ËÄÉ«AV

A method for synthesizing 9-aminomethyl tetracycline compounds is disclosed. The method comprises a) reacting minocycline and an hydroxymethylamide derivative to form a 2,9-(methylamide-substituted) minocycline and a 2-(methylamide-substituted) minocycline; b) reacting the 2,9-(methylamide-substituted) minocycline from step a) and an amine or diamine to form a 9-aminomethyl tetracycline intermediate; and c) reacting the 9-aminomethyl tetracycline intermediate from step b) and an aldehyde in the presence of a reducing agent to form a 9-aminomethyl tetracycline compound; or d) reacting the 9-aminomethyl tetracycline intermediate from step b) and an alkyl halide or an alkyl reagent to form a 9-aminomethyl tetracycline compound Step b) may be operated in the absence of an hydrogenation reaction. The method may be a semi continuous or continuous flow process. Optionally, in a semi continuous flow process, two of steps a), b) and c) or d) may be carried without the use of batch reactors and without the need to isolate intermediate products between the reaction steps, for example steps b) and c) or steps b) and d) may operate in a continuous manner with the 9-aminomethyl tetracycline intermediate formed in step b) being used directly in step c) or d). The 9-aminomethyl tetracycline compound formed in step c) or d) may be omadacycline.
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