Process for preparing aficamten
Inventors
Andersen, Denise • Pfeiffer, Matthew • TOM, Norma • Morgan, Bradley P.
Assignees
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Publication Number
US-11932631-B2
Publication Date
2024-03-19
Expiration Date
Abstract
Provided herein is a process for the preparation of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, intermediates thereof, and salts of the foregoing.
Core Innovation
The document describes a method of preparing a compound of Formula (1), or a salt thereof, through sequential conversion of intermediates. The sequence converts a compound of Formula (7) to a compound of Formula (6), then converts the compound of Formula (6) to a compound of Formula (5), and further converts the compound of Formula (5) to the compound of Formula (1) or salt thereof. The overall approach is presented as a synthetic scheme for aficamten and related intermediates/salts, and as a route for obtaining (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile.
The described route includes a stereoselective step using (R)-tert-butanesulfinamide to produce the compound of Formula (6), followed by conversion of Formula (6) to Formula (5) using a borohydride reducing agent, including sodium borohydride as an example. The scheme also includes optional sulfinamide hydrolysis to an amino intermediate of Formula (4) from Formula (5), and a separate preparation of Formula (4) from Formula (5).
The document further describes transformation of (3) to (2) using hydroxylamine, followed by acylation of (2) to (1) using propionic acid or an activated propionic acid via a carboxylic acid activating agent. It also mentions transformations involving compounds of Formula (8) with palladium-catalyzed cyanation using Zn(CN)2 and specified catalysts, alternate synthesis routes to Formula (4), and polymorphs of the compound of Formula (1), including Forms I-VI supported by XRPD peak lists.
Claims Coverage
The document contains two independent claims. Across the independent claims, the inventive coverage includes the sequential conversion route to a compound of Formula (1) or a salt thereof and a separate preparation method for a compound of Formula (4) or a salt thereof.
Sequential preparation route to Formula (1)
A method of preparing a compound of Formula (1) or a salt thereof by converting a compound of Formula (7) to a compound of Formula (6), converting the compound of Formula (6) to the compound of Formula (5), and converting the compound of Formula (5) to the compound of Formula (1) or salt thereof.
Conversion of Formula (5) to Formula (4)
A method of preparing a compound of Formula (4) or a salt thereof comprising converting a compound of Formula (5) to the compound of Formula (4) or salt thereof.
The claim coverage centers on two linked preparation stages: forming Formula (1) via a three-step sequence from Formula (7), and separately defining preparation of Formula (4) via conversion from Formula (5). Dependent claims refine these stages by specifying reagents and constraints for key transformations.
Stated Advantages
Fewer steps.
Avoiding isolation/purification/protecting groups.
Higher overall yield.
Elimination of tin/azide reagents.
Documented Applications
No documented applications found
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