Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl] piperazin-1-yl]ethyl pyridine-3-carboxylate
Inventors
Buckley, Neil • Belmont, Dan • Hauser, Bryan • Kim, Myoung Goo • Kannan, Kumar
Assignees
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Publication Number
US-12110275-B2
Publication Date
2024-10-08
Expiration Date
Abstract
The invention provides methods of chemical synthesis of the pharmacological agent 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate, also called CV-8972. The methods entail formation of a free base form of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethanol, also called CV-8814, as intermediate without producing a salt form of CV-8814.
Core Innovation
The invention relates to a method for preparing a compound of Formula (X) by a two-step synthetic sequence that proceeds through a free base intermediate. In the first step, a compound of Formula (1) is reacted with a compound of Formula (2) using sodium triacetoxyborohydride in the presence of acetic acid and 2-methyltetrahydrofuran to produce a free base form of a compound of Formula (IX).
In the second step, the free base form of a compound of Formula (IX) is reacted with a compound of Formula (3) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 4-(dimethylamino)pyridine in dichloromethane to produce the compound of Formula (X). The disclosed scheme describes coupling to form CV-8972 from a free base intermediate, including formation and stabilization of the relevant free base intermediate.
The disclosed process further includes isolating and converting the free base and solid forms of the products, including conversion to CV-8972 monohydrate and conversion to a specific crystal form (Form A) via solvent/form conversions, with XRPD confirmation reported. The scheme describes obtaining CV-8814 as a free base intermediate and then converting through to CV-8972 free base, monohydrate, and crystal form (Form A).
Claims Coverage
The identified independent claim recites a two-step method with two main inventive features: formation of a free base intermediate via sodium triacetoxyborohydride under acetic acid and 2-methyltetrahydrofuran conditions, followed by coupling of that free base with a compound of Formula (3) using carbodiimide and DMAP in dichloromethane.
Sodium triacetoxyborohydride free base formation under acetic acid and 2-methyltetrahydrofuran
Reacting a compound of Formula (1) with a compound of Formula (2) with sodium triacetoxyborohydride, in the presence of acetic acid and 2-methyltetrahydrofuran to produce a free base form of a compound of Formula (IX).
Carbodiimide/DMAP coupling of free base intermediate in dichloromethane
Reacting the free base form of a compound of Formula (IX) with a compound of Formula (3) in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 4-(dimethylamino)pyridine in dichloromethane to produce the compound of Formula (X).
Overall, the claim coverage centers on making and using the free base form of Formula (IX) as an intermediate, first by sodium triacetoxyborohydride-mediated formation under acetic acid and 2-methyltetrahydrofuran conditions and then by carbodiimide/DMAP-mediated coupling in dichloromethane to produce Formula (X).
Stated Advantages
Simpler and faster preparation.
Higher yield compared with alternatives described in the document.
Documented Applications
Preparation of CV-8972 (2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate) via conversion from the free base intermediate (CV-8814) to CV-8972 free base, CV-8972 monohydrate, and CV-8972 crystal form (Form A) with XRPD confirmation reported.
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