1075705-01-9Relevant articles and documents
Optimization and Scale-Up of the Continuous Flow Acetylation and Nitration of 4-Fluoro-2-methoxyaniline to Prepare a Key Building Block of Osimertinib
K?ckinger, Manuel,Wyler, Benjamin,Aellig, Christof,Roberge, Dominique M.,Hone, Christopher A.,Kappe, C. Oliver
, p. 2217 - 2227 (2020)
The development of a scalable telescoped continuous flow procedure for the acetylation and nitration of 4-fluoro-2-methoxyaniline is described. A subsequent batch deprotection then affords 4-fluoro-2-methoxy-5-nitroaniline, a key building block in the synthesis of osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is used for the treatment of nonsmall-cell lung carcinomas carrying EGFR-TKI sensitizing and EGFR T790M resistance mutations. The hazards associated with nitration of organic compounds, such as thermal runaway and explosivity of intermediates, make it difficult to scale up nitrations to industrial quantities, particularly within large-scale batch reactors. In this study, we investigated an acetic acid/aqueous nitric acid mixture as a predominantly kinetically controlled nitration regime and a water-free mixture of acetic acid, fuming nitric acid, and fuming sulfuric acid (oleum) as a mass-transfer-limited nitration regime. A modular microreactor platform with in-line temperature measurement was utilized for the nitration. Furthermore, we identified that it was necessary to protect the amine functionality through acetylation to avoid side reactions. The process parameters and equipment configuration were optimized at laboratory scale for the acetylation and nitration to improve the product yield and purity. The two steps could be successfully telescoped, and the laboratory-scale flow process was operated for 80 min to afford the target molecule in 82% isolated yield over two steps, corresponding to a throughput of 25 mmol/h. The developed flow process was then transferred to an industrial partner for commercial implementation and scaled up by the use of higher flow rates and sizing-up of the microreactor platform to pilot scale to afford the product in 83% isolated yield, corresponding to a throughput of 2 mol/h (0.46 kg/h).
Synthesis method of osimertinib intermediate
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Paragraph 0045; 0048-0050; 0053-0055; 0060; 0063-0065; 0068, (2021/02/10)
The invention relates to a synthesis method of an osimertinib intermediate. The synthesis method comprises the following steps: 1, with 3-fluoroanisole as an initial raw material, adding 3-fluoroanisole into concentrated sulfuric acid, dropwise adding the concentrated nitric acid in a low-temperature environment, carrying out primary heating and stirring after completion of the addition, injectingthe formed system into ice water for quenching, carrying out secondary heating and stirring, and carrying out filtering to obtain a product, namely 3-fluoro-4, 6-dinitroanisole; and 2, adding the compound 3-fluoro-4,6-dinitroanisole obtained in the step 1 into water, adding alkali, conducting heating, adding a weak reducing agent in batches, performing stirring while keeping the temperature untila reaction endpoint is reached, carrying out filtering to obtain a crude product, and successively conducting washing, recrystallizing with methanol, crystallizing and filtering at a low temperatureand drying to finally obtain 4-fluoro-2-methoxy-5-nitroaniline. The method of the invention solves the problems that raw materials are expensive and hardly-available in the market, process is complexand yield is low in conventional synthesis methods of the osimertinib intermediate.
BENZIMIDAZOLE DERIVATIVES
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Page/Page column 53; 93, (2021/06/26)
The invention relates to benzimidazoles of Formula (I) and pharmaceutically acceptable salts thereof, wherein R1 to R6 are as defined in the description; to their use in medicine; to compositions containing them; to processes for their preparation; and to intermediates used in such processes. The benzimidazoles of Formula (I) are ITK inhibitors and are therefore potentially useful in the treatment of a wide range of disorders including, atopic dermatitis.