Process for preparing aficamten
Inventors
Andersen, Denise • Pfeiffer, Matthew • TOM, Norma • Morgan, Bradley P.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12247024-B2
Publication Date
2025-03-11
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 invention provides a method of preparing a compound of Formula (1) by converting a compound of Formula (7) to a compound of Formula (6) through reaction with (R)-tert-butanesulfinamide. The method then converts the compound of Formula (6) to a compound of Formula (5) by reacting the compound of Formula (6) with a reducing agent, and finally converts the compound of Formula (5) to the compound of Formula (1).
Additional embodiments specify use of a Lewis acid and/or a water scavenger in the conversion from Formula (7) to Formula (6). The same step is further specified to use toluene at a temperature between about 75° C and about 85° C, and the reduction step can use sodium borohydride.
Further embodiments provide that the compound of Formula (6) is used without work-up or purification in the overall sequence. The partial content also states polymorphs of Formula (1) using XRPD 2-theta peak sets for Forms I–VI, and preparation routes for related intermediates and compounds of Formula (4).
Claims Coverage
The document includes one independent method claim directed to a three-step conversion sequence among compounds of Formulas (7), (6), (5), and (1), using (R)-tert-butanesulfinamide and a reducing agent. Dependent claims refine the intermediate-conversion conditions by adding a Lewis acid and/or a water scavenger, specifying toluene and a temperature range, narrowing the reducing agent to sodium borohydride, and specifying use of the Formula (6) intermediate without work-up or purification.
Three-step conversion to compound of Formula (1)
A method of preparing a compound of Formula (1) comprising: converting a compound of Formula (7) to a compound of Formula (6) by reacting the compound of Formula (7) with (R)-tert-butanesulfinamide; converting the compound of Formula (6) to a compound of Formula (5) by reacting the compound of Formula (6) with a reducing agent; and converting the compound of Formula (5) to the compound of Formula (1).
Lewis acid and water scavenger in (R)-tert-butanesulfinamide step
The conversion of the compound of Formula (7) to the compound of Formula (6) is carried out in the presence of a Lewis acid and/or in the presence of a water scavenger.
Toluene and 75–85 °C for Formula (7) to Formula (6)
The compound of Formula (7) is reacted with (R)-tert-butanesulfinamide in toluene at a temperature between about 75° C and about 85° C.
Sodium borohydride as the reducing agent
The compound of Formula (6) is converted to the compound of Formula (5) using sodium borohydride as the reducing agent.
Use of Formula (6) without work-up or purification
The compound of Formula (6) is used without work-up or purification.
Overall, claim coverage centers on a defined sequence converting Formula (7) to Formula (6) with (R)-tert-butanesulfinamide, converting Formula (6) to Formula (5) using a reducing agent narrowed to sodium borohydride, and converting Formula (5) to Formula (1). Dependent claims further narrow the (R)-tert-butanesulfinamide step using a Lewis acid and/or water scavenger, specify toluene and a temperature range, and restrict handling of the Formula (6) intermediate by omitting work-up or purification.
Stated Advantages
Fewer steps compared with earlier art.
Avoiding intermediate isolation/purification.
Higher overall yield.
Eliminating protecting groups and tin/azide reagents.
Documented Applications
Preparation of a compound of Formula (1) and its polymorphs (XRPD peak sets for Forms I–VI), including formation of HCl salt and preparation routes for related intermediates and compounds of Formula (4).
Interested in licensing this patent?