Process for preparing imidazole derivatives
Inventors
Willot, Matthieu • Fischer, Ruediger • HAGER, Dominik • HOFFMEISTER, LAURA • Mosrin, Marc • WILCKE, David
Assignees
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Publication Number
US-12319697-B2
Publication Date
2025-06-03
Expiration Date
Abstract
The present invention relates to a process for preparing imidazole derivatives of the formula (II) proceeding from compounds of the structure Q-H via intermediates of the formula (IIIa) or (IIIb) in which Q represents a structural element where the symbol # represents the bond to the remainder of the molecule and A, Q1, Q2, Q3, Q4, Q5, Q6 and Q7, and also R2, W, V and Y have the meanings given in the description.
Core Innovation
The invention relates to a process for preparing a compound of formula (II) from a compound Q-H, wherein Q represents a structural element Q2, Q3, or Q13 and the substituent pattern is defined for R7, A, W, R8, n, V, and Y. The process starts with an organozinc base of formula (V), TMPZnCl·LiCl, to form a compound of formula (IIIa) or formula (IIIb).
In a second process step, the intermediate compound of formula (IIIa) or (IIIb) is reacted with a compound of formula (I) in which X represents iodine, in the presence of a catalyst, to give the compound of formula (II). The process is characterized by specific quantitative reagent relationships, reaction temperature selection, and solvent selection limited to THF or N,N-dimethylformamide (DMF).
The partial content further describes concrete synthetic examples and characterization for preparing imidazo[4,5-b]pyridine and related trifluoromethyl/imidazo[4,5-c]pyridine/imidazo[4,5-c]pyridazine derivatives. It states the use of TMPZnCl·LiCl mediated metalation and Pd-catalyzed coupling with iodinated imidazole intermediates, along with characterization data such as HPLC-MS and 1H-NMR, and reports yield figures for examples and a comparison against a prior-art route.
Claims Coverage
One independent claim defines a two-step process to prepare compounds of formula (II), centered on organozinc intermediate formation from Q-H and catalyst-mediated reaction with an iodinated compound of formula (I). Dependent claims add quantitative equivalents, a temperature range, solvent selection, and catalyst identity.
Two-step organozinc-mediated synthesis of formula (II)
In a first process step a), a compound Q-H is reacted with an organozinc base of formula (V) to give a compound of formula (IIIa) or formula (IIIb), and in a second process step b), the compound of formula (IIIa) or (IIIb) is reacted with a compound of formula (I) in which X represents iodine, in the presence of a catalyst, to give the compound of formula (II).
Organozinc base equivalents relative to Q-H
Using the organozinc base of formula (V) in a total amount of 0.5 to 5.0 equivalents based on the compound Q-H.
Iodinated coupling reagent equivalents relative to Q-H
Using the compound of formula (I) in a total amount of 0.5 to 10 equivalents relative to the compound Q-H.
Temperature range for the process steps
Carrying out the process at a temperature between 0°C and 80°C.
Solvent selected from THF or DMF
Carrying out the process in the presence of a solvent selected from THF or N,N-dimethylformamide (DMF).
Tetrakis(triphenylphosphine)palladium(0) catalyst
Carrying out the process using tetrakis(triphenylphosphine)palladium(0) as the catalyst.
The independent claim combines organozinc-base formation of formula (IIIa)/(IIIb) intermediates from Q-H with a catalyst-mediated reaction using a formula (I) coupling partner where X is iodine to furnish formula (II). Dependent claims further narrow the coverage by specifying equivalents, temperature, solvent, and catalyst.
Stated Advantages
Improved regioselectivity.
Functional group tolerance.
Lower temperatures versus prior art.
Good yields and purity.
Documented Applications
Preparing imidazo[4,5-b]pyridine and related trifluoromethyl/imidazo[4,5-c]pyridine/imidazo[4,5-c]pyridazine derivatives.
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