelly, S. M., Lebl, R., Malig, T. C., Bass, T. M., Kummli, D., Kaldre, D., Orcel, U., Tröndlin, L., Linder, D., Sedelmeier, J., Bachmann, S., Han, C., Zhang, H., & Gosselin, F. (2023). Synthesis of a Highly Functionalized Quinazoline Organozinc toward KRAS G12C Inhibitor Divarasib (GDC-6036), Enabled through Continuous Flow Chemistry. Organic Process Research & Development, 28(5), 1546–1555. https://doi.org/10.1021/acs.oprd.3c00164
A Continuous Flow Process for LSN647712 via Double Organometallic Additions to Dimethylcarbamyl Chloride
This study presents a highly efficient continuous flow process for synthesizing LSN647712, a key intermediate in lasmiditan production. The method uses sequential organometallic additions to dimethylcarbamyl chloride, leveraging a Turbo Grignard reagent and lithiated 2,6-dibromopyridine. During the Grignard reagent formation, ReactIR monitored the decay of the C–Cl peak, confirming rapid conversion of the starting material. In the flow process, inline ReactIR cells were used to quantify concentrations of both product and unreacted reagents, ensuring the reaction was proceeding efficiently and under control.
“On the basis of the batch PAT data, we turned the jacketed reactor into a single-stage CSTR, forming larger quantities of Grignard reagent following the approach well-practiced in lab and production scales… Continuous ReactIR monitoring indicated the reaction is performing in a well-controlled state during operation. This on-demand system in a 0.5 L jacketed reaction produced tens of liters of the Turbo Grignard reagent throughout the development duration”.
Li, H., Sheeran, J. W., Kouvchinov, D., Clausen, A. M., Crouch, I. T., Bio, M. M., Fang, Y., Frank, S. A., Johnson, M. D., & Kerr, M. S. (2021). A continuous flow process for LSN647712 via double organometallic additions to dimethylcarbamyl chloride. The Journal of Organic Chemistry, 87(4), 2045–2054. https://doi.org/10.1021/acs.joc.1c01354
Synthesis of BACE1 Inhibitors E2609/E2071 via Oxime–Olefin Cycloaddition Following a Process Risk Mitigation Strategy
E2609/E2071 manufacturing was redesigned to eliminate cryogenic steps, unstable intermediates, hazardous fluorination, and unsafe autocatalytic trifluoromethylations. Key improvements included turbo‑Grignard arylation with in‑situ IR control using ReactIR. This enabled real‑time monitoring of key organometallic species in the turbo‑Grignard arylation, replacing cryogenic lithiation and ensuring safe, complete metalation at 0 °C. It also controlled the autocatalytic trifluoromethylation flow process by tracking acrolein, CF₃TMS, and product formation, preventing thermal runaway.
“Formation of aryl Grignard reagent 29 and tetrahedral adduct 30 could not be directly monitored using conventional in-process control (IPC) methods (e.g., HPLC, GC). Therefore, in-situ IR spectroscopy was employed to monitor these species directly…”
Kim, D.-S., Yoshizawa, K., Mitasev, B., Schnaderbeck, M., Zhang, H., Omori, M., Kayano, A., Nagai, M., Wakasugi, K., Watanabe, Y., Benayoud, F., Suzuki, Y., Motoki, T., Kaneko, T., Takaishi, M., Ishida, T., Takeda, K., Kita, Y., Yamamoto, N., Khan, A., Dimopoulos, P., Farthing, C. N., Hall, A., Chanda, A., Lu, L., Bracke, M., & Fang, F. G. (2022). Synthesis of BACE1 inhibitors E2609/E2071 via oxime–olefin cycloaddition following a process risk mitigation strategy. Organic Process Research & Development, 26(3), 804–816. https://doi.org/10.1021/acs.oprd.1c00223
Real-time and In-Situ Monitoring of Transmetalation of Grignard with Manganese(II) Chloride by Raman Spectroscopy
In-situ Raman spectroscopy was in conjunction with an EasyMax automated reactor to monitor the transmetalation reaction between Grignard reagents and manganese(II) chloride (MnCl₂) in anisole and 2‑methyl tetrahydrofuran (2‑MeTHF). Raman analysis enabled real‑time tracking of MnCl₂ consumption and formation of methylmanganese chloride, revealing that milled MnCl₂ reacts rapidly whereas unmilled MnCl₂ significantly slows the process. This approach provides kinetic insight, supports process optimization, and is well‑suited for air‑ and moisture‑sensitive reaction systems.
