Synthetic method for the preparation of a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol compound
Inventors
Meisenbach, Mark • Martin, Benjamin • RONDE, Niek Johannes • RUIZ, Carmen
Assignees
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Publication Number
US-11649213-B2
Publication Date
2023-05-16
Expiration Date
Abstract
Provided is a process for preparing a compound, comprising the steps of a) Reacting a compound of Formula A (Formula A) with the compound 3 (3) to provide the compound 5 (5) or a salt or solvate thereof, wherein R is a linear or branched C1-C5 alkyl. Further provided is the compound 5 or a salt or solvate thereof. (5) The use of these compounds in the synthesis of 3-[5-Amino-4-(3-Cyanobenzoyl)-Pyrazol-1-yl]-N-Cyclopropyl-4-Methylbenzamide is also provided.
Core Innovation
The invention relates to a scale-up oriented synthetic route to a pyrazole-based kinase inhibitor intermediate and final product, addressing limitations of earlier WO2005/009973 syntheses. The described route improves safety and controllability during cyclization and reduces harmful by-products such as aniline and impurity sources such as tin residues. The synthesis provides a preparation of key intermediates and the final compound, with emphasis on impurity management and yield improvement.
A central aspect is generating an alkoxymethylidene compound of Formula A from compound 1 using a trialkyl orthoformate where R is a linear or branched C1-C5 alkyl. The description highlights azeotrope-assisted removal of alcohol by-products, including ethanol from triethyl orthoformate, to improve controllability and yield. The resulting compound of Formula A is then cyclized with compound 3 to produce key intermediate compound 5, together with alcohol by-products.
The route further converts compound 5 to the final compound 6 by reaction with cyclopropylamine, with isolation and purification options described. The document also discloses an improved preparation of compound 3 from compound 4 by forming a diazonium salt using a nitrite salt and an organic nitrite derivative, followed by reduction via a sulfur-containing reducing agent and formation of a hydrazyl-sulfur complex, with hydrolysis to give compound 3. This preparation is stated to avoid phosphorus- and tin-containing reagents and to improve impurity management.
Claims Coverage
The partial content includes three independent claims (clm-00001, clm-00016, clm-00017). One claim covers preparing compound 5 via cyclization using a compound of Formula A and compound 3 (with R defined), one claim covers compound 5 itself (including salts/solvates), and one claim covers a multi-step process to prepare compound 6 from compound of Formula A and compound 3 followed by reaction with cyclopropylamine (with a heating requirement in step c).
Process to provide compound 5 from Formula A and compound 3
Reacting a compound of Formula A with the compound 3 to provide the compound 5 or a salt or solvate thereof, optionally isolating said compound 5 or a salt or solvate thereof, wherein R is a linear or branched C1-C5 alkyl.
Compound 5 including salts and solvates
The compound 5 or a salt or solvate thereof.
Process to prepare compound 6 via intermediate compound 5 and cyclopropylamine
Reacting a compound of Formula A with the compound 3 to provide the compound 5 or a salt or solvate thereof, optionally isolating said compound 5 or a salt or solvate thereof, and reacting said compound 5 or salt or solvate thereof with cyclopropylamine to provide the compound 6 or a salt or solvate thereof, wherein R is a linear or branched C1-C5 alkyl, and wherein step c includes heating the reaction mass to a temperature of greater than about 30°C.
Across the independent claims, the inventive scope is directed to forming intermediate compound 5 by reacting a compound of Formula A with compound 3 under an R-defined framework, the compound 5 itself including its salts and solvates, and converting compound 5 to the final compound 6 by reaction with cyclopropylamine, including a step c heating requirement greater than about 30°C.
Stated Advantages
Improves safety and controllability during cyclization.
Reduces harmful by-products such as aniline.
Reduces impurity sources such as tin residues.
Improves impurity management and yield.
Improves removal of alcohol by-products (e.g., ethanol) via azeotrope-assisted removal.
Documented Applications
Synthesis of the kinase inhibitor intermediate and final product, including use of compounds 2 and 5 as intermediates in synthesis of 3-[5-Amino-4-(3-Cyanobenzoyl)-Pyrazol-1-yl]-N-Cyclopropyl-4-Methylbenzamide.
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