Methods and processes for the preparation of KDM1A inhibitors
Inventors
Tapper, Amy E. • Celatka, Cassandra • Romero, Arthur Glenn • McCall, John M. • Chancellor, Toni • Chen, Jian-Xie • Chen, Xuemei • Zhao, He • Biolatto, Betina • Brot, Elisabeth C. A. • Li, Zhihua • Liao, Xiaoming
Assignees
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Publication Number
US-11390590-B2
Publication Date
2022-07-19
Expiration Date
Abstract
Provided in this disclosure are methods for the synthesis of substituted 2-arylcyclopropylamines and 2-heteroarylcyclopropylamines and related compounds. Also provided are methods for reduction of thioesters to aldehydes, and methods for reductive animation of cyclopropylamines.
Core Innovation
The document describes process routes for preparing specific N-containing heterocycloalkyl-containing benzamide derivatives, including Compound 7, its bis-tosylate salt (Compound 8), and related intermediates. The routes include converting defined precursor structures into target scaffolds using reductive amination, thioester-to-aldehyde conversion via a silane reducing agent, and formation of salt forms such as bis-tosylate and hydrochloride.
One core approach is preparing Compound 7 by reacting (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (Compound 9) with Compound 6 under reductive amination conditions. The claim set also specifies a borohydride reducing agent, including NaBH4, in a methanol/tetrahydrofuran co-solvent system.
Another core approach is preparing Compound 6 by reacting thioester Compound 5 with a silane reducing agent to produce aldehyde Compound 6. The described claim refinements identify triethylsilane, with palladium on carbon and glacial acetic acid also described in the same reaction framework.
A further component prepares crystalline salt forms from Compound 7, including the bis-tosylate salt (Compound 8), and also prepares a hydrochloride salt form (Compound 5a) of a dodecyl thioester-containing compound. Compound 8 is formed by adding a solution of p-toluenesulfonic acid hydrate in tetrahydrofuran to a stirred solution of Compound 7 in tetrahydrofuran and isopropyl alcohol, while Compound 5a is formed by reacting dodecanethiol with a corresponding carboxylic acid under coupling conditions followed by addition of hydrochloric acid.
Claims Coverage
The independent claims identified in the provided content cover four process families: reductive amination to prepare Compound 7, silane reduction to prepare aldehyde Compound 6, p-toluenesulfonic acid hydrate addition to form the bis-tosylate salt (Compound 8) from Compound 7, and a coupling plus hydrochloric acid addition sequence to form hydrochloride salt (5a).
Reductive amination to prepare Compound 7
Reacting (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (Compound 9) with Compound 6 under reductive amination conditions.
Silane reduction of thioester Compound 5 to aldehyde Compound 6
Reacting thioester Compound 5 with a silane reducing agent to produce aldehyde Compound 6.
Bis-tosylate salt formation for Compound 8
Adding a solution of p-toluenesulfonic acid hydrate in tetrahydrofuran to a stirred solution of Compound 7 in tetrahydrofuran and isopropyl alcohol.
Hydrochloride salt preparation for Compound 5a
Reacting dodecanethiol with (4S)-4-[4-(1H-1,2,3-triazol-1-yl)benzoylamino]-5-(4-methylpiperazin-1-yl)-5-oxopentanoic acid in the presence of a coupling agent and base, and adding hydrochloric acid.
Overall, the independent claims define a connected set of process transformations: preparing aldehyde Compound 6 from thioester Compound 5 via silane reduction, preparing Compound 7 from Compound 9 and Compound 6 via reductive amination, and forming salt forms (Compound 8 bis-tosylate and Compound 5a hydrochloride) using specified acid addition and coupling-plus-hydrochloric-acid steps.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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