“The application of in situ Raman spectroscopy reaction monitoring is essential for this reaction to understand the kinetics and mechanisms of Mg/Mn transmetalation; therefore, to achieve the high chemoselectivity. This analytical technique is also highly desirable for this type of closed reaction with moisture- and air-sensitive contents in order to avoid the sampling difficulties associated with the use of standard analytical techniques.”
Tong, W., Zhou, G., & Waldman, J. H. (2022). Real-time and in situ monitoring of transmetalation of Grignard with manganese(II) chloride by Raman spectroscopy. Organic Process Research & Development, 26(5), 1184–1190. https://doi.org/10.1021/acs.oprd.1c00446
Process Hazard Evaluation and Exothermic Mechanism for the Synthesis of N‑ButylmagnesiumBromide Grignard Reagent in Different Solvents
This study investigates the thermal hazards and exothermic pathways associated with forming n‑butylmagnesium bromide (n‑BuMgBr) across a range of ether solvents. Using reaction calorimetry, in situ IR spectroscopy, and quantum‑chemical calculations, the authors demonstrate that alternative solvents such as 2‑MeTHF, CPME, and DGBE substantially mitigate the risk of thermal runaway compared to conventional diethyl ether and THF. These solvents suppress autocatalytic heat release, reduce initiation‑related exotherms, and stabilize the reaction environment during magnesium insertion. Risk assessments confirm that these media provide inherently safer operating windows, making them superior choices for large‑scale Grignard reagent manufacturing.
“…reaction characteristics were investigated by (1) isothermal and isoperibolic experiments, which provide information about the exothermicity of the reaction, (2) IR spectroscopy, which allows the monitoring of changes in the species during the course of the reaction and could help explain the exothermic mechanism combined with isothermal experiments in different solvents…”
Cheng, Z., Ni, L., Wang, J., Jiang, J., Yao, H., Chen, Q., Cui, F., Jiang, W., & Ye, S. (2021). Process hazard evaluation and exothermic mechanism for the synthesis of n‑butylmagnesium bromide Grignard reagent in different solvents. Process Safety and Environmental Protection, 147, 654–673. https://doi.org/10.1016/j.psep.2020.12.041
CO2 (De)Activation in Carboxylation Reactions: A Case Study Using Grignard Reagents and Nucleophilic Bases
This study investigates how nucleophilic bases, especially DBU (1,8-diazabicycloundec-7-ene), affect the carboxylation of Grignard reagents with CO2. DBU uniquely enhances product yield and CO2 solubility compared to other bases. However, kinetic analysis shows DBU's catalytic effect on the rate limiting step is negligible due to the already low activation barrier. The findings highlight DBU's role in improving CO2 absorption, but not in significantly accelerating the carboxylation reaction itself.
“…we conducted a competitive kinetic analysis - because of the early rate-limiting step of the Grignard carboxylation reactions - to shed light on the role of CO2 nucleophilic base adducts in the organometallic carboxylation reaction…Apart from DBU, most bases showed negative effects, highlighting the unique property of DBU in promoting the Grignard carboxylation…we sought to pinpoint the role of DBU in the carboxylation by in situ infrared spectroscopy.”
Lauridsen, J. M. V., Cho, S. Y., Bae, H. Y., & Lee, J.-W. (2020). CO2 (De)Activation in Carboxylation Reactions: A Case Study Using Grignard Reagents and Nucleophilic Bases. Organometallics, 39(9), 1652–1657. https://doi.org/10.1021/acs.organomet.9b00838
